CA2117434A1 - Piperazine and piperidine derivatives, and their use as antipsychotics - Google Patents
Piperazine and piperidine derivatives, and their use as antipsychoticsInfo
- Publication number
- CA2117434A1 CA2117434A1 CA002117434A CA2117434A CA2117434A1 CA 2117434 A1 CA2117434 A1 CA 2117434A1 CA 002117434 A CA002117434 A CA 002117434A CA 2117434 A CA2117434 A CA 2117434A CA 2117434 A1 CA2117434 A1 CA 2117434A1
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- Prior art keywords
- formula
- compound
- butyl
- piperazinyl
- benzisothiazol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a group of piperazine and piperidine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy, in particular in the treatment of psychotic disorders.
Description
W O 93/16073 C A 2 i 1 7 4 3 4 P(~r/GB93/00285 PIPERAZINE AND PIPERIDINE DERIVATIVES, AND THEIR USE AS AN~ L~UI1CS
The present invention relates to a group of pipero7;- and piperidine d~ oLl~__, to processes for their ~,., ' , to 1' 'co1 compositions ,r~~toining them ant to their w e in therapy, in particular in the tre-tment of psychotic disorders.
Receptors for the chemical messenger dopamine are known to be located in the striatum and the limbic brain area and such receptors have been clossifiod as Dl and D2 based on receptor binding studies and on the presence or absence of a positive coupling between the r-ceptor and adenylate cvclase activity. Activation of the Dl-receptor is a~o-io~ ~ with at' loti~ of adenylate cyclase, whereas the D2-receptor mediates ' , - ~lc effects that do not involve direct st; lotirn of this enzyme tsee Kebabian ~ Calne, Nature, 1979, ~2~, 93 and Harrold et ~1, J. ~ed. Chem., 1987, 30, 1631). Although the distinct functions of the Dl- and D2-receptors are not clear cut, a : strong correl-tion is believed to exist between D2-receptor ~-t Dgr~
snd ~ I.vtlc activity (see SeemAn~ r - 1 . Rev., 1981, 32, 229, Seeman et ~ irrhotr r 1., 1985, 34, 151, Creese et al, 55i~ ~, 1976, 192, 481 nd Leysen in Clinirol Ph9 lo~v in ~svrhiAtrv Neuroleotic __A ~ tti~ Co~rch- Eds Usdin, Dahl, Gram and Lingjaerde, ~ ~ Basingstoke, 1982; pp35-52).
The chenical - _ 5-hydroxy L~ ~ro (5-HT) occurs widely in the central nervo w system and is known to be involved in the control of behavior. A number of different 5-HT receptors and receptor sub-types have been id -'f;oA In addition to the blockade of D2-receptors, it has been r - l~t-d that 5-HT2 receptor antAgr~ is also desirable in an ~ ,' L-r agent (see Janssen t al, J. Yharm.
and EYn~r. ~1 ., 1988, 244(21, 685). In particular it has been postulated that blockade of central dopamine D2-receptors may control the positive symptoms of e~hi r' ~nia (e.g. delusions and ~ol1r-inotj~ ) whilst blockade of 5-hT2 receptors may assist in the 1iorAtio~t of the neegative symptoms of schizophrenia (e.g. apathy CA 2 i i 7434 W O 93/16073 - 2 - PCT/GB93/0028~
and social withdraw l). It has also been suggested that blockade of tne 5-hT2 receptor results in a reduction of the 9A '~91 side effects which are known to occur in the case of neuroleptic 'nr-n-~r~ therapy with many known antipsychotic agents.
P,~ ic b~n7i~othio~~1es and bon~ ys7oles are described in US~968792, EP035713~ and EP0196132. Purther anti-psychotic piperidines and piporo7;n.~ are disclosed in DE2503816, EP0329168 and EP0013612.
A group of pip~ro~i and piperidine derivatives has been discovered tha~ are potent antagonists of dopamine D2 receptors and/'or 5-hT2 receptors and are therefore useful in the trearment of psychotic disorders.
The present inveneion provides a compound of formula (I), a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, and a physiologically functional deLiv~Li~_ thereof Y - Z N ~ ~ - W (I) wherein.
Y ..~.. a group of the formula (a), (b) or (c):
(a) ~ R2 wherein a single line ~ ing a broken line ( ~ .. L~ a single bond or a double bond, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/~ 'G
(b) ~
Rs Rlt V
(C) R10~W~N
Rs ~ R7 wherein Rl L-r~S_.~L~ one or ~ore ring substituen~s comprising hydrogen, halogen, Cl 6alkyl optionally substituted with one or mor-halogens Cl ~alkoxy optionally 5ubsituted with one or more halogens, hydroxy, -N(R )2~ nitro, S(O)nR where n is 0, 1 or 2, C N, CON(R )z, COR , COzR , CO-aryl, azido, benzyloxy, -NR N(R )2~ NR CO2R , -NR N-C(R )2~ -NR (C-O)CH(N(R )2)R and -NR (C-O)R ;
R2 L~r~ 2 2 2 ~ -CH2cx2cH2-~ -S-, -NR3- N N
-(C-O)NR4-R L~r~ ~ hydrogen, Cl 6alkyl, or Cl 6alkoxycarbonyl R4 L~r~e~ L~ hydrogen or Cl 6alkyl R ~ s -N-C- or -C-N-;
R6 L~rL~ hydrogen or Cl 6alkyl;
R ,R , R , R and Rll, which are the same or di7~erent, each L~rrs~ ~ hydrogen, halogen, nitro, Cl 6alkyl optionally substituted with one or more halogens, Cl 6alkoxy optionally substituted with one or more halogens, hydroxy, S(O) R where n is O, 1 or 2, C-N, CON(R )2~ coa, CO2R , CO-aryl, azido, benzyloxy, -N(R )2~ NR N(R )2~
-NR N-C(R )7, -NR (C-O)CH(N(R )2)R , -NR (C-O)R , NR CO2R ,Cl-6 alkoxy-carbonylamino or ~hN-N, or when considered in pairw~se CA2i i 7434 conbination, R7 and R8 or R8 and R9 or R9 and RlO or RlO and R
represenc V ~ LtaenC:. O or S;
Z ..y.._e.l~ C4 8alkylene, op~ional1y i-1ceL-~L_d by -S~O) - where n is 0, l or 2, C4 8alkenylene or C4 3alkynylene;
X .e~r~e_..c, N or C and U ..~ ..L~ a group of fornula (d) ~ 3 (d) R1~
where A ~e~__.. L~ CR or N, 3 ~ oxygen, NR or S(0) , where n and R are as defined herein and ~12 ,,~ hydrogen or halogen.
Conpounds of fornula (I) nay forn sol~ares, in particular hydrates or partial hydrat-s, and all such solvates are also included within the scope of the invention.
As used herein, the tera "alkyl~ as a group or a part of a group 2ay be a straight or branched chain alkyl group, for exanple, nethyl, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl. Alkyl groups are most preferably methyl or ethyl.
As used herein, the term "alkylene" refers to a straight, branched or C5 6cyclic alkylene group, for example, butylene, pentylene, hexylene, cyclohexylene, or 2)mC3 6cycloalkyl(CH2) - where m-0-4, in particular where C3 6cycloalkyl is a cyclopropylene group.
As used herein, the terms ~aryl" refers to phenyl, nDphthAlDnyl~
thienyl, pyridinyl, furanyl or pyrrolyl optionally substituted by one or more halo, hydroxy, nitro, cyano, trifl~ Ll.~l, lower alkyl, lower alkylthio, amino, mono- and di-alkyl amino or alkanoyl.
As used herein, the term "alkenylene~ refers to a straight, branched or cyclic alkenyl group having from 4 to 8 carbon atoms, such as, for example, butenylene, pentenylene, hexenylene and the like.
As used herein, the term "alkynylene" refers to a straight or branched alkynyl group having from 4 to 8 carbon atoms, such as, for example, butynylene, pentynylene, hexynylene and the like.
As ~sed herein, the term rhalo" refers to fluoro, chloro, bromo and iodo.
As used herein, the term "phye1~1~gi~Dlly r ~ derivative" means any physiologically acceptable ester, or salt of such ester, of a compound of formula (I) or a compound which upbn administration to the recipient is capable of providing (directly or indirectly) such a compound or an active metabolite or residue thereof.
As used herein 'Ac' refers to the moiety -(C-O)CH3.
The present invention includes all optical isomers of compounds of formula (I) and mixtures thereof including racemic mixtures. The CA 2 i 1 7 4 34 invention also includes all geometric isomers of compounds of formula (I) including mixtures thereof.
The invention further provides compounts of formula (I) and salts, solvates and derivatives thereof in which the nitrogen atom shown in formula (I) in the position adjacent to Z is in its oxidised form as N-oxide.
The present invention includes compounds of formula (I) in the form of physiologically acc.t ' 1P salts thereof. Suitable salts are, in particular, acid addition salts including those formed with both organic and inorganic acids. Such acids will normally be physiologically ~ 1P although salts of non-physiologically -~~Ppt-~lP acids may be of utility in the p~, ~nn and purification of the compound in question. Thus preferred salts include those formed from hydrochloric, 1.~ c, sulphuric, citric, tartaric, I ' ,' ~ r, lactic, pyruvic, triflvv.~ - ~, acetic, succinic, oxalic, fumaric, maleic, c~ n th -- - l phn-i r, ~j' lphAnir~ p-tnl 1 ' 'r, ' lr~ 'r and isethionic acids. Salts of compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acit.
According to preferred : ' ~- of the present invention, when Y is a group of formula (a~ , . a double hond in each case; R
is H or Cl, most preferably H; R2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -N-N-, -NR or -(C-O)NH-, more preferably -N-N-, -CH2, -CH2CH2-or -CH2CH2CH2-, most preferably -CH2- or -CH2CH2-; R is -CO2Et or H, most preferably H; R is H or Me, most preferably H.
According to further preferred - ~ ' of the present invention, when Y is a group of formula (b), R is preferably H, Cl, F, Me, OH, OMe, NO2 or di-Cl, more preferably H, Me, F, NO2 or OMe, most preferably H or NO2 and R is preferably -C-N-.
W O 93/16073 C ~ 2 1 1 7 4 3 4 PCT/GB93/00285 - 7 -According to further preferret '- ' of the present invention, when Y is a group of formula (c), R6 is H or Me, most preferably H; R7 is H, NH2, NHMe, OH, OMe or NHAc, more preferably NH2, OMe, NhAc or NHMe, most preferably NH2 or NHMe; R8 is H, Cl, NHCO2~-Bu, Br or NH2, more preferably H or Br, most preferably H; R is H, OMe, CF3, _-Bu, -N-N-Ph, NHAc, NHCO2t-Bu, NH2 or Br, more preferably H or Br, most preferably Br; Rl is H, NO2, Br or Cl, more preferably H or Br, most preferably H and Rll is H, OMe or OH, more preferably OMe or OH, most preferably OH.
According to further preferred . ' ' of the present invention V
is O or S, preferably O; Z is C4 6 alkylene, preferably C4 alkylene; B
is -S-, NH or -O- more preferably -5- or -O-, most preferably -S-; A
is CH or N, preferably N and R12 is H or F, preferably H.
Preferred compounds of formula (I) include:-2-(4-(4-;1,2-b-n~ieothiD7Al-3-yl)-l-piper~zinyl)butyl)-l-isoindoli-none;
N-(4-(4-(1,2,benzisothiazol-3-yl)-1-piperazinyl)butyl)-3,4-dihydro-1(2H)-i ~ 'n~l{
2-Amino-N-(4-(4-(1,2 ~ '~othiD~ol-3-yl)piperidino)butyl)benzamide;
6-(4-(4-(1,2-~ ~orh;D~ol-3-yl)-1-piperazinyl)butyl)-6,7-dihydro-SH--pyrrolo(3,4-B)pyridine-5,7-dione;
N-(4-(4-(1,2-~ 'eothiD~~1-3-yl)-1-piperazinyl)butyl)-2-(methyl-~mino)benzsmide;
N-(4-(4-(1,2-b~n~i~oth~ 1-3-yl)-1-piperazinyl)butyl)benzamide.
2-Amino-N-(4-(4-(1,2-~ ' _1.iazol-3-yl)-1-piperazinyl)butyl)benz-amide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hy-droxy-6 ' ~ ~A~;
2-Amino-N-(4-(4-(1,2-b~n7ie~vD~~l-3-yl)-l-piperaZinyl)butyl)benzsmide;
2-Amino-N-(4-(4-benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-(6-fluoro-l~2-b~n7;c~vD7~l-3-yl)piperidino)butyl)ben amide;
and physiologically acceptable salts ant solvates, in particulsr hydrates, thereof and phycinlogirslly ' L-n~A1 derivatives and N-oxides thereof.
More preferred compounds of formula (I) include:-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydro xy-6 : t' ~L '~' ;
2-Amino-N-(4-(4-(1,2-b~ icothio~ol-3-yl)-1-piperazinyl)butyl)benz-amide;
2-Amino-N-(4-(4-(1,2-b~eic~-A7r,1-3-yl)-l-piperAzinyl)butyl)benzamide;
2-Amino-N-(4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-(1,2 ~ c~rhi~7ol-3-yl)piperidine)butyl)benzamide;
and phyciolr~gir~lly ~lr salts and solvates, in particular hydrates thereof, physinlogirslly functional derivatives and N-oxides thereof.
Most ,L~efe..~' compound of formula (I) is:-2-Amino-N-(4-(4-(1,2-b-~i L' 'A~~1-3-Y1)-1-PiPeraZinY1)bUtY1)benZ-amide hydrochloride and solvates and phycinlogir~lly functional derLvatives thereof.
The compounds of formula (I) show an ~vP-r~e~ profile of 1' lrgir~l activiry and are useful in the trestment of a number of - ' riO~C. The compounds show, for example anxiolytic, centr-lly-acting muscle relaxant, and ~ti~ L activity. They may also be useful in the treatment of aggression ~CcociAte~ with senile dementia, borderline personal1ty disorders and as a broad-spectrum ~ti~ tir, In particular the compounds are useful in the treatment of psychotic disorders such as 5rhi r~ ~.,ia.
-CA2i 1 7434 W O 93/16073 PC~r/GB93/00285 Potential antipsychotic activity can be assessed by the ability of acompound to block ~ l~in~_induced climbing in the mouse (see Ogren et al, F~lr. J, Pharmacol., 1984, 12, 459, Iversen, Science, 1975, 188, 1084 and Gudelsky & hoore, J. Neural Transm., 1976, 38, 95). The tendency of a compound to induce catalepsy and its ability to block ~ ro induced ~Le~. L~t ~ are behavioural measures which indicate the potential of a compound to induce ~ALL~t~ 'A91 side effects.
The compounds of formula (I) are, in general, potent antagonists at dopamine D2 receptors and at 5-HT2 receptors suggesting potential utility as antipsychotics. This profile of activity has been confirmed by the potency of compounds of formula (I) in the mouse-climbing assay and by good ratios of the dose required for potency in this assay to the dose required for the induction of catalepsy.
Certain compounds of formula (I) are also potent agonists at the SHTlA
- receptor. This activity has been sccociAr~d with anti-depressant and anAiolytic effects as well as with a reduction of . ,~
side-effects. The - i ~n of potent dopamine D2 receptor sntserni~~ and 5-hT2 receptor -_tsgoni~ with 5-HTlA receptor agonism which is to be found in preferred compounds of formula (I) is a particularly r ~ gr profile of activity for an anti-psychotic agent and, in particular, for a drug for use in the treatment of 5~h~ r~ ,.,ia.
According to a further aspect, the present invention also provides a methot for the treatment or prophylaAis in a mammal of a disorder selected from the following:
anAiety, muscle spasm, depression, aggression accocir~tod with senile dementia, borderline personality disorders, emesis and psychosis W O 93/16073 C A ? i~ 7 4 3 4 PCT/GB93/00285 which comprises administering to the mAmmAl an effective treatment amount of a compound of formula ~I) or a physiologically acceptable salt, or solvate or physinl~Ginslly fnnrtirno1 derivative or N-oxide thereof. In particular the invention provides a method for the treatment or prophylaxis in a mammal of a psychotic disorder which comprises administering to the mammal an anti-psychotic effective treatment amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically f~nrti OnAl derivative or N-oxide thereof. In particular, the invention provides such a ~ethod wherein the psychotic disorder is schizophrenia.
According to a yet further aspect, the present invention provides a compound of formula (I) or a physiA1~girs11y acceptable salt or solvate thereof or a physiologically f -n~ti nnAl deriative or N-oxide thereof for use in therapy, in particular the therapy or prophylaxis of a psychotic disorder such as schizophrenia. The invention also provides the use of a compound of formula (I) or a physiologically .e ~10 salt or solvate thereof for the r .- r.~ . e of a ~- r for the treatment or prophylaxis of a psychotic disorder such as 5rhi r A
hilst it may be possible for the compounds of the present invention to be administered as the raw chemical, it is preferable to present them as a 1' rDl - 1AtiAn. According to a further aspect, the present invention provides a ,' rDl f 1Ation comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically fnnrtirnAl d~lv~Li~- or N-oxide thereof together with one or more 1' -'~A11y acceptable carriers therefor and optionally one or more other L' r ingredients.
The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the f~ lAtiAn and not deleterious to the recipient thereof.
The f: lAtiOnC include those suitable for oral, parenteral (including 5~h, " ., ~,., 1, intrPAorr~ Ar and ~ Le~ S), rectal and topical (including dermal, buccal and 5..hl 1 1 ) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The f~ 1At1~ne may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
All methods include the step of bringing into ~csociAti~r a compound of the present irvention as herein defined or a pharmacologically ~ ptr~lP salt or solvate thereof (-active inereAi~nt') with the carrier which constitutes one or more accessory ingredients. In general the i 1 Ati ~n~ are prepared by uniformly and intimately bringing into ~e~o~iAti~n the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired f 1 Ati An F~ 1 Ati A~e of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each nine a ~L~ ' amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non--queous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. C~ _d tablets may be prepared by - , ~ne in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or 'nC agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be f 1rr~d so as to provide slow or controlled release of the active ingredient therein.
F~ 1Ati~nC for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain W O 93/16073 PCT/GB93/0028' anti-oxidants, buffers, bacteriostats and solutes which render the f 1At~on isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile , Ane which may include , ''ne agents and thlr~nln3 agents. The f lAt;An~ may be presented in unit-dose or multi-dose c~ntAinpre~ for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophi1ieed) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, i ~ Ar-1y prior to w e.
r , injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
F~ lAtiAnc for i ' 1 administration may be delivered by passive diffusion or by electrically assisted transport, for example, oiS (see, for example, Ph ~Al Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of a compound of formula (I) or a salt or acid derivative thereof. Suitable ' lAtiA-. comprise citrate or bis/tris buffer (pH6) or ethanol/water.
r. lAtiAnC for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
F~ lAti~Ae for topical administration in the mouth, for example buccally or sublingually, include 1O2enges comprising the active ingredient in a n avoured basis such as sucrose and acacia or troee~~nth, and pastilles comprising the active inereAl~nt in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage f lAtiAnc are those cAntAinine an effective dose, as hereirbelow recited, or an appropriate fraction thereof, of the active ingredient.
C~ 2 1 1 7434 It should be ~I~L~Od that in atdition to the ingredients particularly , nn~A above, the f~ l Ati O~c of this invention may _ include other agents c~ Al in the art having regard to the type of f lA~i~n in question, for example those suitable for oral administration may include flavouring agents.
The compounds of the invention are preferably used to treat psychotic disorders such as srhi ,' ~..ia by oral administration or injection ~ l or suhc~t ). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration may vary depending on the condition and its severity.
The compounds of the invention may typically be administered orally or via injection at a dose of from 0.02 to 50.0 mg/kg per day. The dose range for adult humans is generally from 1.4 to 3500mg/day and preferably 2.8 to 1750mg/day, more preferably 7 to 700mg/day.
The present invention also provides processes for the preparation of compounds of formula (I) and physiologically acceptable salts and solvates and N-oxides thereof and physiologically functional derivatives thereof. In general the compounds of formula (I) can be prepared by any process known in the prior art for the ~ n of analogous compounds. In the following description, the groups Y, Z, X, W, V, A, B, and R to R have the meanings ascribed to them in formula (I) unless otherwise stated.
According to a first general process (A), compounds of formula (I) can be prepared by reaction of a compound of formula (II) YH (II) W O 93/16073 - 14 - PCT/GB93/0028"
with a compound of formula (III) L Z N X - W (III) / , where L s a leaving group, for example, a halogen such as bromine, chlorine or iodine, an alkyl or arylsulfonyloxy such as me~hane-sulfonyloxy or p-tol~ ~n~c~l fn~yloxy, in the presence of an appropriate solvene and base, ~he process may be carried out either at room i . ,L Le or at elevated , , rAr~re such as 60 C to 140 C. Suitable solven~s include N,~-dimethy~ , acetonitrile, benzene, toluene, xylene etc. and appropriate bases may be chosen from organic bases such as triethyl amine, pyridine etc., alkali metal ~~ or bir~ such as sodium carbonate, pot~ im carbonate, sodium bir~rb~~ potassium hi r~rn~t- etc., or alkali metal hydrides such as sodium hydride, potassium hydride etc.
According to a second general process (B), compounds of formula (I) wherein Z is 4 or 5 can be prepared by reaction of a compound of formula (I~) with a compound of formula (IV) ~ ~ (IV) R13 N ~ X - W
A-where A is a suitable anion, such as a halogen, for example, bromine or chlorine, sulphonic acid esters such as mesylate or tosylate and R i5 -(C~2)4- or -(CH2)5, more psrticularly -(C~2)4. ~he r~n~itinte of reaction may be the same as those described for general process (A) above. ~itinnolly a - lrY;ng agent such as 1,4,7,10,13,16-hexa-oxacyrlr~oL may be included.
According to a third general process (C), compounds of formula (I) can be prepared by reaction of a compound of for_ula (V) W O 93/16073 C A 2 1 1I~ 4 3 4 PCT/GB93/00285 Y--Z--L (V) in which L _s as hereinbefore defined, with a compound of formula (VI) ~\
HN~JX--W (VI ) The process ~ay be carried out as described for general process (A) above According ~o a fourth general process (D), compounds of a formula (I) in which ~ _s N can be prepared by reaction of a compound of formula (VII) Y Z N NH (VII) wi~h a compound of formula (VIII) L W (VIII) in which L is as h-reinbefore defined ~he process may be carried out as described for general process (A) above According to a fifth general process (E), compounds of formula (I) in which Y is a group of forDula (a) in which R2 is -CH2- or -N-N- where a single line , ~.ng a broken line (-----) Le~.c__ _, a double bond and can be prep-red by cyclisation of a compound of formula (rX) Rl ~N-- Z N X--W (IX) RU
. _, in which V is O and R is -CH2OH or -NH2.
~hen R is -CH2OH, the general proc-ss (E) may be carried oue as described in Annalen der Chemie 584, p87 [1953] ~o provide compounds of formula (I) wherein R2 is -CH2-.
~hen R14 is -NH2 the process may be carried ou~ as described in ;he following documencs;
J. Ort. Chem., 26, 613, (1961), . Or~. Chem.. 27, 1383, (1962) and J. t . Chem. Soc. 77, 6562 (1955), to provide compounds of formula (I) wherein R2 is -N-N-.
According to a sixth general process (F), compounds of formula (I~
wherein '8 is a group of formula (a) wherein R is -CH2-, -S-, or -N-N-or Y is a group of formula (b) or (c) can be prepared by reaction of a compound of formula (X) or (Xl) ~RIs wherein R1 is -CH2-, or -N(R )(C-V)- and R16 is R or -C-C-CA 2 i 1 7434 ~ O
R10~L~ (xl) R9 ~RI7 Ra wherein Rl is R7, 8 L2 or CH2-L2 and Ll is e.g. Cl, Br, OMe or O~
L2 is e.g. Cl, 3r, OMs or OTs with a compound of formula (XI) R6 ~
r Z N X - W (XI) H
For example, compounds of formula (I) where Y ~c~ a group of formula (c) and R7 ..,_ -N(R4)2 can be prepared by the creatmenc of a compound of formula X , where L L~rL- hydrox,Y, V L-r-~c_..L~
oxygen and R16 L~rL~ -N(R )2' with a compound of formula (XI) in ~he presence of silicon t-tr~rhl Aride in a refluxing solvent such as anhydrous pyridine. ~Xornet, M.J. J heterocvclir Chem.. 29, 103 (1992)].
Compounds of formula (I) nay also be prepared from otber compounds of formula (I). The following constitute examples of such i..LeL--~..._-~ions .
Compounds of formula (I) in which Z is C4 8alkylene can b- prepared by ..' 'An of a compound of formula (I) in which Z i5 C4 8alkenylene or C4 8alkynylene. Reduction nay be achieved by catalytic L~ 5_.~.ion wi~h hydrogen in ~he presence of a suitable catalyst such as WO 93/16073 - 18 PCI-/GB93/0028~
p911 r~i platinum, nickel, rhodium etc. in an appropriate solvent such as ethanol, te~ dL~r~-n--, methanol, ether, ethyl acetate, benzene, toluene, hexane etc. The reaction may be carried out at ~ r or elevated pressure and at room or elevated temperatures such as 20 to 100~C. Partial reduction of an acetylene (-C-C-) to the alkylene (-C-C-) may be accomplished by reduction using a poisoned catalyst such as Lindlar catalyst.
Compounds of formula (I) wherein Y is a group of formula (a),(b) or ( ) d Rl R7 R8 R9 R10 or Rll is OH can be prepared from the ~.-.sr~.,ding methoxy derivatives by known methods. [For example, by treatment with a Lewis acid such as boron tribromide or aluminium trichloride in a solvent such as ~irhll at room ~ , ~L~Le (Mcomie, J.F.U. and Uest, D.E. Org. Synth. Coll. Vol. V., 412(1973)., Dillard, R.D. et al., J.Med.Chem. 34, 2768-2778(1991)].
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10, or R11 is N(R )2 or NR N(R4)2 can be prepared by hydrolysis of the c~ ' ng alk~ a-bv.,~lamino derivatives by known methods, for example, by treatment of a (tert-butoxycarbonyl)-amino derivative with an acid such as trifluroacetic acid, and a t-butyl cation scavenger such as anisole or thiophenol in a solvent such as chloroform at room ~ . c (Lundt, B.F. Int. J. Pre~t.
Protein B~~. 12, 258(1978).
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R , R , Rl or Rll is N(R )2 may also be prepared by reduction of the c~--.s, ' ng nitro derivatives by known methods.
IFor example by catalytic l.~d-~6~ Lion wlth hydrogen with a catalyst, e.g., platinum, rsllr~i . raney nickel. (Org. Svnth. 49, 116, 1969, J.Med.Chem. 16, 1043, 1973; J.Or~.Chem. 38, 60, 1973).
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R8, R9, R10 or Rll is -NR (C-O)R , -NR CO2R or -NR4(C-o)CH(N(R )2)R can be prepared by acetylation of the W O 93/16073 PCT/GB93/0028~
cv,.~ , ne amino derivatives by known methods. [For example by treatment with an acid chloride such as acetyl chloride or eehyl chluL~f - and an organic base such as triethylamine in a solvent such as tichloromethane].
Compounds of formula (I) where Y is a group of formula (c) and R is Cl 6 alkyl can be prepared by alkylation of the cu,,._y~,.ling secondary amide by known methods. [For example, by treatment with a base such as sodium hydride in a suitable solvent such as dimethylformamide, followed by treatment with an alkylating agent such as methyl iodide].
Compounds of formula (I) where Y is a group of formula (c), where V
..~L~__..L~ sulphur, may be prepared by treatment of compounds of formula (I) where Y is a group of formula (c), where V L_~,e;c,.L~
oxygen, with a E~l' ne reagent such as Lawesson's reagent [2,4-bis(~l-. ~' ~...'._..~1)-1.3-dithia-2,4-A~ ,' t-n~-2,4-disulfide]
in a solvent such as toluene at an elevated ; , e. iSvnthesis, 941 (1979); T~LLd~_1,U~. 35, 2433 (1979), ~LL~Le1L~ Lett, 21 404.
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R8, R9, R10 or Rll is NhN-C(R )2 may be prepared from the c~ ne hydrazine derivatives and the appropriate ketones by known methods.
Compounds of formula (I) where the nitrogen is oxidized to the N-oxide can be prepared by oxidation of compounds of formula (I) with an ~V~*171 Ig reagent such as _-chlo,~ b_.L~ic acid in an appropriate solvent such as dichlo,~ ' .
W O 93/16073 - Z~ - PCT/GB93/00285 Compounds of formula ~II) in which Y is a group of formula (a) in which R is -CH2- and where s single line ~ ing a broken line (-----) .~yL~__..L~ a double bond i.e. phth~limj~ 5 of formula (IIA) o R - ~NH ( IIA) can be prepared by reduction of the cu,,.~ ding r~rh~ Of formula ~IIB) Rl ~NH (IIB) Suitable r-ducing agents include Sn/HCl in acetic acid at elevated i , e.g. lOO to 130~C. Other suitable reducing agents include Zn/ac-tic acid (J. Chem. Soc. 2038 (1977)) and CuCr2O~/diox-ane/H2 (Helv. Çhia- Acta, 1650 (1977)).
Compounds of formula (II) in which Y is a group of forcula (a) in which R2 is -CH2CH2-, and where a single line c ~ing a broken line (-----~ __..L~ a double bond, i.e. isoquinolines of formula (IIC) ~NH (IIC) R1~
can be prepared by reaction of the aryleth~lamine of formula (XII) R1 ~ NH2 (XII) with ~thylchlo.~ r ~ for exampl- in the presence of a base such a triethylamine in a suitable solvent such as dichlv. ~' , e g at 0~C, to produce the ethyl carbamate of formula (XIII) which can then be cyclised, for example, by treatment with pol~ho,~lv-ic acid at ele~atet ~ , e g 140 to 160~C
R~ -NC0zEl (XIII~
Compounds of formula (II) in which Y i5 a group of formula (a) in which R2 is -CH2CH2CH2- and where a single line - , ~ing a broken line (~ _ L~ a double bond, i e, b~n7s7epin~e of formula (IID) CA 2 i 1 7434 ~ H (IID) can be preparet by the procedure of GiLman, ~Y~Sh 5~E~- 12(5), 373-380 (1982~ This involves ~he following reaction scheme o ~CJ ~ R1- ~
R1 ~CN ' R1 ~ OMCN
J~
~ OMo , ( ~D ) ~ NH2 According ~o this reaction scbeme the dil~d.~l ~LCl is converted eo the dil~d~ by r--ction with pyritinium chl~ ~ in a suitable solvent suc_ as ~ rhl ~ ' at elevated i , - e .
Successive tre-tment of the dil~d.~ with sodium cyanide at elev ted i , (for example 205~C), then with w ter at, for example 75 C, and finally ~Cl at 0~C, yielded the cy noethylbenzoic acid Successive tre-tment of the cyanoethylbenzoic acid with thionyl chloride and methanol, both at ~l-v ted , yielded the methylcyanoethylbenzo-te Reduction of tbis compound with borane in tetrahydrofuran at O C yielded the methylamino propyl benzoate and tre-tment with sodium methoxide/methar,ol at room i m e yielded the ' ~ n~_- (IID) CA2i 1 7434 Compounds of formula (II) in which Y is a group of formula (a) in which R2 is -S- and where a single line accompanying a broken line ( = ) represents a double bond i e benzisochiazolones of for_ula ~ (IIE) O
Rl - ~ S/ H (IIE) can be prepared by the meehot of Yevich et al J ~ed ~h-m,, 29 359-369 (1986) This i m olves the following reaction scheme ~C~
AccordLng to this re-ction sche_e 2 2'-dLthiosalicylic acid is treated wLth thionyl chloride snd dimethyl~ *~ in refluxing toluene to gLv 2 2 _~irh1 ~ ~l chloride The acid chloride is co merted to 1 2- ~A-hio~ol-3(2h)-one by cleaving tne ~ rhi*-bond with chlorine gas in ~rhll Reac~ion of the resulting A;rhlr~;*~ with au~onium hydroxide yields the ~ ~orh1~lr~ (IIE) Co pounds of formula (II) in which Y is a group of formu1a (a) in which R2 is -~R3- where R3 is alkoxycarbonyl and where a single line CA 2 i 1 7434 W O 93/1607~ 2~ PCT/GB93/00285 a . ~ing a broken line (---~ .. L~ a douole bond, i.e.
inta~oles of formula (IIG) R - ~ / H (IIG) can oe prepared by r-ac~ion of the .u..~ g ~ compound of formula (IIG) where R3 is H with the appropriate chlu-,{ ,- R3Cl~
Co_pounds of formula (IIG) where R3 is N may be prepared for example ~y reacting the a~ite of formula (XVI) ~ CC~R
Rl_ I (XVI) ~ z~N3 (where R is alkyl e.g. Me, Et, eec.) with hytra_ine hytrate in ethanol at elevated I , ,, (see J.rh~m.soc.~rrk;n Tr~m~ I. l260 (197~)).
Co_pounts of for_u1a (II) in which Y is a group of for_ul- (a) in which R is -(C-O)~N- ant where a single line . , _ a broken line (--_ _~ a douhle 13Ond, i.e. ph~h~1~7ir.~ of formul- (IIJ) R1 - ~o Nl H (IIJ) W O 93/16073 - 25 - P(~r/GB93/00285 can be prepared by reacting either the phthalic anhydride (XIX) R~--~0 (XIX) or a phth~l ;mi~- of formula (XX) Rl ~NR
where R13 is alkyl (e g ~e, Et, etc ) with hydrazine hydrate (see J Or? rh-~ , 32, 1921 (1967)) Compounds of formula ~II) in which Y is a group of formula (a) in which R2 is -N-~- and wher- a single line , ~ing a broken line e~ a double bond, i e ben~o~;7~in~n~c of formula (IIK) Rl ~NH
~N (IIR) CA 2 i i 7434 W O 93/16073 - 26 - PCT/GB93/0028~
may be synrhesised as disclosed in the following documenCs which are incorpora~ed in che disclosure by reference.
i) El-Shafei and Gharras A.A.C., J TnaiA~ Chem.Soc. 61(1), 65-67 [1984~
ii) Lar ~., Gugnani H.C., and Madumere V.A. PbArr-7ie 35(8), 466-468 [1980]
Compounds of formula (II~) where Rl is H are commercially available.
Compounds of formula (II) in which Y is a group of formula (b), i.e.
compounds of formula (IIL) Rl ~ NH (IIL) o can be prepar-d by re-ction of the c~ rz cyclic anhydride of formula (X~I) o ~0 (~XI) Rs o with urea and acetic acid or wich ammonium hydroxide (see ~h~. Zvesri., 16, 574 (1962) and Org. Syn., Coll. Vol. 1, 457 (1941)).
W O 93/16073 C A 2 1 1, 4 3 4 PCT/GB93/00285 Compounds of formula (II) in which Y is a group of formula (c), i.e.
compounds of formula (IIH) Rll V
~NH (IIH) R9Jl~R~ R~
are eioher known conpounds or can be prepared by standard ~echods kno~n in che ar~.
Compounds of formula (III) can be prepsred by alkylacion of a compound of formula (VI) with a compound of formula (XXII) L - Z L (XXII) where L is a leaving group such as ior e y le a halogen such as bromine chlorine or iodine, an alkyl or an arylsulfonyloxy such as mechane~sulfonyloxy or p . rnl 1 f ~-yloxy.
In some cases, for example when both L groups are halogen and Z is Rl3, particularly (C~2)4, the same reaction may lead co ~he compound of formula ~IV) (J.~ ' Chem. 1986, Z9, 359-369).
Compounds of formula (V) may be prepared by alkylaeion of che appropriate compound of formula ~II) wich a compound of formula (XXII). Al r~ n~t1vely the compound of formula (V) may be prepared by ~ of the hydroxyl group in a compound of formula (XX~II) - Y Z OH (XXIII) W O 93/16073 - 28 - PCr/GB93/00285 into a leaving group L as hereinbefor- defined by known methods.
The compount of formula (XXIII) may in turn be prepared by - ~inn of a compound of formula tX) or (Xl) with an amino alcohol of formula (XXrV) H2N Z ~H (XXI~) or by ~r-atmenc of a compound of formula (II) with a compound of formula L-Z-OH. The proc-ss may be carried out either at room i . _ or at elevated t -r~t~re such as 60~C to 140 C.
Suitable solvents include N.N-dime~hyl ~- acetonitrile ben_ene toluene xylene etc. and ~ t- bases may be chosen from organic bases such as triethyl amine pyridine etc. alkali metal ~ or bi. ~ such as sodium csrbon te potassium carbon te sotium hic~rh~t~ potassium bic~r~~~-t- ecc. or alkali oe~al hydrides such as sodium hydride potassium hydride e~c.
Compounds of formula (VI) are either known compourds or can be prepared by know methods for e~ample:
when A - N and U is a group of formula ~d~ wherein A - N and B - S :
Yevich et al J. Y-~. ~ 29 359-69 (1986).
US-A-4 590 196.
X - C and U is a group of formula (d) wherein A - N atld B - S :
US-A-4 528 292.
X - ~ and U is a group of formula (d) wherein A - N and B - O :
J. ~ed. r~.~ 29 359-69 (1986).
X - C and U is a group of fortrul- (d) wherein A - N and B - O :
J. Ued. ~h-~ 28 761-69 (1985).
A - ~, and U is a group of formula (d) wherein A - N and B - S02;
J. ~ed. C~hem. 34 3316-3328 (1991). Alternatively ~his i - ~re can be prepared by ~he ~reatment of 3-chlu-- ~o~ le-l l-dioxide (Eur. ~at.~ Appl. 0 196096) W O 93/16073 P(~r/GB93/0028 ~ 29 -with piperazine in a solvent such as toluene at elevated ~emperatures such as 150-160 C.
X - N, and W is a group of formula (d) wherein A - N and B
S(0): J. Med. Chem., 34, 3316-3328 (1991).
X - C, and '~ is a group of formula (d) wherein A - C and B - NR :
U.S. Pat. No. 4,335,127, June 15th, 1982.
U.S. Pat. No. 4,710,500, December 1st, 1987.
X - N, and U is a group of formula (d) wherein A - C and B - S
can be prepared according to the following reaction scheme; by heating appropriately substituted ~~innbPn7A[blthiophPnPc with piperazine in a solvent such as l-methyl-2-pyrrolidinone. The requisite I nAhPn~A[b]thioFhApnpc can be prepared by treatment of appropria~ely substituted 2-fluorobenzonitrile with the anion of methyl thioglycola~e followed by decarbomethoxylateon of the resulting benzo[blthiophene.
RIZ ~ ~CN R12 ~i:,Mt q~ ~ R'~--~
X - C, and W is a group of formula (d) wherein A - C and B - S:
FR Pat. No. 2253519 (1975).
X - N, and W is a group of formula (d) wherein A - N and B = NR ;
U.S. Pat. No. 4,957,916, September 18th, 1990.
X - C, and W is a group of formula (d) wherein A - C and B - S02:
JP 03264583 A2 November 25th, 1991.
X - C, and W is a group of formula (d) wherein A - N and B - NR
can be prepared by d~.uL__Lion of N-protected piperinylindazoles obtained from the reaction of an appropriately substituted 4-(2-fluoroaroyl)piperidine (J.Med.Chem.. 2S, 761, (1985)) with a hydrazine in a refluxing solvent such as n-butanol according to the following scheme:
W O 93/16073 30 PCT/GB93/0028s NN~
R12 ~ ~ ~ R ~ ~N ~ R12 ~ N
X - C, and W is a group of formula (d) wherein A - C and B - S02:
JP 03264583 A2 November 25th, 1991, X - C, and U is a group of formula (d) wherein A - C and B - NR :
Ger. Offen. DE 3500898 Al July 17th, 1986.
Compounds of formula (VII) may be prepared by alkylation of piperazine with a compound of formula (V).
Compounds of formula (VIII) are either known compounds or can be prepared by known methods, for example:
~hen L is Cl, and ~ is a group of formula (d) wherein A - N and B
- S: US-A-4,590,196.
L is Cl, and U is a group of formula (d) wherein A - N and B - 0:
J. Med, Chem., 29, 359 (1986).
L is Cl, and ~ is a group of formula (d) wherein A - N and B
The present invention relates to a group of pipero7;- and piperidine d~ oLl~__, to processes for their ~,., ' , to 1' 'co1 compositions ,r~~toining them ant to their w e in therapy, in particular in the tre-tment of psychotic disorders.
Receptors for the chemical messenger dopamine are known to be located in the striatum and the limbic brain area and such receptors have been clossifiod as Dl and D2 based on receptor binding studies and on the presence or absence of a positive coupling between the r-ceptor and adenylate cvclase activity. Activation of the Dl-receptor is a~o-io~ ~ with at' loti~ of adenylate cyclase, whereas the D2-receptor mediates ' , - ~lc effects that do not involve direct st; lotirn of this enzyme tsee Kebabian ~ Calne, Nature, 1979, ~2~, 93 and Harrold et ~1, J. ~ed. Chem., 1987, 30, 1631). Although the distinct functions of the Dl- and D2-receptors are not clear cut, a : strong correl-tion is believed to exist between D2-receptor ~-t Dgr~
snd ~ I.vtlc activity (see SeemAn~ r - 1 . Rev., 1981, 32, 229, Seeman et ~ irrhotr r 1., 1985, 34, 151, Creese et al, 55i~ ~, 1976, 192, 481 nd Leysen in Clinirol Ph9 lo~v in ~svrhiAtrv Neuroleotic __A ~ tti~ Co~rch- Eds Usdin, Dahl, Gram and Lingjaerde, ~ ~ Basingstoke, 1982; pp35-52).
The chenical - _ 5-hydroxy L~ ~ro (5-HT) occurs widely in the central nervo w system and is known to be involved in the control of behavior. A number of different 5-HT receptors and receptor sub-types have been id -'f;oA In addition to the blockade of D2-receptors, it has been r - l~t-d that 5-HT2 receptor antAgr~ is also desirable in an ~ ,' L-r agent (see Janssen t al, J. Yharm.
and EYn~r. ~1 ., 1988, 244(21, 685). In particular it has been postulated that blockade of central dopamine D2-receptors may control the positive symptoms of e~hi r' ~nia (e.g. delusions and ~ol1r-inotj~ ) whilst blockade of 5-hT2 receptors may assist in the 1iorAtio~t of the neegative symptoms of schizophrenia (e.g. apathy CA 2 i i 7434 W O 93/16073 - 2 - PCT/GB93/0028~
and social withdraw l). It has also been suggested that blockade of tne 5-hT2 receptor results in a reduction of the 9A '~91 side effects which are known to occur in the case of neuroleptic 'nr-n-~r~ therapy with many known antipsychotic agents.
P,~ ic b~n7i~othio~~1es and bon~ ys7oles are described in US~968792, EP035713~ and EP0196132. Purther anti-psychotic piperidines and piporo7;n.~ are disclosed in DE2503816, EP0329168 and EP0013612.
A group of pip~ro~i and piperidine derivatives has been discovered tha~ are potent antagonists of dopamine D2 receptors and/'or 5-hT2 receptors and are therefore useful in the trearment of psychotic disorders.
The present inveneion provides a compound of formula (I), a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, and a physiologically functional deLiv~Li~_ thereof Y - Z N ~ ~ - W (I) wherein.
Y ..~.. a group of the formula (a), (b) or (c):
(a) ~ R2 wherein a single line ~ ing a broken line ( ~ .. L~ a single bond or a double bond, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/~ 'G
(b) ~
Rs Rlt V
(C) R10~W~N
Rs ~ R7 wherein Rl L-r~S_.~L~ one or ~ore ring substituen~s comprising hydrogen, halogen, Cl 6alkyl optionally substituted with one or mor-halogens Cl ~alkoxy optionally 5ubsituted with one or more halogens, hydroxy, -N(R )2~ nitro, S(O)nR where n is 0, 1 or 2, C N, CON(R )z, COR , COzR , CO-aryl, azido, benzyloxy, -NR N(R )2~ NR CO2R , -NR N-C(R )2~ -NR (C-O)CH(N(R )2)R and -NR (C-O)R ;
R2 L~r~ 2 2 2 ~ -CH2cx2cH2-~ -S-, -NR3- N N
-(C-O)NR4-R L~r~ ~ hydrogen, Cl 6alkyl, or Cl 6alkoxycarbonyl R4 L~r~e~ L~ hydrogen or Cl 6alkyl R ~ s -N-C- or -C-N-;
R6 L~rL~ hydrogen or Cl 6alkyl;
R ,R , R , R and Rll, which are the same or di7~erent, each L~rrs~ ~ hydrogen, halogen, nitro, Cl 6alkyl optionally substituted with one or more halogens, Cl 6alkoxy optionally substituted with one or more halogens, hydroxy, S(O) R where n is O, 1 or 2, C-N, CON(R )2~ coa, CO2R , CO-aryl, azido, benzyloxy, -N(R )2~ NR N(R )2~
-NR N-C(R )7, -NR (C-O)CH(N(R )2)R , -NR (C-O)R , NR CO2R ,Cl-6 alkoxy-carbonylamino or ~hN-N, or when considered in pairw~se CA2i i 7434 conbination, R7 and R8 or R8 and R9 or R9 and RlO or RlO and R
represenc V ~ LtaenC:. O or S;
Z ..y.._e.l~ C4 8alkylene, op~ional1y i-1ceL-~L_d by -S~O) - where n is 0, l or 2, C4 8alkenylene or C4 3alkynylene;
X .e~r~e_..c, N or C and U ..~ ..L~ a group of fornula (d) ~ 3 (d) R1~
where A ~e~__.. L~ CR or N, 3 ~ oxygen, NR or S(0) , where n and R are as defined herein and ~12 ,,~ hydrogen or halogen.
Conpounds of fornula (I) nay forn sol~ares, in particular hydrates or partial hydrat-s, and all such solvates are also included within the scope of the invention.
As used herein, the tera "alkyl~ as a group or a part of a group 2ay be a straight or branched chain alkyl group, for exanple, nethyl, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 ethyl, propyl, prop-2-yl, butyl, but-2-yl or 2-methylprop-2-yl. Alkyl groups are most preferably methyl or ethyl.
As used herein, the term "alkylene" refers to a straight, branched or C5 6cyclic alkylene group, for example, butylene, pentylene, hexylene, cyclohexylene, or 2)mC3 6cycloalkyl(CH2) - where m-0-4, in particular where C3 6cycloalkyl is a cyclopropylene group.
As used herein, the terms ~aryl" refers to phenyl, nDphthAlDnyl~
thienyl, pyridinyl, furanyl or pyrrolyl optionally substituted by one or more halo, hydroxy, nitro, cyano, trifl~ Ll.~l, lower alkyl, lower alkylthio, amino, mono- and di-alkyl amino or alkanoyl.
As used herein, the term "alkenylene~ refers to a straight, branched or cyclic alkenyl group having from 4 to 8 carbon atoms, such as, for example, butenylene, pentenylene, hexenylene and the like.
As used herein, the term "alkynylene" refers to a straight or branched alkynyl group having from 4 to 8 carbon atoms, such as, for example, butynylene, pentynylene, hexynylene and the like.
As ~sed herein, the term rhalo" refers to fluoro, chloro, bromo and iodo.
As used herein, the term "phye1~1~gi~Dlly r ~ derivative" means any physiologically acceptable ester, or salt of such ester, of a compound of formula (I) or a compound which upbn administration to the recipient is capable of providing (directly or indirectly) such a compound or an active metabolite or residue thereof.
As used herein 'Ac' refers to the moiety -(C-O)CH3.
The present invention includes all optical isomers of compounds of formula (I) and mixtures thereof including racemic mixtures. The CA 2 i 1 7 4 34 invention also includes all geometric isomers of compounds of formula (I) including mixtures thereof.
The invention further provides compounts of formula (I) and salts, solvates and derivatives thereof in which the nitrogen atom shown in formula (I) in the position adjacent to Z is in its oxidised form as N-oxide.
The present invention includes compounds of formula (I) in the form of physiologically acc.t ' 1P salts thereof. Suitable salts are, in particular, acid addition salts including those formed with both organic and inorganic acids. Such acids will normally be physiologically ~ 1P although salts of non-physiologically -~~Ppt-~lP acids may be of utility in the p~, ~nn and purification of the compound in question. Thus preferred salts include those formed from hydrochloric, 1.~ c, sulphuric, citric, tartaric, I ' ,' ~ r, lactic, pyruvic, triflvv.~ - ~, acetic, succinic, oxalic, fumaric, maleic, c~ n th -- - l phn-i r, ~j' lphAnir~ p-tnl 1 ' 'r, ' lr~ 'r and isethionic acids. Salts of compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acit.
According to preferred : ' ~- of the present invention, when Y is a group of formula (a~ , . a double hond in each case; R
is H or Cl, most preferably H; R2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -N-N-, -NR or -(C-O)NH-, more preferably -N-N-, -CH2, -CH2CH2-or -CH2CH2CH2-, most preferably -CH2- or -CH2CH2-; R is -CO2Et or H, most preferably H; R is H or Me, most preferably H.
According to further preferred - ~ ' of the present invention, when Y is a group of formula (b), R is preferably H, Cl, F, Me, OH, OMe, NO2 or di-Cl, more preferably H, Me, F, NO2 or OMe, most preferably H or NO2 and R is preferably -C-N-.
W O 93/16073 C ~ 2 1 1 7 4 3 4 PCT/GB93/00285 - 7 -According to further preferret '- ' of the present invention, when Y is a group of formula (c), R6 is H or Me, most preferably H; R7 is H, NH2, NHMe, OH, OMe or NHAc, more preferably NH2, OMe, NhAc or NHMe, most preferably NH2 or NHMe; R8 is H, Cl, NHCO2~-Bu, Br or NH2, more preferably H or Br, most preferably H; R is H, OMe, CF3, _-Bu, -N-N-Ph, NHAc, NHCO2t-Bu, NH2 or Br, more preferably H or Br, most preferably Br; Rl is H, NO2, Br or Cl, more preferably H or Br, most preferably H and Rll is H, OMe or OH, more preferably OMe or OH, most preferably OH.
According to further preferred . ' ' of the present invention V
is O or S, preferably O; Z is C4 6 alkylene, preferably C4 alkylene; B
is -S-, NH or -O- more preferably -5- or -O-, most preferably -S-; A
is CH or N, preferably N and R12 is H or F, preferably H.
Preferred compounds of formula (I) include:-2-(4-(4-;1,2-b-n~ieothiD7Al-3-yl)-l-piper~zinyl)butyl)-l-isoindoli-none;
N-(4-(4-(1,2,benzisothiazol-3-yl)-1-piperazinyl)butyl)-3,4-dihydro-1(2H)-i ~ 'n~l{
2-Amino-N-(4-(4-(1,2 ~ '~othiD~ol-3-yl)piperidino)butyl)benzamide;
6-(4-(4-(1,2-~ ~orh;D~ol-3-yl)-1-piperazinyl)butyl)-6,7-dihydro-SH--pyrrolo(3,4-B)pyridine-5,7-dione;
N-(4-(4-(1,2-~ 'eothiD~~1-3-yl)-1-piperazinyl)butyl)-2-(methyl-~mino)benzsmide;
N-(4-(4-(1,2-b~n~i~oth~ 1-3-yl)-1-piperazinyl)butyl)benzamide.
2-Amino-N-(4-(4-(1,2-~ ' _1.iazol-3-yl)-1-piperazinyl)butyl)benz-amide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hy-droxy-6 ' ~ ~A~;
2-Amino-N-(4-(4-(1,2-b~n7ie~vD~~l-3-yl)-l-piperaZinyl)butyl)benzsmide;
2-Amino-N-(4-(4-benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-(6-fluoro-l~2-b~n7;c~vD7~l-3-yl)piperidino)butyl)ben amide;
and physiologically acceptable salts ant solvates, in particulsr hydrates, thereof and phycinlogirslly ' L-n~A1 derivatives and N-oxides thereof.
More preferred compounds of formula (I) include:-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydro xy-6 : t' ~L '~' ;
2-Amino-N-(4-(4-(1,2-b~ icothio~ol-3-yl)-1-piperazinyl)butyl)benz-amide;
2-Amino-N-(4-(4-(1,2-b~eic~-A7r,1-3-yl)-l-piperAzinyl)butyl)benzamide;
2-Amino-N-(4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-(1,2 ~ c~rhi~7ol-3-yl)piperidine)butyl)benzamide;
and phyciolr~gir~lly ~lr salts and solvates, in particular hydrates thereof, physinlogirslly functional derivatives and N-oxides thereof.
Most ,L~efe..~' compound of formula (I) is:-2-Amino-N-(4-(4-(1,2-b-~i L' 'A~~1-3-Y1)-1-PiPeraZinY1)bUtY1)benZ-amide hydrochloride and solvates and phycinlogir~lly functional derLvatives thereof.
The compounds of formula (I) show an ~vP-r~e~ profile of 1' lrgir~l activiry and are useful in the trestment of a number of - ' riO~C. The compounds show, for example anxiolytic, centr-lly-acting muscle relaxant, and ~ti~ L activity. They may also be useful in the treatment of aggression ~CcociAte~ with senile dementia, borderline personal1ty disorders and as a broad-spectrum ~ti~ tir, In particular the compounds are useful in the treatment of psychotic disorders such as 5rhi r~ ~.,ia.
-CA2i 1 7434 W O 93/16073 PC~r/GB93/00285 Potential antipsychotic activity can be assessed by the ability of acompound to block ~ l~in~_induced climbing in the mouse (see Ogren et al, F~lr. J, Pharmacol., 1984, 12, 459, Iversen, Science, 1975, 188, 1084 and Gudelsky & hoore, J. Neural Transm., 1976, 38, 95). The tendency of a compound to induce catalepsy and its ability to block ~ ro induced ~Le~. L~t ~ are behavioural measures which indicate the potential of a compound to induce ~ALL~t~ 'A91 side effects.
The compounds of formula (I) are, in general, potent antagonists at dopamine D2 receptors and at 5-HT2 receptors suggesting potential utility as antipsychotics. This profile of activity has been confirmed by the potency of compounds of formula (I) in the mouse-climbing assay and by good ratios of the dose required for potency in this assay to the dose required for the induction of catalepsy.
Certain compounds of formula (I) are also potent agonists at the SHTlA
- receptor. This activity has been sccociAr~d with anti-depressant and anAiolytic effects as well as with a reduction of . ,~
side-effects. The - i ~n of potent dopamine D2 receptor sntserni~~ and 5-hT2 receptor -_tsgoni~ with 5-HTlA receptor agonism which is to be found in preferred compounds of formula (I) is a particularly r ~ gr profile of activity for an anti-psychotic agent and, in particular, for a drug for use in the treatment of 5~h~ r~ ,.,ia.
According to a further aspect, the present invention also provides a methot for the treatment or prophylaAis in a mammal of a disorder selected from the following:
anAiety, muscle spasm, depression, aggression accocir~tod with senile dementia, borderline personality disorders, emesis and psychosis W O 93/16073 C A ? i~ 7 4 3 4 PCT/GB93/00285 which comprises administering to the mAmmAl an effective treatment amount of a compound of formula ~I) or a physiologically acceptable salt, or solvate or physinl~Ginslly fnnrtirno1 derivative or N-oxide thereof. In particular the invention provides a method for the treatment or prophylaxis in a mammal of a psychotic disorder which comprises administering to the mammal an anti-psychotic effective treatment amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically f~nrti OnAl derivative or N-oxide thereof. In particular, the invention provides such a ~ethod wherein the psychotic disorder is schizophrenia.
According to a yet further aspect, the present invention provides a compound of formula (I) or a physiA1~girs11y acceptable salt or solvate thereof or a physiologically f -n~ti nnAl deriative or N-oxide thereof for use in therapy, in particular the therapy or prophylaxis of a psychotic disorder such as schizophrenia. The invention also provides the use of a compound of formula (I) or a physiologically .e ~10 salt or solvate thereof for the r .- r.~ . e of a ~- r for the treatment or prophylaxis of a psychotic disorder such as 5rhi r A
hilst it may be possible for the compounds of the present invention to be administered as the raw chemical, it is preferable to present them as a 1' rDl - 1AtiAn. According to a further aspect, the present invention provides a ,' rDl f 1Ation comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof or a physiologically fnnrtirnAl d~lv~Li~- or N-oxide thereof together with one or more 1' -'~A11y acceptable carriers therefor and optionally one or more other L' r ingredients.
The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the f~ lAtiAn and not deleterious to the recipient thereof.
The f: lAtiOnC include those suitable for oral, parenteral (including 5~h, " ., ~,., 1, intrPAorr~ Ar and ~ Le~ S), rectal and topical (including dermal, buccal and 5..hl 1 1 ) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The f~ 1At1~ne may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
All methods include the step of bringing into ~csociAti~r a compound of the present irvention as herein defined or a pharmacologically ~ ptr~lP salt or solvate thereof (-active inereAi~nt') with the carrier which constitutes one or more accessory ingredients. In general the i 1 Ati ~n~ are prepared by uniformly and intimately bringing into ~e~o~iAti~n the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired f 1 Ati An F~ 1 Ati A~e of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each nine a ~L~ ' amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non--queous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. C~ _d tablets may be prepared by - , ~ne in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or 'nC agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be f 1rr~d so as to provide slow or controlled release of the active ingredient therein.
F~ 1Ati~nC for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain W O 93/16073 PCT/GB93/0028' anti-oxidants, buffers, bacteriostats and solutes which render the f 1At~on isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile , Ane which may include , ''ne agents and thlr~nln3 agents. The f lAt;An~ may be presented in unit-dose or multi-dose c~ntAinpre~ for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophi1ieed) condition requiring only the addition of the sterile liquid carrier, for example, water-for-injection, i ~ Ar-1y prior to w e.
r , injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
F~ lAtiAnc for i ' 1 administration may be delivered by passive diffusion or by electrically assisted transport, for example, oiS (see, for example, Ph ~Al Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of a compound of formula (I) or a salt or acid derivative thereof. Suitable ' lAtiA-. comprise citrate or bis/tris buffer (pH6) or ethanol/water.
r. lAtiAnC for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
F~ lAti~Ae for topical administration in the mouth, for example buccally or sublingually, include 1O2enges comprising the active ingredient in a n avoured basis such as sucrose and acacia or troee~~nth, and pastilles comprising the active inereAl~nt in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage f lAtiAnc are those cAntAinine an effective dose, as hereirbelow recited, or an appropriate fraction thereof, of the active ingredient.
C~ 2 1 1 7434 It should be ~I~L~Od that in atdition to the ingredients particularly , nn~A above, the f~ l Ati O~c of this invention may _ include other agents c~ Al in the art having regard to the type of f lA~i~n in question, for example those suitable for oral administration may include flavouring agents.
The compounds of the invention are preferably used to treat psychotic disorders such as srhi ,' ~..ia by oral administration or injection ~ l or suhc~t ). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also the route of administration may vary depending on the condition and its severity.
The compounds of the invention may typically be administered orally or via injection at a dose of from 0.02 to 50.0 mg/kg per day. The dose range for adult humans is generally from 1.4 to 3500mg/day and preferably 2.8 to 1750mg/day, more preferably 7 to 700mg/day.
The present invention also provides processes for the preparation of compounds of formula (I) and physiologically acceptable salts and solvates and N-oxides thereof and physiologically functional derivatives thereof. In general the compounds of formula (I) can be prepared by any process known in the prior art for the ~ n of analogous compounds. In the following description, the groups Y, Z, X, W, V, A, B, and R to R have the meanings ascribed to them in formula (I) unless otherwise stated.
According to a first general process (A), compounds of formula (I) can be prepared by reaction of a compound of formula (II) YH (II) W O 93/16073 - 14 - PCT/GB93/0028"
with a compound of formula (III) L Z N X - W (III) / , where L s a leaving group, for example, a halogen such as bromine, chlorine or iodine, an alkyl or arylsulfonyloxy such as me~hane-sulfonyloxy or p-tol~ ~n~c~l fn~yloxy, in the presence of an appropriate solvene and base, ~he process may be carried out either at room i . ,L Le or at elevated , , rAr~re such as 60 C to 140 C. Suitable solven~s include N,~-dimethy~ , acetonitrile, benzene, toluene, xylene etc. and appropriate bases may be chosen from organic bases such as triethyl amine, pyridine etc., alkali metal ~~ or bir~ such as sodium carbonate, pot~ im carbonate, sodium bir~rb~~ potassium hi r~rn~t- etc., or alkali metal hydrides such as sodium hydride, potassium hydride etc.
According to a second general process (B), compounds of formula (I) wherein Z is 4 or 5 can be prepared by reaction of a compound of formula (I~) with a compound of formula (IV) ~ ~ (IV) R13 N ~ X - W
A-where A is a suitable anion, such as a halogen, for example, bromine or chlorine, sulphonic acid esters such as mesylate or tosylate and R i5 -(C~2)4- or -(CH2)5, more psrticularly -(C~2)4. ~he r~n~itinte of reaction may be the same as those described for general process (A) above. ~itinnolly a - lrY;ng agent such as 1,4,7,10,13,16-hexa-oxacyrlr~oL may be included.
According to a third general process (C), compounds of formula (I) can be prepared by reaction of a compound of for_ula (V) W O 93/16073 C A 2 1 1I~ 4 3 4 PCT/GB93/00285 Y--Z--L (V) in which L _s as hereinbefore defined, with a compound of formula (VI) ~\
HN~JX--W (VI ) The process ~ay be carried out as described for general process (A) above According ~o a fourth general process (D), compounds of a formula (I) in which ~ _s N can be prepared by reaction of a compound of formula (VII) Y Z N NH (VII) wi~h a compound of formula (VIII) L W (VIII) in which L is as h-reinbefore defined ~he process may be carried out as described for general process (A) above According to a fifth general process (E), compounds of formula (I) in which Y is a group of forDula (a) in which R2 is -CH2- or -N-N- where a single line , ~.ng a broken line (-----) Le~.c__ _, a double bond and can be prep-red by cyclisation of a compound of formula (rX) Rl ~N-- Z N X--W (IX) RU
. _, in which V is O and R is -CH2OH or -NH2.
~hen R is -CH2OH, the general proc-ss (E) may be carried oue as described in Annalen der Chemie 584, p87 [1953] ~o provide compounds of formula (I) wherein R2 is -CH2-.
~hen R14 is -NH2 the process may be carried ou~ as described in ;he following documencs;
J. Ort. Chem., 26, 613, (1961), . Or~. Chem.. 27, 1383, (1962) and J. t . Chem. Soc. 77, 6562 (1955), to provide compounds of formula (I) wherein R2 is -N-N-.
According to a sixth general process (F), compounds of formula (I~
wherein '8 is a group of formula (a) wherein R is -CH2-, -S-, or -N-N-or Y is a group of formula (b) or (c) can be prepared by reaction of a compound of formula (X) or (Xl) ~RIs wherein R1 is -CH2-, or -N(R )(C-V)- and R16 is R or -C-C-CA 2 i 1 7434 ~ O
R10~L~ (xl) R9 ~RI7 Ra wherein Rl is R7, 8 L2 or CH2-L2 and Ll is e.g. Cl, Br, OMe or O~
L2 is e.g. Cl, 3r, OMs or OTs with a compound of formula (XI) R6 ~
r Z N X - W (XI) H
For example, compounds of formula (I) where Y ~c~ a group of formula (c) and R7 ..,_ -N(R4)2 can be prepared by the creatmenc of a compound of formula X , where L L~rL- hydrox,Y, V L-r-~c_..L~
oxygen and R16 L~rL~ -N(R )2' with a compound of formula (XI) in ~he presence of silicon t-tr~rhl Aride in a refluxing solvent such as anhydrous pyridine. ~Xornet, M.J. J heterocvclir Chem.. 29, 103 (1992)].
Compounds of formula (I) nay also be prepared from otber compounds of formula (I). The following constitute examples of such i..LeL--~..._-~ions .
Compounds of formula (I) in which Z is C4 8alkylene can b- prepared by ..' 'An of a compound of formula (I) in which Z i5 C4 8alkenylene or C4 8alkynylene. Reduction nay be achieved by catalytic L~ 5_.~.ion wi~h hydrogen in ~he presence of a suitable catalyst such as WO 93/16073 - 18 PCI-/GB93/0028~
p911 r~i platinum, nickel, rhodium etc. in an appropriate solvent such as ethanol, te~ dL~r~-n--, methanol, ether, ethyl acetate, benzene, toluene, hexane etc. The reaction may be carried out at ~ r or elevated pressure and at room or elevated temperatures such as 20 to 100~C. Partial reduction of an acetylene (-C-C-) to the alkylene (-C-C-) may be accomplished by reduction using a poisoned catalyst such as Lindlar catalyst.
Compounds of formula (I) wherein Y is a group of formula (a),(b) or ( ) d Rl R7 R8 R9 R10 or Rll is OH can be prepared from the ~.-.sr~.,ding methoxy derivatives by known methods. [For example, by treatment with a Lewis acid such as boron tribromide or aluminium trichloride in a solvent such as ~irhll at room ~ , ~L~Le (Mcomie, J.F.U. and Uest, D.E. Org. Synth. Coll. Vol. V., 412(1973)., Dillard, R.D. et al., J.Med.Chem. 34, 2768-2778(1991)].
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10, or R11 is N(R )2 or NR N(R4)2 can be prepared by hydrolysis of the c~ ' ng alk~ a-bv.,~lamino derivatives by known methods, for example, by treatment of a (tert-butoxycarbonyl)-amino derivative with an acid such as trifluroacetic acid, and a t-butyl cation scavenger such as anisole or thiophenol in a solvent such as chloroform at room ~ . c (Lundt, B.F. Int. J. Pre~t.
Protein B~~. 12, 258(1978).
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R , R , Rl or Rll is N(R )2 may also be prepared by reduction of the c~--.s, ' ng nitro derivatives by known methods.
IFor example by catalytic l.~d-~6~ Lion wlth hydrogen with a catalyst, e.g., platinum, rsllr~i . raney nickel. (Org. Svnth. 49, 116, 1969, J.Med.Chem. 16, 1043, 1973; J.Or~.Chem. 38, 60, 1973).
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R8, R9, R10 or Rll is -NR (C-O)R , -NR CO2R or -NR4(C-o)CH(N(R )2)R can be prepared by acetylation of the W O 93/16073 PCT/GB93/0028~
cv,.~ , ne amino derivatives by known methods. [For example by treatment with an acid chloride such as acetyl chloride or eehyl chluL~f - and an organic base such as triethylamine in a solvent such as tichloromethane].
Compounds of formula (I) where Y is a group of formula (c) and R is Cl 6 alkyl can be prepared by alkylation of the cu,,._y~,.ling secondary amide by known methods. [For example, by treatment with a base such as sodium hydride in a suitable solvent such as dimethylformamide, followed by treatment with an alkylating agent such as methyl iodide].
Compounds of formula (I) where Y is a group of formula (c), where V
..~L~__..L~ sulphur, may be prepared by treatment of compounds of formula (I) where Y is a group of formula (c), where V L_~,e;c,.L~
oxygen, with a E~l' ne reagent such as Lawesson's reagent [2,4-bis(~l-. ~' ~...'._..~1)-1.3-dithia-2,4-A~ ,' t-n~-2,4-disulfide]
in a solvent such as toluene at an elevated ; , e. iSvnthesis, 941 (1979); T~LLd~_1,U~. 35, 2433 (1979), ~LL~Le1L~ Lett, 21 404.
Compounds of formula (I) where Y is a group of formula (a), (b) or (c) and Rl, R7, R8, R9, R10 or Rll is NhN-C(R )2 may be prepared from the c~ ne hydrazine derivatives and the appropriate ketones by known methods.
Compounds of formula (I) where the nitrogen is oxidized to the N-oxide can be prepared by oxidation of compounds of formula (I) with an ~V~*171 Ig reagent such as _-chlo,~ b_.L~ic acid in an appropriate solvent such as dichlo,~ ' .
W O 93/16073 - Z~ - PCT/GB93/00285 Compounds of formula ~II) in which Y is a group of formula (a) in which R is -CH2- and where s single line ~ ing a broken line (-----) .~yL~__..L~ a double bond i.e. phth~limj~ 5 of formula (IIA) o R - ~NH ( IIA) can be prepared by reduction of the cu,,.~ ding r~rh~ Of formula ~IIB) Rl ~NH (IIB) Suitable r-ducing agents include Sn/HCl in acetic acid at elevated i , e.g. lOO to 130~C. Other suitable reducing agents include Zn/ac-tic acid (J. Chem. Soc. 2038 (1977)) and CuCr2O~/diox-ane/H2 (Helv. Çhia- Acta, 1650 (1977)).
Compounds of formula (II) in which Y is a group of forcula (a) in which R2 is -CH2CH2-, and where a single line c ~ing a broken line (-----~ __..L~ a double bond, i.e. isoquinolines of formula (IIC) ~NH (IIC) R1~
can be prepared by reaction of the aryleth~lamine of formula (XII) R1 ~ NH2 (XII) with ~thylchlo.~ r ~ for exampl- in the presence of a base such a triethylamine in a suitable solvent such as dichlv. ~' , e g at 0~C, to produce the ethyl carbamate of formula (XIII) which can then be cyclised, for example, by treatment with pol~ho,~lv-ic acid at ele~atet ~ , e g 140 to 160~C
R~ -NC0zEl (XIII~
Compounds of formula (II) in which Y i5 a group of formula (a) in which R2 is -CH2CH2CH2- and where a single line - , ~ing a broken line (~ _ L~ a double bond, i e, b~n7s7epin~e of formula (IID) CA 2 i 1 7434 ~ H (IID) can be preparet by the procedure of GiLman, ~Y~Sh 5~E~- 12(5), 373-380 (1982~ This involves ~he following reaction scheme o ~CJ ~ R1- ~
R1 ~CN ' R1 ~ OMCN
J~
~ OMo , ( ~D ) ~ NH2 According ~o this reaction scbeme the dil~d.~l ~LCl is converted eo the dil~d~ by r--ction with pyritinium chl~ ~ in a suitable solvent suc_ as ~ rhl ~ ' at elevated i , - e .
Successive tre-tment of the dil~d.~ with sodium cyanide at elev ted i , (for example 205~C), then with w ter at, for example 75 C, and finally ~Cl at 0~C, yielded the cy noethylbenzoic acid Successive tre-tment of the cyanoethylbenzoic acid with thionyl chloride and methanol, both at ~l-v ted , yielded the methylcyanoethylbenzo-te Reduction of tbis compound with borane in tetrahydrofuran at O C yielded the methylamino propyl benzoate and tre-tment with sodium methoxide/methar,ol at room i m e yielded the ' ~ n~_- (IID) CA2i 1 7434 Compounds of formula (II) in which Y is a group of formula (a) in which R2 is -S- and where a single line accompanying a broken line ( = ) represents a double bond i e benzisochiazolones of for_ula ~ (IIE) O
Rl - ~ S/ H (IIE) can be prepared by the meehot of Yevich et al J ~ed ~h-m,, 29 359-369 (1986) This i m olves the following reaction scheme ~C~
AccordLng to this re-ction sche_e 2 2'-dLthiosalicylic acid is treated wLth thionyl chloride snd dimethyl~ *~ in refluxing toluene to gLv 2 2 _~irh1 ~ ~l chloride The acid chloride is co merted to 1 2- ~A-hio~ol-3(2h)-one by cleaving tne ~ rhi*-bond with chlorine gas in ~rhll Reac~ion of the resulting A;rhlr~;*~ with au~onium hydroxide yields the ~ ~orh1~lr~ (IIE) Co pounds of formula (II) in which Y is a group of formu1a (a) in which R2 is -~R3- where R3 is alkoxycarbonyl and where a single line CA 2 i 1 7434 W O 93/1607~ 2~ PCT/GB93/00285 a . ~ing a broken line (---~ .. L~ a douole bond, i.e.
inta~oles of formula (IIG) R - ~ / H (IIG) can oe prepared by r-ac~ion of the .u..~ g ~ compound of formula (IIG) where R3 is H with the appropriate chlu-,{ ,- R3Cl~
Co_pounds of formula (IIG) where R3 is N may be prepared for example ~y reacting the a~ite of formula (XVI) ~ CC~R
Rl_ I (XVI) ~ z~N3 (where R is alkyl e.g. Me, Et, eec.) with hytra_ine hytrate in ethanol at elevated I , ,, (see J.rh~m.soc.~rrk;n Tr~m~ I. l260 (197~)).
Co_pounts of for_u1a (II) in which Y is a group of for_ul- (a) in which R is -(C-O)~N- ant where a single line . , _ a broken line (--_ _~ a douhle 13Ond, i.e. ph~h~1~7ir.~ of formul- (IIJ) R1 - ~o Nl H (IIJ) W O 93/16073 - 25 - P(~r/GB93/00285 can be prepared by reacting either the phthalic anhydride (XIX) R~--~0 (XIX) or a phth~l ;mi~- of formula (XX) Rl ~NR
where R13 is alkyl (e g ~e, Et, etc ) with hydrazine hydrate (see J Or? rh-~ , 32, 1921 (1967)) Compounds of formula ~II) in which Y is a group of formula (a) in which R2 is -N-~- and wher- a single line , ~ing a broken line e~ a double bond, i e ben~o~;7~in~n~c of formula (IIK) Rl ~NH
~N (IIR) CA 2 i i 7434 W O 93/16073 - 26 - PCT/GB93/0028~
may be synrhesised as disclosed in the following documenCs which are incorpora~ed in che disclosure by reference.
i) El-Shafei and Gharras A.A.C., J TnaiA~ Chem.Soc. 61(1), 65-67 [1984~
ii) Lar ~., Gugnani H.C., and Madumere V.A. PbArr-7ie 35(8), 466-468 [1980]
Compounds of formula (II~) where Rl is H are commercially available.
Compounds of formula (II) in which Y is a group of formula (b), i.e.
compounds of formula (IIL) Rl ~ NH (IIL) o can be prepar-d by re-ction of the c~ rz cyclic anhydride of formula (X~I) o ~0 (~XI) Rs o with urea and acetic acid or wich ammonium hydroxide (see ~h~. Zvesri., 16, 574 (1962) and Org. Syn., Coll. Vol. 1, 457 (1941)).
W O 93/16073 C A 2 1 1, 4 3 4 PCT/GB93/00285 Compounds of formula (II) in which Y is a group of formula (c), i.e.
compounds of formula (IIH) Rll V
~NH (IIH) R9Jl~R~ R~
are eioher known conpounds or can be prepared by standard ~echods kno~n in che ar~.
Compounds of formula (III) can be prepsred by alkylacion of a compound of formula (VI) with a compound of formula (XXII) L - Z L (XXII) where L is a leaving group such as ior e y le a halogen such as bromine chlorine or iodine, an alkyl or an arylsulfonyloxy such as mechane~sulfonyloxy or p . rnl 1 f ~-yloxy.
In some cases, for example when both L groups are halogen and Z is Rl3, particularly (C~2)4, the same reaction may lead co ~he compound of formula ~IV) (J.~ ' Chem. 1986, Z9, 359-369).
Compounds of formula (V) may be prepared by alkylaeion of che appropriate compound of formula ~II) wich a compound of formula (XXII). Al r~ n~t1vely the compound of formula (V) may be prepared by ~ of the hydroxyl group in a compound of formula (XX~II) - Y Z OH (XXIII) W O 93/16073 - 28 - PCr/GB93/00285 into a leaving group L as hereinbefor- defined by known methods.
The compount of formula (XXIII) may in turn be prepared by - ~inn of a compound of formula tX) or (Xl) with an amino alcohol of formula (XXrV) H2N Z ~H (XXI~) or by ~r-atmenc of a compound of formula (II) with a compound of formula L-Z-OH. The proc-ss may be carried out either at room i . _ or at elevated t -r~t~re such as 60~C to 140 C.
Suitable solvents include N.N-dime~hyl ~- acetonitrile ben_ene toluene xylene etc. and ~ t- bases may be chosen from organic bases such as triethyl amine pyridine etc. alkali metal ~ or bi. ~ such as sodium csrbon te potassium carbon te sotium hic~rh~t~ potassium bic~r~~~-t- ecc. or alkali oe~al hydrides such as sodium hydride potassium hydride e~c.
Compounds of formula (VI) are either known compourds or can be prepared by know methods for e~ample:
when A - N and U is a group of formula ~d~ wherein A - N and B - S :
Yevich et al J. Y-~. ~ 29 359-69 (1986).
US-A-4 590 196.
X - C and U is a group of formula (d) wherein A - N atld B - S :
US-A-4 528 292.
X - ~ and U is a group of formula (d) wherein A - N and B - O :
J. ~ed. r~.~ 29 359-69 (1986).
X - C and U is a group of fortrul- (d) wherein A - N and B - O :
J. Ued. ~h-~ 28 761-69 (1985).
A - ~, and U is a group of formula (d) wherein A - N and B - S02;
J. ~ed. C~hem. 34 3316-3328 (1991). Alternatively ~his i - ~re can be prepared by ~he ~reatment of 3-chlu-- ~o~ le-l l-dioxide (Eur. ~at.~ Appl. 0 196096) W O 93/16073 P(~r/GB93/0028 ~ 29 -with piperazine in a solvent such as toluene at elevated ~emperatures such as 150-160 C.
X - N, and W is a group of formula (d) wherein A - N and B
S(0): J. Med. Chem., 34, 3316-3328 (1991).
X - C, and '~ is a group of formula (d) wherein A - C and B - NR :
U.S. Pat. No. 4,335,127, June 15th, 1982.
U.S. Pat. No. 4,710,500, December 1st, 1987.
X - N, and U is a group of formula (d) wherein A - C and B - S
can be prepared according to the following reaction scheme; by heating appropriately substituted ~~innbPn7A[blthiophPnPc with piperazine in a solvent such as l-methyl-2-pyrrolidinone. The requisite I nAhPn~A[b]thioFhApnpc can be prepared by treatment of appropria~ely substituted 2-fluorobenzonitrile with the anion of methyl thioglycola~e followed by decarbomethoxylateon of the resulting benzo[blthiophene.
RIZ ~ ~CN R12 ~i:,Mt q~ ~ R'~--~
X - C, and W is a group of formula (d) wherein A - C and B - S:
FR Pat. No. 2253519 (1975).
X - N, and W is a group of formula (d) wherein A - N and B = NR ;
U.S. Pat. No. 4,957,916, September 18th, 1990.
X - C, and W is a group of formula (d) wherein A - C and B - S02:
JP 03264583 A2 November 25th, 1991.
X - C, and W is a group of formula (d) wherein A - N and B - NR
can be prepared by d~.uL__Lion of N-protected piperinylindazoles obtained from the reaction of an appropriately substituted 4-(2-fluoroaroyl)piperidine (J.Med.Chem.. 2S, 761, (1985)) with a hydrazine in a refluxing solvent such as n-butanol according to the following scheme:
W O 93/16073 30 PCT/GB93/0028s NN~
R12 ~ ~ ~ R ~ ~N ~ R12 ~ N
X - C, and W is a group of formula (d) wherein A - C and B - S02:
JP 03264583 A2 November 25th, 1991, X - C, and U is a group of formula (d) wherein A - C and B - NR :
Ger. Offen. DE 3500898 Al July 17th, 1986.
Compounds of formula (VII) may be prepared by alkylation of piperazine with a compound of formula (V).
Compounds of formula (VIII) are either known compounds or can be prepared by known methods, for example:
~hen L is Cl, and ~ is a group of formula (d) wherein A - N and B
- S: US-A-4,590,196.
L is Cl, and U is a group of formula (d) wherein A - N and B - 0:
J. Med, Chem., 29, 359 (1986).
L is Cl, and ~ is a group of formula (d) wherein A - N and B
5~2 Eur. Pat. Appl. 0196096A2 C A 2 i 1 7 434 W O 93/16073 - 31 - PCT/GB93/0028~
Compounds of formula ~rX) in ~hich Rl is -CH20H and V is oxygen ~ay be m de bv the method described in Annslen der Chemie, 584, 87 (1953).
Te..~hedL~.. Lett. 25(20) p2093, (1984) and Te..OI.ed.~.. Let~. 27(20), p2275, (1986). Compounds of formula (rX) in which Rl is NH2 and V is oxygen may be made by reaction of an isatoic annydride of for~ula (X~V) ~N~o (~v) ~ith a compound of formula ~X}). The reaction may be carried out in a suitable solvent such as ethanol, for example at room i , ~.
~hth~ oe of formulOa (XA) O
Rl - ~ ~ (XA) phthalic aDhydrides of formula (X8) ~ (~8) Rs compounds of formula (X~) CA2i 174~4 R~1 o R~~~ (Xl) R3--~R~7 Ra isatoic annydrides of formula (XE) R~ V
=9 ~ I ~ V (XE) Ra R~
are ~ither known compounds or can be prepared by known methods For example. isatoic anhydrides of formula (XE) can be prepared by ~he tre-tment of the ,, , Ar~ly substitute Anth~ acids with phosg-ne or a phosgene substitute (i.e. trichloromethyl chl~.~LuL e) in an appropriate solvent such as benzene or dioxane (J.Het.Chem. 12.
565 (1975); J.~ .Che~.Soc., 72, 4887, (1950) J.OrE.Che~. 41, 2070 (1976)). Is-toic anhydrides of formula (XE) where V represcnts oxygen car. also be prepared by treatment of the appropriately substituted phthalic anhydrides of formula (XB) with azidoerimeChylsilane in an appropriate solvent such as chloroform. ~hioisatoic anhydrides of ~he formula (XE) where V 5-r.~__..LY sulphur can be prepared by treatment of the zrproFrlAt~ly substituted isatoic anhydrides with ~h~ oL~A
F ~ lf~' in refluxing xylenes.
CA2i 1 7434 W O 93/16073 ~ 33 ~ PCT/GB93/0028 Compounds of for_ula (XF) J~
R1 ~ L
where, for cxample L is cethoxy and L2 is 8r, can be prepared as described in U.S. ~aeen~ No. 4,289,781 which is inc~ L,d herein in i~s entirety.
Compounds of fotmula (XI) wherein R5-H can be obtained by clea~age of ph~h~1im1~ of for_ula (I), i.e. compounds of for_ula (I) in which Y
LLrL~ a group of for_ula (b) in which R5 is C-C and Rl-H. The reaction can be carried out wi~h hydrazine hydra~e in methanol.
Compounds of for_ula (XI) wherein R6-Cl 6 alkyl can be prepared from compounds of for_ula (XIa) (XIa) Z N X W
\J
W O 93/16073 P~ /GB93/0028S
wherein P is a protecting group, for example trifluoroacetate, by removal of the protecting group by known methods, for example aqueous potassium carbonate.
Compounds of formula (XIa) wherein R -Cl 6 alkyl can be prepared from compounds of formula (XI), wherein R -H, by protection of the amino group, for example as the triflu~ ~ 'A~, followed by alkylation of the resulting protected amine with a Cl 6 alkyl halide, for example methyliodide.
A further - '~'' of the present invention comprises the following compounds;
N-(4-(4-(l~2-Benzisothiazol-3-yl)piperidino)butyl)phthslimillr;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A I 'JdLu-1(2H)-rhthAlA7i-rnr;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A~ u-1(2N)-rhthslD7inrn_;
N-(4-(4-(6-Fluoro-1,2-b e~ 7ol-3-yl)piperidino)butyl)rhthAl;m~
and phye;r1-Eirs11y acceptable salts, solvates and N-oxides thereof and physi~ rgirDlly functional derivatives thereof.
Further ~ ' ' of the present invention comprise the following:
the use of one of the following compounds and salt, solvates, N-oxides and derivatives thereof in therapy; the use of one of the following compounds and salts, solvates, N-oxides and derivatives thereof in the preparation of a ' r for use in the treatment of any of the hereinbefore described disorders; a method for the treatment or prophylaxis in a mammal of any of the disorders hereinbefore described which comprises administering to the mammal a th. rA11y effective treatment amount of one of the following compounds or a salt, solvate, N-oxide or derivative thereof: a rhAr~~-e~-tiCAl composition comprising one of the following compounds and salt, solvate, N-oxides and d.Llve~ s thereof; a process for the preparation of one of the following compounds or a salt, solvate, _ N-oxide or derivative thereof wherein the following compounds comprise -N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-nitro-phth-1 ;miA~;
3-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4(3H)-quina-zolinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1(2H)-phth91 97i 2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,3(2H,4H)-icol~in~~ nn-;
N-(4-(4-(1,2-~ 'e~thio~~1-3-yl)piperidino)butyl)phth-limiAa;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piporP7inyl)butyl) 4A,5,6,7,8,8A-hexahydro-1(2N)-pl~thAla7in~.--;
(+-)-Trans-2-(4-(4-(1,2-r '~othis7~1-3-yl)-l-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-r' '-ls7ir~~;
N-(4-(4-(6-Fluoro-l~2-b~n7i~~ya7~l-3-yl)piperidino)butyl)phth~
BIOLOGI~AI DATA
A Antinqychotic ~rag~ni~- of apomorphine (S~g/kg S C ) - induced climbing in the mouse i8 a measure of dopamine receptor --t-go~ in the mesolimbic brain region and in turn reflects potential antipsychotic activity Compounds were administered orally to the mice 1 hour prior to scoring 2-Amino-N-(4-(4-(l~2-benzisothiazol-3-yl)-l-piperazinyl)but-yl)benzamide (Example 36) a~t9gonice~ apomorphine-induced climbing in the mouse at an ED50 ~ 11 0 mg/kg, p o; 2-(4-(4-(1,2-Benzisothiazol-3-yl)-l-piperazinyl)butyl)-l-isoindolinone (Example (3)) at an W 0 93/16073 C A 2 1 i 7 4 3 4 PCT/GR93/00285 ED50-6.3mg/kg,p.o. and 6-(4-(4-(1,2-Benzisothiazol-3-yl~-1-piperazin-yl)butyl)-6,7-dihydro-5~-pyrrolo-(3,4-B)pyridine-5,7-dione (Example 18) at an ED50-14.4mg/kg,p.o.
[Costall, B., Naylor, R.J. and Nohria, V. Climbing behaviour induced by apomorphine in mice: A potential model for the detection of neuroleptic activity. EuroDean Journal of Pharmacolo,Y, 1978 50:
39-50]-B. Anti-emetic The anti-emetic activity of 2-amino-N-(4-(4-(1,2-benziothiazol-3-yl)-l-piperazinyl)butyl)benzamide was assayed by its ability to relieve cisplatin-induced emesis in ferrets (Florczyk, A.P. et al.
Cisplatin-induced emesis in the ferret: A new animal model. Cancer I.~ ~ Reports, Vol.66, 1, 187-189. l1982]).
The test compound was administered orally. Cisplatin was ehen given i.v. (10-15mg/kg), 30 minutes later via jugular catheter. At 60 minutes ~ second dose of the test compound was administered. Onset of emesis and the number of emetic episodes was recorded over a 3 hr.
period. Vehicle treated animals exhibited 3-5 episodes of emesis whereas animals given 3 mg/kg of the compound of Example 36 exhibited no episodes of emesis.
C. AnxiolYtic When 2-amino-N-(4-(4-(1,2-b~n~;eothio7ol-3-yl)-l-piperazinyl)butyl)-benzamide (Example 36) was assayed for anxiolytic activity using the pigeon conflict procedure an increase was observed in punished responding (ED50-0.17 mg/kg i.m.) relecting potential anxiolytic activity.
lBarrett, J.E. Witskin, J.M. Mansbach, R.S. Skolnick, P. and Weissman, B.A. Behavioral studies with anxiolytic drugs III. Antip..ni ~
C~21 1 7434 actions of buspirone in the pigeon do not involve a bon7~A;D7Opine receptor , '9n;-- J, Pharmacol. Experiment. Ther. 238:1009-1013, - 1987].
D. AntideDressant/anxiolytic 2-Amino-N-(4-(4-(1,2-b~ ~,th~s-~1-3-yl)-1-piperazinyl)butyl)benzami-de (Example 36) was tested 8S an 5HT1 agonist by assay of inhibition of firing of sc.uLu.,eLr9ic neurons in the dorsal raphe nucleus. An ID50-23~g/kg i.v. was observed.
IRobinson, D.S, et al. ScLut~ L~ic Anxiolytics and treatment of Depression. Ps~l.u~ 1,ology 1989; 22 (suppl.l): 27-36].
E. CentrallY-actin~ 1 9 relAYant 2-Amino-N-(4-(4-(1,2-' '~othis~~1-3-yl)-1-piperazinyl)butyl)benzami-de (Example 36) showed ~ of morphine-induced Straub-tail in mice at sn ED5o-2~smg/kB P~~-[Novack, G.D. Studies on the Efficacy and r . e - Potential of Muscle Relaxants in Mice. Drug Dev.Res. 2:383-386 (1986)~.
ph, rAl FG 1~ti~~ ExamDle The following examples illustrate the preparation of ~n~ ir91 f 19tiAnc in which the active ingredient is a compound of formula (I) or a phyeinl~girs11y acceptable salt or solvate thereof, for example the compound of Example No. 36.
.
C~2i 1 7434 W 0 93/16073 - 38 - PC~/GB93/00285 A. Tablets Active ingredient 150mg) Lactose 200mg) Maize Starch 50mg) Polyvinylpyrrolidone 4mg) ~' v ' Stesrate 4mg) ) - contents per tablet.
The active ingredient was mixed with the lactose and starch and grr~.lAt~d with a solution of the polyvinylpyrrolidone in water.
The resultant granules were dried, mixed with r~gn~ci stearate and , . ' to give tablets.
B. Injections Tnjection I
The salt of a compound ~ccording to the invention W85 dissolved in sterile water for injection.
T.l.~ s iniection r~ IAtio~ 11 Active ingredient 0.20g Sterile, pyrogen-free phosphate buffer (pH9.0) to lOml The active ingredient as a salt is dissolved in most of the phosphate buffer at 35-40 C, then made up to volume and filtered through a sterile micropore filter into sterile lOml glass vials (Type 1) which are sealed with sterile closures and overseals.
C. CaDsule formulations 1P F- lAtion I
F. lDtiA~ I msy be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture.
(a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycollate 25 (d) ~ - ' Stearate 2 r 1P F lAt~rn II
/rJ~nc..l P
(a) Active Ingredient 250 (b) Macrogel 4000 BP 350 Capsules may be prepared by melting the ~acrogel 4000 BP, 'n~ the active ingredient in the melt, and filling two-part hard gelatin capsules therewith.
CaDsule F~ l~rirn III (controllp~ release caDsule~
/caDsule (a) Active Ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose Bp 125 (d) Ethyl Cellulose 13 The controlled-release cspsule fo lAti~n may be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose (d) as a controlled-release membrane and filled into two-part hard gelatin capsules.
D. SyruD fv 1Ati~n Active ingredient 0.2500g Sorbitol Solution 1.5000g ~;
Glycerol 1.0000g Sodium Banzoate 0,0050g Flavour 0.0125ml Purified Water q.s. to 5.0ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.
E. SuDDositorv fv lAtio~
m~/SUDDOSitOrv Active ingredient (63~1) * 250 Hard Fat, BP
(~itepsol H15 - Dynamit Nobel) 1770 * The active ingredient is used as a powder wherein at least 90~ of the particles are of 63ym diameter or less.
One fifth of the Witepsol H15 is meleted in a steam-jacketed pan at 45~C maximum. The active ingredient is sifted through a 200~m sieve and added to the molten base with mixing, using a Silverson W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
fitted with a cutting head, until a smooth dispersion is achieved. Msintsini e the mixture at 45~C, the remaining ~ ~itepsol H15 is added to the suspension which is stirred toensure a l ~ O mix. The entire suspension is then passed through a 250~m stainless steel screen and, with cnntin~
seirring, allowed to cool to 40 C. At a t . ~ of 38-40 C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the .~-sit~ries allowed to cool to room temperature.
F. I,~,.sd.,~l F lAri~n Compositions suitable for 1. j_ -_A~ .. 1 administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the actlve compound 1) in an optionally buffered, aqueous solution or 2) dissolved in an a &esive or 3) ~ in a polymer. A suitable c ~ ;on of the active compount is about 18 to 208, preferably about 38 to 158. As one particular possibility, the active compound must be delivered from the patch by ic r~ '~oiS as generally described in ~'- r Research, 3(6), 318(1986).
The invention is illustrated by the following Examples.
Fxammles General Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as dimethyl formamide (DMF), teL,~ lLuL~,~.. (THF), dichloromethane, toluene, pyridine, and dimethyl sulfoxide (DhS0) were obtained from Aldrich Chemical Company in sure seal bottles.
Triethylamine was distilled from calcium hydride prior to use. All reactions involving air- or moisture-sensitive compounds were W O 93/16073 P(~r/GB93/0028 performed under a nitrogen ~ r~ C. Flash .1.............. ..................................................~ ~Layll~ (Still, ~. C. t al. J. Or.............. ......................Chem. 1978, 43, 2923) and Flush chL. togrorhy were I ~ ' using EM Science silica gel 60 (230-400 mesh ASTM).
Thin-layer ~ (TLC) was F -~ ' with Analtech silica gel FG TLC plates (250 ~m). lH NMR and 13C NMR were determined with ~c..A l ling, FT NMR ,! LL~ ttL~ operating at 200, 300, and 500 MHz. Chemical shifts are expressed in ppm downfield from internal trimethylsilane F,ieni~;r lH NMR data are reported in order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons, and coupling constants in Hz.
Elemental analyses were performed by either Atlantic Microlab, Inc., Norcross Georgia, or Galbraith Laboratories, Inc., Knoxville, Tennessee. Melting points were d~t~rmi~i with a Thomas Hoover capillary melting point appsratus and are uncorrected. Piperidine and pirero7in. ~ cothio7~le ir~ ''At-s were prepared according to known ~ ' .s: 3-(4-piperidinyl)-1~2-h~ othiP zAle (U.5. Pat. 4 528 292, July 9, 1985), 3-(l-piperazinyl)-1,2-b~ o~h;o7ole and 8-(1,2 L '~oth1o-rl-3-gl)-5,8-diazaspiro(4.5)decane bromide (Yevich, J.P. t al. J.Med.Chem. 1986, 29, 359-369), Piperidine and piperazine b-~; 1o i ~ ~t~ w~re prepared or could be prepared according to known ~L~ 5 6-Fluoro-3-(4-piperidinyl)-1,2-' 'a~vo7ole (Strupelewski, J.T. et al. J.Med.Chem. 1985, 28, 761-769) and 1-(1,2-be~;aAvo~Al-3-yl)piperazine (Yevich, J.P. et al, J.Med.Chem. 1986, 29, 359-369).
W O 93/16073 P(~r/GB93/0028 FY~pT.F. 1 (a) Pre~aration of 2-(2-1.YdL~ LIl~l)-l-isoin~~lin~n~
This compound was preparet according to a modified procedure of R. Murata (Bull, Chem. Soc. Jpn. 1973, 46, 1752). Ethanol amine (50.09 g, 0.820 mL) (Aldrich Chemical Company ) was added to a 300-mL, round-bottomed flask equipped with a Dean-Stark trap, a reflux condenser, a magnetic stirring bar and a nitrogen inlet.
Phthalide (110.0 g, 0.820 mol, 1.0 eq) (Aldrich Chemical Company) was then added as a light tan powder with stirring. The resulting slurry was placed under N2 and heated in an oil bath at 150-C for 4 h. The oil bath t- ,~ ' e was increased to 205-210'C and the melt was heated for an additional 17 h. ~ater (12 mL) was collected in the Dean-Stark trap. The product solidified upon cooling to give a light brown solid. The crude material was taken up in hot toluene and the solution was filtered hot. The solids that formed upon cooling were filtered, washed with cold toluene and dried in a vacuum oven to give 129.75 g (88~) of 2-(2 h~ _LL~l)-l-i~oin~olin~~ as a light tan powder. mp: 117-119-C. lH NMR (CDC13): C 3.28 (br s, 1), 3.69 (m, 2), 3.85 (m, 2), 4.46 (s, 2), 7.40 (m, 3), 7.73 (m, 1).
13C NMR (CDC13): C 45.84, 51.63, 61.30, 122.60, 123.44, 127.91, 131.34, 132.44, 141.53, 169.55.
Anal. Calcd for CloHllN02: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.76; H, 6.27; N, 7.89.
(b) PreDaration of 2-(2-chloroethvl3-1-isoindolinone 2-(2-Hydroxyethyl)-l-isoindolinone (117.95 g, 0.666 mol) and toluene (400 mL) were added to a l-L, round-bottomed flask. The solution was cooled with an ice-water bath and thionyl chloride (55.0 mL, 89.7 g, 0.754 mol, 1.13 eq) was added dropwise over a 0.5 h period. The slurry was allowed to stand at room CA 2 i 1 7 4 34 r . e for 4 h with periodic swirling. A condenser was attached and the reaction mixture was heated at 60-C for 3 h.
The toluene and excess thionyl chloride were removed by distillation under aspirator pressure. The hot residue was poured into petroleum ether (500 mL) and brown solids formed.
The crude solids were filtered and taken up in hot toluene. The solution was filtered hot and the hot toluene solution was poured into petroleum ether (300 mL) with stirring. The solids that formed were filtered, washed with petroleum ether, and dried in a vacuum oven to give 103.08 g of a powdery tan solid. A second crop of 15.99 g was obtained, which gave a total of 119.07 g (91~) of 2-(2-chloroethyl)-1-isoindolinone. mp: 80-81-C. H NMR
(CDC13): ~ 3.80 (t, 2, J - 5.4), 3.96 (t, 2, J - 5.4), 4.57 (s, 2), 7.50 (m, 3), 7.86 (m, 1). 13C NMR (DMS0-d6): ~ 7.50, 48.74, 54.98, 128.01, 128.60, 133.08, 136.68, 137.15, 147.11, 172.80.
Anal- Calcd for CloHloNOCl C, 61.39; H, 5.15; N, 7.16. Found C, 61.29; H, 5.18; N, 7.15.
(c) r.e :'on of 2-(2-(4-(1.2-b~n~ie~th-P~~1-3-yl)-l-~ioerazinYll-ethvl)-2.3-dihvdro-lH-1e~in~~1-1-one hv~norhl~ride 2-(2-Chloroethyl)-l-i~rin~rlin~nP (6.03 g, 30.82 mmol), 3-(1-pip-erazinyl)-1,2-' eothiP~ole (6.76 g, 30.82 mmol, 1.0 eq), triethylamine (5.15 mL, 3.74 g, 36.99 mmol, 1.2 eq.) and acetonitrile (30.0 mL) was added to a 100-mL, round-bottomed flask. The resulting orange mixture was placed under N2 and heated at reflux for 24 h. The solution was allowed to cool to room t e and was L,~ fe...d to a ~ , -ng funnel with the aid of ethyl acetate. The dark orange solution was washed with saturated potassium carbonate and the organics were dried over MgS04, filtered, and _ ' to give 13.44 g of an orange oil. This crude material was purified by flash chromato-graphy with 5:1 ethyl acetate/hexanes as eluant to give 7.15 g of 2-(2-(4-(1,3-benzisothiazol-3-yl)-l-piperazinyl)ethyl)-2,3-dihyd-C~ 2 1 1 7434 W O 93/16073 P(~r/GB93/0028S
ro-lH-isinol-l-one. The free amine was taken up in acetone and HCl (24.5 mL of a 1 N solution in ether, 1.0 eq) was added. The - salt was recrystallized twice from 95% ethanol to give 3.05 g (24i) of the hydrochloride salt as an off-white powder. Spectral ~ and analytical data indicated one equivalent of HCl and 0.5 eq of ethanol. mp: 264-267-C (dec). H NMR (DMSO-d6): ~ 1.03 (t, 3, J
Compounds of formula ~rX) in ~hich Rl is -CH20H and V is oxygen ~ay be m de bv the method described in Annslen der Chemie, 584, 87 (1953).
Te..~hedL~.. Lett. 25(20) p2093, (1984) and Te..OI.ed.~.. Let~. 27(20), p2275, (1986). Compounds of formula (rX) in which Rl is NH2 and V is oxygen may be made by reaction of an isatoic annydride of for~ula (X~V) ~N~o (~v) ~ith a compound of formula ~X}). The reaction may be carried out in a suitable solvent such as ethanol, for example at room i , ~.
~hth~ oe of formulOa (XA) O
Rl - ~ ~ (XA) phthalic aDhydrides of formula (X8) ~ (~8) Rs compounds of formula (X~) CA2i 174~4 R~1 o R~~~ (Xl) R3--~R~7 Ra isatoic annydrides of formula (XE) R~ V
=9 ~ I ~ V (XE) Ra R~
are ~ither known compounds or can be prepared by known methods For example. isatoic anhydrides of formula (XE) can be prepared by ~he tre-tment of the ,, , Ar~ly substitute Anth~ acids with phosg-ne or a phosgene substitute (i.e. trichloromethyl chl~.~LuL e) in an appropriate solvent such as benzene or dioxane (J.Het.Chem. 12.
565 (1975); J.~ .Che~.Soc., 72, 4887, (1950) J.OrE.Che~. 41, 2070 (1976)). Is-toic anhydrides of formula (XE) where V represcnts oxygen car. also be prepared by treatment of the appropriately substituted phthalic anhydrides of formula (XB) with azidoerimeChylsilane in an appropriate solvent such as chloroform. ~hioisatoic anhydrides of ~he formula (XE) where V 5-r.~__..LY sulphur can be prepared by treatment of the zrproFrlAt~ly substituted isatoic anhydrides with ~h~ oL~A
F ~ lf~' in refluxing xylenes.
CA2i 1 7434 W O 93/16073 ~ 33 ~ PCT/GB93/0028 Compounds of for_ula (XF) J~
R1 ~ L
where, for cxample L is cethoxy and L2 is 8r, can be prepared as described in U.S. ~aeen~ No. 4,289,781 which is inc~ L,d herein in i~s entirety.
Compounds of fotmula (XI) wherein R5-H can be obtained by clea~age of ph~h~1im1~ of for_ula (I), i.e. compounds of for_ula (I) in which Y
LLrL~ a group of for_ula (b) in which R5 is C-C and Rl-H. The reaction can be carried out wi~h hydrazine hydra~e in methanol.
Compounds of for_ula (XI) wherein R6-Cl 6 alkyl can be prepared from compounds of for_ula (XIa) (XIa) Z N X W
\J
W O 93/16073 P~ /GB93/0028S
wherein P is a protecting group, for example trifluoroacetate, by removal of the protecting group by known methods, for example aqueous potassium carbonate.
Compounds of formula (XIa) wherein R -Cl 6 alkyl can be prepared from compounds of formula (XI), wherein R -H, by protection of the amino group, for example as the triflu~ ~ 'A~, followed by alkylation of the resulting protected amine with a Cl 6 alkyl halide, for example methyliodide.
A further - '~'' of the present invention comprises the following compounds;
N-(4-(4-(l~2-Benzisothiazol-3-yl)piperidino)butyl)phthslimillr;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A I 'JdLu-1(2H)-rhthAlA7i-rnr;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A~ u-1(2N)-rhthslD7inrn_;
N-(4-(4-(6-Fluoro-1,2-b e~ 7ol-3-yl)piperidino)butyl)rhthAl;m~
and phye;r1-Eirs11y acceptable salts, solvates and N-oxides thereof and physi~ rgirDlly functional derivatives thereof.
Further ~ ' ' of the present invention comprise the following:
the use of one of the following compounds and salt, solvates, N-oxides and derivatives thereof in therapy; the use of one of the following compounds and salts, solvates, N-oxides and derivatives thereof in the preparation of a ' r for use in the treatment of any of the hereinbefore described disorders; a method for the treatment or prophylaxis in a mammal of any of the disorders hereinbefore described which comprises administering to the mammal a th. rA11y effective treatment amount of one of the following compounds or a salt, solvate, N-oxide or derivative thereof: a rhAr~~-e~-tiCAl composition comprising one of the following compounds and salt, solvate, N-oxides and d.Llve~ s thereof; a process for the preparation of one of the following compounds or a salt, solvate, _ N-oxide or derivative thereof wherein the following compounds comprise -N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-nitro-phth-1 ;miA~;
3-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4(3H)-quina-zolinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1(2H)-phth91 97i 2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,3(2H,4H)-icol~in~~ nn-;
N-(4-(4-(1,2-~ 'e~thio~~1-3-yl)piperidino)butyl)phth-limiAa;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piporP7inyl)butyl) 4A,5,6,7,8,8A-hexahydro-1(2N)-pl~thAla7in~.--;
(+-)-Trans-2-(4-(4-(1,2-r '~othis7~1-3-yl)-l-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-r' '-ls7ir~~;
N-(4-(4-(6-Fluoro-l~2-b~n7i~~ya7~l-3-yl)piperidino)butyl)phth~
BIOLOGI~AI DATA
A Antinqychotic ~rag~ni~- of apomorphine (S~g/kg S C ) - induced climbing in the mouse i8 a measure of dopamine receptor --t-go~ in the mesolimbic brain region and in turn reflects potential antipsychotic activity Compounds were administered orally to the mice 1 hour prior to scoring 2-Amino-N-(4-(4-(l~2-benzisothiazol-3-yl)-l-piperazinyl)but-yl)benzamide (Example 36) a~t9gonice~ apomorphine-induced climbing in the mouse at an ED50 ~ 11 0 mg/kg, p o; 2-(4-(4-(1,2-Benzisothiazol-3-yl)-l-piperazinyl)butyl)-l-isoindolinone (Example (3)) at an W 0 93/16073 C A 2 1 i 7 4 3 4 PCT/GR93/00285 ED50-6.3mg/kg,p.o. and 6-(4-(4-(1,2-Benzisothiazol-3-yl~-1-piperazin-yl)butyl)-6,7-dihydro-5~-pyrrolo-(3,4-B)pyridine-5,7-dione (Example 18) at an ED50-14.4mg/kg,p.o.
[Costall, B., Naylor, R.J. and Nohria, V. Climbing behaviour induced by apomorphine in mice: A potential model for the detection of neuroleptic activity. EuroDean Journal of Pharmacolo,Y, 1978 50:
39-50]-B. Anti-emetic The anti-emetic activity of 2-amino-N-(4-(4-(1,2-benziothiazol-3-yl)-l-piperazinyl)butyl)benzamide was assayed by its ability to relieve cisplatin-induced emesis in ferrets (Florczyk, A.P. et al.
Cisplatin-induced emesis in the ferret: A new animal model. Cancer I.~ ~ Reports, Vol.66, 1, 187-189. l1982]).
The test compound was administered orally. Cisplatin was ehen given i.v. (10-15mg/kg), 30 minutes later via jugular catheter. At 60 minutes ~ second dose of the test compound was administered. Onset of emesis and the number of emetic episodes was recorded over a 3 hr.
period. Vehicle treated animals exhibited 3-5 episodes of emesis whereas animals given 3 mg/kg of the compound of Example 36 exhibited no episodes of emesis.
C. AnxiolYtic When 2-amino-N-(4-(4-(1,2-b~n~;eothio7ol-3-yl)-l-piperazinyl)butyl)-benzamide (Example 36) was assayed for anxiolytic activity using the pigeon conflict procedure an increase was observed in punished responding (ED50-0.17 mg/kg i.m.) relecting potential anxiolytic activity.
lBarrett, J.E. Witskin, J.M. Mansbach, R.S. Skolnick, P. and Weissman, B.A. Behavioral studies with anxiolytic drugs III. Antip..ni ~
C~21 1 7434 actions of buspirone in the pigeon do not involve a bon7~A;D7Opine receptor , '9n;-- J, Pharmacol. Experiment. Ther. 238:1009-1013, - 1987].
D. AntideDressant/anxiolytic 2-Amino-N-(4-(4-(1,2-b~ ~,th~s-~1-3-yl)-1-piperazinyl)butyl)benzami-de (Example 36) was tested 8S an 5HT1 agonist by assay of inhibition of firing of sc.uLu.,eLr9ic neurons in the dorsal raphe nucleus. An ID50-23~g/kg i.v. was observed.
IRobinson, D.S, et al. ScLut~ L~ic Anxiolytics and treatment of Depression. Ps~l.u~ 1,ology 1989; 22 (suppl.l): 27-36].
E. CentrallY-actin~ 1 9 relAYant 2-Amino-N-(4-(4-(1,2-' '~othis~~1-3-yl)-1-piperazinyl)butyl)benzami-de (Example 36) showed ~ of morphine-induced Straub-tail in mice at sn ED5o-2~smg/kB P~~-[Novack, G.D. Studies on the Efficacy and r . e - Potential of Muscle Relaxants in Mice. Drug Dev.Res. 2:383-386 (1986)~.
ph, rAl FG 1~ti~~ ExamDle The following examples illustrate the preparation of ~n~ ir91 f 19tiAnc in which the active ingredient is a compound of formula (I) or a phyeinl~girs11y acceptable salt or solvate thereof, for example the compound of Example No. 36.
.
C~2i 1 7434 W 0 93/16073 - 38 - PC~/GB93/00285 A. Tablets Active ingredient 150mg) Lactose 200mg) Maize Starch 50mg) Polyvinylpyrrolidone 4mg) ~' v ' Stesrate 4mg) ) - contents per tablet.
The active ingredient was mixed with the lactose and starch and grr~.lAt~d with a solution of the polyvinylpyrrolidone in water.
The resultant granules were dried, mixed with r~gn~ci stearate and , . ' to give tablets.
B. Injections Tnjection I
The salt of a compound ~ccording to the invention W85 dissolved in sterile water for injection.
T.l.~ s iniection r~ IAtio~ 11 Active ingredient 0.20g Sterile, pyrogen-free phosphate buffer (pH9.0) to lOml The active ingredient as a salt is dissolved in most of the phosphate buffer at 35-40 C, then made up to volume and filtered through a sterile micropore filter into sterile lOml glass vials (Type 1) which are sealed with sterile closures and overseals.
C. CaDsule formulations 1P F- lAtion I
F. lDtiA~ I msy be prepared by admixing the ingredients and filling two-part hard gelatin capsules with the resulting mixture.
(a) Active ingredient 250 (b) Lactose B.P. 143 (c) Sodium Starch Glycollate 25 (d) ~ - ' Stearate 2 r 1P F lAt~rn II
/rJ~nc..l P
(a) Active Ingredient 250 (b) Macrogel 4000 BP 350 Capsules may be prepared by melting the ~acrogel 4000 BP, 'n~ the active ingredient in the melt, and filling two-part hard gelatin capsules therewith.
CaDsule F~ l~rirn III (controllp~ release caDsule~
/caDsule (a) Active Ingredient 250 (b) Microcrystalline Cellulose 125 (c) Lactose Bp 125 (d) Ethyl Cellulose 13 The controlled-release cspsule fo lAti~n may be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with ethyl cellulose (d) as a controlled-release membrane and filled into two-part hard gelatin capsules.
D. SyruD fv 1Ati~n Active ingredient 0.2500g Sorbitol Solution 1.5000g ~;
Glycerol 1.0000g Sodium Banzoate 0,0050g Flavour 0.0125ml Purified Water q.s. to 5.0ml The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.
E. SuDDositorv fv lAtio~
m~/SUDDOSitOrv Active ingredient (63~1) * 250 Hard Fat, BP
(~itepsol H15 - Dynamit Nobel) 1770 * The active ingredient is used as a powder wherein at least 90~ of the particles are of 63ym diameter or less.
One fifth of the Witepsol H15 is meleted in a steam-jacketed pan at 45~C maximum. The active ingredient is sifted through a 200~m sieve and added to the molten base with mixing, using a Silverson W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
fitted with a cutting head, until a smooth dispersion is achieved. Msintsini e the mixture at 45~C, the remaining ~ ~itepsol H15 is added to the suspension which is stirred toensure a l ~ O mix. The entire suspension is then passed through a 250~m stainless steel screen and, with cnntin~
seirring, allowed to cool to 40 C. At a t . ~ of 38-40 C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the .~-sit~ries allowed to cool to room temperature.
F. I,~,.sd.,~l F lAri~n Compositions suitable for 1. j_ -_A~ .. 1 administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the actlve compound 1) in an optionally buffered, aqueous solution or 2) dissolved in an a &esive or 3) ~ in a polymer. A suitable c ~ ;on of the active compount is about 18 to 208, preferably about 38 to 158. As one particular possibility, the active compound must be delivered from the patch by ic r~ '~oiS as generally described in ~'- r Research, 3(6), 318(1986).
The invention is illustrated by the following Examples.
Fxammles General Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as dimethyl formamide (DMF), teL,~ lLuL~,~.. (THF), dichloromethane, toluene, pyridine, and dimethyl sulfoxide (DhS0) were obtained from Aldrich Chemical Company in sure seal bottles.
Triethylamine was distilled from calcium hydride prior to use. All reactions involving air- or moisture-sensitive compounds were W O 93/16073 P(~r/GB93/0028 performed under a nitrogen ~ r~ C. Flash .1.............. ..................................................~ ~Layll~ (Still, ~. C. t al. J. Or.............. ......................Chem. 1978, 43, 2923) and Flush chL. togrorhy were I ~ ' using EM Science silica gel 60 (230-400 mesh ASTM).
Thin-layer ~ (TLC) was F -~ ' with Analtech silica gel FG TLC plates (250 ~m). lH NMR and 13C NMR were determined with ~c..A l ling, FT NMR ,! LL~ ttL~ operating at 200, 300, and 500 MHz. Chemical shifts are expressed in ppm downfield from internal trimethylsilane F,ieni~;r lH NMR data are reported in order:
multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), number of protons, and coupling constants in Hz.
Elemental analyses were performed by either Atlantic Microlab, Inc., Norcross Georgia, or Galbraith Laboratories, Inc., Knoxville, Tennessee. Melting points were d~t~rmi~i with a Thomas Hoover capillary melting point appsratus and are uncorrected. Piperidine and pirero7in. ~ cothio7~le ir~ ''At-s were prepared according to known ~ ' .s: 3-(4-piperidinyl)-1~2-h~ othiP zAle (U.5. Pat. 4 528 292, July 9, 1985), 3-(l-piperazinyl)-1,2-b~ o~h;o7ole and 8-(1,2 L '~oth1o-rl-3-gl)-5,8-diazaspiro(4.5)decane bromide (Yevich, J.P. t al. J.Med.Chem. 1986, 29, 359-369), Piperidine and piperazine b-~; 1o i ~ ~t~ w~re prepared or could be prepared according to known ~L~ 5 6-Fluoro-3-(4-piperidinyl)-1,2-' 'a~vo7ole (Strupelewski, J.T. et al. J.Med.Chem. 1985, 28, 761-769) and 1-(1,2-be~;aAvo~Al-3-yl)piperazine (Yevich, J.P. et al, J.Med.Chem. 1986, 29, 359-369).
W O 93/16073 P(~r/GB93/0028 FY~pT.F. 1 (a) Pre~aration of 2-(2-1.YdL~ LIl~l)-l-isoin~~lin~n~
This compound was preparet according to a modified procedure of R. Murata (Bull, Chem. Soc. Jpn. 1973, 46, 1752). Ethanol amine (50.09 g, 0.820 mL) (Aldrich Chemical Company ) was added to a 300-mL, round-bottomed flask equipped with a Dean-Stark trap, a reflux condenser, a magnetic stirring bar and a nitrogen inlet.
Phthalide (110.0 g, 0.820 mol, 1.0 eq) (Aldrich Chemical Company) was then added as a light tan powder with stirring. The resulting slurry was placed under N2 and heated in an oil bath at 150-C for 4 h. The oil bath t- ,~ ' e was increased to 205-210'C and the melt was heated for an additional 17 h. ~ater (12 mL) was collected in the Dean-Stark trap. The product solidified upon cooling to give a light brown solid. The crude material was taken up in hot toluene and the solution was filtered hot. The solids that formed upon cooling were filtered, washed with cold toluene and dried in a vacuum oven to give 129.75 g (88~) of 2-(2 h~ _LL~l)-l-i~oin~olin~~ as a light tan powder. mp: 117-119-C. lH NMR (CDC13): C 3.28 (br s, 1), 3.69 (m, 2), 3.85 (m, 2), 4.46 (s, 2), 7.40 (m, 3), 7.73 (m, 1).
13C NMR (CDC13): C 45.84, 51.63, 61.30, 122.60, 123.44, 127.91, 131.34, 132.44, 141.53, 169.55.
Anal. Calcd for CloHllN02: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.76; H, 6.27; N, 7.89.
(b) PreDaration of 2-(2-chloroethvl3-1-isoindolinone 2-(2-Hydroxyethyl)-l-isoindolinone (117.95 g, 0.666 mol) and toluene (400 mL) were added to a l-L, round-bottomed flask. The solution was cooled with an ice-water bath and thionyl chloride (55.0 mL, 89.7 g, 0.754 mol, 1.13 eq) was added dropwise over a 0.5 h period. The slurry was allowed to stand at room CA 2 i 1 7 4 34 r . e for 4 h with periodic swirling. A condenser was attached and the reaction mixture was heated at 60-C for 3 h.
The toluene and excess thionyl chloride were removed by distillation under aspirator pressure. The hot residue was poured into petroleum ether (500 mL) and brown solids formed.
The crude solids were filtered and taken up in hot toluene. The solution was filtered hot and the hot toluene solution was poured into petroleum ether (300 mL) with stirring. The solids that formed were filtered, washed with petroleum ether, and dried in a vacuum oven to give 103.08 g of a powdery tan solid. A second crop of 15.99 g was obtained, which gave a total of 119.07 g (91~) of 2-(2-chloroethyl)-1-isoindolinone. mp: 80-81-C. H NMR
(CDC13): ~ 3.80 (t, 2, J - 5.4), 3.96 (t, 2, J - 5.4), 4.57 (s, 2), 7.50 (m, 3), 7.86 (m, 1). 13C NMR (DMS0-d6): ~ 7.50, 48.74, 54.98, 128.01, 128.60, 133.08, 136.68, 137.15, 147.11, 172.80.
Anal- Calcd for CloHloNOCl C, 61.39; H, 5.15; N, 7.16. Found C, 61.29; H, 5.18; N, 7.15.
(c) r.e :'on of 2-(2-(4-(1.2-b~n~ie~th-P~~1-3-yl)-l-~ioerazinYll-ethvl)-2.3-dihvdro-lH-1e~in~~1-1-one hv~norhl~ride 2-(2-Chloroethyl)-l-i~rin~rlin~nP (6.03 g, 30.82 mmol), 3-(1-pip-erazinyl)-1,2-' eothiP~ole (6.76 g, 30.82 mmol, 1.0 eq), triethylamine (5.15 mL, 3.74 g, 36.99 mmol, 1.2 eq.) and acetonitrile (30.0 mL) was added to a 100-mL, round-bottomed flask. The resulting orange mixture was placed under N2 and heated at reflux for 24 h. The solution was allowed to cool to room t e and was L,~ fe...d to a ~ , -ng funnel with the aid of ethyl acetate. The dark orange solution was washed with saturated potassium carbonate and the organics were dried over MgS04, filtered, and _ ' to give 13.44 g of an orange oil. This crude material was purified by flash chromato-graphy with 5:1 ethyl acetate/hexanes as eluant to give 7.15 g of 2-(2-(4-(1,3-benzisothiazol-3-yl)-l-piperazinyl)ethyl)-2,3-dihyd-C~ 2 1 1 7434 W O 93/16073 P(~r/GB93/0028S
ro-lH-isinol-l-one. The free amine was taken up in acetone and HCl (24.5 mL of a 1 N solution in ether, 1.0 eq) was added. The - salt was recrystallized twice from 95% ethanol to give 3.05 g (24i) of the hydrochloride salt as an off-white powder. Spectral ~ and analytical data indicated one equivalent of HCl and 0.5 eq of ethanol. mp: 264-267-C (dec). H NMR (DMSO-d6): ~ 1.03 (t, 3, J
- 6.9), 3.48 (m, 7), 3.70 (br d, 2, J - 11.0), 4.02 (m, 4), 4.60 (s, 2), 7.55 (m, 6), 8.10 (t, 2, J - 9.2), 11.28 (br s, 1). 13C
~MR (DMSO-d6): ~ 8.50, 36.51, 46.17, 49.66, 50.49, 52.88, 55.94, 121.10, 122.84, 123.34, 124.01, 124.55, 126.81, 127.71, 128.05, 131.48, 131.86, 142.24, 152.06, 162.09, 168.00.
Anal Calcd for CZlH22~405'HCl' 0-5 C2H6~
12.79. Found: C, 60.24; H, 6.08; ~, 12.55.
F~ A VpLE 2 (a) PrDnArAt1~ of 2-(3-1,Jd~ v.~.l)-l-isoirA~lir~~
This compound was prepared according to the method described for Example l(a). By employing 3-amino-1-propanol (Aldrich Chemical Company) as the amino alcohol, 2-(3~ 1,uA~.u~l)-l-isoindolin-one 1156.83 g (86.)] was obtained. lH NMR (CDC13): ~ 1.91 (quintet, 2, J - 6.2), 3.55 (br s, 2), 3.74 (t, 2, J - 6.2), 3.82 (br s, 1), 4.38 (s, 2), 7.47 (m, 3), 7.80 (m, 1). 13C ~MR
(CDC13): ~ 30.85, 38.81, 50.39, 58.37, 122.73, 123.64, 128.12, 131.45, 132.30, 141.18, 169.67.
Anal. Calcd for CllH13N02: C, 69.09; H, 6.85; ~, 7.32. Found: C, - 68.99; H, 6.86: ~, 7.28.
(b) PreDaration of 2-(3-chloroDroDvl)-l-isoindolinone This compound was prepared according to the method described for example in Example l(b). By employing 2-(3-1.~lLu~.u~yl)-l-iso-Lnolinone (127.53 g), 130.94 g (94~) of the crude chloride was obtained. A small sample (5 g) was purified by flash ch.. O .'~ with 4:1 hexanes/ethyl acetate as eluant to give 4.29 g of an analytically pure white solid. mp 56-57.5-C. H
NHR ~CDC13): ~ 2.15 (quintet, 2, J - 6.7), 3.58 (t, 2, J - 6.5).
3.74 (t, 2, J - 6.9), 4.41 (s, 2), 7.46 (m, 3), 7.81 (m, 1). 13C
NMR (CDC13): ~ 31.29, 40.17, 42.22, 50.57, 122.71, 123.63, 128.68, 131.36, 132.68, 141.11, 168.75.
(c) PreDaration of 2-(3-(4-(l.2-benzisothiazol-3-xl)-1-DiDerazinYl~-DroDYl)-l-isoindolinone hydrochloride This material was prepared according to the method described in Example l(c), by employing 2-(3-chloropropyl)-l-isoindolinone.
The hydrochloride salt was prepared and recrystallized from ethanol to give 1.58 g of the title compound as a yellow powder.
mp: 225-226-C. lH NMR (DMS0-d6): ~ 2.16 (m, 2), 3.30 (m, 8), 3.60 (m, 4), 4.05 (br d, 2, J - 12.5), 4.53 (s, 2), 7.55 (m, 6), 8.09 (dd, 2, J - 8.0, 3.9), io.70 (br s, 1.5). 13C NMR (CDC13):
~ 23.06, 39.37, 46.58, 50.08, 51.00, 55.09, 120.77, 123.15, 123.22, 123.54, 124.53, 127.26, 128.03, 128.10, 131.76, 131.92, 141.40, 152.95, 161.47, 169.37.
Anal- Calcd for C22H24N405.1.5 HCl: C, 59.09; H, 5.75; N, 12.53.
Found: C, 59.06; H, 6.10; N, 12.52.
FXAMPJ.F 3 (a) PreDaration of 2-(4-bromobutYl)-l-isoindolinone N-(4-Bromobutyl)phtholimi~ (Aldrich Chemical Company) (15.6 O, 0.056 mL), glacial acetic acid (100 mL), tin metal (15.83, 0.133 mol, 2.4 eq) and ~ L~bLI ~ acid (20.0 mL) was added to a 250-mL, round-bottomed flask. The resulting light yellow reaction mixture was placed under N2 and heated at reflux for 6 h. The solution W85 filtered and the tin was washed with acetic acid. Most of the acetic acid was removed with a rotary - e~O~LUL and the resulting creamy residue was taken up in dichl~.. ' and washed with water. The organics were dried over MgS04, filtered, and ~ d to give 9.37 g of a light orange oil. This material was purified by flash ~ O .'~
with 3:1 hexanes/ethyl acetate as eluant to give 0.89 g (6~) of 2-(4-brOmObUtY1)-1-;~O~ as a colorless oil. H NMR
(CDC13): ~ 1.86 (m, 4), 3.47 (t, 2, J - 6.2), 3.66 (t, 2, J
6.7), 4.39 (s, 2), 7.46 (t, 2, J - 6.4), 7.53 (m, 1), 7.84 (dd, 1, J - 6.8, 0.38). 13C NMR (CDC13): ~ 26.84, 29.64, 33.44, 41.25, 49.80, 122.70, 123.71, 128.08, 131.30, 132.75, 141.03, 179.05.
Anal. Calcd for C12H14NOBr: C, 53.75; H, 5.26; N, 5.22. Found: C, 53.81; H, 5.29; N, 5.21.
Hydrochloric acid msy be w ed instead of l.~d.~b.. ~o acid in the above method and thus results in higher yields, however, the resulting product is a chloride and bromide mixture.
(b) ~ ~n of 2-(4-~4-(1.2-benzis~~hiP7~1-3-yl)-l-DiDerazinY1) butyl)-1-isoin~~linone hydrochloride A 40:60 mixture of 2-(4-bromobutyl)-1-isoindolinone and 2-(4-chlorobutyl)-l-isoindolinone (3.69 g, 15.27 mmol) was added to a lûû-mL, round-bottomed flask. Triethylamine (2.77 mL, 2.01 g, 19.85 mmol, 1.3 eq), acetonitrile (25.0 mL) and 3-(1-piperazin-yl)-1,2-benzisothiazole (3.68 g, 16.80 mmol, 1.1 eq) were added to the chloride/bromide mixture snd the light orange reaction mixture was heated at reflux for 19 h under N2. The solution was allowed to cool and was transferred to a s , ng funnel with the aid of ethyl acetate. The organics were washed with saturated K2C03, dried over MgS04, filtered and ~u-~ L~L~d to give 7.31 g of a dark orange oil which so1i~ifi~d upon standing.
The crude solids were recrystallized from acetonitrile to give 4.38 g of free amine. The hydrochloride salt was prepared via the addition of HCl (10.8 mL, 1.0 eq of a 1 N solution in ether) to a solution of the free amine in ethanol. The salt was recrystallized from 95~ ethanol to give 3.47 g (51~) of 2-(4-(4-(1,2-~ ~ot~s7~1-3-yl)-l-piperazinyl)butyl)-l-isoindol inone hydrochloride as an off-white powder. mp: 232-233-C. lH
NMR (DMS0-d6): 6 1.77 (m, 4), 3.23 (m, 4), 3.57 (m, 6), 4.05 (br d, 2, J - 13.8), 4.52 (s, 2), 7.48 (m, 2), 7.60 (d, 3, J - 8.9), 7.69 (d, 1, J - 7.5), 8.12 (t, 2, J - 7.6), 11.32 (br s, 1). 13C
NMR (DMS0-d6): ~ 20.49, 25.05, 40.96, 46.29, 49.41, 50.43, 55.12, 121.15, 122.65, 123.30, 123.96, 124.57, 126.92, 127.74, 128.07, 131.17, 132.33, 141.84, 152.06, 162.19, 167.34.
Anal. Calcd for C23H26N40S.HCl: C, 62.36; H, 6.14; N, 12.65.
Found: C, 62.23; H, 6.16; N, 12.62.
FY~vPT.~. 4 (8) Pr~n9rAt;~n of 6-~itro-1(3~ r,.. ~;
This compound was prepsred according to the method of J.Tirouflet (Bull. Soc. Sci. Bretagne 1951, Spec. No. 26, 7-122). mp:
143-145 ~C. [lit. mp - 143-C]. H NMR (CDC13): ~ 5.44 (s, 2), 7.71 (d, 1, J - 8.4), 8.57 (dd, 1, J - 8.4, 2.0), 8.76 (d, 1, J -2.0). 13C NMR (DMSO-d6): ~ 75.57, 125.20, 130.08, 131.76, 134.02, 153.58, 158.44, 174.02.
Ansl. Calcd for C8H5NO4: C, 53.64; H, 2.81; N, 7.82. Found: C, 53.70; H, 2.85; N, 7.82.
(b) Pre~sration of 6-amino-1~3H)-isobenzofuranone This compound was prepared according to the method of J.Tirouflet (Bull. Soc. Sci. Bretagne 1951, Spec. No. 26, 7-122). mp:
C~ 2 1 i 7434 181-182-C. lH NMR (CDC13): C 3.94 (br s, 2), 5.21 (s, 2), 6,97 (dd, 1, J - 8.2, 2.3), 7.13 (d, 1, J - 2.3), 7.03 (d, 1, J
- 8.2). 13C NMR (CDC13): C 69.63, 109.79, 121.64, 122.66, 126.95, 136.36, 147.49, 171.47.
Anal. Calcd for C8H7N02: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.48; H, 4.73; N, 9.38.
(c) Prevaration of 6-chloro-1(3H~-icA~ -r~L~.,ull~
Distilled water (2.0 mL), conc. HCl (4.0 mL), and 6-amino-1(3H)-i~ub..~uCuL~.lu.._ (1.37 g, 9.18 mmol) were placed in a round-bottomed flask equipped with a magnetic stirring bar. The resulting white slurry was cooled in an ice-water bath and a solution of sodium nitrite (0.70 g) in distilled water (1.5 mL) was added dropwise. The reaction mixture was allowed to stir at 0-C for 20 min and a solution of copper (II) chloride hydrate (3.13 g, 18.36 mmol, 2.0 eq) in distilled water (2.0 mL) was added dropwise. The resulting bright green solution was allowed to stir at O-C for 1 h. The mixture was heated on a steam bath for 10 min inducing solids to form. Ethyl acetate was added to dissolve the solids and the layers were separated. The ~reen aqueous layer was extracted with ethyl acetate. The organics were combined, dried over MgS04, filtered, and c--~ d to give 1.35 g of a tan solid. This crude material was recrystallized from ethanol and dried in a vacuum oven to give 0.83 g (54~) of 6-chloro-1(3H)-i L ~ ~ as a light yellow powder. mp: 107-108-C. H NMR (CDC13): C 5.29 (s, 2), 7.44 (dd, 1, J - 8.2, 0.68), 7.64 (dd, 1, J - 8.2, 1.8), 7.86 (d, 1, J
1.8). C NMR (CDC13): C 69.50, 123.48, 125.69, 127.58, 134.87, 135.39, 144.63, 169.65.
Anal. Calcd for C8H502Cl: C, 57.00; H, 2.99. Found: C, 57.16; H, 3.03.
(d) Pret~aration of 6-chloro-2-(2-hvdroxvethyl)-1-isoindolinone 6-Chloro-1(3H)-i~ob~ r~ (9.15 g, 0.0543 mol), ethanol amine (Aldrich Chemical Company) (3.32 8. 1.0 eq) and toluene (10.0 mL) was added to a 100-mL, round-bottomed flask equipped with a magnetic stirring bar and a 10-mL Dean-Stark trap. The solution was heated with an oil bath. The toluene which was collected in the Dean-Stark trap was not allowed to return to the reaction pot. The resulting orange melt was heated at 210-C for 22 h. Upon cooling, the material solidified to give 11.75 g of a brown solid. The crude material was used without further purifi-~eti~n (e) PreDaration of 6-chloro-2-(2-chloroethyl~-1-isoindolinone This compound was prepared by a method analogous to that describet in Example l(b). Employing 6-chloro-2-(2-hydroxyeth-yl)-l-isoindolinone (11.75 g), as prepared above, gave 10.03 g of the target compound as a light yellow powder (80~ yield based on 6-chloro-1(3H)-icv~ -.--,r~ ). mp: 112-114-C. H NMR
(CDC13): C 3.79 (t, 2, J - 5.8), 3.94 (t, 2, J - 5.8), 4.55 (s, 2), 7.38 (d, 1, J - 8.1), 7.50 (dd, 1, J - 8.1, 1.8), 7.80 (d, 1, J - 2.1). 1 C N~R (CDC13): C 42.64, 44.82, 51.22, 123.91, 124.02, 131.76, 134.02, 134.43, 139.51, 167.52.
Anal. Calcd for CloHgNOC12 C, 52.20; H, 3.94; N, 6.09. Found: C, 52.30; H, 3.96; N, 6.03.
(f) Preoaration of 2-(2-(4-(12.-benzisothiazol-3-vl~-1-Dioerazinvl)-ethYl)-6-chloro-1-isoindolinone hYdrochloride This compound was prepared according to the method described in Example l(c). The crude product was purified by flash .1... ~ O ,'~ with ethyl acetate as eluant. The free amine was treated with 1 N HCl in ether and the resulting hydrochloride C ~ 2 i 1 7 ~ 3 ~
salt was triturated with 95~ ethanol to give 3.78 ~ of an off-white powder. mp: 272-275-C (dec). H NMR (DMS0-d6):
3.24-3.62 (m, 6), 3.71 (br d, 2, J - 10.8), 4.03 (m, 4), 4.60 (s, 2), 7.44 (dt, 1, J - 8.0, 1.0), 7.58 (dt, 1, J - 7.0, 1.0), 7.69 (m, 3), 8.11 (t, 2, J - 8.9), 11.08 (br s, 1). 13C NMR
(DMS0-d6): ~ 36.53, 46.09, 49.39, 50.47, 52.83, 121.07, 122.49, 123.96, 124.51, 125.30, 126.85, 128.02, 131.34, 132.60, 133.90, 140.93, 152.01, 162.01, 166.73.
Anal. Calcd for C2lH21N405Cl.HCl: C, 56.13; H, 4.93; N, 12-47-Found: C, 56.22; H, 4.95; N, 12.40.
(a) Pre~aration of 6-chloro-2-~4-chlorobutyl~-1-isoindolinone This compound was prepared by the method analogo w to that used in Example l(b). The starting material, 6-(Chloro-2-(4-hydroxy-butyl))-l-$~o$n~~l$n~, was obtained by following the procedure outlined in Example 4(d). The crude material obtained in this reaction was purified by flash ~IIL~ rAp~y to give 5.42 g (39 based on 6-chloro-1(3H)-i~ ~ r ) of an orange solid.
mp: 71-72'C. lH NMR (CDC13): ~ 1.83 (m, 4), 3.59 (t, 2, J
5.9), 3.65 (t, 2, J - 6.6), 4.36 (s, 2), 7.37 (d, l, J - 8.1), 7.49 (dd, l, J - 8.1, l.9), 7.79 (d, 1, J - 1.9). 13C NMR
(CDCl3): ~ 25.52, 29.49, 41.53, 44.49, 49.44, 123.84, 123.96, 131.44, 134.36, 134.52, 139.10, 167.28.
Anal- Calcd for Cl2Hl3NOC12: C, 55-83; H, 5-08; N, 5.43. Found:
C, 55.90; H, 5.12; N, 5.38.
W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~ - 52 -(b) Preoaration of 2-(4-~4~ 2-benzisothis7nl-3-yl~-l-Dinerazinyl) butyl)-6-chloro-1-iso~AAAlinAns hydrschloride hydrate This compound was prepared using the procedure described in Example l(c). From 6-chloro-2-(4-chlorobutyl)-1-isoindolinone (5.02 g, 19.4 mmol), a crude orange solid was obtained which was purified by recrysts~ st~An. The hydrochloride salt formed by treatment of the free base with 1 N HCl in ether was triturated vith hot ethanol and dried in a vacuum oven to give 4.84 g (51~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-6-ch-loro-l-isoinAAlir~A- hydrochloride hydrate as a tan powder. mp:
241-242-C. lH NMR (DMS0-d6): ~ 1.71 (br s, 4), 3.20 (m, 4), 3.35 (m, 6), 4.02 (br d, 2, J - 13.1), 4.50 (s, 2), 7.45 (m, 1), 7.53 (m, 1), 7.65 (m, 3), 8.10 (dd, 2, J - 8.0, 4.5), 11.14 (br s, 1).
13C NMR (DMS0-d6): ~ 20.46, 24.93, 41.11, 46.31, 49.22, 50.45, 55.10, 121.14, 122.35, 123.94, 124.56, 125.31, 126.90, 128.06, 131.11, 132.66, 134.33, 140.56, 152.04, 162.16, 166.02.
Anal. Calcd for C23H25N405Cl:0.4 H2O: C, 57.00; H, 5.57; N, 11.56; H20, 1.49. Found: C, 56.62; H, 5.65; N, 11.31; H2O, 1.34.
~PT~ 6 (a) p,~ of 2-(5-~hlAropentvl)-l-isoindolinone gAA
2 (5 ~ yl)-l-i~A~ nAAl 1 nAAO
These compounds were prepared by the method described in Example 3(a). A mixture of 2-(5-chloropentyl)-1-isoindolinone and 2-(5-b.~ r yl)-l-isoindolinone 4.24g (53~) was obtained by the reduction of N-(5 b,. r ~lpth~limiAo (10.00 g, 0.0338 mol)(~ransworld Chemicals, Inc.) with tin metal (9.62 g, 0.081 mol, 2.4 eq.), acetic acid (75 mL) and conc. HCl (15.0 mL). This mixture was used directly without SorsrAtiAn of each halide.
W O 93/16073 C A ~31.1 7 4 3 4 PCT/GB93/00285 ~b) PreDaration of 2-(5-(4-(1.2-benzisothiazol-3-yl)-1-Diverazinvl)-rentY~ - isoir~nl i n~n9 hydrochloride This compound was prepared according to the procedure described in Example 3(b). From a mixture of 2-(5-chloropentyl)-1-isoindo-linone and 2-(S-b~ l)-l-isoindolinone (4.24 g, 0.0178 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (4.30 g, 0.0196 mol, 1.1 eq), 2-(5-(4-(1,2-~ co-h~ol-3-yl)-1-piperazinyl)pentyl)-l-isoindolinone hydrochloride was obtained as an orange powder.
The hydrochloride salt was obtained as a tan powder (4.28 g, 53~) after recrystslli~otinn from ethanol. mp: 174-175-C. H NMR
(DMS0-d6): C 1.34 (m, 2), 1.65 (m, 2), 1.79 (m, 2), 3.20 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, ~ - 13.5), 4.47 (s, 2), 7.55 (m, 6), 8.10 (dd, 2, J - 8.0, 5.3), 11.28 (br s, 1). 13C NMR (DMSO-d6):
~ 22.58, 23.42, 27.20, 41.16, 46.29, 50.37, 55.28, 121.14, 122.59, 123.28, 123.95, 124.56, 126.91, 127.72, 128.06, 131.10, 132.38, 141.76, 150.05, 162.18, 167.20.
Anal. Calcd for C24H28N40S.HCl: C, 63.07; H, 6.40; N, 12 26.
Found: C, 63.10; H, 6.39; N, 12.22.
T~MPT.T~' 7 (a) Preraration of 2-(6-rhlnrnhon7yl)-l-iso~ n~nD and 2-(6-bromohexyl)-l i5Oindol in~s These compounds were prepared according to the method described in Example 3(a). A 50:50 mixture of 2-(6-chloroben_yl)-1-isoin-dolinone and 2-(6-bromohexyl)-1-isoindolinone was obtained by the reduction of N-(6-bromohexyl)-phthslimi~D (Transworld Chemicals Inc.). This material vas used as a mixture of halides.
CA2i 1 7434 (b) PreDaration of 2-(6-~4-(l~2-benzisorhi~7nl-3-yl)-l-DiDerazinyl) hex~yl)-l-isoindol in~n~ hydrnrhl nride This compound was prepsred following the procedure described in Lxample 3(b). Ihe crude product was purified by flash cl... v ~ with ethyl acetate/0.1~ triethylamine as eluant to give 4.65 g of a light yellow solid. The hydrochloride salt was formed by treatment with 1 N HCl in ether to give 4.18 g (61~) of 2-(6-(4-(1,2-ber.zisothiazol-3-yl)-1-piperazinyl)hexyl)-1-isoindo-linone hydrochloride as an off-white powder. mp: 263-264-C. lH
NMa (DNS0-d6): ~ 1.35 (m, 4), 1.64 (t, 2, J - 6.9), 1.75 (m, 2), 3.25 (m, 4), 3.50 (m, 2), 3.54 (t, 2, J - 7.0), 4.05 (m, 2), 4.49 (s, 2), 7.48 (m, 2), 7.60 (m, 3), 7.67 (br d, 1, J - 7.5), 8.12 (t, 2, J - 7.2), 10.99 (br s, 1). 13C NNR (DNSO-d6): ~ 25.78, 27.46, 41.27, 49.23, 122.58, 123.027, 123.95, 124.49, 127.72, 128.01, 131.08, 141.72, 152.02.
Anal- Calcd for C25H30N405.HCl: C, 63.74; H, 6.63; N, 11.89.
Found: C, 63.81; H, 6.65; N, 11.84.
FY~MPJ.F 8 (a) PreDaration of methYl 2-bromomethvl benzoate by using the method of W. Davies and ~. H. Perkin (J. Chem. Soc.
1922, 121, 2202), 2-bromomethyl benzoyl bromide was obtained by b~ ~nrinn of o-toluoyl chloride. The 2-b.. Lhyl benzoyl bromide (0.184 mol) was taken up in dichlu-~ thnn~ (40 mL) and the solution was cooled in an ice-water bath. Absolute methanol (15 mL) was added and the reaction mixture was allowed to warm to room L . ~ ~ and stir for 0.5 h. The solution was washed with saturated ~2C03 and extracted with ethyl acetate. The organics were dried over NgS04, filtered, and c~ with a rotary ~ L to give 42.08 g of a pale yellow oil. This material was used without further p~rifi~otinn H NMR (CDC13):
~ 3.94 (s, 3), 4.96 (s, 2), 7.40 (m, 3), 7.97 (m, 1).
b) PreDaration of 3-(4-(2-(2-aminoethoxy)ethvl~ DiDerazinvl)-1.2-bPn7i e~th; 07~le N-(2-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethoxy)ethyl)-pht~limi~o (7.45 g, 0.017 mol), as prepared in Cxample 24, was placed in a 100-mL, round-bottomed flask and taken up in methanol (20.0 mL). To this stirred solution was added hydrazine hydrate (1.49 g of an 85~ solution in water, 0.025 mol, 1.5 eq) dropwise and the mixrure was heated at reflux under N2 for 2 h. The reaction mixture was allowed to cool to room t, . _~L~.~ and 1 N
NCl (50.0 mL) was added. The resulting precipitant was filtered and washed with distilled water. The filtraee was made basic by the addition of 50~ NaOH and extracted with dichl~-- th- . The organics were dried over MgSO4, filtered, and ' with a rotary c.., ~ I to give 5.31 g of 3-(4-(2-(2- ~ Ll.~)eth-yl)-l-piperazinyl)-1,2-~ ~othl07ole as a viscous orange oil.
This crude material was used without further pur~4icotion (c) P-~_ _~ of 2-(2-(2-(4-(1.2-ho"7i~nrhiO~nl-3-yl~-l-D~n~ro~invl)ethoxv~ethyl) -l-i~nirA~lin~r~
A solution of toluene (100 mL) and 3-(4-(2-( -~ethn~y)ethyl)-l-piperazinyl)-1,2-' ~othio7nl~ (5.31 g, 0.017 mol) was heated in an oil bath at 100-110-C. A solution of methyl 2-b., Ll.~l benzoate (3.97 g, 0.017 mL, 1.0 eq) and toluene (25 mL) was added to the amine solution dropwise, over a 15-20 min period. The reaction mixture was heated under N2 for 0.75 h after the addition was complete. The solution was allowed to cool to room t . - ~ and washed with saturated R2CO3. The organics were dried over MgSO4, filtered, and c~ .-LL~L~d to give 6.22 g of a red-orange oil. This crude material was purified by flash with ethyl acetate/0.2~ triethylamine as eluant, W O 93/16073 - 56 - P~r/GB93/0028~
followed by recrystsll;7~t;~n from an ethyl acetate/ethanol solution to give 0.95 g of a tan solid. lH NMR indicated a small amount of ethyl acetate present in the sample. mp: 108-llO-C.
lH NMR (CDC13): ~ 2.69 (m. 6), 3.49 (br t, 4, J - 5.0), 3.66 (t, 2, J - 5.6), 3.74 (dt, 2, J - 1.0, 5.2), 3.82 (br t, 2, J - 4.73, 4.57 (s, 2), 7.34 (ddd, 1, J - 8.2, 7.0, 1.1), 7.47 (m, 4), 7.82 (m, 3). 13C NMR (CDC13): ~ 42.36, 49.80, 51.55, 53.28, 57.82, 68.59, 69.77, 120.53, 122.63, 123.57, 123.85, 127.50, 127.87, 127.97, 131.23, 132.71, 141.64, 152.73, 163.74, 168.55.
Anal. CalCd for C23H26N4~25 ~ l5 C4H8~2 12.86. Found: C, 64.74; H, 6.33; N, 12.76.
EXAMpLF 9 (a) PreDaration of tron~-2-~4-hYdroxy-l-cYclohexyl)-l-isoindolinone ~ethyl 2-b~ LL~l benzoate (30.00 g, 0.131 mol) (Example 8(a)), trans-4-amino cyclohexanol hydrochloride (Aldrich Chemical Company) (20.85 g, 0.137 mol, 1.05 eq), F-: ~ carbonate (27.15 g, 0.196 mol, 1.5 eq), toluene (110 mL) and water (20 mL) were added to a 500-mL, ,~ ' b~, ' flask equipped with a magnetic stirring bar and a Dean-Stark trap. The two-phase mixture was heated at reflux for 19 h. The toluene-water azeotrope was collected and the water was not allowed to re-enter the reaction pot. Fresh toluene (300 mL) was added and ehe tnl '' 1 azeotrope was removed through the Dean-Stark trap. After an additional 24 h of heating, the solution was decanted from the salts into a clean round-bottomed flask. The solvent was removed with a rotary ~ L~L~L to give 25.16 g of a viscous orange oil. This crude material was purified by flash CLL~ J with ethyl acetate/0.1~ triethyl amine as eluant to give 11.88 g (39'L) of trans-2-(4-hydroxy-1-cyclohexyl)-1-iso-indolinone as an off-white solid. mp: 133-134-C. lH NMR (CDC13):
~ 156 (m, 4), 1.41 (m, 3), 2.11 (m, 2), 3.66 (m, 1), 4.26 (tt, 1, W O 93/16073 C A ' I 7 4 3 PCT/GB93/00285 J - 11.5, 3.9), 4.32 (s, 2), 7~47 (m, 3), 7.84 (dd, 1, J - 7.7, 1.6). 13C NMR (CDC13): i~ 29.02, 34.46, 46.04, 49.67, 69.90, 122.68, 123.60, 128.01, 131.12, 133.12, 141.12, 165.11.
Anal. Calcd for C14N17N02: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.63; H, 7.41; N, 6.04.
(b) PreDaration of ~ -4~ oxo-2-isoin~~linvl)-1-cvclohexyl 1 fr~nLt-~
-2-(4-hydroxy-1-cyclohexyl)-1-isoindolinone (3.94 g, 0.017 mol) was taken up in anhydrous dichlu-~ t~-n~ (150 mL) and triethylamine (13.56 mL, 2.59 g, 0.025 mol, 1.5 eq) was added.
The orange solution w-s placet unter N2 ant cooled in an ice-water bath. To this stirred solution was slowly added a mixture of mesyl chloride (Aldrich Chemical Company) (1.98 mL, 2.93 g, 0.025 mol, 1.5 eq) in anhydrous dichlu~ (3.0 mL).
The reaction mixture was allowed to stir at 0-5-C for 1.25 h. An -'''t1r 1 portion of dichl~.- ' was added and the solution was washed with saturated R2C03. The layers were separated and the aqueous phase was extracted with dichloromethane. The organics were combined, dried over MgS04, filtered, and c d with a rotary e.., .~Lui to give 5.40 g of trans-4~ oxo-2-isoidolinyl)-1-cyclohexyl mei- lf~n~r~ as an orange solid. This crude material was used without further I fi~ti~n (c) Pre~aration of (+/-~-cis-2-(4-(4-(1.2-h~n7i~~th;o~~l-3-vl~-l-~in~r~7;nvl)-l-cyclohexyl)-l-isoindolinone hvdrochloride ~l~d~l~Le Trans-4-(oxo-2-isoindolinyl)-1-cyclohexyl mei' lfnn~t~ (5.27 g, 0.017 mL), 3-(1-piperazinyl)-1,2-benzisothiazole (3.92 g, 0.079 mol, 1.05 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq) and - ' CA2i 1 7434 acetonitrile (20 mL) were combined, placed under N2 and heated at reflux for 2.5 d. The mixture was allowed to cool to room I . e and washed with saturated K2C03. The organics were dried over HgS04, filtered and c----- .ar.~ with a rotary e~., . to give 8.29 g of a viscous orange oil. This crude material was purified by flash ~1.-. g ,'~ with ethyl acetate as eluant. The material isolated was purified further by flash cl..~ with 2:1 ethyl acetate/hexanes as eluant yielding 0.224 g of a sticlcy orange oil. The hydrochloride salt of this free base was formed, recrystallized from ethanol, and dried in a vacuum oven to give 0.120 g (24, based on trans-2-(4-hydroxy-1-cyclohexyl)-l-isoindolinone) of (+/-)-c s-2-(4-(4-(1,2-benzisoth-iazol-3-yl)-1-piperazinyl)-1-cyclohexyl)-1-isoindolinone hydro-chloride '~dLa~ as light peach crystals. mp: 231-232-C. lH
NHR (DMS0-d6): 8 1.72 (m, 2), 1.95 (m, 2), 2.20 (m, 2), 2.35 (m, 2), 3,33 (m, 2), 3.45 (m, 1), 3.77 (br d, 2, J - 13.4), 3.85 (br d, 2, J - 12.2), 4.05 (br d, 2, J - 13.4), 4.20 (quintet, 1, J
3.7), 4.74 (s, 2), 7.46 (m, 2), 7.58 (m, 3), 7.67 (d, 1, J
7.3), 8.11 (dd, 2, J - 8.0, 4.7), 10.80 (br s, l). 13C NMR
(DHS0-d6): ~ 23.37, 25.25, 45.96, 47.95, 48.75, 62.03, 121.17, 122.51, 123.15, 123.91, 124.56, 126.93, 127.69, 128.07, 131.13, 132.37, 142.06, 152.09, 162.15, 167.08.
Anal. Calcd for C25H28N405.HCl.H20: C, 61.65; H, 6.41; N, 11.50;
H20, 3.69. Found: C, 61.65; H, 6.45; N, 11.46; H20, 3.97.
FXAMPF.F~ 10 (a) PreDaration of 3-(4-(4-amino-2-butvnyl)-1-DiDerazinvl)-1.2-ho~ rhi 07nle This compound was prepared according to the method described for Example 8(b). From N-(4-(4-(1,2-benzisothiazol-3-yl)-l-pipera-zinyl)-2-butynyl)pbt~olimiA~, Example 25, (12.54 g, 0.630 mol), hydrazine hydrate (2.66 g of an 85% aqueous solution) and W O 93/16073 C A 2 i 1 ~ 4 3 4 P(~r/GB93/0028S
methanol (30 mL), 6.23 g (72.3%) of 3-(4-(4-amino-2-butynyl)-1-piperazinyl)-1,2-b~n7i~othio~ole was obtained as a crude orange oil. This material w-s used without further purification.
(b) PreDaration of 2-(4-(4-(1.2-hon~i~~thiazol-3-yl)-l-siserazinvl) 2-butvnvl)-1-isoindoli hydrochloride Tke crude amine, as prepared in lO(a) above, (6.23 g, 0.022 mol) was taken up in toluene (50 mL). To the stirred mixture was added a solution of methyl 2-bromomethyl benzoate (Example 8(a)), The resulting orange solution was heated at reflux under N2 for 18 h. The reaction mixture was allowed to cool to room ~ . ~ e and L.~.~re...d to a ~ funnel. The solution was washed with saturated ~2CO3, dried over ~gS04, filtered and r ~ .t . _t. A to give an orange oil. This crude material was purified by flash cl..~ on flash silica gel with 3:1 ethyl acetate/hexanes as eluant. The hydrochloride salt of the pure free base was prepared by the addition of 1 N HCl. The salt was recrystallized from ethanol/ethyl acetate and dried in a vacuum oven to give 0.24 g (3%) of 2-(4-(4-(1,2-b-n7i~othio-~1-3-yl)-l-piperazinyl)-2-butynyl)-1-isoi~A~li hydrochloride as an off-white powder, mp: 194-196-C. lH NMR (DHS0-d6): ~ 3.40 (m, 3), 3.51 (m, 3), 4.08 (m, 2), 4.22 (br s, 2), 4.59 (s, 2), 4.61 (s, 2), 7.48 (m, 2), 7.58 (m, 1), 7.63 (m, 2), 7.71 (dt, 1, J - 7.5, 1.0), 8.10 (dt, 1, J - 8.2, 0.9), 8.14 (dt, 1, J - 8.2, 0.9), 12.00 (s, 1).
C NMR (DMS0-d6): ~ 31.32, 44.53, 49.05, 49.85, 73.23, 84.95, 121.13, 122.91, 123.54, 123.98, 124.56, 126.91, 127.96, 128.07, 131.42, 131.70, 141.76, 152.03, 162.15, 166.80.
Anal. Calcd for C23H22N405: C, 62.93; H, 5.28; N, 12.76. Found:
C, 62.79; H, 5.31; N, 12.70.
.
CA2 l 17434 (a) PreDaration of l-isoindol~n~n~
phrho1imi~ (Aldrich Chemical Company ) (30.0 g, 0.204 mol) was placed in a 500-mL, round-bottomed flask with glacial acetic acid (150.0 mL), co~ d HCl (75.0 mL) and tin metal (Fisher Sciontifir) (58.08 g, 0.489 _L, 2.4 eq). The creamy slurry was heated in an oil bath at reflux. As the solution was heated the ph~limiAo dissolved, resulting in a light yellow solution. The reaction mixture was allowed to heat at reflux for 2 h, the solution was filtered hot, and the tin shavings were washed with fresh acetic acid. The majority of the acetic acid was removed with a rotary e.., , resulting in a light yellow creamy solution. This material was taken up in dichloromethane and washed with distilled water and a saturated sodium chloride solution. The organics were dried over MgS04, filtered, and c ~ to give 17.61 g of a light yellow solid. This crude material was purified by flash cl.~ with ethyl acetate as eluant to give 11.93 g (47S) of l-isoindolinone as a light yellow powder. mp: 150-151-C. H NMR (CDC13): ~ 4.48 (s, 2), 7.48 (m, 2), 7.57 (m, 1), 7.76 (br s, 1), 7.88 (m, 1). 13C NMR
(CDC13): ~ 45.83, 123.16, 123.64, 127.95, 131.69, 143.72, 172.35.
Anal. Calcd for C8H7N0: C, 73.16; H, 5.30; 10.52. Found: C, 72.08; H, 5.35; N, 10.49.
(b) PreDaration of (E)-2-(4-chloro-2-butenvl)-l-isoin~lin~n~
Sodium hydride (1.54 g of an 80S oil dispersion, 1.25 eq) was placed under N2 in an oven-dried, 500-mL, round-bottomed flask.
The sodium hydride was washed with hexanes (2X), and the waste hexanes were pipetted off of the solids. Anhydrous dimethylformamide (DMF) (100 mL) was added to the washed sodium hydride. To this grey ~ n was added a solution of W O 93/16073 - 61 - P(~r/GB93/00285 1-isoindolinone (5.47 g, 0.041 mol) in dry DMF (50.0 mL). In a separate oven-dried, 500-mL, round-bottomed flask was placed trans-1,4-dichloro-2-butene (Aldrich Chemical Company) (13.51. g, 0.103 mol, 2.5 eq) and dry DMF ( 100.0 mL). This solution was cooled in an ice-water bath and the l-iso;~Anlinnn~ solution was slowly added via a cannula. After the addition was complete the reaction mixture was allowed to warm to room ; , e and stir for 0.5 h. The majority of the DMF was r-moved with a rotary ev~ L~. and the residue was taken up in dichloromethane and washed several times with water. The organics were dried over MgS04, filtered, and ~ ~ to give 20.12 8 of a dark orange oil. This crude material was purified by flash ~L~ e .~ ~ with 1:1 hexanes/ethyl acetate as eluant to give 6.48 g (71S) of (E)-2-(4-chloro-2-butenyl)-1-isoinAn1i as a light yellow oil. The 1~ and C NMR spectra of this material were consistent for the N-alkylated p-_duct. 13C NMR (CDC13):
43.45, 43.99, 49.61, 122.78, 123.79, 128.08, 129.26, 129.56, 131.43, 132.54, 141.16, 168.28. A s~all amount (0.80 g) of the bis-alkylation product, (E)-2,2'-(2-butene-1,4-diyl)-bis-(1-~ A~l - ) was also obtained as light yellow crystals.
mp: 193-196-C.
(c) PreDaration of (E)-2-(4-(4-(1.2-~ ~nrhio7nl-3-yl) DiDerazir~yl) -2-butellyl) -l-isoindol ;nnn- hydrn~-hlnride This compound was prepared by an analogous method to that used in Example l(c). A mixture of (E)-2-(4-chloro-2-butenyl)-1-isoindo-linone (3.00 g, 0.014 mol), 3-(1-piperzinyl)-1,2-~ ~othlo7nle (2.97 g, 0.014 mol, 1.0 eq), and triethylamine (2.26 mL) in acetonitrile (20.0mL) was heated under N2 at reflux for 1 h. The crude material obtained was purified by flash cl..~ yh~ with ethyl acetate as eluant to give 3.47 g of the free base as a light yellow solid. The hydrochloride salt was prepared, recrystallized from ethanol, and dried in a vacuum oven to give 2.86 g (48S) of (E)-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazi-W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
nyl)-2-butenyl)-1-1eoin~~1in~~ hydrochloride as a tan powder.
mp: 232-235-C. lH NMR (DMS0-d6): ~ 3.10-3.58 (m, 6), 3.82 (br s, 2), 4.07 (br d, 2, J - 13.5), 4.22 (d, 2, J - S.l), 4.49 (s, 2), 5.08 (dt, 1, J - 15.4, 6.9), 6.04 (dt, 1, J - 15.4, 5.4), 7.55 (m, 5), 7.69 ~d, 1, J - 7.3), 8.10 (dd, 2, J - 7.5, 5.4), 11.36 (br s, 1). 13C NMR (DMS0-d6): ~ 42.95, 46.38, 49.37, 49.92, 56.33, 120.98, 121.14, 122.77, 123.44, 123.95, 124.56, 126.91, 127.83, 128.07, 131.36, 132.01, 136.08, 141.89, 152.06, 162.13, 167.08.
Anal. Calcd for C23H24N405.HCl: C, 62.64; H, 5.71; N, 12.70.
Found: C, 62.41; H, 5.67; H, 12.60.
EXAM~J~ 17 (a) F~ 'nn of (z~-2-(4-rhlnro-2-butenvl)-l-isoindolinone This compound was prepared according to the method described in ExaDple ll(b). Alkylation of l-isoi ~ lin~~- (5.75 g, 0.043 mol) with cis-1,4-dichloro-2-butene (Aldrich Chemical Company ) (6.25 g, 0.047 mol, 1.1 eq) in anhydrous DMF provided 3.43 g (36~) of (Z)-2-(4-chloro-2-butenyl)-1-isointolinone after purification by flash cl... ~ . lH, 13C and difference n.O.e. NMR spectra of the light or-nge oil were consistent with the N-alkylated product. 13C NMR (CDC13): 6 38.42, 38.50, 49.57, 122.77, 123.75, 128.08, 129.01, 129.44, 131.43, 132.44, 141.15, 168.26. The by-product of bis-alkylation, (Z)-2,2'-(2-butene-1,4-diyl)-bis-(l-isoindolinone) (0.88 g), was obtained as a light yellow solid.
mp: 148-150-C.
(b) F~ 'or of (Z)-2-(4-(4-(1.2-ben_isothiazol-3-vl)-1-pi~ 7inYl)-2-butenYl)-l-isoindolinone hvdrochloride hvdrate This compound was prepared by a method analo~ous to that used in Example l(c). A mixture of (Z)-2-(4-chloro-2-butenyl)-1-isoindo-linone (3.26 g, 0.015 mol), 3-(1-piperazinyl)-1,2-benzisothiazole (3.23 g, 0.015 mol, 1.0 eq), triethylamine (2.46 mL, 1.78 g, 0.018 mol, 1.2 eq) and acetonitrile (20.0 mL) W8S heated under N2 at reflux for 3 h. The crude product obtainet after work up was purified by flash ChL~ on flash silica gel with ethyl acetste as eluant to giYe 4.76 g of a viscous orange oil. The hydrochloride salt was prepared and recrystallized twice from 95 ethanol to give 2.16 g (33~) of (Z)-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-2-butenyl)-1-isoindolinone hydrochloride hydrate as a tan powder. mp: 234-236-C. H NMR (DMS0-d6):
3.34 (m, 4), 3.55 (m, 3), 4.10 (m, 4), 4.33 (d, 2, J - 5.9), 4.49 (s, 2), 7.95 (m, 2), 7.52 (m, 5), 7.6B (dd, 1, J - 7.3, 1.0), 8.12 (t, 2, J - 8.0), 11.65 (br s, 1). C NMR (DMS0-d6):
38.68, 46.40, 49.26, 50.04, 51.79, 121.15, 121.50, 121.71, 123.40, 123.95, 124.58, 126.94, 127.81, 128.08, 131.34, 131.99, 133.93, 141.86, 152.07, 162.13, 167.06.
Anal. Calcd for C23H24N40S.HClØ5 H20: C, 61.39; H, 5-82; N, 12.45; H20, 2.00. Found: C, 61.05, H, 5.79, N, 12.19, H20, 2.28.
(a) F,~ on of 2-(4-(4-(l~2-b~n7i~~thiazol-3-yl~-l-DiDerazinyl) butyl~hthAl mi ~- hvdrochloride N-(4-Bromobutyl)l' ' li~i~ (Aldrich Chemical Company ) (3.50 g, 0.0124 mol), 3-(1-piperazinyl)-1,2-benzisothiazole (Yevich J.P.
et al J.Med.Chem. 1986, 29, 359-369) (2.72 g, 0.0124 mol, 1.0 eq), triethylamine (2.24 mL, 0.0161 mol, 1.3 eq) and acetonitrile (15.0 mL) was added to a 100-mL, ~v~.l b~L ' flask. The cloudy orange solution was heated under N2 at reflux for 17 h.
The mixture was allowed to cool to room L , ~ and taken up in dichlvL- i' . The or_anic solution was washed with --t~-Ate~ K2C03, dried over MgS04, filtered, and c~"~e"L,~tcd to give 5.48 g of a light orange solid. This crude material was CA 2 i i 74~4 recrystallized from acetonitrile and dried in a vacuum oven to give 4.35 g of a tan powder. The hydrochloride salt was prepared by the addition of lN HCl in ether and recrystallized from 95%
ethanol to give 4.53 g (82~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl) phthDlmi~ hydrochloride as an off-white powder. mp: 258-260-C (dec). lH NMR (DMSO-d6): 6 1.72 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.02 (br d, 2, J - 13.7), 7.44 (ddd, 1, J - 8.1, 7.0, 1.1), 7.57 (ddd, 1, J - 8.1, 7.0, 1.0), 7.85 (m, 4), 8.09 (dd, 2, J - 8.0, 4.5), 11.18 (br s, 1). 13C NMR
(DMSO-d6): C 20.52, 25.25, 36.82, 46.30, 50.44, 54.98, 121.13, 122.98, 123.94, 124.56, 126.90, 128.06, 131.58, 134.33, 152.04, 162.16, 167.93.
Anal. Calcd for C23H24N402S.HCl: C, 60.45; H, 5.51: N, 12.26.
Found: C, 60.46; H, 5.55; N, 12.17.
(b) Pr~n~Dti~~ of 3-(4-(4- nAh..~yl)-l-~i ~yl)-1.2-hDn7i D7~1e To a solution of 2-(4-(4-(1,2-bon7i~othiD7ol-3-yl)-l-piperazin-yl)butyl)pht~limiio (12.46 8, 0.0296 mol) and methanol (30.0 mL) was added 85% hydrazine hydrate (2.62 g, 1.5 eq). The reaction mixture was heated at reflux for 3.5 h and allowed to cool to room i , ~ e. lN HCl (59.0 mL) was added to the solution and the resulting white precipitant was filtered and washed with water. The filtrate was made basic by the addition of 50~ NaOH
and extracted with dichl~.~ ' . The organics were dried over MgS04, filtered, and - ~ ' with a rotary e... ~LUL to give 8.1 g (94~) of 3-(4-(4-aminobut-:)-1-piperazinyl)-1,2-benzi-sothiazole as an orange-brown oil. H NMR (CDC13): 6 1.38 (br s, 2), 1.55 (m, 4), 2.45 (t, 2, J - 7.4), 2.68 (t, 4, J - 5.0), 2.74 (t, 2, J - 6.8), 3.57 (t, 4, J - 5.0), 7.35 (ddd, 1, J - 1.1, 7.0, 8.1), 7.46 (ddd, 1, J - 1.1, 7.0, 8.1), 7.81 (d, 1, J
8.1), 7.91 (d, 1, J - 8.2). This crude amine was used without further purification.
W O 93/16073 C A 2 i 1 /645 3 4 PCT/GB93/00285 (c) PreDaration of 2-(4-(4-(1.2-h~n7;e~thio7Al-3-yl)-l-Din~rp7invl) butvl)-4-methYlnhthAl mi ~- hYdrochloride 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benzisothiazole (2.70 g, 9.3 mmol) and pyridine (27.0 mL) was added to a 300-mL, round-bottoDed flask. To this stirred solution was added 4-methylphthalic snhydride (1.66 g, 10.2 mmol, 1.1 eq). The react{on mixture was placed under N2 and heated at reflux for 5 h. The solution was c ~ ' and the residue was taken up in dichl~.~ t~ and washed with saturated R2C03. The organics were dried over MgS04, filtered, and ~ ' to give the crude product. This material was purified by flash cl.L~ ~ g ,'~
with 3:1 hexanes/ethyl acetate as eluant to yield 3.82 g of white crystals. This free amine was taken up in ethyl acetate and HCl (8.7 mL of a lN solution in ether, 8.7 mmol, 1.0 eq) was added.
The resulting hydrochloride salt was recrystallized from 95~
ethanol and dried in a vacuum oven to give 2.70 g (67~) of 2-(4-(4-(1,2-~ 'eoth;o~l-3-yl)-1-piperazinyl)butyl)-4-methyl-~ - hydrochloride as a white powder. mp: 255.5-258-C.
NNR (DNS0-d6): 6 1.74 (m, 4), 2.46 (s, 3), 3.25 (m, 4), 3.53 (m, 6), 4.02 (br d, 2, J - 13.6), 7.44 (ddd, 1, J - 8.1, 7.1, 0.9), 7.62 (m, 4), 8.10 (dd, 2, J - 8.0, 4.7), 11.18 (br s, 1). 13C
NNR (DNS0-d6); ~ 20.54, 21.29, 25.28, 36.75, 46.31, 50.45, 55.00, 121.12, 122.90, 123.42, 123.94, 124.56, 126.90, 128.06, 128.96, 131.94, 134.63, 145.24, 152.05, 162.15, 167.90, 168.00.
Anal. Calcd for C24H26N40S.HCl: C, 61.20; H, 5.78; N, 11.89.
Found: C, 60.91; H, 5.78; N, 11.75.
FV-~PT F~ 14 to 22 The compounds of Examples 14 to 20 and 22 were prepared from their c~ s~,.ding substituted phthalic anhydride ~ by the method described in Lxample 13 (c). The phthalic anhydrides employed were obtained from commercial suppliers or prepared by known literature CA2i 1 7434 methods as ;nA;rot-~ The analytical dAta for these ,' '-limi~o~ are shown below.
F'XAMPT F 14 PreDaration of N-(4-(4-(1.2-hon7;~~th;D~nl-3-yl)-l-DirorA7;r!yl) butyl)-3-fluornnhthsl;mi~io hytrArhlnride Starting material: 3-Fl ~hLl.~lic anhydride (Lancaster Synthesis Inc). Yield: 1.22 g (16~). mp: 258-260-C. H NMR (DMS0-d6): ~ 1.67 (m, 2), 1.80 (m, 2), 3.22 (m, 2), 3.55 (m, 6), 4.05 (br t, 2, J
13.5), 7.47 (ddd, 1, J - 8.1, 7.0, 1.1), 7.46 (ddd, 1, J - 8.1, 7.0, 1.1), 7.74 (dt, 1, J - 7.3, 0.7), 7.90 (ddd, 1, J - 8.4, 7.3, 4.6), 8.11 (tm, 1, J - 7.5), 11.12 (br s, 1). 13C NMR (DMSO-d6): C 20.48, 25.09, 36.98, 46.30, 50.46, 55.00, 117.28, 117.53, 119.49, 119.55, 121.12, 122.19, 122.58, 123.94, 124.56, 126.90, 128.06, 133.98, 134.01, 137.27, 137.43, 152.05, 153.94, 159.13, 162.14, 164.79, 166.ô7, 166.93.
Anal. Calcd for C23H23N402SF.HCl: C, 58.16; H, 5.09, N, 11.79. Found:
C, 57.93; H, 5.15; N, 11.71.
EXAMPT~ 15 PrA~-rot;r~ of N-(4-(4-(1.2-t ~~thi 07nl - 3-yl)-1-DiDerazinyl) bUtYl)-3-~ AYI.~ 51 ;m;~ hYdrnrhlnride Starting material: 3-H~ l.Llalic anhydride (Aldrich Chemical Company). Yield: 0.94 g (24~). mp: 247-248-C. H NMR (DMSO-d6): 8 1.65 (D, 2), 1.77 (m, 2), 3.23 (_, 4), 3.54 (m, 6), 4.05 (br d, 2, J -13.6), 7.27 (dd, 1, J - 3.5, 0.8), 7.29 (dd, 1, J - 4.8, 0.8), 7.47 (ddd, 1, J - 8.2, 7.0, 1.1), 7.60 (m, 2), 8.02 (tt, 2, J - 7.7, 1.1), 11.02 (br s, 1), 11.19 (s, 1). C NMR (DMSO-d6): ~ 20.57, 22.30, 36.44, 38.21, 40.71, 46.32, 50.48, 55.05, 113.82, 114.57, 121.12, 123.19, 123.94, 124.56, 126.90, 128.06, 133.47, 135.77, 152.05, 155.19, 162.14, 166.63, 167.74.
Anal. Calcd for C22H23N5025.HCl: C, 58.44; H, 5.34; N, 11-86- Found C, 58.48; H, 5.35; N, 11.90.
PreDaration of 2-(4-~4-(1.2-benzisothiazol-3-yl)-1-DiDerazinyl) butyl~-2.3--lih,ydro-lH-DYrrolo~3.4-C)Dvridine-1.3-dione hYdrochloride Starting material: 2,3-Pyri~ino~i~Arb~Yylic anhydride (Aldrich Chemical Company). Yield: 3.03 g (76~). mp: 258-259-C. H NMR
(DMS0-d6): ~ 1.71 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.03 (br d, 2, J -13.4), 7.45 (ddt, 1, J - 8.1, 6.9, 1.0), 7.58 (ddd, 1, J - 8.1, 6.9, 1.0), 7.89 (dd, 1, J - 4.8, 1.1), 8.10 (dd, 1, J - 8.0, 4.2), 9.09 (d, 1, J - 4.9), 9.12 (d, 1, J - 0.8), 10.86 (br s, 1). 13C NMR
(DMSO-d6): ~ 20.49, 25.01, 37.13, 46.32, 50.49, 55.01, 116.78, 121.13, 123.93, 124.56, 125.87, 126.90, 128.07, 139.34, 143.79, 152.06, 155.74, 162.13, 166.89, 167.29.
Anal. Calcd for C22H23N5025.HCl: C, 57.75; H, 5.29; N, 15.32. Found:
C, 57.60; H, 5.30; N, 15.33.
PrerArPtiQn of N-(4-(4-(1.2-h~n7i~nthiazol-3-vl~-l-Dinorazinyl) butvl~-4-ritrnnhthAl1~i Ao h~drochloride Starting material: 4-NiL.. r~ anhydride (Aldrich Chemical Company). Yield: 3.30 g (73~). mp: 258.5-259-C. H NMR (DMSO-d6): 6 1.69 (m, 4), 3.20 (m, 2), 3.50 (m, 2), 3.66 (m, 2), 4.04 (br d, 2, J -13.3), 7.45 (t, 1, J - 7.4), 7.'8 (6, l, J - 7.2), 8.08 (d, l, J
4.5), 8.11 (s, 1), 8.14 (d, 1, J - 3.3), 8.49 (d, 1, J - 1.8), 8.62 (dd, 1, J - 8.2, 2.0), 10.88 (br s, 1). C NMR (DMS0-d6): ~ 20.50, 25.02, 37.40, 46.32, 50.48, 54.98, 117.70, 121.14, 123.93, 124.44, 124.57, 126.89, 128.07, 129.51, 133.09, 136.36, 151.31, 152.05, 162.13, 166.09, 166.35.
Anal. Calcd for C23H23Nso4s~Hcl: C, 55.03; H, 4-82; N, 13-95- Found:
C, 55.06; H, 4.85; N, 13.96.
F.~AMP!.F. 18 PreDaration of 6-(4-(4-(l~2-h~n7ic~thiazol-3-~l)-l-DiDerazinyl) butyl~-6,7-~ihvdro-SH-Dvrrolo(3.4-BlDvridine-5,7-dione hvdrochloride b ~ ~IL ~It~:
Starting material: 3~4-pyri~in~ nrboxylic aDhydride (Aldrich Chemical Company). Yield: 1.52 g (34%): mp: 253-254-C. H NMR
(DMSO-d6): ~ 1.70 (m, 4), 3.27 (m, 6), 3.52 (m, 2), 3.65 (t, 2, J
6.3), 4.05 (br d, 2, J - 12.7), 7.45 (t, 1, J - 8.0), 7.58 (t, 1, J
7.6), 7.78 (dd, 1, J - 7.6, 5.1), 8.09 (d, 1, J - 8.0), 8.12 (d, 1, J
- 8.0), 8.30 (dd, 1, J - 7.6, 1.4), 8.97 (dd, 1, J - S.l, 1.4), 10.52 (br s, 1). 13C NMR (DMS0-d6): ~ 20.46, 25.13, 36.94, 46.29, 50.43, 54.99, 121.12, 123.94; 124.56, 126.90, 127.24, 127.73, 128.06, 131.14, 151.49, 152.05, 154.66, 162.15, 166.28, 166.37.
Anai. Calcd for C22H23N5025.HCl.H20: C, SS.Sl; H, S-Sl; N, 14-71; H20, 3.78, Found: C, 55.75; H, 5.52; N, 14.71; H20, 3.92.
PreDaration of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-DiDerazinYl) butyl)-3-methvlDhthalimide hydrochloride , '~d,~t~
Starting material: 3-Methylphthalic anhydride (Kodak Laboratory Chemicals). Yield: 3.34 g (73%). mp: 272-274-C. H NMR (DMS0-d6): ~
1.68 (m, 4), 2.62 (s, 3), 3.17 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, J -12.4), 7.45 (m, 1), 7.63 (m, 4), 8.10 (dd, 2, J - 7.9, 4.4), 10.98 (br W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 s, 1). 3C NMR (DMS0-d6): 6 16.98, 20.59, 25.26, 36.64, 46,36, 50.52, 55.06, 120.61, 121.13, 123.94, 124.55, 126.90, 128.06, 128.20, 131.95, 133.83, 136.41, 137.04, 152.05, 162.17, 167.80, 168.62.
Anal- Calcd for C24H26N4~25'HCl H2 Found: C, 59.07; H, 5.99; N, 11.32.
FY~MPJ .F 20 PrPnAration of N-(4-(4-(l~2-benzisothiazol-3-yl)-l-vin~razin~l) butvl~-3.6-dichlornnhrhAll~iA~ hydrochloride ~ ~vd.~L~
Starting material: 3~6-Dichl~ lir anhydride (Fluka Chemic AG).
Yield: 2.23 g (49~). mp: 265-267-C. lH NHR (DMS0-d6): 6 1.73 (m, 4), 3.20 (m, 4), 3.57 (m, 6), 4.03 (br d, 2, J - 13.5), 7.45 (t, l, J
8.0), 7.58 (t, l, J - 8.0), 7.83 (s, 2), 8.09 (d, l, J - 8.0), 8.11 (d, 1, J - 8.0), 11.05 (br s, 1). 13C NMR (DMS0-d6): 6 20.48, 24.93, 37.24, 46.31, 50.47, 55.01, 121.13, 123.93, 124.56, 126.89, 128.06, 128.16, 129.28, 136.72, 152.05, 162.}4, 164.35.
Anal. Calcd for C23H22N402SC12.HCl.H20: C, 50.79; H, 4.63; N, 10.30.
Found: C, 50.63; H, 4.67; N, 10.23.
A second crop of crystals gave 0.44 g of the hydrochloride dihydrate.
mp: 262-265-C.
Anal- Calcd for C23H22N4025Cl2 HCl-2 H20: C, 49.16; H, 4.84; N, 9,97, Found: C, 49.21; H, 4.83; N, 9.93.
FYI~MPJ F 21 (a) Preraration of 4-chlororhrhAli~
4-Aminopthalimide (Rodak) (lO.Og, 0.0671mol), distilled wster (14.0 mL) snd ~ ~ ' HCl (27.0 mL) were plsced in a 500 mL, CA2~, 7~34 W O 93/16073 PCT/~b53/~
i~ ' b~. ' flask. Th- resulting li p t yellow solution was cooled with an ice/water bath and a solution of sodium nitrite (Malinckrodt) (4.57 g, 0.0679 mol,l.l eq) in distilled water (100 ml) was added dropwise. The reaction mixture turned a golden yellow color upon this addition. The solution was allowed to stir at 0~C for 20 minutes and a solution of CuC12.2H20 (21.0 g, 0.123 mol, 2.0 eq) in distilled water (140 mL) was added dropwise. The resulting green solution was allowed to stir at 0 C for lh followed by warming on a steam bath for 15 min. The mixture was extracted with ethyl acetate. The organics were co_bined, dried over MgS04, filtered and ~ - ' with a rotary ~., to give 9.61 g of the title compound as a tan solid. This material was used without further purif1rDti~~
(b) FL~ on of N-(4-nhlnrobut~1~-4'-rhlnroothAlim~ and N-(4-b.~_ b~v1~-4' nhlnroDthAlim{~o The title compounds were prepared by a method analogous to E~ample ll(b). From 4-rhl~L ,' '-limi~ (9.61 g, 0.0529 mol) and l-bromo-4-chl~..rL limi~ (Aldrich Chemical Company) (9.98 g, 0.0582 mol) was obtained 15.91 g of an 80:20 mixture of the - . . ~-ng chloride and bromide after flash ~ g .-~with 8:1 hexanes/ethyl acetate as eluant. This material was used as a mixture of the halides without further p~nif;r~ti~n (c) PrA~~ration of N-(4-(4-(1.2-brn~in--thi~7nl-3-yl)-l-DinnrA7ir~
butyl~-4-rhlrrnnhthAlimi~' hydrnrhlnrid~
This compound was prepared according to the method described in Example 13(a). From an 80:20 mixture of N-(4-chlorobutyl)-4'-chl~.. , -l;mii~ and N-(4-bromobutyl)-4'-chlorop:hDlimi~ ~
(2.50 g, 0.0029 mol) and 3-(l-piperazinyl)-1,2-b~n7in5Othi~7nl~
(1.95 g, 0.0089 mol) was obtained 2.30 g of the target compound as the free base. The l.~d,. ~ ide salt was prepared, recrystallized from 95~ ethanol and dried in a vacuum oven to ' CA2 i 1 7434 give 1.79 g (41i~ of the title compound 85 light yellow crystals, mp: 253-255-C. H NMR (DMS0-d6): ~ 1.69 (m, 4), 3.23 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, J - 13.1), 7.44 (t, 1, J - 7.7), 7.57 (t, 1, J - 6.9), 7.88 (d, 2, J - 1.1), 7.94 (d, 1, J - 1.1), 8.09 (dd, 2, J - 4.3, 8.0), 11.18 (br s, 1). C N~R (DMSO-d6):
20.46, 25.14, 37.06, 46.29, 50.42, 54.96, 121.13, 123.10, 123.93, 124.55, 124.71, 126.89, 128.05, 130.20, 133.67, 134.04, 139.08, 152.04, 162.14, 166.69, 167.05.
Anal. Calcd for C23H24N4025C12 Found: C, 56.18; H, 4.95; N, 11.34.
ExAMPLe 22 PreDsration of N-(4-(4-(1.3-benzisothiazol-3-vl)-1-DiDerazinYl) butyl~-3 _ tl,~J~Ih-lim-~ hvdrochloride hydrate Starting material: 3-Mei' ~,' '-11r anhydride (Alfred Bader Library).
Yield: 2.17 g (47~). mp: 232-234-C. lH NMR (DMSO-d6): 6 1.70 (m, 4), 3.25 (m, 4), 3.54 (m, 6), 3.94 (s, 3), 4.03 (br d, 2, J - 13.4), 7.48 (d, 2, J - 8.5), 7.60 (tm, 1, J - 5.0), 7.79 (tm, 1, J - 7.3), 8.10 (dd, 2, J - 7.9, 4.6), 1}.19 (br s, 1). 13C NMR (DMS0-d6): ~ 20.52, 25.26, 36.59, 46.29, 50.42, 54.99, 56.16, 114.88, 116.42, 118.52, 121.13, 123.94, 124.56, 126.90, 128.06, 133.56, 136.57, 152.05, 156.13, 162.16, 166.16, 167.54.
Anal. Calcd for C24H26N4035.1.25 HClØ25 H20: C, 57.58; H, 5.57; N, 11.19; H20, 0.89. Found: C, 57.65; H, 5.87; N, 10.92; H20, 1.17.
(a) Preoaration of (+/-)-trans-1.2-cvcloDroDanedimethanol Lithium aluminum hydride (LAH) (7.60 g, 0.201 mol, 1.5 eq) was adted to an oven-dried, 500-mL, three-necked, round-bottomed flask equipped with a pressure-eq~Ali7ing addition funnel. Tne LAH was placed under N2, cooled with an ice-water bath, and anhydrous teL.~,~ILufu.~,, (200.0 mL) was added. After the addition was complete the cold bath was removed and the solution was allowed to stir at room ~ , e for 10 min. To this grey r ~on was added a solution of trans-diethyl 1,2-cyclopropane dicarboxylate (Aldrich Chemical Company) (25.0 g, 0.134 mol) dropwise. The reaction mixture was heated at reflux for 6 h and allowed to stir at room I , e for 20 h. The solution was cooled in an ice/water bath and saturated NH4Cl (45 mL) was slowly added. Ethyl acetate (50.0 mL) was added, the solids were filtered and washed with ethyl acetate. The filtrate was dried over MgS04, filtered, and co..~ L~L~d to give 8.00 g of a cloudy oil. This crude material was purified by flash ~I.L~ - O ,' ~
with ethyl acetate/methanol 19:1 as eluant to give (+/-)-trans-1,2-cycl~ r 1 as a colorless oil. lh N~R (CDC13): ~ 0.41 (t, 2, J - 6.8), 1.00 (m, 2), 3.00 (dd, 2, J
- 11.3, 8.8), 3.83 (dd, 2, J - 11.3, 4.4), 4.22 (br s, 2). 13C
NMR (CDC13): ~ 7.16, 19.98, 66.08.
(b) PreDaration of (+/-)-trAn~-2-(chloromethyl)-l-cyclo~romane methanol (+/-)-Tralls-l~2-cy~ r L 1 (4.0 g, 0.039 mol), tosylchloride (TsCl) (8.96 g, 0.047 mol, 1.2 eq), dimethylamino pyridine (DMAP) 5.30 g and anhydrous dichloromethane (75.0 mL) was added to an oven-dried, S00-mL, round-bottomed flask. The reaction mixture was placed under N2 and allowed to stir at room r , c for 24 h. Additional portions of the reagents were added, TsCl (2.24 g), DMAP (1.0 g), and dichlvL~ L'~ (1.0 mL).
The solution was allowed to stir at room r , e for an additional 6 d. Triethylamine (5.43 mL, 3.95 g, 0.039 mol, 1.0 eq) was added and the solution was allowed to stir for 24 h. The reaction was still not complete. The mixture was heated at reflux for 1.5 h and the solvent was removed with a rotary W 0 9 /I CA21 i 7434 e~ tuL to give a sticky tan solid. This crude material was purified by flash .1,.. ~ with hexanes/ethyl acetate 1:1, followed by ethyl acetate/methanol 19:1 as eluant to give 1.85 g of (+/-)-trans-2-(chloromethyl)-l-cyclopropane methanol. A
portion of the starting diol (0.87 g) was recovered unchanged.
(c) PreDaration of (+/-)-trans-N-((2-(hydroxvmethyl)cvcloDroDYl) Dethyl) ~hthAl im~
PotassiuD 1' '-limi~ (1.44 g, 7.62 mDol~, (+/-)-trans-2-(chloro-methyl)-l-cy~ , methanol (1.59 g, 13.20 mmol, 1.7 eq), and anhydrous dimethyl' '~- (50.0 mL) were placed in a 1OO-DL~
round-bottomed flask. The resulting cloudy ~ n was heated at reflux for 20 h. The r-action mixture was allowed to cool to room ~ nd most of the DMF was removed in vacuo with a rotary e~_, s. The residue was taken up in dichloromethane and washed with two portions of water. The organics were dried over MgS04, filtered, ~nd c ~ ' to give 3.55 g of a dark orange oil. This crude material was purified by flash ch~ with hex nes/ethyl acetate 5:1 as eluant to give 1.12 g (64~) of (+/-)-trans-N-((2-(1.Jd-u~ Ll,~l)cyclopropyl)me-thyl) pht~_limi~ as a white powder. DP: 117-118-C. lH NMR
(CDC13): ~ 0.48 (ddd, 1, J - 13.6, 10.3, 5.2), 0.65 (ddd, 1, J
13.6, 10.3, 5.0), 1.17 (m, 2), 1.52 (br s, 1), 3.45 (m, 2), 3.59 (dd, 2, J - 7.0, 2.2), 7.70 (m, 2), 7.84 (m, 2). 13C NMR
(CDC13): ~ 8.99, 16.17, 20.68, 41.57, 66.09, 123.43, 132.12, 133.95, 168.48.
Anal. Calcd for C13N13N03: C, 67.52; N, 5.67; N, 6.06. Found: C, 67.45; N, 5.71; N, 5.99.
C~2i 17434 (d) PreDaration of (+/-)-trans-(2-(Dhtholimi~ tl,~l)-l-cYcloDroDyl) methyl methvlsulfonate (+/-)-Trans-N-((2-(1.,~1.uA,~. Ll~l)cyclopropyl)methyl)-rhth7limi~lo (1.04 g, 4.50 mmol), freshly distilled (over Cah2) triethylamine (0.94 mL, 0.68 g, 6.75 mmol, 1.5 eq) and anhydrous dichlorometh-ane (14.0 mL) was added to a 50-mL, round-bottomed flask. The solution was placed under a N2 I ,' e and cooled with sn ice-water bath. To this cooled mixture was added a solution of mesyl chloride (0.52 mL, 0.77 g, 6.75 mmol, 1.5 eq) in dichlu.~ ' (2.0 mL). Upon this addition the white alcohol , ' became a clear light orange solution which was allowed to stir at O-C for 1 h. The reaction mixture was allowed to warm to room ; , e and was washed with saturated R2C03. The organics were dried over MgS04, filtered, and c~ *~d to give 1.40 g of an off-white solid. This material was purified by flash ~1"~ on silica gel with 1:1 hexanes/ethyl acetate as eluant to give 1.29 g (93~) of (+/-)-trans-(2-(pht~limi~
thyl)-l-cyclopropyl)methyl methyl~ fA~ot~ as a white powder.
mp 118-121-C. ~ NMR (CDC13): 6 0.65 (dt, 1, J - 8.6, 5.4), 0.83 (dt, 1, J - 8.4, 5.4), 1.33 (m, 2), 2.94 (s, 3), 3.58 (dd, 1, J - 14.2, 7.2), 3.65 (dd, 1, J - 14.2, 6.9), 3.99 (dd, 1, 3 10.8, 7.5), 4.09 (dd, 1, J - 10.8, 7.0), 7.74 (m, 2), 7.86 (m, 2). 13C ~MR (CDC13): ~ 9.97, 16.90, 17.26, 37.79, 40.86, 73.22, 123.29, 132.09, 134.02, 168.29.
(e) FL~_ :ion of (+/-)-trans-N-((2-((4-(1.2-benzisothiazol-3-yl)-1-Din~rP7inYl)methYl)CycloDroDYl) methYl) T~hthol imide hvdrochloride hvdrate (+/-)-Trans-(2-(phth~limi~ tl.~l)-l-cyclopropyl)methyl methane-sulfonate (1.17 g, 3.78 mmol), 3-(1-piperazinyl)-1,2-benzisothia-zole (0.912 g, 4.16 mmol, 1.1 eq), triethylamine (0.633 mL, 0.459 g, 4.54 m~ol, 1.2 eq) and acetonitrite (10.0 mL) were added to a 100-mL, round-bottomed flask. The cloudy solution was placed under N2 and heated at reflux for 3.5 h. An additional portion of the pirers7in~ b~ ~this7ole (0.083 8, 0.10 eq) was added and heating was continued for a total of 20 h. The solution was allowed to cool to room ~ . ~ and dichloromethane WdS
added. The solution was washet with saturated K2C03 and the organics were dried over MgS04, filtered, and o~ LL~L~d to give 1.92 g of a viscous orange oil. This crude material was purified by flash cl.~ with 2:1 hexanes/ethyl acetate as eluant to give 1.30 g of the free base. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.11 g (61~) of (+/-)-trans-N-((2-((4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)methyl)cyclopropyl) methyl) rhr~slimi~ hydrochlor-ide hydrate as an off-white powder after drying in a vacuum oven, mp: 246-248-C. lH NMR (DMS0-d6): C 0.74 (m, 2), 1.29 (m, 2), 3.12 (br s, 2), 3.20-3.67 (m, 8), 4.05 (m, 2), 7.45 (t, 1, J
7.5), 7.58 (t, 1, J - 7.5), 7.18 (m, 4), 8.09 (d, 2, J - 8.2), 11.12 (br s, 1). 13C NMR (DMSO-d6): C 9.64, 12.01, 17.07, 46.24, 49.87, 50.22, 58.47, 121.16, 12~.02, 124.01, 124.61, 126.93, 128.11, 131.67, 134.37, 152.08, 162.16, 168.02.
Anal. Calcd for C24H24N4025.HCl.0 5 H20: C, 60.30, H, 5.48; N, 11.72; H20, 1.88. Found: C, 60.37; H, 5.51; N, 11.72; H20, 1.85.
FY~PLF 24 (a) PrA-s~ation of N-(2-(2-rhlnroethoxY)ethYl)ohth~limide Fotassium p~thslimi~ (Aldrich Chemical Company) (15.0 g, 0.081 mol) as a fluffy powder and 2-chloroethyl ether (Aldrich Chemical Company) (28.5 mL, 34.74 g, 0.243 mol, 3.0 eq) as a colorless oil was added to a 250-mL, round-bottomed flask. The reaction mixture was heated under nitrogen with an oil bath at 170-C for 19 h. As the mixture was heated the solution became more liquid in consistency and brown in color. The mixture was removed from the oil bath and distilled water was added. The solution was sllowed to cool to room t ,-rPt--re and extracted with dichlo,. tl,~ . The organic extracts were washed with water, dried over MgS04, filtered, and c~nr~ntrAr~d to give 36.1 g of a dark orange-brown oil. This crude material was purified by flush cl.,. e . ~ ~ with 3:1 hexanes/ethyl acetate as eluant to give 13.53 g (67%) of a light orange oil which quickly solidified upon standing. An analytically pure white powder was obtained by recrysts1li7sti~n from ethyl acetate. mp: 67-70-C. lH NMR
(CDC13): ~ 3.54 (dt, 2, J - 6.2, 0.8), 3.72 (dt, 2, J - 5.9, 0.6), 3.75 (dt, 2, J - 5.8, 0.9), 3.89 (dt, 2, J - 5.4, 1.2), 7.71 (m, 2), 7.83 (m, 2). 13C NMR (CDC13): ~ 37.14, 42.70, 67.92, 70.61, 123.27, 132.06, 133.97, 168.27.
Anal. Calcd for C12H12N03Cl: C, 56-81; H, 4.77; N, 5-52- Found:
C, 56.88; H, 4.79; N, 5.49.
(b) P,., _ s of N-~2-(2-(4-(1.2-benzisothiazol-3-yl)-1-DiDera-zi~yl)ethoxv)ethyl)~hrhA1imide hydrochloride This compound was prepared by the method analogous to that used in Example 13(a). From N-(2-(2-chloroethoxy)ethyl) phrh~limilig (1.33 g, 5.2 mmol), 3-(l-piperazinyl)-1,2-b~n~i~othis7A~le (1.15 g, 5.2 mmol, 1.0 eq), triethylamine (0.94 mL, 0.0685 g, 6.8 mmol, 1.3 eq) and acetonitrile (6.0 mL) 1.17 g of the free base was obtained. Ihe hydrochloride salt was prepared and recrystallized from ethanol to give 0.87 g (35%) of N-(2-(2-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)ethoxy)ethyl) phths1imi~s hydrochloride compound as off-white crystals. mp: 199-200-C. lH NMR (DMS0-d6):
3.26-3.56 (m, B), 3.70 (t, 2, J - 5.4), 3.82 (t, 2, J - 5.4), 3.88 (m, 4), 7.48 (ddd, 1, J - 8.1, 7.0, 1.1), 7.60 (ddd, 1, J
8.1, 7.0, 1.1), 7.80 (m, 2), 7.85 (m, 2), 8.06 (dt, 1, J - 8.2, 0.9), 8.11 (dt, 1, J - 8.1, 0.9), 11.12 (br s, 1) 13C NMR
(DMSO-d6): ~ 36.93, 46.21, 51.06, 54.86, 64.35, 67.25, 121.14, 122.96, 123.88, 124.57, 126.85, 128.06, 131.46, 134.35, 152.04, 162.05, 167.82.
Anal. Calcd for C23H24N4035.HCl: C, 58.40; H, 5.33; N, 11.84.
Found: C, 58.50; H, 5.36; N, 11.81.
.
EXAMPT~ 25 (a) PreDaration of N-(4 rhloro-2-butynyl~DhthAl imi*-This compound was prepared according to the method described in Example 24(a) from potassium phthslimi*e (Aldrich Chemical Company) (13.0 g, 0.0702 mol) and 1,4-dichloro-2-butyne (Aldrich Chemical Company) (25.9 g, 0.212 mol, 3.0 eq). After flush cl.~ t ~ with 4:1 hexanes/ethyl acetate as eluant, 10.64 g ~65~) of a light yellow solid was obtained. Analytically pure, colorless, diamond-like crystals formed by crysrplli7stion from a hexanes/ethyl acetate solution. mp: 112-115-C. 1H NMR (CDC13):
4.09 (t, 2, J - 2.1), 4.49 (t, 2, J - 2.1), 7.73 (m, 2), 7.87 (m, 2). C NMR (CDC13): ~ 27.22, 30.10, 77.86, 79.91, 123.58, 131.94, 134.24, 166.95.
Anal. Calcd for C12H8N02Cl: C, 61.69; H, 3.45; N, 5.99. Found: C, 61.74; H, 3.48; N, 5.95.
(b) PreDaration of N-(4-(4-(1.2 hon7i-~thi P701- 3-vl)-1-DiDera-ziD~yl)-2-butynvl)nhth~limi*~ hvdro~hloride This compound was prepared according to the method described in Example 13 (a). From N-(4-chloro-2-butynyl) I' ' -limj~- (10.64 g, 0.0455 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (9.98 g, 0.0455 mol, 1.0 eq) was obtained 14.14 g (74~) of the free amine.
The hydrochloride salt was prepared from 4.49 g of the amine to give 3.17 g of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazin-yl)-2-butynyl)phthslimi~ hydrochloride as light yellow flakes after recryst~lli7pti~n from ethanol/ether. mp: 231-233-C. 1H
NMR (DMS0-d6): ~ 3.49 (m, 6), 4.09 (m, 2), 4.23 (br s, 2), 4.54 (s, 2), 7.47 (ddd, 1, J - 8.1, 7.0, 1.0), 7.60 (ddd, 1, J - 8,0, W O 93/16073 C A 2 ~ PCT/GB93/00285 7.0, 0.9), 7.90 (m, 4), 8.12 (dd, 2, J - 11.1, 8.1), 11.82 (br s, 1). 13C NMR (DMS0-d6): 6 26.90, 44.37, 46.32, 49.84, 72.01, 84.25, 121.10, 123.34, 123.97, 124.55, 126.88, 128.06, 131.33, 134.72, 152.04, 162.09, 166.65.
Anal. Calcd for C23H20N402S.HCl: C, 60.99; H, 4.67; N, 12.37.
Found: C, 60.82; H, 4.72; N, 12.27.
(a) PreDaration of (E)-N-(4-bromo-2-butenyl)PhthA1imiao This compound was prepared by a method analogous to that described in Example 24(a). Potassium r~t~limi~e (Aldrich Chemical Company) (8.35 g, 0.0451 mol), trans-1,4-dibromo-2-but-ene (Aldrich Chemical Company) (24.1 g, 0.1127 mol, 2.5 eq) and dimethyl- ~o (400.0 mL) were heated under N2 at 125-C for 3.5 h. The DMF was removed with a rotary e~., . and the crude product was purlfied by flash ~ with 4:1 hexanes/ethyl acetate as eluant to give 3.25 g (26~) of (E)-N-(4-bromo-2-butenyl) rhrhslimi~O An analytically pure sample was obtained by recrystsll17sti~ from ether to give white crystals. mp: 97-99'C. lH NMR (CDC13): 8 3.89 (d, 2, J - 6.4), 4.29 (d, 2, J - 5.1), 5.87 (m, 2), 7.72 (m, 2), 7.84 (m, 2). 13C
NMR (CDC13): ~ 31.27, 38.62, 123.40, 128.36, 129.96, 132.04, 134.09, 167.77.
Anal. Calcd for C12HlON02Br: C, 51-58, H, 3-61; N, 5.01. Found:
C, 51.53; H, 3.60; N, 5.02.
(b) PreDaration of (E)-N-(4-(4-(1.2-benzisothiazol-3-vl)-1-DiDera-zinvl)-2-butenyl)~hthnlimi~o hvdrochloride This compound was prepared according to the procedure described in Example 13(a). From (E)-N-(4-bromo-2-butenyl)phtslimi~o (8.45 W O 93/16073 C A ~ i 1 7 4 3 4 PCr/GB93/00285 g, 0.0302 mol) ant 3~ piperazinyl)1,2-bon7iFothip7ole (6.61 g, 0.0302 mol, 1.0 eq), 14.31 g of a tark orange solid was obtained.
The crude material was purified by flush CLL~ with 1:1 hex-nes/ethyl acetate as eluant to give 7.48 g of the free amine.
The hydrochlorite salt was preparet and recrystallized from 95 ethanol to give 1.99 g of (E)-N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)-2-butenyl)~ 1 imi~- hydrochlorite as a tan po~der. mp: 243-244-C. lH NMR (DMS0-d6): ~ 3.20 (m, 2), 3.45 (m, 4), 3.80 (br s, 2), 4.04 (br d, 2, J - 12.6), 4.24 (d, 2, J -4.8), 5.83 (dt, 1, J - 15.6, 6.8), 6.04 (dt, 1, J - 15.6, S.l), 7.42 (t, 1, J - 7.8), 7.56 (t, 1, J - 7.3), 7.85 (m, 4), 8.08 (dd, 2, J - 7.4, 6.4), 11.72 (br s, 1). 13C NMR (DMS0-d6): 6 38.50, 46.29, 49.80, 56.06, 120.96, 121.09, 123.12, 123.96, 124.53, 126.88, 128.03, 131.50, 134.45, 152.03, 162.12, 167.39.
Anal. Calcd for C23H20N402S.HCl: C, 60.72; H, S.10; N, 12.31.
Found: C, 60.62; H, 5.15; N, 12.25.
Fl~AMP! F. 27 (a) PreDaration of (z)-N-(4-rhloro-2-bute~yl)DhrhAllmi~
This compound was obtained according to the method described for Example 24(a) from I ~ ~ p~thDl imi~' (Aldrich Chemical Company) (13.0 g, 0.0702 mol), and cis-1,4-dichloro-2-butene (26.3 g, 0.211 mol, 3.0 eq). The crude product was purified by flush ~ with 4:1 hexanes/ethyl acetate as eluant to give 12.87 g (78.) of (Z)-N-(4-chloro-2-butenyl) ~ limi~ as a light yellow solid. The product was i~-~t~fipd to be a 90:10 mixture of (Z) and (E) isomers as ~-tDrmi ' by 13C NMR mp:
63-66-C. lH NMR (CDC13): ~ 4.32 (dd, 2, J - 7.7, 0.9), 4.35 (dd, 2, J - 7.4, 1.2), 5.70 (tm, 1, J - 10.6), 5.84 (dm, 1, J - 10.6), 7.72 (m, 2), 7.84 (m, 2). 13C signals observed for the trans-isomer are given in PdL~ ' ~~~~. 3C NMR (CDC13): ~ 34.03, 38.60, (43.48), (58.30), (119.62), 123.34, (123.52), (127.09), 127.15, 132.05, 134.06 (134.20), (135.27), 167.73.
(b) PreDaration of tz)-N-(4-(4-(l~2-h~n7isothiazol-3-yl)-l-Diper zin~Yl)-2-butenyl)~hthAlimi~ hytrochloride hvdrate This compound was prepared according to the method described in Example 13(a). From a 90:10 mixture of (Z)-and (E)-N-(4-chloro-2-butenyl)phtAlimi~ (9.86 g, 0.0418 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (9.17 g, 0.0418 mol, 1.0 eq) was obtained 18.93 g of a dark orange viscous oil. The crude material was purified by flush .1.~ with 1:1 hexanes/ethyl acetate as eluant to give 14.35 g (82~) of an orange oil which solidified upon standing. A portion of this material (8.44 g) was recrystallized from ethyl acetate to give 4.92 g of light yellow crystals. This recrystDlli7Ati~n increased the isomer ratio from approximately 90:10 to 97:3, Z:E. The hydrochloride salt was prepared and recrystallized twice from 95~ ethanol to give 1.34 g (7 ~) of (Z)-N-(4-(4-(1,2-' 'sothiA~nl-3-yl)-1-piperazinyl)-2-butenyl)pht~limi~ hydrochloride hydrate (100~ Z isomer) as light yellow crystals. mp: 247-249-C. H NMR (DHSO-d6): ~ 3.52 (m, 4), 4.13 (m, 4), 4.39 (d, 2, J - 5.6), 5.87 (m, 2), 7.49 (ddd, 1, J - 8.1, 7.0, 1.0), 7.61 (ddd, 1, J - 8.1, 7.0, 1.0), 7.88 (m, 4), 8.14 (dd, 2, J - 11.1, 8.1). 13C NHR (~HS0-d6):
34.59, 46.38, 50.03, 51.87, 121.16, 121.29, 123.06, 123.95, 124.59, 126.92, 128.08, 131.60, 132.85, 134.42, 152.07, 162.10, 167.46.
Anal. Calcd for C23H22N402S.HClØ25 H20: C, 60.12; H, 5.15; N, 12.19 H20, 0.98. Found: C, 59.73; H, 5.17; N, 12.11; H20, 0.61.
W O 93/16073 C ~ 2 i 1 7 4 3 4 PCT/GB93/0028~
(a) P~ 'nn of 2-(2-hvdroxyeth~1)-1.2-benzisothi~7~1-3-(2H)-one 2,2'-Dithiobisbenzoyl chloride (20.0 g, 0.0583 mol) (Yevich, J.P., et. al. J. Med. Chem. 1986, 29, 359-369), and A~t~hlt ' (50.0 mL) was added to a 150-mL beaker. Chlorine ges was bubbled through this cloudy solution with stirring, giving a rust colored mixture. To a separate flask was added a solution of ethanol amine (7.12 g, 0.112 mol, 2.1 eq), triethylamine (16.3 mL, 11.8 g, 0.117 mol, 2.1 eq) and dichl~-~ r~ (50.0 mL). This mixture was cooled in an ice-water bath. The bis-chloride solution was slowly added to the cooled amino-alcohol solution with stirring. The resulting orange mixture was washed with distilled water and the organics were ~ r ' ~ dried over ~gSC4, filtered, and c- -~ A with a rotary e... ~ to give 22.74 g of a crude orange oil. H
~R of thLs material was consistent with 2-(2-hydroxyethyl)-1,2--ol-3(2H)-one ~nd was used without further purifica-tion.
(b) PrtnAe~tiA~ of 2-~2-chloroethyl)-l~2-benzisoth1~ l-3(2H)-one Crude 2-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one (22.74 g, 0.116 mol), was taken up in toluene (100.0 mL). The solution was cooled in an ice-water bath and thionyl chloride (9.61 mol, 15.68 g, 0.132 mol, 1.13 eq) was added dropwise over a 15 min period.
The cold bath was removed and the reaction mixture was allowed to stir at room r , e for 2 h. The toluene and excess thionyl chloride were removed by distillation under reduced pressure through an inverted Hopkins condenser. The red-orange residue was purified by flash cl..~ ~ t7, ,' ~ with 1:1 hexanes/ethyl acetate as eluant to g.ve 10.24 e (41~, based on 2,2'-dithiobis-benzoyl chloride) of 2-(2-chloroethyl)-1,2-benzisothiazol-3(2H)-one as an orange oil which solidified upon standing. mp:
CA 2 i 1 7434 73-78-C. 1 C NHR (CDC13): ~ 42.11, 45.90, 120.31, 125.68, 126.80, 132.18, 140.65, 165.67.
(c) PreDaration of 2-(2-(4-(l~2-h~n7icAthiazol-3-yl)-l-Dipera zinyl~ethyl)-1.2-h~n~i~AthiA~~1-3(2U)-one hYdrochloride This compound was prepared by a method analogous to that descri-bed in Example 13(a). From 2-(2-chloroethyl)-1,2-benzisothiazol-3(2H)-one (3.54 g, 0.0165 mol), and 3-(1-piperazinyl)-1,2-benzi-sothiazole (4.00 g, 0.0182 mol, 1.1 eq) was obtained 6.94 g of crude product. This material was purified by flash cl.~ with 1:1 hexanes/ethyl acetate 85 eluant to give 4.00 g of the free amine. The hydrochloride salt was prepared and recrystallized from 95~ ethanol to give 1.76 g (25~) oi 2-(2-(4-(1,2-~ '~othiD7~1-3-yl)-l-piperazinyl)ethyl)-1,2-benzi-sothiazol-3(2H~-one hydrochloride as a white crystalline solid.
mp: 250-252-C. lH NHR (DHS0-d6): ~ 3.46 (m, 6), 3.76 (br d, 2, J
- 10.2), 4.10 (br d, 2, J - 12.3), 4.36 (br t, 2, J - 5.9), 7.47 (tt, 2, J - 7.1, 1.1), 7.59 (t, 1, J - 7.2), 7.72 (dt, 1, J
8.3, 1.2), 7.91 (dd, 1, J - 7.9, 0.5), 8.11 (m, 3), 11.34 (br s, 1). C NHR (DHS0-d6): ~ 37.78, 46.28, 50.82, 53.73, 121.07, 122.09, 123.59, 123.96, 124.51, 125.53, 125.59, 126.85, 128.02, 132.00, 140.96, 152.02, 162.02, 164.90.
Anal. Calcd for C20H20N4052.HCl: C, 55.48; H, 4.89; N, 12.94.
Found: C, 55.53; H, 4.92; N, 12.89.
EXAHPT~ 29 (a) E.. ~ ~n of 2-(3-(4-(l~2-b~ othio7A~l-3-yl)-l-DiDera-7inyl~DroDyl)-1,2-benzisothiazol-3(2H)-one hvdrochloride This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(3-chloropropyl)-1,2-benzisothiazol-3(2H)-one (5.29 g, 0.0232 mol), and 3-(1-piperazinyl)-1,2-benzi-sothiazole (5.09 g, 0.0232 mol, 1.0 eq) was obtained 4.40 g ofthe c~.L~ ,,dLng product after flash cl..~ O~ with ethyl acetate as eluant. The hydrochloride salt was prepsred and recrystallized from 95i ethanol to give 3.45 g (32~) of 2-(3-(4-(l,2-bon7ieothiD7~l-3-yl)-l-piperazinyl)propyl)-l~2-benzisothia ol-3(2H)-one hydrochlorite as an off-white powder. mp:
185-187-C. lH NMR (DMSO-d6): ~ 2.19 (m, 2), 3.28 (m, 4), 3.55 (m, 4), 4.00 (m, 4), 7.44 (tt, 2, J - 7.5, 1.0), 7.57 (ddd, 1, J
- 8.3, 6.8, 1.0), 7.69 (ddd, 1, J - 8.5, 7.3, 1.2), 7.87 (dq, 1, J - 7.2, 0.8), 8.01 (dt, 1, J - 8.3, 0.8), 8,09 (m, 2). C NKR
(DMSO-d6): ~ 23.55, 40.48, 46.28, 50.49, 52.93, 121.08, 121.94, 123.90, 123.90, 124.51, 125.45, 125.52, 126.85, 128.02, 131.79, 140.51, 152.01, 162.07, 164.48.
AD~1~ Calcd for C21H22N4~52-1-5 HCl C, 54.21; H, S.09 N, 12.04 Found: C, 54.48; H, 5.46; N, 11.93.
FYA''~! F 30 P~ sn of 2-(4-(4-(1.2 ,~thi97~1-3.yl)-l-Di nyl)-butvl)-1.2-hon7ie~thiP7~1-3(2U)-one hvdrArhlnride This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(4-chlorobutyl)-1,2-benzLsothiazole-3(2H)-one (6.61 g, 0.0273 mol), and 3-(l-piperazinyl)-l~2-b~n7icothi~7n1o (6.78 g, 0.0309 mol, 1.13 eq) was obtained 14.16 g of a dark orange oil. This crude material was purified by flash ~1..- ~ O .'~ with 4:1 ethyl acetate/dichlu.~ ' as eluant, followed by recryst~lli7st1~n of the free amine from 9S~ ethanol to yield 3.68 g of an off-white powder. The hydrochloride salt was prepared, recrystallized from 95~ ethanol, and dried in a vacuum oven to give 2.81 g (22~) of 2-(4-(4-(1,2 ~ eo-hi,7r,le-3-yl)-l-piperazinyl)but-yl)-1,2-b~n7ic~th~7~1e-3(2H)-one hydrochloride as an off-white powder. mp: 215-216-C. lH NMR (DMS0-d6): ~ 1.75 (br s, 4), 3.19 (m, 4), 3.49 (m, 4), 3.87 (m, 2), 4.02 (br d, 2), 7.44 (dddd, 2, J - 1.1, 2.8, 7.0, 8.2), 7.57 (ddd, 1, J - 1.1, 7.0, 8.0), 7.68 (ddd, 1, J
1.3, 7.1, 8.4), 7.86 (dq, 1, J - 7.8, 0.7), 8.00 (dt, 1, J - 8.1, 0.9), 8.09 (m, 2), 11.15 (br s, 1). 13C NMR (DMS0-d6): ~ 20.26, 26.27, 42.34, 46.29, 50.45, 54.93, 121.12, 121.91, 123.94, 124.05, 124.55, 125.47, 125.54, 126.90, 128.06, 131.75, 140.38, 152.04, 162.16, 164.34.
Anal. Calcd for C22U24N4052.HCl: C, 57.31; H, 5.46; N, 12.15. Found:
C, 57.21; H, 5.51; N, 12.06.
Pl F 31 (a) PreDaration of 2-(4-chlorobutyl)-l(2H)-Dhthple-7jnnno Sodium hydride (2.56 g, 0.0855 mol, 1.25 eq of an 80~ 0.1 ) was placed under N2 in a 250-mL, round-bottomed flask. The sodium hydride was washed twice wi~h hexanes and the waste hexanes were reDoved. Anhydrous dimethyl~ ~o (DMF) (100.0 mL) was added. To this grey suspension a solution of 1-(2H)-~ 7i (10.0 g, 0.0684 mol) anhydrous DMF (50.0 mL) was added and the resulting solution was allowed to stir at room r . ~ for 0.5 h. This anion solution was added, via cannula, to a 500-mL, round-bottoDed flask r~t9ining a solution of l-bromo-4-chlorobutane (8.67 mL, 12.91 g, 0.0753 mol, 1.1 eq) in anhydrous DMF (100.0 mL). The reaction mixture was allowed to stir at room I , tllre for 4 h. As the reaction proceeded, the mixture became a clear orange solution. Distilled water (10.0 mL) was added and most of the solvent was removed with a rotary e~y~.~L~I. The residue was taken up in dichloromethane and washed with water (2 x 50 ml). The organics were dried over MgS04, filtered and ~ to provide 16.49 g of crude material. The product was purified by flash ~I-L~ with 2:1 hexanes/ethyl acetate as eluant to give 13.11 g of a light orange oil. H NMR indicates that the product is an 80:20 mixture of 2-(4-chlorobutyl)-l(2H)-rhth~l~7innno to its W O 93/16073 C A 2 1851 i 4 3 4 P(~r/GB93/00285 C~L~ , ''ng bromide, as determined by Ir~egr~tiAn of the triplets at 3.56 and 3.43 ppm, respectively. Difference n.O.e.
. ' indicate N-alkylated vs. O-alkylated products. The chloride-bromide mixture was used without further purification.
(b~ PreDaration of 2-(4-(4-(1.2-benzisothiazol-3-vl)-1-DiDera-z1nyl~butvl)-l(~U)-~hthsID7innn~ hydrochloride This compound was prepared according to a method analogous to that described in fxample 13(a). From 3-(1-piperazinyl)-1,2-b~n~1~othio~Ale (3.93 g, 0.0179 mol, 1.1 eq) and an 80:20 mixture of 2-(4-chlorobutyl)-1(2H)-I' ' lo71 and 2-(4-bromobutyl)-1(2H)-I' ' l07~ (4.00 g, 0.163 mol), was obtained 7.75 g of crude material which was purified by flash ~ O ,'~ with 3:1 ethyl acetate/hexanes as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 4.09 g (55~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl-1(2H)-phthoIo~inA~ hydrochloride as a white crystalline solid. mp: 252-253-C. lH NMR (DMSO-d6): ~ 1.83 (m, 4), 3.22 (m, 4), 3.61 (br q, 4, J - lO.S), 4.25 (d, 2, J
~MR (DMSO-d6): ~ 8.50, 36.51, 46.17, 49.66, 50.49, 52.88, 55.94, 121.10, 122.84, 123.34, 124.01, 124.55, 126.81, 127.71, 128.05, 131.48, 131.86, 142.24, 152.06, 162.09, 168.00.
Anal Calcd for CZlH22~405'HCl' 0-5 C2H6~
12.79. Found: C, 60.24; H, 6.08; ~, 12.55.
F~ A VpLE 2 (a) PrDnArAt1~ of 2-(3-1,Jd~ v.~.l)-l-isoirA~lir~~
This compound was prepared according to the method described for Example l(a). By employing 3-amino-1-propanol (Aldrich Chemical Company) as the amino alcohol, 2-(3~ 1,uA~.u~l)-l-isoindolin-one 1156.83 g (86.)] was obtained. lH NMR (CDC13): ~ 1.91 (quintet, 2, J - 6.2), 3.55 (br s, 2), 3.74 (t, 2, J - 6.2), 3.82 (br s, 1), 4.38 (s, 2), 7.47 (m, 3), 7.80 (m, 1). 13C ~MR
(CDC13): ~ 30.85, 38.81, 50.39, 58.37, 122.73, 123.64, 128.12, 131.45, 132.30, 141.18, 169.67.
Anal. Calcd for CllH13N02: C, 69.09; H, 6.85; ~, 7.32. Found: C, - 68.99; H, 6.86: ~, 7.28.
(b) PreDaration of 2-(3-chloroDroDvl)-l-isoindolinone This compound was prepared according to the method described for example in Example l(b). By employing 2-(3-1.~lLu~.u~yl)-l-iso-Lnolinone (127.53 g), 130.94 g (94~) of the crude chloride was obtained. A small sample (5 g) was purified by flash ch.. O .'~ with 4:1 hexanes/ethyl acetate as eluant to give 4.29 g of an analytically pure white solid. mp 56-57.5-C. H
NHR ~CDC13): ~ 2.15 (quintet, 2, J - 6.7), 3.58 (t, 2, J - 6.5).
3.74 (t, 2, J - 6.9), 4.41 (s, 2), 7.46 (m, 3), 7.81 (m, 1). 13C
NMR (CDC13): ~ 31.29, 40.17, 42.22, 50.57, 122.71, 123.63, 128.68, 131.36, 132.68, 141.11, 168.75.
(c) PreDaration of 2-(3-(4-(l.2-benzisothiazol-3-xl)-1-DiDerazinYl~-DroDYl)-l-isoindolinone hydrochloride This material was prepared according to the method described in Example l(c), by employing 2-(3-chloropropyl)-l-isoindolinone.
The hydrochloride salt was prepared and recrystallized from ethanol to give 1.58 g of the title compound as a yellow powder.
mp: 225-226-C. lH NMR (DMS0-d6): ~ 2.16 (m, 2), 3.30 (m, 8), 3.60 (m, 4), 4.05 (br d, 2, J - 12.5), 4.53 (s, 2), 7.55 (m, 6), 8.09 (dd, 2, J - 8.0, 3.9), io.70 (br s, 1.5). 13C NMR (CDC13):
~ 23.06, 39.37, 46.58, 50.08, 51.00, 55.09, 120.77, 123.15, 123.22, 123.54, 124.53, 127.26, 128.03, 128.10, 131.76, 131.92, 141.40, 152.95, 161.47, 169.37.
Anal- Calcd for C22H24N405.1.5 HCl: C, 59.09; H, 5.75; N, 12.53.
Found: C, 59.06; H, 6.10; N, 12.52.
FXAMPJ.F 3 (a) PreDaration of 2-(4-bromobutYl)-l-isoindolinone N-(4-Bromobutyl)phtholimi~ (Aldrich Chemical Company) (15.6 O, 0.056 mL), glacial acetic acid (100 mL), tin metal (15.83, 0.133 mol, 2.4 eq) and ~ L~bLI ~ acid (20.0 mL) was added to a 250-mL, round-bottomed flask. The resulting light yellow reaction mixture was placed under N2 and heated at reflux for 6 h. The solution W85 filtered and the tin was washed with acetic acid. Most of the acetic acid was removed with a rotary - e~O~LUL and the resulting creamy residue was taken up in dichl~.. ' and washed with water. The organics were dried over MgS04, filtered, and ~ d to give 9.37 g of a light orange oil. This material was purified by flash ~ O .'~
with 3:1 hexanes/ethyl acetate as eluant to give 0.89 g (6~) of 2-(4-brOmObUtY1)-1-;~O~ as a colorless oil. H NMR
(CDC13): ~ 1.86 (m, 4), 3.47 (t, 2, J - 6.2), 3.66 (t, 2, J
6.7), 4.39 (s, 2), 7.46 (t, 2, J - 6.4), 7.53 (m, 1), 7.84 (dd, 1, J - 6.8, 0.38). 13C NMR (CDC13): ~ 26.84, 29.64, 33.44, 41.25, 49.80, 122.70, 123.71, 128.08, 131.30, 132.75, 141.03, 179.05.
Anal. Calcd for C12H14NOBr: C, 53.75; H, 5.26; N, 5.22. Found: C, 53.81; H, 5.29; N, 5.21.
Hydrochloric acid msy be w ed instead of l.~d.~b.. ~o acid in the above method and thus results in higher yields, however, the resulting product is a chloride and bromide mixture.
(b) ~ ~n of 2-(4-~4-(1.2-benzis~~hiP7~1-3-yl)-l-DiDerazinY1) butyl)-1-isoin~~linone hydrochloride A 40:60 mixture of 2-(4-bromobutyl)-1-isoindolinone and 2-(4-chlorobutyl)-l-isoindolinone (3.69 g, 15.27 mmol) was added to a lûû-mL, round-bottomed flask. Triethylamine (2.77 mL, 2.01 g, 19.85 mmol, 1.3 eq), acetonitrile (25.0 mL) and 3-(1-piperazin-yl)-1,2-benzisothiazole (3.68 g, 16.80 mmol, 1.1 eq) were added to the chloride/bromide mixture snd the light orange reaction mixture was heated at reflux for 19 h under N2. The solution was allowed to cool and was transferred to a s , ng funnel with the aid of ethyl acetate. The organics were washed with saturated K2C03, dried over MgS04, filtered and ~u-~ L~L~d to give 7.31 g of a dark orange oil which so1i~ifi~d upon standing.
The crude solids were recrystallized from acetonitrile to give 4.38 g of free amine. The hydrochloride salt was prepared via the addition of HCl (10.8 mL, 1.0 eq of a 1 N solution in ether) to a solution of the free amine in ethanol. The salt was recrystallized from 95~ ethanol to give 3.47 g (51~) of 2-(4-(4-(1,2-~ ~ot~s7~1-3-yl)-l-piperazinyl)butyl)-l-isoindol inone hydrochloride as an off-white powder. mp: 232-233-C. lH
NMR (DMS0-d6): 6 1.77 (m, 4), 3.23 (m, 4), 3.57 (m, 6), 4.05 (br d, 2, J - 13.8), 4.52 (s, 2), 7.48 (m, 2), 7.60 (d, 3, J - 8.9), 7.69 (d, 1, J - 7.5), 8.12 (t, 2, J - 7.6), 11.32 (br s, 1). 13C
NMR (DMS0-d6): ~ 20.49, 25.05, 40.96, 46.29, 49.41, 50.43, 55.12, 121.15, 122.65, 123.30, 123.96, 124.57, 126.92, 127.74, 128.07, 131.17, 132.33, 141.84, 152.06, 162.19, 167.34.
Anal. Calcd for C23H26N40S.HCl: C, 62.36; H, 6.14; N, 12.65.
Found: C, 62.23; H, 6.16; N, 12.62.
FY~vPT.~. 4 (8) Pr~n9rAt;~n of 6-~itro-1(3~ r,.. ~;
This compound was prepsred according to the method of J.Tirouflet (Bull. Soc. Sci. Bretagne 1951, Spec. No. 26, 7-122). mp:
143-145 ~C. [lit. mp - 143-C]. H NMR (CDC13): ~ 5.44 (s, 2), 7.71 (d, 1, J - 8.4), 8.57 (dd, 1, J - 8.4, 2.0), 8.76 (d, 1, J -2.0). 13C NMR (DMSO-d6): ~ 75.57, 125.20, 130.08, 131.76, 134.02, 153.58, 158.44, 174.02.
Ansl. Calcd for C8H5NO4: C, 53.64; H, 2.81; N, 7.82. Found: C, 53.70; H, 2.85; N, 7.82.
(b) Pre~sration of 6-amino-1~3H)-isobenzofuranone This compound was prepared according to the method of J.Tirouflet (Bull. Soc. Sci. Bretagne 1951, Spec. No. 26, 7-122). mp:
C~ 2 1 i 7434 181-182-C. lH NMR (CDC13): C 3.94 (br s, 2), 5.21 (s, 2), 6,97 (dd, 1, J - 8.2, 2.3), 7.13 (d, 1, J - 2.3), 7.03 (d, 1, J
- 8.2). 13C NMR (CDC13): C 69.63, 109.79, 121.64, 122.66, 126.95, 136.36, 147.49, 171.47.
Anal. Calcd for C8H7N02: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.48; H, 4.73; N, 9.38.
(c) Prevaration of 6-chloro-1(3H~-icA~ -r~L~.,ull~
Distilled water (2.0 mL), conc. HCl (4.0 mL), and 6-amino-1(3H)-i~ub..~uCuL~.lu.._ (1.37 g, 9.18 mmol) were placed in a round-bottomed flask equipped with a magnetic stirring bar. The resulting white slurry was cooled in an ice-water bath and a solution of sodium nitrite (0.70 g) in distilled water (1.5 mL) was added dropwise. The reaction mixture was allowed to stir at 0-C for 20 min and a solution of copper (II) chloride hydrate (3.13 g, 18.36 mmol, 2.0 eq) in distilled water (2.0 mL) was added dropwise. The resulting bright green solution was allowed to stir at O-C for 1 h. The mixture was heated on a steam bath for 10 min inducing solids to form. Ethyl acetate was added to dissolve the solids and the layers were separated. The ~reen aqueous layer was extracted with ethyl acetate. The organics were combined, dried over MgS04, filtered, and c--~ d to give 1.35 g of a tan solid. This crude material was recrystallized from ethanol and dried in a vacuum oven to give 0.83 g (54~) of 6-chloro-1(3H)-i L ~ ~ as a light yellow powder. mp: 107-108-C. H NMR (CDC13): C 5.29 (s, 2), 7.44 (dd, 1, J - 8.2, 0.68), 7.64 (dd, 1, J - 8.2, 1.8), 7.86 (d, 1, J
1.8). C NMR (CDC13): C 69.50, 123.48, 125.69, 127.58, 134.87, 135.39, 144.63, 169.65.
Anal. Calcd for C8H502Cl: C, 57.00; H, 2.99. Found: C, 57.16; H, 3.03.
(d) Pret~aration of 6-chloro-2-(2-hvdroxvethyl)-1-isoindolinone 6-Chloro-1(3H)-i~ob~ r~ (9.15 g, 0.0543 mol), ethanol amine (Aldrich Chemical Company) (3.32 8. 1.0 eq) and toluene (10.0 mL) was added to a 100-mL, round-bottomed flask equipped with a magnetic stirring bar and a 10-mL Dean-Stark trap. The solution was heated with an oil bath. The toluene which was collected in the Dean-Stark trap was not allowed to return to the reaction pot. The resulting orange melt was heated at 210-C for 22 h. Upon cooling, the material solidified to give 11.75 g of a brown solid. The crude material was used without further purifi-~eti~n (e) PreDaration of 6-chloro-2-(2-chloroethyl~-1-isoindolinone This compound was prepared by a method analogous to that describet in Example l(b). Employing 6-chloro-2-(2-hydroxyeth-yl)-l-isoindolinone (11.75 g), as prepared above, gave 10.03 g of the target compound as a light yellow powder (80~ yield based on 6-chloro-1(3H)-icv~ -.--,r~ ). mp: 112-114-C. H NMR
(CDC13): C 3.79 (t, 2, J - 5.8), 3.94 (t, 2, J - 5.8), 4.55 (s, 2), 7.38 (d, 1, J - 8.1), 7.50 (dd, 1, J - 8.1, 1.8), 7.80 (d, 1, J - 2.1). 1 C N~R (CDC13): C 42.64, 44.82, 51.22, 123.91, 124.02, 131.76, 134.02, 134.43, 139.51, 167.52.
Anal. Calcd for CloHgNOC12 C, 52.20; H, 3.94; N, 6.09. Found: C, 52.30; H, 3.96; N, 6.03.
(f) Preoaration of 2-(2-(4-(12.-benzisothiazol-3-vl~-1-Dioerazinvl)-ethYl)-6-chloro-1-isoindolinone hYdrochloride This compound was prepared according to the method described in Example l(c). The crude product was purified by flash .1... ~ O ,'~ with ethyl acetate as eluant. The free amine was treated with 1 N HCl in ether and the resulting hydrochloride C ~ 2 i 1 7 ~ 3 ~
salt was triturated with 95~ ethanol to give 3.78 ~ of an off-white powder. mp: 272-275-C (dec). H NMR (DMS0-d6):
3.24-3.62 (m, 6), 3.71 (br d, 2, J - 10.8), 4.03 (m, 4), 4.60 (s, 2), 7.44 (dt, 1, J - 8.0, 1.0), 7.58 (dt, 1, J - 7.0, 1.0), 7.69 (m, 3), 8.11 (t, 2, J - 8.9), 11.08 (br s, 1). 13C NMR
(DMS0-d6): ~ 36.53, 46.09, 49.39, 50.47, 52.83, 121.07, 122.49, 123.96, 124.51, 125.30, 126.85, 128.02, 131.34, 132.60, 133.90, 140.93, 152.01, 162.01, 166.73.
Anal. Calcd for C2lH21N405Cl.HCl: C, 56.13; H, 4.93; N, 12-47-Found: C, 56.22; H, 4.95; N, 12.40.
(a) Pre~aration of 6-chloro-2-~4-chlorobutyl~-1-isoindolinone This compound was prepared by the method analogo w to that used in Example l(b). The starting material, 6-(Chloro-2-(4-hydroxy-butyl))-l-$~o$n~~l$n~, was obtained by following the procedure outlined in Example 4(d). The crude material obtained in this reaction was purified by flash ~IIL~ rAp~y to give 5.42 g (39 based on 6-chloro-1(3H)-i~ ~ r ) of an orange solid.
mp: 71-72'C. lH NMR (CDC13): ~ 1.83 (m, 4), 3.59 (t, 2, J
5.9), 3.65 (t, 2, J - 6.6), 4.36 (s, 2), 7.37 (d, l, J - 8.1), 7.49 (dd, l, J - 8.1, l.9), 7.79 (d, 1, J - 1.9). 13C NMR
(CDCl3): ~ 25.52, 29.49, 41.53, 44.49, 49.44, 123.84, 123.96, 131.44, 134.36, 134.52, 139.10, 167.28.
Anal- Calcd for Cl2Hl3NOC12: C, 55-83; H, 5-08; N, 5.43. Found:
C, 55.90; H, 5.12; N, 5.38.
W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~ - 52 -(b) Preoaration of 2-(4-~4~ 2-benzisothis7nl-3-yl~-l-Dinerazinyl) butyl)-6-chloro-1-iso~AAAlinAns hydrschloride hydrate This compound was prepared using the procedure described in Example l(c). From 6-chloro-2-(4-chlorobutyl)-1-isoindolinone (5.02 g, 19.4 mmol), a crude orange solid was obtained which was purified by recrysts~ st~An. The hydrochloride salt formed by treatment of the free base with 1 N HCl in ether was triturated vith hot ethanol and dried in a vacuum oven to give 4.84 g (51~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-6-ch-loro-l-isoinAAlir~A- hydrochloride hydrate as a tan powder. mp:
241-242-C. lH NMR (DMS0-d6): ~ 1.71 (br s, 4), 3.20 (m, 4), 3.35 (m, 6), 4.02 (br d, 2, J - 13.1), 4.50 (s, 2), 7.45 (m, 1), 7.53 (m, 1), 7.65 (m, 3), 8.10 (dd, 2, J - 8.0, 4.5), 11.14 (br s, 1).
13C NMR (DMS0-d6): ~ 20.46, 24.93, 41.11, 46.31, 49.22, 50.45, 55.10, 121.14, 122.35, 123.94, 124.56, 125.31, 126.90, 128.06, 131.11, 132.66, 134.33, 140.56, 152.04, 162.16, 166.02.
Anal. Calcd for C23H25N405Cl:0.4 H2O: C, 57.00; H, 5.57; N, 11.56; H20, 1.49. Found: C, 56.62; H, 5.65; N, 11.31; H2O, 1.34.
~PT~ 6 (a) p,~ of 2-(5-~hlAropentvl)-l-isoindolinone gAA
2 (5 ~ yl)-l-i~A~ nAAl 1 nAAO
These compounds were prepared by the method described in Example 3(a). A mixture of 2-(5-chloropentyl)-1-isoindolinone and 2-(5-b.~ r yl)-l-isoindolinone 4.24g (53~) was obtained by the reduction of N-(5 b,. r ~lpth~limiAo (10.00 g, 0.0338 mol)(~ransworld Chemicals, Inc.) with tin metal (9.62 g, 0.081 mol, 2.4 eq.), acetic acid (75 mL) and conc. HCl (15.0 mL). This mixture was used directly without SorsrAtiAn of each halide.
W O 93/16073 C A ~31.1 7 4 3 4 PCT/GB93/00285 ~b) PreDaration of 2-(5-(4-(1.2-benzisothiazol-3-yl)-1-Diverazinvl)-rentY~ - isoir~nl i n~n9 hydrochloride This compound was prepared according to the procedure described in Example 3(b). From a mixture of 2-(5-chloropentyl)-1-isoindo-linone and 2-(S-b~ l)-l-isoindolinone (4.24 g, 0.0178 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (4.30 g, 0.0196 mol, 1.1 eq), 2-(5-(4-(1,2-~ co-h~ol-3-yl)-1-piperazinyl)pentyl)-l-isoindolinone hydrochloride was obtained as an orange powder.
The hydrochloride salt was obtained as a tan powder (4.28 g, 53~) after recrystslli~otinn from ethanol. mp: 174-175-C. H NMR
(DMS0-d6): C 1.34 (m, 2), 1.65 (m, 2), 1.79 (m, 2), 3.20 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, ~ - 13.5), 4.47 (s, 2), 7.55 (m, 6), 8.10 (dd, 2, J - 8.0, 5.3), 11.28 (br s, 1). 13C NMR (DMSO-d6):
~ 22.58, 23.42, 27.20, 41.16, 46.29, 50.37, 55.28, 121.14, 122.59, 123.28, 123.95, 124.56, 126.91, 127.72, 128.06, 131.10, 132.38, 141.76, 150.05, 162.18, 167.20.
Anal. Calcd for C24H28N40S.HCl: C, 63.07; H, 6.40; N, 12 26.
Found: C, 63.10; H, 6.39; N, 12.22.
T~MPT.T~' 7 (a) Preraration of 2-(6-rhlnrnhon7yl)-l-iso~ n~nD and 2-(6-bromohexyl)-l i5Oindol in~s These compounds were prepared according to the method described in Example 3(a). A 50:50 mixture of 2-(6-chloroben_yl)-1-isoin-dolinone and 2-(6-bromohexyl)-1-isoindolinone was obtained by the reduction of N-(6-bromohexyl)-phthslimi~D (Transworld Chemicals Inc.). This material vas used as a mixture of halides.
CA2i 1 7434 (b) PreDaration of 2-(6-~4-(l~2-benzisorhi~7nl-3-yl)-l-DiDerazinyl) hex~yl)-l-isoindol in~n~ hydrnrhl nride This compound was prepsred following the procedure described in Lxample 3(b). Ihe crude product was purified by flash cl... v ~ with ethyl acetate/0.1~ triethylamine as eluant to give 4.65 g of a light yellow solid. The hydrochloride salt was formed by treatment with 1 N HCl in ether to give 4.18 g (61~) of 2-(6-(4-(1,2-ber.zisothiazol-3-yl)-1-piperazinyl)hexyl)-1-isoindo-linone hydrochloride as an off-white powder. mp: 263-264-C. lH
NMa (DNS0-d6): ~ 1.35 (m, 4), 1.64 (t, 2, J - 6.9), 1.75 (m, 2), 3.25 (m, 4), 3.50 (m, 2), 3.54 (t, 2, J - 7.0), 4.05 (m, 2), 4.49 (s, 2), 7.48 (m, 2), 7.60 (m, 3), 7.67 (br d, 1, J - 7.5), 8.12 (t, 2, J - 7.2), 10.99 (br s, 1). 13C NNR (DNSO-d6): ~ 25.78, 27.46, 41.27, 49.23, 122.58, 123.027, 123.95, 124.49, 127.72, 128.01, 131.08, 141.72, 152.02.
Anal- Calcd for C25H30N405.HCl: C, 63.74; H, 6.63; N, 11.89.
Found: C, 63.81; H, 6.65; N, 11.84.
FY~MPJ.F 8 (a) PreDaration of methYl 2-bromomethvl benzoate by using the method of W. Davies and ~. H. Perkin (J. Chem. Soc.
1922, 121, 2202), 2-bromomethyl benzoyl bromide was obtained by b~ ~nrinn of o-toluoyl chloride. The 2-b.. Lhyl benzoyl bromide (0.184 mol) was taken up in dichlu-~ thnn~ (40 mL) and the solution was cooled in an ice-water bath. Absolute methanol (15 mL) was added and the reaction mixture was allowed to warm to room L . ~ ~ and stir for 0.5 h. The solution was washed with saturated ~2C03 and extracted with ethyl acetate. The organics were dried over NgS04, filtered, and c~ with a rotary ~ L to give 42.08 g of a pale yellow oil. This material was used without further p~rifi~otinn H NMR (CDC13):
~ 3.94 (s, 3), 4.96 (s, 2), 7.40 (m, 3), 7.97 (m, 1).
b) PreDaration of 3-(4-(2-(2-aminoethoxy)ethvl~ DiDerazinvl)-1.2-bPn7i e~th; 07~le N-(2-(2-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)ethoxy)ethyl)-pht~limi~o (7.45 g, 0.017 mol), as prepared in Cxample 24, was placed in a 100-mL, round-bottomed flask and taken up in methanol (20.0 mL). To this stirred solution was added hydrazine hydrate (1.49 g of an 85~ solution in water, 0.025 mol, 1.5 eq) dropwise and the mixrure was heated at reflux under N2 for 2 h. The reaction mixture was allowed to cool to room t, . _~L~.~ and 1 N
NCl (50.0 mL) was added. The resulting precipitant was filtered and washed with distilled water. The filtraee was made basic by the addition of 50~ NaOH and extracted with dichl~-- th- . The organics were dried over MgSO4, filtered, and ' with a rotary c.., ~ I to give 5.31 g of 3-(4-(2-(2- ~ Ll.~)eth-yl)-l-piperazinyl)-1,2-~ ~othl07ole as a viscous orange oil.
This crude material was used without further pur~4icotion (c) P-~_ _~ of 2-(2-(2-(4-(1.2-ho"7i~nrhiO~nl-3-yl~-l-D~n~ro~invl)ethoxv~ethyl) -l-i~nirA~lin~r~
A solution of toluene (100 mL) and 3-(4-(2-( -~ethn~y)ethyl)-l-piperazinyl)-1,2-' ~othio7nl~ (5.31 g, 0.017 mol) was heated in an oil bath at 100-110-C. A solution of methyl 2-b., Ll.~l benzoate (3.97 g, 0.017 mL, 1.0 eq) and toluene (25 mL) was added to the amine solution dropwise, over a 15-20 min period. The reaction mixture was heated under N2 for 0.75 h after the addition was complete. The solution was allowed to cool to room t . - ~ and washed with saturated R2CO3. The organics were dried over MgSO4, filtered, and c~ .-LL~L~d to give 6.22 g of a red-orange oil. This crude material was purified by flash with ethyl acetate/0.2~ triethylamine as eluant, W O 93/16073 - 56 - P~r/GB93/0028~
followed by recrystsll;7~t;~n from an ethyl acetate/ethanol solution to give 0.95 g of a tan solid. lH NMR indicated a small amount of ethyl acetate present in the sample. mp: 108-llO-C.
lH NMR (CDC13): ~ 2.69 (m. 6), 3.49 (br t, 4, J - 5.0), 3.66 (t, 2, J - 5.6), 3.74 (dt, 2, J - 1.0, 5.2), 3.82 (br t, 2, J - 4.73, 4.57 (s, 2), 7.34 (ddd, 1, J - 8.2, 7.0, 1.1), 7.47 (m, 4), 7.82 (m, 3). 13C NMR (CDC13): ~ 42.36, 49.80, 51.55, 53.28, 57.82, 68.59, 69.77, 120.53, 122.63, 123.57, 123.85, 127.50, 127.87, 127.97, 131.23, 132.71, 141.64, 152.73, 163.74, 168.55.
Anal. CalCd for C23H26N4~25 ~ l5 C4H8~2 12.86. Found: C, 64.74; H, 6.33; N, 12.76.
EXAMpLF 9 (a) PreDaration of tron~-2-~4-hYdroxy-l-cYclohexyl)-l-isoindolinone ~ethyl 2-b~ LL~l benzoate (30.00 g, 0.131 mol) (Example 8(a)), trans-4-amino cyclohexanol hydrochloride (Aldrich Chemical Company) (20.85 g, 0.137 mol, 1.05 eq), F-: ~ carbonate (27.15 g, 0.196 mol, 1.5 eq), toluene (110 mL) and water (20 mL) were added to a 500-mL, ,~ ' b~, ' flask equipped with a magnetic stirring bar and a Dean-Stark trap. The two-phase mixture was heated at reflux for 19 h. The toluene-water azeotrope was collected and the water was not allowed to re-enter the reaction pot. Fresh toluene (300 mL) was added and ehe tnl '' 1 azeotrope was removed through the Dean-Stark trap. After an additional 24 h of heating, the solution was decanted from the salts into a clean round-bottomed flask. The solvent was removed with a rotary ~ L~L~L to give 25.16 g of a viscous orange oil. This crude material was purified by flash CLL~ J with ethyl acetate/0.1~ triethyl amine as eluant to give 11.88 g (39'L) of trans-2-(4-hydroxy-1-cyclohexyl)-1-iso-indolinone as an off-white solid. mp: 133-134-C. lH NMR (CDC13):
~ 156 (m, 4), 1.41 (m, 3), 2.11 (m, 2), 3.66 (m, 1), 4.26 (tt, 1, W O 93/16073 C A ' I 7 4 3 PCT/GB93/00285 J - 11.5, 3.9), 4.32 (s, 2), 7~47 (m, 3), 7.84 (dd, 1, J - 7.7, 1.6). 13C NMR (CDC13): i~ 29.02, 34.46, 46.04, 49.67, 69.90, 122.68, 123.60, 128.01, 131.12, 133.12, 141.12, 165.11.
Anal. Calcd for C14N17N02: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.63; H, 7.41; N, 6.04.
(b) PreDaration of ~ -4~ oxo-2-isoin~~linvl)-1-cvclohexyl 1 fr~nLt-~
-2-(4-hydroxy-1-cyclohexyl)-1-isoindolinone (3.94 g, 0.017 mol) was taken up in anhydrous dichlu-~ t~-n~ (150 mL) and triethylamine (13.56 mL, 2.59 g, 0.025 mol, 1.5 eq) was added.
The orange solution w-s placet unter N2 ant cooled in an ice-water bath. To this stirred solution was slowly added a mixture of mesyl chloride (Aldrich Chemical Company) (1.98 mL, 2.93 g, 0.025 mol, 1.5 eq) in anhydrous dichlu~ (3.0 mL).
The reaction mixture was allowed to stir at 0-5-C for 1.25 h. An -'''t1r 1 portion of dichl~.- ' was added and the solution was washed with saturated R2C03. The layers were separated and the aqueous phase was extracted with dichloromethane. The organics were combined, dried over MgS04, filtered, and c d with a rotary e.., .~Lui to give 5.40 g of trans-4~ oxo-2-isoidolinyl)-1-cyclohexyl mei- lf~n~r~ as an orange solid. This crude material was used without further I fi~ti~n (c) Pre~aration of (+/-~-cis-2-(4-(4-(1.2-h~n7i~~th;o~~l-3-vl~-l-~in~r~7;nvl)-l-cyclohexyl)-l-isoindolinone hvdrochloride ~l~d~l~Le Trans-4-(oxo-2-isoindolinyl)-1-cyclohexyl mei' lfnn~t~ (5.27 g, 0.017 mL), 3-(1-piperazinyl)-1,2-benzisothiazole (3.92 g, 0.079 mol, 1.05 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq), triethylamine (2.85 mL, 2.07 g, 0.020 mol, 1.2 eq) and - ' CA2i 1 7434 acetonitrile (20 mL) were combined, placed under N2 and heated at reflux for 2.5 d. The mixture was allowed to cool to room I . e and washed with saturated K2C03. The organics were dried over HgS04, filtered and c----- .ar.~ with a rotary e~., . to give 8.29 g of a viscous orange oil. This crude material was purified by flash ~1.-. g ,'~ with ethyl acetate as eluant. The material isolated was purified further by flash cl..~ with 2:1 ethyl acetate/hexanes as eluant yielding 0.224 g of a sticlcy orange oil. The hydrochloride salt of this free base was formed, recrystallized from ethanol, and dried in a vacuum oven to give 0.120 g (24, based on trans-2-(4-hydroxy-1-cyclohexyl)-l-isoindolinone) of (+/-)-c s-2-(4-(4-(1,2-benzisoth-iazol-3-yl)-1-piperazinyl)-1-cyclohexyl)-1-isoindolinone hydro-chloride '~dLa~ as light peach crystals. mp: 231-232-C. lH
NHR (DMS0-d6): 8 1.72 (m, 2), 1.95 (m, 2), 2.20 (m, 2), 2.35 (m, 2), 3,33 (m, 2), 3.45 (m, 1), 3.77 (br d, 2, J - 13.4), 3.85 (br d, 2, J - 12.2), 4.05 (br d, 2, J - 13.4), 4.20 (quintet, 1, J
3.7), 4.74 (s, 2), 7.46 (m, 2), 7.58 (m, 3), 7.67 (d, 1, J
7.3), 8.11 (dd, 2, J - 8.0, 4.7), 10.80 (br s, l). 13C NMR
(DHS0-d6): ~ 23.37, 25.25, 45.96, 47.95, 48.75, 62.03, 121.17, 122.51, 123.15, 123.91, 124.56, 126.93, 127.69, 128.07, 131.13, 132.37, 142.06, 152.09, 162.15, 167.08.
Anal. Calcd for C25H28N405.HCl.H20: C, 61.65; H, 6.41; N, 11.50;
H20, 3.69. Found: C, 61.65; H, 6.45; N, 11.46; H20, 3.97.
FXAMPF.F~ 10 (a) PreDaration of 3-(4-(4-amino-2-butvnyl)-1-DiDerazinvl)-1.2-ho~ rhi 07nle This compound was prepared according to the method described for Example 8(b). From N-(4-(4-(1,2-benzisothiazol-3-yl)-l-pipera-zinyl)-2-butynyl)pbt~olimiA~, Example 25, (12.54 g, 0.630 mol), hydrazine hydrate (2.66 g of an 85% aqueous solution) and W O 93/16073 C A 2 i 1 ~ 4 3 4 P(~r/GB93/0028S
methanol (30 mL), 6.23 g (72.3%) of 3-(4-(4-amino-2-butynyl)-1-piperazinyl)-1,2-b~n7i~othio~ole was obtained as a crude orange oil. This material w-s used without further purification.
(b) PreDaration of 2-(4-(4-(1.2-hon~i~~thiazol-3-yl)-l-siserazinvl) 2-butvnvl)-1-isoindoli hydrochloride Tke crude amine, as prepared in lO(a) above, (6.23 g, 0.022 mol) was taken up in toluene (50 mL). To the stirred mixture was added a solution of methyl 2-bromomethyl benzoate (Example 8(a)), The resulting orange solution was heated at reflux under N2 for 18 h. The reaction mixture was allowed to cool to room ~ . ~ e and L.~.~re...d to a ~ funnel. The solution was washed with saturated ~2CO3, dried over ~gS04, filtered and r ~ .t . _t. A to give an orange oil. This crude material was purified by flash cl..~ on flash silica gel with 3:1 ethyl acetate/hexanes as eluant. The hydrochloride salt of the pure free base was prepared by the addition of 1 N HCl. The salt was recrystallized from ethanol/ethyl acetate and dried in a vacuum oven to give 0.24 g (3%) of 2-(4-(4-(1,2-b-n7i~othio-~1-3-yl)-l-piperazinyl)-2-butynyl)-1-isoi~A~li hydrochloride as an off-white powder, mp: 194-196-C. lH NMR (DHS0-d6): ~ 3.40 (m, 3), 3.51 (m, 3), 4.08 (m, 2), 4.22 (br s, 2), 4.59 (s, 2), 4.61 (s, 2), 7.48 (m, 2), 7.58 (m, 1), 7.63 (m, 2), 7.71 (dt, 1, J - 7.5, 1.0), 8.10 (dt, 1, J - 8.2, 0.9), 8.14 (dt, 1, J - 8.2, 0.9), 12.00 (s, 1).
C NMR (DMS0-d6): ~ 31.32, 44.53, 49.05, 49.85, 73.23, 84.95, 121.13, 122.91, 123.54, 123.98, 124.56, 126.91, 127.96, 128.07, 131.42, 131.70, 141.76, 152.03, 162.15, 166.80.
Anal. Calcd for C23H22N405: C, 62.93; H, 5.28; N, 12.76. Found:
C, 62.79; H, 5.31; N, 12.70.
.
CA2 l 17434 (a) PreDaration of l-isoindol~n~n~
phrho1imi~ (Aldrich Chemical Company ) (30.0 g, 0.204 mol) was placed in a 500-mL, round-bottomed flask with glacial acetic acid (150.0 mL), co~ d HCl (75.0 mL) and tin metal (Fisher Sciontifir) (58.08 g, 0.489 _L, 2.4 eq). The creamy slurry was heated in an oil bath at reflux. As the solution was heated the ph~limiAo dissolved, resulting in a light yellow solution. The reaction mixture was allowed to heat at reflux for 2 h, the solution was filtered hot, and the tin shavings were washed with fresh acetic acid. The majority of the acetic acid was removed with a rotary e.., , resulting in a light yellow creamy solution. This material was taken up in dichloromethane and washed with distilled water and a saturated sodium chloride solution. The organics were dried over MgS04, filtered, and c ~ to give 17.61 g of a light yellow solid. This crude material was purified by flash cl.~ with ethyl acetate as eluant to give 11.93 g (47S) of l-isoindolinone as a light yellow powder. mp: 150-151-C. H NMR (CDC13): ~ 4.48 (s, 2), 7.48 (m, 2), 7.57 (m, 1), 7.76 (br s, 1), 7.88 (m, 1). 13C NMR
(CDC13): ~ 45.83, 123.16, 123.64, 127.95, 131.69, 143.72, 172.35.
Anal. Calcd for C8H7N0: C, 73.16; H, 5.30; 10.52. Found: C, 72.08; H, 5.35; N, 10.49.
(b) PreDaration of (E)-2-(4-chloro-2-butenvl)-l-isoin~lin~n~
Sodium hydride (1.54 g of an 80S oil dispersion, 1.25 eq) was placed under N2 in an oven-dried, 500-mL, round-bottomed flask.
The sodium hydride was washed with hexanes (2X), and the waste hexanes were pipetted off of the solids. Anhydrous dimethylformamide (DMF) (100 mL) was added to the washed sodium hydride. To this grey ~ n was added a solution of W O 93/16073 - 61 - P(~r/GB93/00285 1-isoindolinone (5.47 g, 0.041 mol) in dry DMF (50.0 mL). In a separate oven-dried, 500-mL, round-bottomed flask was placed trans-1,4-dichloro-2-butene (Aldrich Chemical Company) (13.51. g, 0.103 mol, 2.5 eq) and dry DMF ( 100.0 mL). This solution was cooled in an ice-water bath and the l-iso;~Anlinnn~ solution was slowly added via a cannula. After the addition was complete the reaction mixture was allowed to warm to room ; , e and stir for 0.5 h. The majority of the DMF was r-moved with a rotary ev~ L~. and the residue was taken up in dichloromethane and washed several times with water. The organics were dried over MgS04, filtered, and ~ ~ to give 20.12 8 of a dark orange oil. This crude material was purified by flash ~L~ e .~ ~ with 1:1 hexanes/ethyl acetate as eluant to give 6.48 g (71S) of (E)-2-(4-chloro-2-butenyl)-1-isoinAn1i as a light yellow oil. The 1~ and C NMR spectra of this material were consistent for the N-alkylated p-_duct. 13C NMR (CDC13):
43.45, 43.99, 49.61, 122.78, 123.79, 128.08, 129.26, 129.56, 131.43, 132.54, 141.16, 168.28. A s~all amount (0.80 g) of the bis-alkylation product, (E)-2,2'-(2-butene-1,4-diyl)-bis-(1-~ A~l - ) was also obtained as light yellow crystals.
mp: 193-196-C.
(c) PreDaration of (E)-2-(4-(4-(1.2-~ ~nrhio7nl-3-yl) DiDerazir~yl) -2-butellyl) -l-isoindol ;nnn- hydrn~-hlnride This compound was prepared by an analogous method to that used in Example l(c). A mixture of (E)-2-(4-chloro-2-butenyl)-1-isoindo-linone (3.00 g, 0.014 mol), 3-(1-piperzinyl)-1,2-~ ~othlo7nle (2.97 g, 0.014 mol, 1.0 eq), and triethylamine (2.26 mL) in acetonitrile (20.0mL) was heated under N2 at reflux for 1 h. The crude material obtained was purified by flash cl..~ yh~ with ethyl acetate as eluant to give 3.47 g of the free base as a light yellow solid. The hydrochloride salt was prepared, recrystallized from ethanol, and dried in a vacuum oven to give 2.86 g (48S) of (E)-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazi-W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
nyl)-2-butenyl)-1-1eoin~~1in~~ hydrochloride as a tan powder.
mp: 232-235-C. lH NMR (DMS0-d6): ~ 3.10-3.58 (m, 6), 3.82 (br s, 2), 4.07 (br d, 2, J - 13.5), 4.22 (d, 2, J - S.l), 4.49 (s, 2), 5.08 (dt, 1, J - 15.4, 6.9), 6.04 (dt, 1, J - 15.4, 5.4), 7.55 (m, 5), 7.69 ~d, 1, J - 7.3), 8.10 (dd, 2, J - 7.5, 5.4), 11.36 (br s, 1). 13C NMR (DMS0-d6): ~ 42.95, 46.38, 49.37, 49.92, 56.33, 120.98, 121.14, 122.77, 123.44, 123.95, 124.56, 126.91, 127.83, 128.07, 131.36, 132.01, 136.08, 141.89, 152.06, 162.13, 167.08.
Anal. Calcd for C23H24N405.HCl: C, 62.64; H, 5.71; N, 12.70.
Found: C, 62.41; H, 5.67; H, 12.60.
EXAM~J~ 17 (a) F~ 'nn of (z~-2-(4-rhlnro-2-butenvl)-l-isoindolinone This compound was prepared according to the method described in ExaDple ll(b). Alkylation of l-isoi ~ lin~~- (5.75 g, 0.043 mol) with cis-1,4-dichloro-2-butene (Aldrich Chemical Company ) (6.25 g, 0.047 mol, 1.1 eq) in anhydrous DMF provided 3.43 g (36~) of (Z)-2-(4-chloro-2-butenyl)-1-isointolinone after purification by flash cl... ~ . lH, 13C and difference n.O.e. NMR spectra of the light or-nge oil were consistent with the N-alkylated product. 13C NMR (CDC13): 6 38.42, 38.50, 49.57, 122.77, 123.75, 128.08, 129.01, 129.44, 131.43, 132.44, 141.15, 168.26. The by-product of bis-alkylation, (Z)-2,2'-(2-butene-1,4-diyl)-bis-(l-isoindolinone) (0.88 g), was obtained as a light yellow solid.
mp: 148-150-C.
(b) F~ 'or of (Z)-2-(4-(4-(1.2-ben_isothiazol-3-vl)-1-pi~ 7inYl)-2-butenYl)-l-isoindolinone hvdrochloride hvdrate This compound was prepared by a method analo~ous to that used in Example l(c). A mixture of (Z)-2-(4-chloro-2-butenyl)-1-isoindo-linone (3.26 g, 0.015 mol), 3-(1-piperazinyl)-1,2-benzisothiazole (3.23 g, 0.015 mol, 1.0 eq), triethylamine (2.46 mL, 1.78 g, 0.018 mol, 1.2 eq) and acetonitrile (20.0 mL) W8S heated under N2 at reflux for 3 h. The crude product obtainet after work up was purified by flash ChL~ on flash silica gel with ethyl acetste as eluant to giYe 4.76 g of a viscous orange oil. The hydrochloride salt was prepared and recrystallized twice from 95 ethanol to give 2.16 g (33~) of (Z)-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-2-butenyl)-1-isoindolinone hydrochloride hydrate as a tan powder. mp: 234-236-C. H NMR (DMS0-d6):
3.34 (m, 4), 3.55 (m, 3), 4.10 (m, 4), 4.33 (d, 2, J - 5.9), 4.49 (s, 2), 7.95 (m, 2), 7.52 (m, 5), 7.6B (dd, 1, J - 7.3, 1.0), 8.12 (t, 2, J - 8.0), 11.65 (br s, 1). C NMR (DMS0-d6):
38.68, 46.40, 49.26, 50.04, 51.79, 121.15, 121.50, 121.71, 123.40, 123.95, 124.58, 126.94, 127.81, 128.08, 131.34, 131.99, 133.93, 141.86, 152.07, 162.13, 167.06.
Anal. Calcd for C23H24N40S.HClØ5 H20: C, 61.39; H, 5-82; N, 12.45; H20, 2.00. Found: C, 61.05, H, 5.79, N, 12.19, H20, 2.28.
(a) F,~ on of 2-(4-(4-(l~2-b~n7i~~thiazol-3-yl~-l-DiDerazinyl) butyl~hthAl mi ~- hvdrochloride N-(4-Bromobutyl)l' ' li~i~ (Aldrich Chemical Company ) (3.50 g, 0.0124 mol), 3-(1-piperazinyl)-1,2-benzisothiazole (Yevich J.P.
et al J.Med.Chem. 1986, 29, 359-369) (2.72 g, 0.0124 mol, 1.0 eq), triethylamine (2.24 mL, 0.0161 mol, 1.3 eq) and acetonitrile (15.0 mL) was added to a 100-mL, ~v~.l b~L ' flask. The cloudy orange solution was heated under N2 at reflux for 17 h.
The mixture was allowed to cool to room L , ~ and taken up in dichlvL- i' . The or_anic solution was washed with --t~-Ate~ K2C03, dried over MgS04, filtered, and c~"~e"L,~tcd to give 5.48 g of a light orange solid. This crude material was CA 2 i i 74~4 recrystallized from acetonitrile and dried in a vacuum oven to give 4.35 g of a tan powder. The hydrochloride salt was prepared by the addition of lN HCl in ether and recrystallized from 95%
ethanol to give 4.53 g (82~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl) phthDlmi~ hydrochloride as an off-white powder. mp: 258-260-C (dec). lH NMR (DMSO-d6): 6 1.72 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.02 (br d, 2, J - 13.7), 7.44 (ddd, 1, J - 8.1, 7.0, 1.1), 7.57 (ddd, 1, J - 8.1, 7.0, 1.0), 7.85 (m, 4), 8.09 (dd, 2, J - 8.0, 4.5), 11.18 (br s, 1). 13C NMR
(DMSO-d6): C 20.52, 25.25, 36.82, 46.30, 50.44, 54.98, 121.13, 122.98, 123.94, 124.56, 126.90, 128.06, 131.58, 134.33, 152.04, 162.16, 167.93.
Anal. Calcd for C23H24N402S.HCl: C, 60.45; H, 5.51: N, 12.26.
Found: C, 60.46; H, 5.55; N, 12.17.
(b) Pr~n~Dti~~ of 3-(4-(4- nAh..~yl)-l-~i ~yl)-1.2-hDn7i D7~1e To a solution of 2-(4-(4-(1,2-bon7i~othiD7ol-3-yl)-l-piperazin-yl)butyl)pht~limiio (12.46 8, 0.0296 mol) and methanol (30.0 mL) was added 85% hydrazine hydrate (2.62 g, 1.5 eq). The reaction mixture was heated at reflux for 3.5 h and allowed to cool to room i , ~ e. lN HCl (59.0 mL) was added to the solution and the resulting white precipitant was filtered and washed with water. The filtrate was made basic by the addition of 50~ NaOH
and extracted with dichl~.~ ' . The organics were dried over MgS04, filtered, and - ~ ' with a rotary e... ~LUL to give 8.1 g (94~) of 3-(4-(4-aminobut-:)-1-piperazinyl)-1,2-benzi-sothiazole as an orange-brown oil. H NMR (CDC13): 6 1.38 (br s, 2), 1.55 (m, 4), 2.45 (t, 2, J - 7.4), 2.68 (t, 4, J - 5.0), 2.74 (t, 2, J - 6.8), 3.57 (t, 4, J - 5.0), 7.35 (ddd, 1, J - 1.1, 7.0, 8.1), 7.46 (ddd, 1, J - 1.1, 7.0, 8.1), 7.81 (d, 1, J
8.1), 7.91 (d, 1, J - 8.2). This crude amine was used without further purification.
W O 93/16073 C A 2 i 1 /645 3 4 PCT/GB93/00285 (c) PreDaration of 2-(4-(4-(1.2-h~n7;e~thio7Al-3-yl)-l-Din~rp7invl) butvl)-4-methYlnhthAl mi ~- hYdrochloride 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benzisothiazole (2.70 g, 9.3 mmol) and pyridine (27.0 mL) was added to a 300-mL, round-bottoDed flask. To this stirred solution was added 4-methylphthalic snhydride (1.66 g, 10.2 mmol, 1.1 eq). The react{on mixture was placed under N2 and heated at reflux for 5 h. The solution was c ~ ' and the residue was taken up in dichl~.~ t~ and washed with saturated R2C03. The organics were dried over MgS04, filtered, and ~ ' to give the crude product. This material was purified by flash cl.L~ ~ g ,'~
with 3:1 hexanes/ethyl acetate as eluant to yield 3.82 g of white crystals. This free amine was taken up in ethyl acetate and HCl (8.7 mL of a lN solution in ether, 8.7 mmol, 1.0 eq) was added.
The resulting hydrochloride salt was recrystallized from 95~
ethanol and dried in a vacuum oven to give 2.70 g (67~) of 2-(4-(4-(1,2-~ 'eoth;o~l-3-yl)-1-piperazinyl)butyl)-4-methyl-~ - hydrochloride as a white powder. mp: 255.5-258-C.
NNR (DNS0-d6): 6 1.74 (m, 4), 2.46 (s, 3), 3.25 (m, 4), 3.53 (m, 6), 4.02 (br d, 2, J - 13.6), 7.44 (ddd, 1, J - 8.1, 7.1, 0.9), 7.62 (m, 4), 8.10 (dd, 2, J - 8.0, 4.7), 11.18 (br s, 1). 13C
NNR (DNS0-d6); ~ 20.54, 21.29, 25.28, 36.75, 46.31, 50.45, 55.00, 121.12, 122.90, 123.42, 123.94, 124.56, 126.90, 128.06, 128.96, 131.94, 134.63, 145.24, 152.05, 162.15, 167.90, 168.00.
Anal. Calcd for C24H26N40S.HCl: C, 61.20; H, 5.78; N, 11.89.
Found: C, 60.91; H, 5.78; N, 11.75.
FV-~PT F~ 14 to 22 The compounds of Examples 14 to 20 and 22 were prepared from their c~ s~,.ding substituted phthalic anhydride ~ by the method described in Lxample 13 (c). The phthalic anhydrides employed were obtained from commercial suppliers or prepared by known literature CA2i 1 7434 methods as ;nA;rot-~ The analytical dAta for these ,' '-limi~o~ are shown below.
F'XAMPT F 14 PreDaration of N-(4-(4-(1.2-hon7;~~th;D~nl-3-yl)-l-DirorA7;r!yl) butyl)-3-fluornnhthsl;mi~io hytrArhlnride Starting material: 3-Fl ~hLl.~lic anhydride (Lancaster Synthesis Inc). Yield: 1.22 g (16~). mp: 258-260-C. H NMR (DMS0-d6): ~ 1.67 (m, 2), 1.80 (m, 2), 3.22 (m, 2), 3.55 (m, 6), 4.05 (br t, 2, J
13.5), 7.47 (ddd, 1, J - 8.1, 7.0, 1.1), 7.46 (ddd, 1, J - 8.1, 7.0, 1.1), 7.74 (dt, 1, J - 7.3, 0.7), 7.90 (ddd, 1, J - 8.4, 7.3, 4.6), 8.11 (tm, 1, J - 7.5), 11.12 (br s, 1). 13C NMR (DMSO-d6): C 20.48, 25.09, 36.98, 46.30, 50.46, 55.00, 117.28, 117.53, 119.49, 119.55, 121.12, 122.19, 122.58, 123.94, 124.56, 126.90, 128.06, 133.98, 134.01, 137.27, 137.43, 152.05, 153.94, 159.13, 162.14, 164.79, 166.ô7, 166.93.
Anal. Calcd for C23H23N402SF.HCl: C, 58.16; H, 5.09, N, 11.79. Found:
C, 57.93; H, 5.15; N, 11.71.
EXAMPT~ 15 PrA~-rot;r~ of N-(4-(4-(1.2-t ~~thi 07nl - 3-yl)-1-DiDerazinyl) bUtYl)-3-~ AYI.~ 51 ;m;~ hYdrnrhlnride Starting material: 3-H~ l.Llalic anhydride (Aldrich Chemical Company). Yield: 0.94 g (24~). mp: 247-248-C. H NMR (DMSO-d6): 8 1.65 (D, 2), 1.77 (m, 2), 3.23 (_, 4), 3.54 (m, 6), 4.05 (br d, 2, J -13.6), 7.27 (dd, 1, J - 3.5, 0.8), 7.29 (dd, 1, J - 4.8, 0.8), 7.47 (ddd, 1, J - 8.2, 7.0, 1.1), 7.60 (m, 2), 8.02 (tt, 2, J - 7.7, 1.1), 11.02 (br s, 1), 11.19 (s, 1). C NMR (DMSO-d6): ~ 20.57, 22.30, 36.44, 38.21, 40.71, 46.32, 50.48, 55.05, 113.82, 114.57, 121.12, 123.19, 123.94, 124.56, 126.90, 128.06, 133.47, 135.77, 152.05, 155.19, 162.14, 166.63, 167.74.
Anal. Calcd for C22H23N5025.HCl: C, 58.44; H, 5.34; N, 11-86- Found C, 58.48; H, 5.35; N, 11.90.
PreDaration of 2-(4-~4-(1.2-benzisothiazol-3-yl)-1-DiDerazinyl) butyl~-2.3--lih,ydro-lH-DYrrolo~3.4-C)Dvridine-1.3-dione hYdrochloride Starting material: 2,3-Pyri~ino~i~Arb~Yylic anhydride (Aldrich Chemical Company). Yield: 3.03 g (76~). mp: 258-259-C. H NMR
(DMS0-d6): ~ 1.71 (m, 4), 3.20 (m, 4), 3.54 (m, 6), 4.03 (br d, 2, J -13.4), 7.45 (ddt, 1, J - 8.1, 6.9, 1.0), 7.58 (ddd, 1, J - 8.1, 6.9, 1.0), 7.89 (dd, 1, J - 4.8, 1.1), 8.10 (dd, 1, J - 8.0, 4.2), 9.09 (d, 1, J - 4.9), 9.12 (d, 1, J - 0.8), 10.86 (br s, 1). 13C NMR
(DMSO-d6): ~ 20.49, 25.01, 37.13, 46.32, 50.49, 55.01, 116.78, 121.13, 123.93, 124.56, 125.87, 126.90, 128.07, 139.34, 143.79, 152.06, 155.74, 162.13, 166.89, 167.29.
Anal. Calcd for C22H23N5025.HCl: C, 57.75; H, 5.29; N, 15.32. Found:
C, 57.60; H, 5.30; N, 15.33.
PrerArPtiQn of N-(4-(4-(1.2-h~n7i~nthiazol-3-vl~-l-Dinorazinyl) butvl~-4-ritrnnhthAl1~i Ao h~drochloride Starting material: 4-NiL.. r~ anhydride (Aldrich Chemical Company). Yield: 3.30 g (73~). mp: 258.5-259-C. H NMR (DMSO-d6): 6 1.69 (m, 4), 3.20 (m, 2), 3.50 (m, 2), 3.66 (m, 2), 4.04 (br d, 2, J -13.3), 7.45 (t, 1, J - 7.4), 7.'8 (6, l, J - 7.2), 8.08 (d, l, J
4.5), 8.11 (s, 1), 8.14 (d, 1, J - 3.3), 8.49 (d, 1, J - 1.8), 8.62 (dd, 1, J - 8.2, 2.0), 10.88 (br s, 1). C NMR (DMS0-d6): ~ 20.50, 25.02, 37.40, 46.32, 50.48, 54.98, 117.70, 121.14, 123.93, 124.44, 124.57, 126.89, 128.07, 129.51, 133.09, 136.36, 151.31, 152.05, 162.13, 166.09, 166.35.
Anal. Calcd for C23H23Nso4s~Hcl: C, 55.03; H, 4-82; N, 13-95- Found:
C, 55.06; H, 4.85; N, 13.96.
F.~AMP!.F. 18 PreDaration of 6-(4-(4-(l~2-h~n7ic~thiazol-3-~l)-l-DiDerazinyl) butyl~-6,7-~ihvdro-SH-Dvrrolo(3.4-BlDvridine-5,7-dione hvdrochloride b ~ ~IL ~It~:
Starting material: 3~4-pyri~in~ nrboxylic aDhydride (Aldrich Chemical Company). Yield: 1.52 g (34%): mp: 253-254-C. H NMR
(DMSO-d6): ~ 1.70 (m, 4), 3.27 (m, 6), 3.52 (m, 2), 3.65 (t, 2, J
6.3), 4.05 (br d, 2, J - 12.7), 7.45 (t, 1, J - 8.0), 7.58 (t, 1, J
7.6), 7.78 (dd, 1, J - 7.6, 5.1), 8.09 (d, 1, J - 8.0), 8.12 (d, 1, J
- 8.0), 8.30 (dd, 1, J - 7.6, 1.4), 8.97 (dd, 1, J - S.l, 1.4), 10.52 (br s, 1). 13C NMR (DMS0-d6): ~ 20.46, 25.13, 36.94, 46.29, 50.43, 54.99, 121.12, 123.94; 124.56, 126.90, 127.24, 127.73, 128.06, 131.14, 151.49, 152.05, 154.66, 162.15, 166.28, 166.37.
Anai. Calcd for C22H23N5025.HCl.H20: C, SS.Sl; H, S-Sl; N, 14-71; H20, 3.78, Found: C, 55.75; H, 5.52; N, 14.71; H20, 3.92.
PreDaration of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-DiDerazinYl) butyl)-3-methvlDhthalimide hydrochloride , '~d,~t~
Starting material: 3-Methylphthalic anhydride (Kodak Laboratory Chemicals). Yield: 3.34 g (73%). mp: 272-274-C. H NMR (DMS0-d6): ~
1.68 (m, 4), 2.62 (s, 3), 3.17 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, J -12.4), 7.45 (m, 1), 7.63 (m, 4), 8.10 (dd, 2, J - 7.9, 4.4), 10.98 (br W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 s, 1). 3C NMR (DMS0-d6): 6 16.98, 20.59, 25.26, 36.64, 46,36, 50.52, 55.06, 120.61, 121.13, 123.94, 124.55, 126.90, 128.06, 128.20, 131.95, 133.83, 136.41, 137.04, 152.05, 162.17, 167.80, 168.62.
Anal- Calcd for C24H26N4~25'HCl H2 Found: C, 59.07; H, 5.99; N, 11.32.
FY~MPJ .F 20 PrPnAration of N-(4-(4-(l~2-benzisothiazol-3-yl)-l-vin~razin~l) butvl~-3.6-dichlornnhrhAll~iA~ hydrochloride ~ ~vd.~L~
Starting material: 3~6-Dichl~ lir anhydride (Fluka Chemic AG).
Yield: 2.23 g (49~). mp: 265-267-C. lH NHR (DMS0-d6): 6 1.73 (m, 4), 3.20 (m, 4), 3.57 (m, 6), 4.03 (br d, 2, J - 13.5), 7.45 (t, l, J
8.0), 7.58 (t, l, J - 8.0), 7.83 (s, 2), 8.09 (d, l, J - 8.0), 8.11 (d, 1, J - 8.0), 11.05 (br s, 1). 13C NMR (DMS0-d6): 6 20.48, 24.93, 37.24, 46.31, 50.47, 55.01, 121.13, 123.93, 124.56, 126.89, 128.06, 128.16, 129.28, 136.72, 152.05, 162.}4, 164.35.
Anal. Calcd for C23H22N402SC12.HCl.H20: C, 50.79; H, 4.63; N, 10.30.
Found: C, 50.63; H, 4.67; N, 10.23.
A second crop of crystals gave 0.44 g of the hydrochloride dihydrate.
mp: 262-265-C.
Anal- Calcd for C23H22N4025Cl2 HCl-2 H20: C, 49.16; H, 4.84; N, 9,97, Found: C, 49.21; H, 4.83; N, 9.93.
FYI~MPJ F 21 (a) Preraration of 4-chlororhrhAli~
4-Aminopthalimide (Rodak) (lO.Og, 0.0671mol), distilled wster (14.0 mL) snd ~ ~ ' HCl (27.0 mL) were plsced in a 500 mL, CA2~, 7~34 W O 93/16073 PCT/~b53/~
i~ ' b~. ' flask. Th- resulting li p t yellow solution was cooled with an ice/water bath and a solution of sodium nitrite (Malinckrodt) (4.57 g, 0.0679 mol,l.l eq) in distilled water (100 ml) was added dropwise. The reaction mixture turned a golden yellow color upon this addition. The solution was allowed to stir at 0~C for 20 minutes and a solution of CuC12.2H20 (21.0 g, 0.123 mol, 2.0 eq) in distilled water (140 mL) was added dropwise. The resulting green solution was allowed to stir at 0 C for lh followed by warming on a steam bath for 15 min. The mixture was extracted with ethyl acetate. The organics were co_bined, dried over MgS04, filtered and ~ - ' with a rotary ~., to give 9.61 g of the title compound as a tan solid. This material was used without further purif1rDti~~
(b) FL~ on of N-(4-nhlnrobut~1~-4'-rhlnroothAlim~ and N-(4-b.~_ b~v1~-4' nhlnroDthAlim{~o The title compounds were prepared by a method analogous to E~ample ll(b). From 4-rhl~L ,' '-limi~ (9.61 g, 0.0529 mol) and l-bromo-4-chl~..rL limi~ (Aldrich Chemical Company) (9.98 g, 0.0582 mol) was obtained 15.91 g of an 80:20 mixture of the - . . ~-ng chloride and bromide after flash ~ g .-~with 8:1 hexanes/ethyl acetate as eluant. This material was used as a mixture of the halides without further p~nif;r~ti~n (c) PrA~~ration of N-(4-(4-(1.2-brn~in--thi~7nl-3-yl)-l-DinnrA7ir~
butyl~-4-rhlrrnnhthAlimi~' hydrnrhlnrid~
This compound was prepared according to the method described in Example 13(a). From an 80:20 mixture of N-(4-chlorobutyl)-4'-chl~.. , -l;mii~ and N-(4-bromobutyl)-4'-chlorop:hDlimi~ ~
(2.50 g, 0.0029 mol) and 3-(l-piperazinyl)-1,2-b~n7in5Othi~7nl~
(1.95 g, 0.0089 mol) was obtained 2.30 g of the target compound as the free base. The l.~d,. ~ ide salt was prepared, recrystallized from 95~ ethanol and dried in a vacuum oven to ' CA2 i 1 7434 give 1.79 g (41i~ of the title compound 85 light yellow crystals, mp: 253-255-C. H NMR (DMS0-d6): ~ 1.69 (m, 4), 3.23 (m, 4), 3.53 (m, 6), 4.03 (br d, 2, J - 13.1), 7.44 (t, 1, J - 7.7), 7.57 (t, 1, J - 6.9), 7.88 (d, 2, J - 1.1), 7.94 (d, 1, J - 1.1), 8.09 (dd, 2, J - 4.3, 8.0), 11.18 (br s, 1). C N~R (DMSO-d6):
20.46, 25.14, 37.06, 46.29, 50.42, 54.96, 121.13, 123.10, 123.93, 124.55, 124.71, 126.89, 128.05, 130.20, 133.67, 134.04, 139.08, 152.04, 162.14, 166.69, 167.05.
Anal. Calcd for C23H24N4025C12 Found: C, 56.18; H, 4.95; N, 11.34.
ExAMPLe 22 PreDsration of N-(4-(4-(1.3-benzisothiazol-3-vl)-1-DiDerazinYl) butyl~-3 _ tl,~J~Ih-lim-~ hvdrochloride hydrate Starting material: 3-Mei' ~,' '-11r anhydride (Alfred Bader Library).
Yield: 2.17 g (47~). mp: 232-234-C. lH NMR (DMSO-d6): 6 1.70 (m, 4), 3.25 (m, 4), 3.54 (m, 6), 3.94 (s, 3), 4.03 (br d, 2, J - 13.4), 7.48 (d, 2, J - 8.5), 7.60 (tm, 1, J - 5.0), 7.79 (tm, 1, J - 7.3), 8.10 (dd, 2, J - 7.9, 4.6), 1}.19 (br s, 1). 13C NMR (DMS0-d6): ~ 20.52, 25.26, 36.59, 46.29, 50.42, 54.99, 56.16, 114.88, 116.42, 118.52, 121.13, 123.94, 124.56, 126.90, 128.06, 133.56, 136.57, 152.05, 156.13, 162.16, 166.16, 167.54.
Anal. Calcd for C24H26N4035.1.25 HClØ25 H20: C, 57.58; H, 5.57; N, 11.19; H20, 0.89. Found: C, 57.65; H, 5.87; N, 10.92; H20, 1.17.
(a) Preoaration of (+/-)-trans-1.2-cvcloDroDanedimethanol Lithium aluminum hydride (LAH) (7.60 g, 0.201 mol, 1.5 eq) was adted to an oven-dried, 500-mL, three-necked, round-bottomed flask equipped with a pressure-eq~Ali7ing addition funnel. Tne LAH was placed under N2, cooled with an ice-water bath, and anhydrous teL.~,~ILufu.~,, (200.0 mL) was added. After the addition was complete the cold bath was removed and the solution was allowed to stir at room ~ , e for 10 min. To this grey r ~on was added a solution of trans-diethyl 1,2-cyclopropane dicarboxylate (Aldrich Chemical Company) (25.0 g, 0.134 mol) dropwise. The reaction mixture was heated at reflux for 6 h and allowed to stir at room I , e for 20 h. The solution was cooled in an ice/water bath and saturated NH4Cl (45 mL) was slowly added. Ethyl acetate (50.0 mL) was added, the solids were filtered and washed with ethyl acetate. The filtrate was dried over MgS04, filtered, and co..~ L~L~d to give 8.00 g of a cloudy oil. This crude material was purified by flash ~I.L~ - O ,' ~
with ethyl acetate/methanol 19:1 as eluant to give (+/-)-trans-1,2-cycl~ r 1 as a colorless oil. lh N~R (CDC13): ~ 0.41 (t, 2, J - 6.8), 1.00 (m, 2), 3.00 (dd, 2, J
- 11.3, 8.8), 3.83 (dd, 2, J - 11.3, 4.4), 4.22 (br s, 2). 13C
NMR (CDC13): ~ 7.16, 19.98, 66.08.
(b) PreDaration of (+/-)-trAn~-2-(chloromethyl)-l-cyclo~romane methanol (+/-)-Tralls-l~2-cy~ r L 1 (4.0 g, 0.039 mol), tosylchloride (TsCl) (8.96 g, 0.047 mol, 1.2 eq), dimethylamino pyridine (DMAP) 5.30 g and anhydrous dichloromethane (75.0 mL) was added to an oven-dried, S00-mL, round-bottomed flask. The reaction mixture was placed under N2 and allowed to stir at room r , c for 24 h. Additional portions of the reagents were added, TsCl (2.24 g), DMAP (1.0 g), and dichlvL~ L'~ (1.0 mL).
The solution was allowed to stir at room r , e for an additional 6 d. Triethylamine (5.43 mL, 3.95 g, 0.039 mol, 1.0 eq) was added and the solution was allowed to stir for 24 h. The reaction was still not complete. The mixture was heated at reflux for 1.5 h and the solvent was removed with a rotary W 0 9 /I CA21 i 7434 e~ tuL to give a sticky tan solid. This crude material was purified by flash .1,.. ~ with hexanes/ethyl acetate 1:1, followed by ethyl acetate/methanol 19:1 as eluant to give 1.85 g of (+/-)-trans-2-(chloromethyl)-l-cyclopropane methanol. A
portion of the starting diol (0.87 g) was recovered unchanged.
(c) PreDaration of (+/-)-trans-N-((2-(hydroxvmethyl)cvcloDroDYl) Dethyl) ~hthAl im~
PotassiuD 1' '-limi~ (1.44 g, 7.62 mDol~, (+/-)-trans-2-(chloro-methyl)-l-cy~ , methanol (1.59 g, 13.20 mmol, 1.7 eq), and anhydrous dimethyl' '~- (50.0 mL) were placed in a 1OO-DL~
round-bottomed flask. The resulting cloudy ~ n was heated at reflux for 20 h. The r-action mixture was allowed to cool to room ~ nd most of the DMF was removed in vacuo with a rotary e~_, s. The residue was taken up in dichloromethane and washed with two portions of water. The organics were dried over MgS04, filtered, ~nd c ~ ' to give 3.55 g of a dark orange oil. This crude material was purified by flash ch~ with hex nes/ethyl acetate 5:1 as eluant to give 1.12 g (64~) of (+/-)-trans-N-((2-(1.Jd-u~ Ll,~l)cyclopropyl)me-thyl) pht~_limi~ as a white powder. DP: 117-118-C. lH NMR
(CDC13): ~ 0.48 (ddd, 1, J - 13.6, 10.3, 5.2), 0.65 (ddd, 1, J
13.6, 10.3, 5.0), 1.17 (m, 2), 1.52 (br s, 1), 3.45 (m, 2), 3.59 (dd, 2, J - 7.0, 2.2), 7.70 (m, 2), 7.84 (m, 2). 13C NMR
(CDC13): ~ 8.99, 16.17, 20.68, 41.57, 66.09, 123.43, 132.12, 133.95, 168.48.
Anal. Calcd for C13N13N03: C, 67.52; N, 5.67; N, 6.06. Found: C, 67.45; N, 5.71; N, 5.99.
C~2i 17434 (d) PreDaration of (+/-)-trans-(2-(Dhtholimi~ tl,~l)-l-cYcloDroDyl) methyl methvlsulfonate (+/-)-Trans-N-((2-(1.,~1.uA,~. Ll~l)cyclopropyl)methyl)-rhth7limi~lo (1.04 g, 4.50 mmol), freshly distilled (over Cah2) triethylamine (0.94 mL, 0.68 g, 6.75 mmol, 1.5 eq) and anhydrous dichlorometh-ane (14.0 mL) was added to a 50-mL, round-bottomed flask. The solution was placed under a N2 I ,' e and cooled with sn ice-water bath. To this cooled mixture was added a solution of mesyl chloride (0.52 mL, 0.77 g, 6.75 mmol, 1.5 eq) in dichlu.~ ' (2.0 mL). Upon this addition the white alcohol , ' became a clear light orange solution which was allowed to stir at O-C for 1 h. The reaction mixture was allowed to warm to room ; , e and was washed with saturated R2C03. The organics were dried over MgS04, filtered, and c~ *~d to give 1.40 g of an off-white solid. This material was purified by flash ~1"~ on silica gel with 1:1 hexanes/ethyl acetate as eluant to give 1.29 g (93~) of (+/-)-trans-(2-(pht~limi~
thyl)-l-cyclopropyl)methyl methyl~ fA~ot~ as a white powder.
mp 118-121-C. ~ NMR (CDC13): 6 0.65 (dt, 1, J - 8.6, 5.4), 0.83 (dt, 1, J - 8.4, 5.4), 1.33 (m, 2), 2.94 (s, 3), 3.58 (dd, 1, J - 14.2, 7.2), 3.65 (dd, 1, J - 14.2, 6.9), 3.99 (dd, 1, 3 10.8, 7.5), 4.09 (dd, 1, J - 10.8, 7.0), 7.74 (m, 2), 7.86 (m, 2). 13C ~MR (CDC13): ~ 9.97, 16.90, 17.26, 37.79, 40.86, 73.22, 123.29, 132.09, 134.02, 168.29.
(e) FL~_ :ion of (+/-)-trans-N-((2-((4-(1.2-benzisothiazol-3-yl)-1-Din~rP7inYl)methYl)CycloDroDYl) methYl) T~hthol imide hvdrochloride hvdrate (+/-)-Trans-(2-(phth~limi~ tl.~l)-l-cyclopropyl)methyl methane-sulfonate (1.17 g, 3.78 mmol), 3-(1-piperazinyl)-1,2-benzisothia-zole (0.912 g, 4.16 mmol, 1.1 eq), triethylamine (0.633 mL, 0.459 g, 4.54 m~ol, 1.2 eq) and acetonitrite (10.0 mL) were added to a 100-mL, round-bottomed flask. The cloudy solution was placed under N2 and heated at reflux for 3.5 h. An additional portion of the pirers7in~ b~ ~this7ole (0.083 8, 0.10 eq) was added and heating was continued for a total of 20 h. The solution was allowed to cool to room ~ . ~ and dichloromethane WdS
added. The solution was washet with saturated K2C03 and the organics were dried over MgS04, filtered, and o~ LL~L~d to give 1.92 g of a viscous orange oil. This crude material was purified by flash cl.~ with 2:1 hexanes/ethyl acetate as eluant to give 1.30 g of the free base. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.11 g (61~) of (+/-)-trans-N-((2-((4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)methyl)cyclopropyl) methyl) rhr~slimi~ hydrochlor-ide hydrate as an off-white powder after drying in a vacuum oven, mp: 246-248-C. lH NMR (DMS0-d6): C 0.74 (m, 2), 1.29 (m, 2), 3.12 (br s, 2), 3.20-3.67 (m, 8), 4.05 (m, 2), 7.45 (t, 1, J
7.5), 7.58 (t, 1, J - 7.5), 7.18 (m, 4), 8.09 (d, 2, J - 8.2), 11.12 (br s, 1). 13C NMR (DMSO-d6): C 9.64, 12.01, 17.07, 46.24, 49.87, 50.22, 58.47, 121.16, 12~.02, 124.01, 124.61, 126.93, 128.11, 131.67, 134.37, 152.08, 162.16, 168.02.
Anal. Calcd for C24H24N4025.HCl.0 5 H20: C, 60.30, H, 5.48; N, 11.72; H20, 1.88. Found: C, 60.37; H, 5.51; N, 11.72; H20, 1.85.
FY~PLF 24 (a) PrA-s~ation of N-(2-(2-rhlnroethoxY)ethYl)ohth~limide Fotassium p~thslimi~ (Aldrich Chemical Company) (15.0 g, 0.081 mol) as a fluffy powder and 2-chloroethyl ether (Aldrich Chemical Company) (28.5 mL, 34.74 g, 0.243 mol, 3.0 eq) as a colorless oil was added to a 250-mL, round-bottomed flask. The reaction mixture was heated under nitrogen with an oil bath at 170-C for 19 h. As the mixture was heated the solution became more liquid in consistency and brown in color. The mixture was removed from the oil bath and distilled water was added. The solution was sllowed to cool to room t ,-rPt--re and extracted with dichlo,. tl,~ . The organic extracts were washed with water, dried over MgS04, filtered, and c~nr~ntrAr~d to give 36.1 g of a dark orange-brown oil. This crude material was purified by flush cl.,. e . ~ ~ with 3:1 hexanes/ethyl acetate as eluant to give 13.53 g (67%) of a light orange oil which quickly solidified upon standing. An analytically pure white powder was obtained by recrysts1li7sti~n from ethyl acetate. mp: 67-70-C. lH NMR
(CDC13): ~ 3.54 (dt, 2, J - 6.2, 0.8), 3.72 (dt, 2, J - 5.9, 0.6), 3.75 (dt, 2, J - 5.8, 0.9), 3.89 (dt, 2, J - 5.4, 1.2), 7.71 (m, 2), 7.83 (m, 2). 13C NMR (CDC13): ~ 37.14, 42.70, 67.92, 70.61, 123.27, 132.06, 133.97, 168.27.
Anal. Calcd for C12H12N03Cl: C, 56-81; H, 4.77; N, 5-52- Found:
C, 56.88; H, 4.79; N, 5.49.
(b) P,., _ s of N-~2-(2-(4-(1.2-benzisothiazol-3-yl)-1-DiDera-zi~yl)ethoxv)ethyl)~hrhA1imide hydrochloride This compound was prepared by the method analogous to that used in Example 13(a). From N-(2-(2-chloroethoxy)ethyl) phrh~limilig (1.33 g, 5.2 mmol), 3-(l-piperazinyl)-1,2-b~n~i~othis7A~le (1.15 g, 5.2 mmol, 1.0 eq), triethylamine (0.94 mL, 0.0685 g, 6.8 mmol, 1.3 eq) and acetonitrile (6.0 mL) 1.17 g of the free base was obtained. Ihe hydrochloride salt was prepared and recrystallized from ethanol to give 0.87 g (35%) of N-(2-(2-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)ethoxy)ethyl) phths1imi~s hydrochloride compound as off-white crystals. mp: 199-200-C. lH NMR (DMS0-d6):
3.26-3.56 (m, B), 3.70 (t, 2, J - 5.4), 3.82 (t, 2, J - 5.4), 3.88 (m, 4), 7.48 (ddd, 1, J - 8.1, 7.0, 1.1), 7.60 (ddd, 1, J
8.1, 7.0, 1.1), 7.80 (m, 2), 7.85 (m, 2), 8.06 (dt, 1, J - 8.2, 0.9), 8.11 (dt, 1, J - 8.1, 0.9), 11.12 (br s, 1) 13C NMR
(DMSO-d6): ~ 36.93, 46.21, 51.06, 54.86, 64.35, 67.25, 121.14, 122.96, 123.88, 124.57, 126.85, 128.06, 131.46, 134.35, 152.04, 162.05, 167.82.
Anal. Calcd for C23H24N4035.HCl: C, 58.40; H, 5.33; N, 11.84.
Found: C, 58.50; H, 5.36; N, 11.81.
.
EXAMPT~ 25 (a) PreDaration of N-(4 rhloro-2-butynyl~DhthAl imi*-This compound was prepared according to the method described in Example 24(a) from potassium phthslimi*e (Aldrich Chemical Company) (13.0 g, 0.0702 mol) and 1,4-dichloro-2-butyne (Aldrich Chemical Company) (25.9 g, 0.212 mol, 3.0 eq). After flush cl.~ t ~ with 4:1 hexanes/ethyl acetate as eluant, 10.64 g ~65~) of a light yellow solid was obtained. Analytically pure, colorless, diamond-like crystals formed by crysrplli7stion from a hexanes/ethyl acetate solution. mp: 112-115-C. 1H NMR (CDC13):
4.09 (t, 2, J - 2.1), 4.49 (t, 2, J - 2.1), 7.73 (m, 2), 7.87 (m, 2). C NMR (CDC13): ~ 27.22, 30.10, 77.86, 79.91, 123.58, 131.94, 134.24, 166.95.
Anal. Calcd for C12H8N02Cl: C, 61.69; H, 3.45; N, 5.99. Found: C, 61.74; H, 3.48; N, 5.95.
(b) PreDaration of N-(4-(4-(1.2 hon7i-~thi P701- 3-vl)-1-DiDera-ziD~yl)-2-butynvl)nhth~limi*~ hvdro~hloride This compound was prepared according to the method described in Example 13 (a). From N-(4-chloro-2-butynyl) I' ' -limj~- (10.64 g, 0.0455 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (9.98 g, 0.0455 mol, 1.0 eq) was obtained 14.14 g (74~) of the free amine.
The hydrochloride salt was prepared from 4.49 g of the amine to give 3.17 g of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazin-yl)-2-butynyl)phthslimi~ hydrochloride as light yellow flakes after recryst~lli7pti~n from ethanol/ether. mp: 231-233-C. 1H
NMR (DMS0-d6): ~ 3.49 (m, 6), 4.09 (m, 2), 4.23 (br s, 2), 4.54 (s, 2), 7.47 (ddd, 1, J - 8.1, 7.0, 1.0), 7.60 (ddd, 1, J - 8,0, W O 93/16073 C A 2 ~ PCT/GB93/00285 7.0, 0.9), 7.90 (m, 4), 8.12 (dd, 2, J - 11.1, 8.1), 11.82 (br s, 1). 13C NMR (DMS0-d6): 6 26.90, 44.37, 46.32, 49.84, 72.01, 84.25, 121.10, 123.34, 123.97, 124.55, 126.88, 128.06, 131.33, 134.72, 152.04, 162.09, 166.65.
Anal. Calcd for C23H20N402S.HCl: C, 60.99; H, 4.67; N, 12.37.
Found: C, 60.82; H, 4.72; N, 12.27.
(a) PreDaration of (E)-N-(4-bromo-2-butenyl)PhthA1imiao This compound was prepared by a method analogous to that described in Example 24(a). Potassium r~t~limi~e (Aldrich Chemical Company) (8.35 g, 0.0451 mol), trans-1,4-dibromo-2-but-ene (Aldrich Chemical Company) (24.1 g, 0.1127 mol, 2.5 eq) and dimethyl- ~o (400.0 mL) were heated under N2 at 125-C for 3.5 h. The DMF was removed with a rotary e~., . and the crude product was purlfied by flash ~ with 4:1 hexanes/ethyl acetate as eluant to give 3.25 g (26~) of (E)-N-(4-bromo-2-butenyl) rhrhslimi~O An analytically pure sample was obtained by recrystsll17sti~ from ether to give white crystals. mp: 97-99'C. lH NMR (CDC13): 8 3.89 (d, 2, J - 6.4), 4.29 (d, 2, J - 5.1), 5.87 (m, 2), 7.72 (m, 2), 7.84 (m, 2). 13C
NMR (CDC13): ~ 31.27, 38.62, 123.40, 128.36, 129.96, 132.04, 134.09, 167.77.
Anal. Calcd for C12HlON02Br: C, 51-58, H, 3-61; N, 5.01. Found:
C, 51.53; H, 3.60; N, 5.02.
(b) PreDaration of (E)-N-(4-(4-(1.2-benzisothiazol-3-vl)-1-DiDera-zinvl)-2-butenyl)~hthnlimi~o hvdrochloride This compound was prepared according to the procedure described in Example 13(a). From (E)-N-(4-bromo-2-butenyl)phtslimi~o (8.45 W O 93/16073 C A ~ i 1 7 4 3 4 PCr/GB93/00285 g, 0.0302 mol) ant 3~ piperazinyl)1,2-bon7iFothip7ole (6.61 g, 0.0302 mol, 1.0 eq), 14.31 g of a tark orange solid was obtained.
The crude material was purified by flush CLL~ with 1:1 hex-nes/ethyl acetate as eluant to give 7.48 g of the free amine.
The hydrochlorite salt was preparet and recrystallized from 95 ethanol to give 1.99 g of (E)-N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)-2-butenyl)~ 1 imi~- hydrochlorite as a tan po~der. mp: 243-244-C. lH NMR (DMS0-d6): ~ 3.20 (m, 2), 3.45 (m, 4), 3.80 (br s, 2), 4.04 (br d, 2, J - 12.6), 4.24 (d, 2, J -4.8), 5.83 (dt, 1, J - 15.6, 6.8), 6.04 (dt, 1, J - 15.6, S.l), 7.42 (t, 1, J - 7.8), 7.56 (t, 1, J - 7.3), 7.85 (m, 4), 8.08 (dd, 2, J - 7.4, 6.4), 11.72 (br s, 1). 13C NMR (DMS0-d6): 6 38.50, 46.29, 49.80, 56.06, 120.96, 121.09, 123.12, 123.96, 124.53, 126.88, 128.03, 131.50, 134.45, 152.03, 162.12, 167.39.
Anal. Calcd for C23H20N402S.HCl: C, 60.72; H, S.10; N, 12.31.
Found: C, 60.62; H, 5.15; N, 12.25.
Fl~AMP! F. 27 (a) PreDaration of (z)-N-(4-rhloro-2-bute~yl)DhrhAllmi~
This compound was obtained according to the method described for Example 24(a) from I ~ ~ p~thDl imi~' (Aldrich Chemical Company) (13.0 g, 0.0702 mol), and cis-1,4-dichloro-2-butene (26.3 g, 0.211 mol, 3.0 eq). The crude product was purified by flush ~ with 4:1 hexanes/ethyl acetate as eluant to give 12.87 g (78.) of (Z)-N-(4-chloro-2-butenyl) ~ limi~ as a light yellow solid. The product was i~-~t~fipd to be a 90:10 mixture of (Z) and (E) isomers as ~-tDrmi ' by 13C NMR mp:
63-66-C. lH NMR (CDC13): ~ 4.32 (dd, 2, J - 7.7, 0.9), 4.35 (dd, 2, J - 7.4, 1.2), 5.70 (tm, 1, J - 10.6), 5.84 (dm, 1, J - 10.6), 7.72 (m, 2), 7.84 (m, 2). 13C signals observed for the trans-isomer are given in PdL~ ' ~~~~. 3C NMR (CDC13): ~ 34.03, 38.60, (43.48), (58.30), (119.62), 123.34, (123.52), (127.09), 127.15, 132.05, 134.06 (134.20), (135.27), 167.73.
(b) PreDaration of tz)-N-(4-(4-(l~2-h~n7isothiazol-3-yl)-l-Diper zin~Yl)-2-butenyl)~hthAlimi~ hytrochloride hvdrate This compound was prepared according to the method described in Example 13(a). From a 90:10 mixture of (Z)-and (E)-N-(4-chloro-2-butenyl)phtAlimi~ (9.86 g, 0.0418 mol) and 3-(1-piperazinyl)-1,2-benzisothiazole (9.17 g, 0.0418 mol, 1.0 eq) was obtained 18.93 g of a dark orange viscous oil. The crude material was purified by flush .1.~ with 1:1 hexanes/ethyl acetate as eluant to give 14.35 g (82~) of an orange oil which solidified upon standing. A portion of this material (8.44 g) was recrystallized from ethyl acetate to give 4.92 g of light yellow crystals. This recrystDlli7Ati~n increased the isomer ratio from approximately 90:10 to 97:3, Z:E. The hydrochloride salt was prepared and recrystallized twice from 95~ ethanol to give 1.34 g (7 ~) of (Z)-N-(4-(4-(1,2-' 'sothiA~nl-3-yl)-1-piperazinyl)-2-butenyl)pht~limi~ hydrochloride hydrate (100~ Z isomer) as light yellow crystals. mp: 247-249-C. H NMR (DHSO-d6): ~ 3.52 (m, 4), 4.13 (m, 4), 4.39 (d, 2, J - 5.6), 5.87 (m, 2), 7.49 (ddd, 1, J - 8.1, 7.0, 1.0), 7.61 (ddd, 1, J - 8.1, 7.0, 1.0), 7.88 (m, 4), 8.14 (dd, 2, J - 11.1, 8.1). 13C NHR (~HS0-d6):
34.59, 46.38, 50.03, 51.87, 121.16, 121.29, 123.06, 123.95, 124.59, 126.92, 128.08, 131.60, 132.85, 134.42, 152.07, 162.10, 167.46.
Anal. Calcd for C23H22N402S.HClØ25 H20: C, 60.12; H, 5.15; N, 12.19 H20, 0.98. Found: C, 59.73; H, 5.17; N, 12.11; H20, 0.61.
W O 93/16073 C ~ 2 i 1 7 4 3 4 PCT/GB93/0028~
(a) P~ 'nn of 2-(2-hvdroxyeth~1)-1.2-benzisothi~7~1-3-(2H)-one 2,2'-Dithiobisbenzoyl chloride (20.0 g, 0.0583 mol) (Yevich, J.P., et. al. J. Med. Chem. 1986, 29, 359-369), and A~t~hlt ' (50.0 mL) was added to a 150-mL beaker. Chlorine ges was bubbled through this cloudy solution with stirring, giving a rust colored mixture. To a separate flask was added a solution of ethanol amine (7.12 g, 0.112 mol, 2.1 eq), triethylamine (16.3 mL, 11.8 g, 0.117 mol, 2.1 eq) and dichl~-~ r~ (50.0 mL). This mixture was cooled in an ice-water bath. The bis-chloride solution was slowly added to the cooled amino-alcohol solution with stirring. The resulting orange mixture was washed with distilled water and the organics were ~ r ' ~ dried over ~gSC4, filtered, and c- -~ A with a rotary e... ~ to give 22.74 g of a crude orange oil. H
~R of thLs material was consistent with 2-(2-hydroxyethyl)-1,2--ol-3(2H)-one ~nd was used without further purifica-tion.
(b) PrtnAe~tiA~ of 2-~2-chloroethyl)-l~2-benzisoth1~ l-3(2H)-one Crude 2-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-one (22.74 g, 0.116 mol), was taken up in toluene (100.0 mL). The solution was cooled in an ice-water bath and thionyl chloride (9.61 mol, 15.68 g, 0.132 mol, 1.13 eq) was added dropwise over a 15 min period.
The cold bath was removed and the reaction mixture was allowed to stir at room r , e for 2 h. The toluene and excess thionyl chloride were removed by distillation under reduced pressure through an inverted Hopkins condenser. The red-orange residue was purified by flash cl..~ ~ t7, ,' ~ with 1:1 hexanes/ethyl acetate as eluant to g.ve 10.24 e (41~, based on 2,2'-dithiobis-benzoyl chloride) of 2-(2-chloroethyl)-1,2-benzisothiazol-3(2H)-one as an orange oil which solidified upon standing. mp:
CA 2 i 1 7434 73-78-C. 1 C NHR (CDC13): ~ 42.11, 45.90, 120.31, 125.68, 126.80, 132.18, 140.65, 165.67.
(c) PreDaration of 2-(2-(4-(l~2-h~n7icAthiazol-3-yl)-l-Dipera zinyl~ethyl)-1.2-h~n~i~AthiA~~1-3(2U)-one hYdrochloride This compound was prepared by a method analogous to that descri-bed in Example 13(a). From 2-(2-chloroethyl)-1,2-benzisothiazol-3(2H)-one (3.54 g, 0.0165 mol), and 3-(1-piperazinyl)-1,2-benzi-sothiazole (4.00 g, 0.0182 mol, 1.1 eq) was obtained 6.94 g of crude product. This material was purified by flash cl.~ with 1:1 hexanes/ethyl acetate 85 eluant to give 4.00 g of the free amine. The hydrochloride salt was prepared and recrystallized from 95~ ethanol to give 1.76 g (25~) oi 2-(2-(4-(1,2-~ '~othiD7~1-3-yl)-l-piperazinyl)ethyl)-1,2-benzi-sothiazol-3(2H~-one hydrochloride as a white crystalline solid.
mp: 250-252-C. lH NHR (DHS0-d6): ~ 3.46 (m, 6), 3.76 (br d, 2, J
- 10.2), 4.10 (br d, 2, J - 12.3), 4.36 (br t, 2, J - 5.9), 7.47 (tt, 2, J - 7.1, 1.1), 7.59 (t, 1, J - 7.2), 7.72 (dt, 1, J
8.3, 1.2), 7.91 (dd, 1, J - 7.9, 0.5), 8.11 (m, 3), 11.34 (br s, 1). C NHR (DHS0-d6): ~ 37.78, 46.28, 50.82, 53.73, 121.07, 122.09, 123.59, 123.96, 124.51, 125.53, 125.59, 126.85, 128.02, 132.00, 140.96, 152.02, 162.02, 164.90.
Anal. Calcd for C20H20N4052.HCl: C, 55.48; H, 4.89; N, 12.94.
Found: C, 55.53; H, 4.92; N, 12.89.
EXAHPT~ 29 (a) E.. ~ ~n of 2-(3-(4-(l~2-b~ othio7A~l-3-yl)-l-DiDera-7inyl~DroDyl)-1,2-benzisothiazol-3(2H)-one hvdrochloride This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(3-chloropropyl)-1,2-benzisothiazol-3(2H)-one (5.29 g, 0.0232 mol), and 3-(1-piperazinyl)-1,2-benzi-sothiazole (5.09 g, 0.0232 mol, 1.0 eq) was obtained 4.40 g ofthe c~.L~ ,,dLng product after flash cl..~ O~ with ethyl acetate as eluant. The hydrochloride salt was prepsred and recrystallized from 95i ethanol to give 3.45 g (32~) of 2-(3-(4-(l,2-bon7ieothiD7~l-3-yl)-l-piperazinyl)propyl)-l~2-benzisothia ol-3(2H)-one hydrochlorite as an off-white powder. mp:
185-187-C. lH NMR (DMSO-d6): ~ 2.19 (m, 2), 3.28 (m, 4), 3.55 (m, 4), 4.00 (m, 4), 7.44 (tt, 2, J - 7.5, 1.0), 7.57 (ddd, 1, J
- 8.3, 6.8, 1.0), 7.69 (ddd, 1, J - 8.5, 7.3, 1.2), 7.87 (dq, 1, J - 7.2, 0.8), 8.01 (dt, 1, J - 8.3, 0.8), 8,09 (m, 2). C NKR
(DMSO-d6): ~ 23.55, 40.48, 46.28, 50.49, 52.93, 121.08, 121.94, 123.90, 123.90, 124.51, 125.45, 125.52, 126.85, 128.02, 131.79, 140.51, 152.01, 162.07, 164.48.
AD~1~ Calcd for C21H22N4~52-1-5 HCl C, 54.21; H, S.09 N, 12.04 Found: C, 54.48; H, 5.46; N, 11.93.
FYA''~! F 30 P~ sn of 2-(4-(4-(1.2 ,~thi97~1-3.yl)-l-Di nyl)-butvl)-1.2-hon7ie~thiP7~1-3(2U)-one hvdrArhlnride This compound was prepared according to the methods described in Example 28 (a)-(c). From 2-(4-chlorobutyl)-1,2-benzLsothiazole-3(2H)-one (6.61 g, 0.0273 mol), and 3-(l-piperazinyl)-l~2-b~n7icothi~7n1o (6.78 g, 0.0309 mol, 1.13 eq) was obtained 14.16 g of a dark orange oil. This crude material was purified by flash ~1..- ~ O .'~ with 4:1 ethyl acetate/dichlu.~ ' as eluant, followed by recryst~lli7st1~n of the free amine from 9S~ ethanol to yield 3.68 g of an off-white powder. The hydrochloride salt was prepared, recrystallized from 95~ ethanol, and dried in a vacuum oven to give 2.81 g (22~) of 2-(4-(4-(1,2 ~ eo-hi,7r,le-3-yl)-l-piperazinyl)but-yl)-1,2-b~n7ic~th~7~1e-3(2H)-one hydrochloride as an off-white powder. mp: 215-216-C. lH NMR (DMS0-d6): ~ 1.75 (br s, 4), 3.19 (m, 4), 3.49 (m, 4), 3.87 (m, 2), 4.02 (br d, 2), 7.44 (dddd, 2, J - 1.1, 2.8, 7.0, 8.2), 7.57 (ddd, 1, J - 1.1, 7.0, 8.0), 7.68 (ddd, 1, J
1.3, 7.1, 8.4), 7.86 (dq, 1, J - 7.8, 0.7), 8.00 (dt, 1, J - 8.1, 0.9), 8.09 (m, 2), 11.15 (br s, 1). 13C NMR (DMS0-d6): ~ 20.26, 26.27, 42.34, 46.29, 50.45, 54.93, 121.12, 121.91, 123.94, 124.05, 124.55, 125.47, 125.54, 126.90, 128.06, 131.75, 140.38, 152.04, 162.16, 164.34.
Anal. Calcd for C22U24N4052.HCl: C, 57.31; H, 5.46; N, 12.15. Found:
C, 57.21; H, 5.51; N, 12.06.
Pl F 31 (a) PreDaration of 2-(4-chlorobutyl)-l(2H)-Dhthple-7jnnno Sodium hydride (2.56 g, 0.0855 mol, 1.25 eq of an 80~ 0.1 ) was placed under N2 in a 250-mL, round-bottomed flask. The sodium hydride was washed twice wi~h hexanes and the waste hexanes were reDoved. Anhydrous dimethyl~ ~o (DMF) (100.0 mL) was added. To this grey suspension a solution of 1-(2H)-~ 7i (10.0 g, 0.0684 mol) anhydrous DMF (50.0 mL) was added and the resulting solution was allowed to stir at room r . ~ for 0.5 h. This anion solution was added, via cannula, to a 500-mL, round-bottoDed flask r~t9ining a solution of l-bromo-4-chlorobutane (8.67 mL, 12.91 g, 0.0753 mol, 1.1 eq) in anhydrous DMF (100.0 mL). The reaction mixture was allowed to stir at room I , tllre for 4 h. As the reaction proceeded, the mixture became a clear orange solution. Distilled water (10.0 mL) was added and most of the solvent was removed with a rotary e~y~.~L~I. The residue was taken up in dichloromethane and washed with water (2 x 50 ml). The organics were dried over MgS04, filtered and ~ to provide 16.49 g of crude material. The product was purified by flash ~I-L~ with 2:1 hexanes/ethyl acetate as eluant to give 13.11 g of a light orange oil. H NMR indicates that the product is an 80:20 mixture of 2-(4-chlorobutyl)-l(2H)-rhth~l~7innno to its W O 93/16073 C A 2 1851 i 4 3 4 P(~r/GB93/00285 C~L~ , ''ng bromide, as determined by Ir~egr~tiAn of the triplets at 3.56 and 3.43 ppm, respectively. Difference n.O.e.
. ' indicate N-alkylated vs. O-alkylated products. The chloride-bromide mixture was used without further purification.
(b~ PreDaration of 2-(4-(4-(1.2-benzisothiazol-3-vl)-1-DiDera-z1nyl~butvl)-l(~U)-~hthsID7innn~ hydrochloride This compound was prepared according to a method analogous to that described in fxample 13(a). From 3-(1-piperazinyl)-1,2-b~n~1~othio~Ale (3.93 g, 0.0179 mol, 1.1 eq) and an 80:20 mixture of 2-(4-chlorobutyl)-1(2H)-I' ' lo71 and 2-(4-bromobutyl)-1(2H)-I' ' l07~ (4.00 g, 0.163 mol), was obtained 7.75 g of crude material which was purified by flash ~ O ,'~ with 3:1 ethyl acetate/hexanes as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 4.09 g (55~) of 2-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl-1(2H)-phthoIo~inA~ hydrochloride as a white crystalline solid. mp: 252-253-C. lH NMR (DMSO-d6): ~ 1.83 (m, 4), 3.22 (m, 4), 3.61 (br q, 4, J - lO.S), 4.25 (d, 2, J
13.2), 4.20 (t, 1, J - 5.9), 7.47 (ddd, 1, J - 8.1, 7.0, 1.1), 7.59 (ddd, 1, J - 8.1, 7.0, 1.1), 7.89 (m, 1), 7.96 (m, 2), 8.12 (tt, 2, J - 7.6, 1.4), 8.28 (tm, 1, J - 7.8), 8.48 (d, 1, J
0.7), 11.16 (br s, 1). 13C NMR (DMS0-d6): ~ 20.35, 25.29, 46.32, 49.43, 50.46, 55.11, 121.12, 123.94, 124.55, 125.71, 126.78, 126.91, 126.99, 128.06, 129.28, 132.00, 133.45, 138.01, 152.05, 158.36, 162.16.
Anal. Calcd for C23H25N50.HCl: C, 60.58; H, 5.75; N, 15.36.
Fount: C, 60.47 H, 5.78 N, 15.29.
EXAMPJ.F 32 (a) PreDaration of 4-methyl-1(2H~DhthA1a7innn9 2-Acetylbenzoic acid (75.0 g, 0.46 Dol) was taken up in 9S~
ethanol (800.0 mL) and a solution of 85~ hydrazine hydrate (33,0 mL, 0.57 mol) in 95~ ethsnol (50.0 mL) was added. The solution was heated at reflux for 1 h. White solids formed as the reaction yL- - '. The solution was ~ to one half of its original volume by rotary evsrorAti~n in vacuo. The solids were filtered and dried in a vacuum oven to give 68.19 e (93~) of 4-Dethgl-1(2H)rhth~1P7i as a white solid. mp: 222-224-C
[lit. Dp - 222-223-C (Hisrch, A.; Orphanos, D.G. J. Het. Chem..
1966, 3, 38)]. lH NMR (DNSO-d6): 6 2.50 (s, 3), 7.81-8.26 (m, 4), 12.40 (br s, 1).
Anal. Calcd for CgH8N20 C, 67.49; H, 5.03; N, 17.49. Found: C, 67.62; H, 5.08; N, 17.50.
(b) Pr~Daration of 2-t4-broDobutvl)-4-D~thvl-1(2H)-DhthAlP,in~n~
This compound was prepared by a method analogous to that described in ExaDple 31(a). From 4-methyl-1(2H)rhths1A7in~nP
(50.0 g, 0.31 Dol), and 1,4-dibL~ (80.33 g, 0.37 Dol) was obtained 31.05 g (34~ of 2-(4-bromobutyl)-4-Dethyl-1(2H)-phthal-azinone as orange crystals. mp: 166-172'C. lH NMR (DMSO-d6):
1.85 (D, 4), 2.56 (s, 3), 3.58 (t, 2, J - 6.2), 4.13 (t, 2, J
6.6), 7.88 (D, 1), 7.95 (m, 2), 8.29 (dD, 1, J - 8.7), (c) PreDaration of 2-(4-(4-(1.2-benzisothiP7~l-3-yl)-l-DiDera-7i~yl)butyl)-4-methvl-1(2U)-~hthA1A7in~n~ hvdrochloride hvdrate This compound was prepared according to the method outlined in Example 13(a). The crude product obtained from the reaction of 2-(4- bL~ )-4-D~thyl-l(2H)-rhth~lp7i (2.48 g, 8.4 mDol) 3 ~
and 3~ piperazinyl)-1,2 ~ 'CothlP7olp (1.93 g, 8.80 mmol, 1.05 eq) was purified by recrysrs~ tion from acetonitrile to give 2.89 g of the free base as a light orange solid. The l.~d,~ 'loride salt was prepared, recrystallized from 95~ ethanol, and dried in a vacuum oven to give 2.71 g (68~) of 2-(4-(4-tl,2-'~othio7nlP-3-yl)-l-piperazinyl)butyl)-4-Dethyl-1(2H)-phthala-zinone hydrochloride hydrate as an off-white powder. mp:
228-230'C. lH NMR (DNSO-d6): ~ 1.80 (br s, 4), 2.56 (s, 3), 3.20 (m, 4), 3.52 (m, 4), 4.04 (br d, 2, J - 13.3), 4.14 (m, 2), 7.45 (t, 1, J - 7.5), 7.59 (t, 1, J - 7.5), 7.87 (m, 1), 7.98 (d, 2, J
- 3.7), 8.11 (dd, 2, J - 7.8, 4.9), 8.29 (d, l, J - 7.7), 11.08 (br s, 1). 13C NMR (DNS0-d6): ~ 18.55, 20.37, 25.31, 46.36, 49.14, 50.51, 55.13, 121.15, 123.95, 124.57, 125.61, 126.14, 126.90, 128.08, 129.15, 131.75, 133.31, 143.46, 152.06, 158.19, 162.15.
Anal CalCd for C24H27N505 HCl ~ 25 H20 14.76. Found: C, 60.73; H, 6.11; N, 14.73.
_XAMPLF 33 (a) Preuaration of N- ~-t4-(l.2-benzisoth~ 07nl - 3-vl)riperidino)-butvl)rhthAlim~ n~drochloride hvdrate N-(4-Bromobutyl)-~ m~ (Aldrich Chemical Company) (0.956 g, 3.39 mmol), 3-(4-piperidinyl)-1,2-benzisothiazole (0.740 g, 3.39 mmol, 1.0 eq), triethylamine (0.57 mL, 0.412 g, 4.07 mmol, 1.2 eq) and acetonitrile (5.0 mL) was added to a round-bottomed flask. The resulting mixture was placed under N2 and heated at reflux overnight. The dark orange solution was allowed to cool to room I . _ and , ' ~d to a 5, ' ~ funnel with the aid of dichl~,, r' . The reaction mixture was washed with ~rll ot~ potassium carbonate. ~he organics were dried over NgS04, filtered and rP~ to give 1.65 g of a dark orange oil. This crude material was purified by flash .I.L~ ~ gL~L~
~ .7 ~ ~ ~
with ethyl acetate as eluant to give 1.30 g of N-(4-(4-(1,2-ben-zisothiazol-3-yl)piperidino) butyl) phthgl imi~' as a light orange oil which ~ ifi~d to a pale yellow solid upon standing. The free base was taken up in ethyl acetate and HCl (2.7 mL of a 1 N
solution in ether, 1.0 eq) was added. The salt was recrystalli-zed from ethanol/water to give 0.810 g (53~) of the hydrochloride salt as a white solid. Spectral and analytical data indicate one equivalent of HCL and 0.5 eq of water. mp: 220-222-C. lH NMR
(DMS0-d6): ~ 1.73 (m, 4), 2.21 (m, 4), 3.12 (br s, 4), 3.62 (m, 5), 7.54 (ddd, 1, J - 1.1, 7.0, 8.1), 7.63 (ddd, 1, J - 1.2, 6.9, 8.1), 7.88 (m, 4), 8.21 (d, 1, J - 8.1), 8.28 (d, 1, J - 8.1), 10.13 (br s, 1). C NMR (DMS0-d6): 8 20.55, 25.30, 27.63, 35.50, 36.80, 51.44, 55.48, 120.66, 122.98, 123.50, 124.86, 127.97, 131.59, 133.28, 134.33, 151.89, 167.49, 167.94.
Anal Calcd for C24H25N3025 HCl ~ 5 H20 9.04. Found: C, 61.80; H, 5.89; N, 9.05.
FY~uPJ.F 34 (a) PreDaration of ethyl N-(2-Dhenethyl)carbamate Phenethylamine (Aldrich Chemical Company) (31.1 mL, 30.0 g, 0.248 mol), triethylamine (34.6 mL, 25.1 g, 0.248 mol, 1.0 eq) and anhydrous dichluL~ ' (300.0 mL) were added to a l-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and a nitrogen inlet. The solution was cooled in an ice-water bath and a solution of ethyl chlu~ r - (Aldrich Chemical Company) (23.7 mL, 26.9 g, 0.248 mol, 1.0 eq) in dichlul~ ~'~ (25 mL) was added dropwise. The reaction mixture was stirred for 0.5 h and ether (150 mL) was added. The resulting , '~ was filtered and the filtrate was c~ A to give 46 g (96~) of an oil which soliiifi~d to a white solid upon standing. The crude material was used without further purification.
(b) P,. nn of 3.4-dihvdro-1(2H)-isoouinolinone Ethyl N-(2-phenethyl)carbamate (46.0 g, 0.238 mol) and pol~ ic acid (475.0 g) was added to a l-L, round-bottomed flask equipped with a magnetic stirring bar and reflux condenser, The mixture was heated in an oil bath at 140-160-C for 2 h. The reaction mixture was allowed to cool to room i . ~ and poured into aistilled water (2.4 L). The organics were extracted with ethyl acetate, washed with saturated NaCl, dried over MgS04, filtered and c~ r-d to give 4.36 g of an orange oil. The crude material was purified by flash ol..~ with ethyl acetate as eluant to give 1.85 g (5.1~ based on phenethylamine) of 3,4-dihydro-1(2H)-i , nnli as a light orsnge oil. lH
NMR ~CDC13): ~ 3.01 (t, 2, J - 6.6), 3.58 (dt, 2, J - 2.9, 6.6), 6.20 (br s, 1), 7.22 (dd, 1, J - 0.7, 7.4), 7.36 (ddd, 1, J
1.3, 7.6, 8.3), 7.46 (ddd, 1, J - 1.6, 7.5, 9.0), 8.07 (dd, 1, J
- 1.1, 7.7).
(c) Pre~aration of 2-(4-nhlnrobutvl~-3.4-~ih~vdro-l(2H~ ~nnlinnno Sodium hydride as an 80~ oil ~i~F-rsion (0.945 g, 31.5 mmol, 2.5 ~q) was added to a flame-dried, 100-mL, ,~.d b~ ' flask equipped with a magnetic stirring bar and nitrogen inlet. The sodium hydride was washed with hexanes (3X), and the waste hexanes were removed each time with a pipet. To the washed sodium hydride was added anhydrous N,N-dimethyl' A~ (20.0 mL) and the resulting - ~ ~or was cooled in an ice-water bath.
To the cooled reaction mixture was added a solution of 3,4-dihydro-1(2H)-isoquinolinone (1.85 g, 12.6 mmol, 1.0 eq) in anhydrous N,N-dimethyl' ~ (20.0 mL) dropwise. The cooled reaction mixture was allowed to stir for 15 min and allowed to warm to room ~ . e. After 5 min., the reaction mixture was cooled with an ice-water bath and l-bromo-4-chlorobutane (1.59 mL, 2.37 g, 13.8 mmol, 1.1 eq) was added dropwise. The reaction mixture was allowed to warm to room t . _ and stirred for ~. 1 ' ~ 7 ~ ~ ~
W O 93/16073 PCT/GB93/OOt85 0.5 h. The excess sotium hydride W85 quenched with distilled water (10 mL), the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organics were dried over MgS04, filtered, and c~ i to give 5.16 g of an orange oil. The crude material was purified by flash ~L~ e . ~ ~ with 3:2 hexanes/ethyl acetate as eluant to give 1.90 g (63t) of 2-(4-chlorobutyl)-3,4-dihydro-1(2H)-i , ~nnlin one as a colorless oil.
(d) r.._ _~'on of N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDera-zinyl~butyl)-3.4-~ihvdro-1(2H)-isoouinolin~~o hydrochloride - 2-(4-Chlorobutyl)-3,4-dihydro-1~2H)-isoquinolinone (1.90 g, 7.99 mmol), 3-(1-piperazinyl)-1,2-~ ~othio~ole (2.10 g, 9.59 mmol, 1.2 eq), triethylamine (1.56 mL, 1.13 g, 11.2 mmol, 1.4 eq) snd acetonitrile (25.0 mL) were added to a 100-mL, round-bottoDed flask equipped with a agnetic stirring bar, condenser and nitrogen inlet. The reaction mixture was heated to reflux under nitrogen for 30 h. The reaction was incomplete as indicated by TLC; therefore, ~A~iti. 1 portions of 3-(1-piperazinyl)-1,2-ben-7i~othio7ole (0.350 g, 1.60 mmol, 0.2 eq) and triethylamine (0.670 mL, 0.486 g, 4.81 mmol, 0.6 eq) were added and the reaction mixture was heated to reflux for an additional 24 h.
The solution was allowed to cool to room ~ . e and , ~ ~d to a . ~ funnel with the aid of ethyl acetate.
The solution was washed with saturated potassium carbonate. The organics were dried over MgS04, filtered and c ' to give 5.2 g of an orange oil. The crude material was purified by flash ch.. ~ ~h~ with ethyl acetate/O.l~ triethylamine as eluant to give 2.26 g of an orange oil. The free base was taken up in ethyl acetate and HCl (5.37 mL of a lN solution in ether. 1.0 eq) was added. The resulting salt was recrystallized from ethanol to give 2.0 g (55~) of a light orange solid. mp: 229-231-C. lH NMR
(DMSO-d6): 6 1.66 (m. 2). 1.78 (m, 2), 3.00 (t, 2, J - 6.6), 3.27 (m. 4), 3.52 (m, 8), 4.07(br d, 2. J - 13.0). 7.31 (d, 1, J
W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
8.0), 7.37 (dd, 1, J - 1.5, 7.4), 7.48 (dt, 2, J - 1.2, 7.5), 7.60 (dt, 1, J - 0.8, 7.5), 7.88 (dd, 1, J - 1.1, 7.5), 8.12 (t, 2, J - 7.9), 10.68 (br s, 1). 13C NMR (DMS0-d6): ~ 20.46, 24.37, 27.36, 45.36, 45.69, 46.31, 50.44, 55.22, 121.14, 123.95, 124.56, 126.60, 126.91, 127.17, 127.26, 128.06, 129.15, 131.45, 138.60, 152.05, 162.17, 163.17.
Anal. Calcd for C24H28N40S.HCl: C, 63,07; H, 6.40; N, 12.26.
Found: C, 63.04; H, 6.43; N, 12.23.
(a) Pr~nAr~ri~n of methyl 2-(N.N-dimethvl-N'-~ ~inyl)benzoate This compound was prepared according to the method described by J. T. Gupton et al. ~Tet_ ' '..~.. 1987, 43, 1747). Treatment of ' 'l;r acid (Aldrich Chemical Company) (6.0 g, 43.8 mmol) with N,N-dimethyl' ~- dimethylacetal (Aldrich Chemical Company) (15.5 mL, 13.9 g, 116.8 mmol, 2.67 eq) gave 6.2 g (69~) of methyl 2-(N,N-dimethyl-N'-' ~A;nyl)benzoate as a purple liquid.
(b) F,. _: on of 3-(4~4-(1.2-benzisothi~nl-3-yl)-l-DiDera 7;~yl)butvll-4(3Hl ~ ~r~ ;n~ hvdrochloride 3-(4-(4-~ ' ~1)-1-piperazinyl)-1,2-benzisothiazole (0.960 g, 3.31 mmol, 1.1 eq), (Example 13(b)) p-toluene sulfonic acid (0.1 g), anhydrow 1,4-dioxane (45 mL) and methyl 2-(N,N-dimethyl-N'-f~ ~;nyl)benzoate (0.621 g, 3.01 mmol, 1.0 eq) were added to a flame-dried, 250-mL, round-bottomed flask equipped with a magnetic stirring bar, condenser and nitrogen inlet. The reaction mixture was heated at reflux for 1 h, allowed to cool to rOOm ~ , ~, and c ' to give an orange oil. The oil was dissolved in a solution of ethyl acetate and dlchlur. th~ and the organics were washed with saturated W O 93/16073 921 ~ ~ 3~ PCT/GB93/00285 potassium carbonate. The organics were dried over MgS04, fLltered and o~ t-d to give 1.41 g of a tan solid. The crude material was purified by flash ~LL~ with 24:1 dichluL~ i' /methanol as eluant to give 1.02 g of a white solid. To a solution of the free base in ethyl acetate was added HCl (2.43 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/water to give 0.810 g (59~) of 3-(4-(4-(l~2-b~n7icothio7ol-3-yl)-l-piperazin yl)butyl)-4(3N)-quinazolinone hydrochloride as a white solid.
mp: 238-240-C (dec). lH NMR (DNSO-d6): 8 1.80( br s, 4), 3.28 (m, 4), 3.47 (br t, 2, J - 12.6), 3.58 (br d, 2, J - 12.0), 4.05 (br s, 3), 4.08 (m, 1), 7.47 (ddd, 1, J - 1.1, 6.9, 8.1), 7.58 (qm, 2, J - 8.4), 8.12 (t, 3, J - 8.0), 8.18 (ddd, 3, J - 0.6, 1.6, 8.0), 8.46 (s, 1), 10.86 (br s, 1). C NMR (DNSO-d6):
20.24, 25.78, 45.25, 46.31, 50.42, 54.89, 121.12, 121.48, 123.94, 124.56, 125.97, 126.90, 126.97, 127.11, 128.06, 134.22, 147.87, 147.96, 152.05, 160.17, 162.16.
Anal. Calcd for C~U 5N~.NCl: C, 60.58; H, 5.75; N, 15.36.
Found: C, 60.68; N, 5.75; N, 15.41.
EXAMP! F 36 (a) FL~ . of 2-Pmin~-N-(4-(4-(l.2-~n7ic~thi~7~l-3-yl) nin-rD7lr~Yl)but~yl)~ ' hydr~rhl-ride Isatoic anhydride (Aldrich Chemical Company) (0.894 g, 5.48 mmol), ethanol (15.0 mL) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.59 g, 5.48 mmol, l.0 eq) (Example 13(b)) were added to a round-bottom flask equipped with a magnetic stirring bar and nitrogen inlet. The reaction mixture was stirred at room ~ , ~t~Le for 22 h. The solvent was removed in vacuo to give 2.35 g of a brown oil. The crude material was purified by flash ~LL~ with 19:1 dichlui~ ' /meth-anol as eluant to give 1.28 g of an orange oil which became a W O 93/16073 ~ h ~ i ~ t P<~r/GB93/00285 pale yellow solid upon stanting. To a solution of the free base ~0.35 g, 0.855 mmol) in ethyl acetate and ethanol was added HCl (O.B55 mL of a lN solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystsllized from 95~ ethanol to give 0.230 g (60~) of 2-amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-l-piperazinyl)butyl)benzamide hydrochloride 8S a white solid, mp: 227-228-C. lH NMR (DMS0-d6): 6 1.58 (m, 2), 1.79 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.8), 3.59 (br d, 2, J - 12.4), 4.09 (br d, 2, J - 13.2), 6.41 (br s, 2), 6.51 (ddd, J - 1.1, 7.0, 8.1), 6.69 (dd, 1, J - 1.1, 8.2), 7.13 (ddd, 1, J - 1.5, 7.0, 8.4), 7.48 (m, 2), 7.60 (ddd, 1, J - 1.1, 7.0, 8.0), 8.13 (t, 2, J - 8,4), 8.29 (t, 1, J - 5.5), 10.68 (br s, 1). 13C NMR
(DMS0-d6): ~ 20.64, 26.28, 37.98, 46.35, 50.42, 55.14, 114.49, 114.75, 116.26, 121.14, 123.95, 124.57, 126.10, 126.91, 128.01, 128.07, 131.51, 149,47, 152.06, 162.16, 168.85.
Anal- Calcd for C22H27N505,HCl: C, 59.25; H, 6.33; N, 15.70.
Found: C, 59.18; H, 6.35; N, 15.68.
~XAMP!~ 37 (a) P.._ _~'on of 3-(4-(4-(1.2-hDn~i~Athio~ 3-yl)-l-DiDera zi nyl )butYl)-1.2.3 _h on7 ~triazin-4(3H)-one hydrochloride 2-Amino-N-(4-(4-(1,2 ~ ~orhiD~ol-3-yl)-l-piperazinyl)butyl)be-nzamide (0.960 g, 2.34 mmol) (Example 36(a)), distilled water (11.0 mL) and conc. HCl (1.06 mL) were added to a round-bottomed flask equipped with a magnetic stirring bar, nitrogen inlet and adtition funnel. The reaction mixture was cooled in an ice-water bath and a solution of sodium nitrite (0.186 g, 2.70 mmol, 1.15 eq) in distilled water (2.58 mL) was added dropwise. The reaction mixture was stirred for 2 h and treated with 1.2 mL of 10 N sodium hydroxide. After 1 h, the pH was adjusted to 6-7 by the addition of acetic acid and ~ ly to a pH of 10 with 10 N sotium hydroxide. The organics were extracted with ethyl ~ 2 1 7 ~7 ~ 3 ~
acetate, dried over MgS04, filtered and e ~ ' to give 0.900 g of an orange oil. The crude material was purified by flash ~ . g ,'~ with 2:1 ethyl acetate/hexanes to give 0.630 g of a white solid. The free base was dissolved in ethyl acetate and to this solution was added HCl ~1.5 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/water to give 0.490 g (464) of 3-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2,3 benzotriazin-4t3H)-one hydrochloride as a white solid. mp:
242-243.5-C. H NMR (DHS0-d6): 6 1.89 ~m, 4), 3.24 (m, 4), 3.43 (br t, 2, J - 11.9), 3.59 (br t, 2, J - 11.1), 4.07 (br d, 2, J -11.4), 4.46 (t, 2, J - 6.5), 7.47 (tm, 1, J - 7.5), 7.60 (tm, 1, J - 7.5), 7.96 (ddd, 1, J - 1.3, 7.2, 7.9), 8.12 (m, 3), 8.24 (dd, 1, J - 0.7, 8.1), 8.29 (ddd, 1, J - 0.5, 1.4, 7.9), 10.5 (br s, 1). 13C NMR (DMS0-d6): ~ 20.36, 25.52, 46.33, 48.50, 50.49, 55.02, 119.24, 121.15, 123.96, 124.54, 124.57, 126.91, 127.94, 128.08, 132.89, 135.35, 143.66, 152.06, 154.78, 162.16.
Anal. Calcd for C22H24N605.HCl: C, 57.82; H, 5.51; N, 18.39.
Found: C, 57.92; H, 5.53; N, 18.45.
FY~ PT.~ 38 (a) PreDaration of N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDerazinYl) butyl)-3-~hlnro-5-ethyl-2.6-~ hvdrochloride Anhydrous toluene (100.0 mL) and 3-chloro-5-ethyl-2,6-dimethoxy-benzoic acid (4.32 g, 0.0176 mol) (obtained in three steps from 2,4-dimethylacetophenone (Aldrich Chemical Company) by the method of de Paulis et al. J.Med.Chem. 1985, 28 (9), 1263-1269 J.Med.Chem. 1986, 29(1), 61-69) were added to a oven-dried, 300 mL, round-bottomed flask. The solution was placed under a nitrogen ~- .' e and thionyl chloride (4.13 mL, 0.0476 mol, 2.7 eq) was added. The light yellow solution was heated to is~c and anhydrous dimethyl' ~ (0.25 mL) was added. The reaction mixture was heated at 65-75 C for 1.25 h and the solvent was removed with a rotary e~y~L~LuL. The resulting orange residue was taken up in anhydrous chlorofo D (50 mL) and placed under nitrogen. 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benziso-thiazole (Example 13(b)) (5.63 g, 0.0194 mol, 1.1 eg) in chlorofo D (20.0 mL) followed by anhydrous trithylamine (2.94 mL, 0.021 mol, 1.2 eq) was added to this crude acid chloride. The resulting clear orange mixture was allowed to a stir at room ~ , ~ for 0.75 h. The solvent was removed with a roeary e~ L~toI and the viscous orange oil was taken up in dichluL. Ll.~... and washed with saturated K2C03. The organics were dried over MgS04, filtered and r. .._....Ar/d to give 10.03 g of a viscous orange oil. This crude material was purified by flash ~1.,l ~ .'~ with ethyl acetate as eluant followed by ethyl acetate/0.1~ triethylamine as eluant to give 4.78 g of the free base as a pale yellow oil. The free base was dissolved in ethanol and HCl (9.24 mL of a lN solution in ether) was added.
The solution was heated and fil~ ~ed hot. Ether was added to the ethanolic solution and the mix~ure was allowed to cool. The solids that fo Ded upon cooling were filtered, washed with ether and dried in a vacuum oven to give 2.96 g (30~) of the title compound as a light tan powder. mp: 198.5-200~C. lH NMR
(DMS0-d6): ~ 1.16 (6, 3, J - 7.5), 1.60 (m, 2), 1.83 (br s, 2), 2.58 (q, 2, J - 7.5), 3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br d, 2, J - 12.1), 7.38 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 8.14 (t, 2, J - 7.0), 8.50 (t, 1, J - 5.3), 10.66 (br s, 1). 13C NMR (DMS0-d6): ~ 14.76, 20.73, 21.80, 26.46, 46.57, 50.67, 55.39, 61.89, 62.27, 121.49, 121.76, 124.30, 124.95, 127.28, 128.45, 129.16, 130.17, 134.64, 150.88, 152.48, 153.96, 162.56, 164.26.
Anal. Calcd for C26H33N4035Cl.HCl: C, 56.41; N, 6.19; N, 10.12.
Found: C, 56.31; H, 6.18; N, 10.08.
CA 2 i 1 7434 EXA~pJ.F 39 (a) PreDaration of ethYl 2.3-Aihvdro-3-oxo-lH-indazole-l-carboxylate Starting materials: 3 T~A~7~ (Aldrich Chemical Company), Ethyl Chl~L~f~ (Aldrich Chemical Company). This compound was prepared according to the method described by S. D. Wyrick et al. (J. Med. Chem. 1984, 27, 768). mp:l93-195-C. H NMR
(DMS0-d6): 6 1.37 (t, 3, J - 7.1), 4.41 (q, 2, J - 7.1), 7.34 (ddd, 1, J - 0.8, 7.1, 8.0), 7.61 (ddd, 1, J - 1.2, 7.2, 8.4), 7.75 (dt, 1, J - 7.8, 1.0), 8.04 (d, 1, J - 8.4), 12.13 (br s, 1). 13C NMR (DMSO-d6): ~ 14.14, 62.84, 114.09, 117.16, 120.43, 123.36, 130.00, 140.28, 150.04, 158.50.
CloHloN203: C, 58.25; H, 4.89; N, 13 59 Found C, 58.30; H, 4.93; N, 13.61.
(b) P~ _ on of Ethyl 2-(4-chlorobutyl)-z~3-~ih~ydro-3-oxo-lH-indazole-l-carboxvlate and Ethyi 2-(4-bromobutyl)-2.3-dihydro-3-oxo-lH-indazole-l-carboxYlate Sodium hgdride (1.51 g, 50.3 mmol, 1.2 eq) as an 80~ oil dispersion was added to a flame-dried, 250-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The sodium hydride was washed with hexanes (3X). To the washed sodium hydride was added anhydrous N,N-dimethyl~ ~A~ (50,0 mL) and the resulting grey r~ ~n was cooled in an ice-water bath. Ethyl 2,3-dihydro-3-oxo-lH-indazole-l-carboxylate (8.65 g, 41.9 mmol) was added slowly with a spatula to the cooled reaction mixture. To the cooled reaction mixture was added l-bromo-4-chlorobutane (Aldrich Chemical Company) (5.31 mL, 7.91 g, 46.1 mmol, 1.1 eq). The reaction mixture was slowly warmed to 65-C and stirred overnight at 65-C. The reaction mixture was allowed to cool and the excess sodium hydride was quenched with distilled water (2 mL). The W O 93/16073 ~ A 2 1 1 7 ~ J ~ , PCT/GB93/0028~
ma~ority of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and distilled water. The organics were driet over MgS04, filtered, and c~ ..LLeted to give 12.2 g of an orange oil. lH NMR of this crude material indicated that both N-alkylated and O-alkylated products were forDed. Fu~ i' e, these alkylated products were obtained as mixtures of their C~LL~_r ng chlorides and bromides. The crude oil was purified by flash ~ with 3:1 hexanes/ethyl acetate as eluant to give 2.00 g of Ethyl 2-(4-chlorobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate and Ethyl 2-(4-bromobutyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxy-late as a 60:40 mixture of the chloride and bromide. The chloride/bromide ratio was determined by int-gr~tion of their ..llng methylene triplets at 3.39 and 3.52 ppm, ~ ti~_ly. This material was used as a mixture without further isolation of each halide.
(c) ~ l~n of ethyl 2-(4-(4-(1.2-h~n~ie~th~7~l-3-vl)-l-DiDera-7i~yl~butyl)-2.3-iih~dro-3-oxo-lU-in~i~7~le-l-carbox~late hydrnrhl nride A 60:40 mixture of ethyl 2-(4-chlorobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate and ethyl 2-(4-bromobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate (3.13 g, 9.68 mmol), 3-(1-pipera-zinyl)-1,2-ben~iF7thi~77l~ (3.84 g, 17.5 mmol, 1.8 eq), triethyl-amine (2.44 DL, 1.77 g, 17.5 mmol, 1.8 eq), and acetonitrile (30.0 mL) was added to a 50-mL, round-bottomed flask equipped with a magnetic stirring bar, condenser and nitrogen inlet . The reaction mixture was heated at reflux under nitrogen overnight.
The reaction mixture was allowed to cool to rooD ~ ~ e and partitioned between ethyl acetate and saturated potassium carbonate. The organics were dried over MgS04, filtered and e ~ ' to give 7.18 g of a oily tan solid. The crude material was purified by flash cl.,~ ~ gL~L~ with 2:1 ethyl acetate/hexanes followed by ethyl acetate to give 2.97 g of the CA 2 i 1 7434 free base as B yellow oil. To a solution of the free base in ethyl acetate was added HCl (6.2 mL of a lN solution in ether, 1.0 eq~. The resulting hydrochloride salt was recrystallized from ethanol to give 0.52 6 (8~) of ethyl 2-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxylate hydrochloride as beige solid. mp: 189-l90-C. H
NMR (DMS0-d6): 6 1.41 (t, 2, J - 7.1), 1.66 (br s, 3), 3.23 (m, 6), 3.42 (br t, 2, J - 12.1), 3.53 (br d, 2, J - 12.0), 4.05 (br d, 2, J - 13.2), 4.15 (m, 2), 4.44 (q, 2, J - 7.1), 7.46 (m, 2), 7.60 (ddd, 1, J - 0.9, 7.1, 8.0), 7.78 (ddd, 1, J - 1.3, 7.2, 8.5), 7.84 (ddd, 1, J - 0.8, 1.3, 7.7), 7.94 (d, 1, J - 8,4), 8.12 (t, 2, J - 6.9), 10.53 (br s, 1). 3C NMR (DMSO-d6). 6 14.05, 20.36, 24.51, 45.78, 46.27, 50.41, 54.90, 64.10, 115.39, 117.86, 121.14, 123.37, 123.95, 124.57, 124.90, 126.91, 128.07, 133.88, 142.68, 150.63, 152.05, 162.15, 163.75.
Anal. Calcd for C25H29N5035.HCl: C, 58.19: H, 5.86; N, 13.57.
Found: C, 58.06; H, 5.89; N, 13.51.
FY IluPLF 40 (a) Preoaration of 2-(4-(4-(l.2-ben7i~~thiA7nl-3-vl)-l-DiDerA7in~yl) butvl~-1.2-dihydro-3H-indazol-3-one hvdrochloride hydrate Ethyl 2-(4-(4-(1,2 ~ ~othiA-ol-3-yl)-1-piperazinyl)butyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxylate (1.88 g, 3.92 mmol) (Example 39(c)) and potassium hydroxide (23.7 mL of a 0.67 M
solution in ethanol) were added to a 300-mL, round-bottomed flask equipped with a Dagnetic stirring bar, nitrogen inlet and condenser, The reaction mixture was refluxed under nitrogen for 2 h. The reaction mixture was allowed to cool to room t . e and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium carbonate. The organics were dried over MgSO4, filtered and ' to give 1.37 g of the crude product as an orange W O 93/16073 C k ? i91 7 4 3 4 PCT/GB93/00285 oil. The crude material was purified by flash .1.-~ DLp~
with 92:8 dichloromethane/methanol as eluant to give 1.03 g of the free base as a light yellow solid. To a solution of the free base in ethyl acetate and dichlo-- t~- was added HCl (2.53 mL
of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/ether to give 0.36 g (20~) of 2-(4-(4-~1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2-dihyd-ro-3H-indazol-3-one b~IL~ 'loride hydrate as a white solid. mp:
80-90-C (softens, shrinks), 125-145-C (effervesces). lH NMR
(DMS0-d6): C 1.77 (m, 4?~ 3.25 (m, 4), 3.44 (m, 2), 3.56 (br d, 2, J - 11.4), 3.87 (t, 2, J - 6.0), 4.06 (br d, 2, 3 - 13.3), 7.11 (ddd, 1, J - 0.8, 7.1, 8.0), 7.28 (dt, 1, J - 8.3, 0.8), 7.47 (ddd, 1, J - 1.1, 6.4, 8.2), 7.52 (ddd, 1, J - 1.2, 6.5, 8.3), 7.60 (ddd, 1, J - 1.1, 7.0, 8.2), 7.65 (dt, 1, J - 7.9, 1.1), 8.12 (t, 2, J - 7.8), 10.4 (br s, 1), 10.7 (br s, 1). 13C
NMR (DMS0-d6): C 20.31, 25.04, 42.41, 46.33, 50.49, 54.94, 112.12, 117.20, 120.80, 121.15, 122.87, 123.96, 124.58, 126.91, 128.08, 131.20, 145.91, 152.06, 160.58, 162~16.
Anal. Calcd for C22H25N50S.HClØ75 H20: C, 57.76; H, 6.06; N, lS.31; H20, 2.95. Found: C, 57.71; H, 6.10; N, 15.20; H20, 2.73.
F~AMPJ.F 41 (a) PrPnAration of 2- 'n~-N-(4-(4-(l.2-benzisothi~7~l-3 ~ in"r~ yl ) butyl ) - S - chlor~hPn7 ~ AP hydr~lrhl oride This compound was prepared according to the method described in Example 36, by employing S-chloroisatoic anhydride (Aldrich Chemical Company) (1.02 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (l.S g, 5.17 mmol, 1.0 eq, (Example 13(b)). The free base was purified by flash cl..~ with 1:1 ethyl acetate/hexanes as eluant. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.61 g (65~) of 2-amino-N-(4-(4-(1,2-benzi-CA 2 i i 7434 W O 93/t6073 PCT/GB93/00285 sothiazol-3-yl)-1-piperazinyl)butyl)-5-chlu--L '~le hydrochloride as a white solid. mp: 173-176-C. H NMR (DMS0-d6):
~ 1.57 (m, 2), 1.78 (m, 2), 3.10-3.68 (m, 12), 4.08 (br d, 2, J -13.1), 6.74 (d, 1, J - 8.9), 7.18 (dd, 1, J - 2.4, 8.8), 7.48 (tm, 1, J- 7.2), 7.57 (d, 1, J- 2.4), 7.60 (tm, 1, J- 7.2), 8.13 (t, 2, J- 8.6), 8.45 (t, 1, J- 5.3), 10.70 (br s, 1). 13C
NMR(DMS0-d6): 6 20.64, 26.19, 38.20, 46.35, 50.44, 55.16, 116.75, 118.78, 119.04, 121.18, 124.00, 124.61, 126.95, 127.44, 128.12, 131.37, 146.88, 152.11, 162.21, 167.41.
Anal. Calcd for C22H26N505Cl.HCl: C, SS.00; H, 5.66; N, 14.58.
Found: C, 54.91; H, 5.69; N, 14.51.
FXAMPT.F 42 (a) PreDaration of 2- 'r~-N-(4-(4-(l~2--h~n7ienthip7~l-3 ,DirAr~7ir,~Yl)butyl)-s-nitr-' ~' hYdrnrhlnride The compound was prepared according to the method described in ExamDle 36, by employing 5-nitroisatoic anhydride (Trans Uorld Chemicals) (1.08 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-ben2isothia2O1e (l.S g, 5.17 mmol, 1.0 eq) (Example 13(b)). The free base was purified by flash cl.-~ -ogr~Ahy with ethyl acetate as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 1.10 g (43~) of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl)-S-niL-o~~ hydrochloride as a yellow solid. mp: 224-230'C (dec).H NHR(DMSO-d6): ~ 1.61 (m, 2), 1.80 (m, 2), 3.28 (m, 4), 3.46 (br t, 4, J- 12.1), 3.59 (br d, 2, J- 10.2), 4.08 (br d, 2,J- 12.8), 6.82 (d, 1, J- 9.3), 7.48 (t, 1, J- 7.6), 7.60 (t, 1, J- 7.2), 7.80 (br s, 2), 8.03 (dd, 1, J- 2.5, 9.1), 8.13 (t, 2, J- 8.3), 8.52 (d, 1, J -2.5), 8.80 (t, 1, J- 5.3), 10.72 (br s, 1). C NMR (DMsO-d6j:
~ 20.72, 26.17, 38.34, 46.38, 50.48, 55.20, 112.87, 115.85, CA 2 i i 7434 W O 93/16073 P(~r/GB93/0028~
121.18, 123.99, 124.61, 125.71, 126.95, 127.35, 128.11, 134.86, 152.11, 155.31, 162.21, 167.21.
.
Anal. Calcd for C22H26N6035.HCl: C, 53.B2; H, 5.54; N, 17.12.
Found: C, 53.95; H, 5.57; N, 17.05.
_XAMPLF 43 (a) PreDaration of N-(4-(4-(l.2-h~7i~~thio7~l-3-vl)-l-oi~era 71~yl~butvl~-2-(methylamino)~ hydrochloride This compound was prepared according to the method described in Fxample 36, by employing N-Dethylisatoic anhydride (Aldrich Chemical Comp-ny) (0.92 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 eq) (_xample 13(b)). The free base was purified by flash h~ with ethyl acetate as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/ether, and dried in a vacuum oven to give 1.22 g (51~) of N-(4-(4-(1,2-benzisoth-iazol-3-yl)-1-piperazinyl)butyl)-2-(methylamino)benzamide hydro-chloride as a pale beige solid. mp: 169-173'C. lH NMR
(DMS0-d6): ~ 1.58 (m, 2), 1.81 (m, 2), 2.77 (s, 3), 3.30 (m, 4), 3.48 (br d, 3, 3 - 13.8), 3.58 (br d, 3, J - 12.9), 4.07 (br d, 2, J - 14.8), 6.56 (t, 1, J - 7.4), 6.63 ( d, 1, J - 8.3), 7.29 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.5), 7.57 (d, 1, J - 7.2), 7.61 (d, 1, J - 7.4), 7.64 (br s, 1), 8.13 (t, 2, J - 8.3), 8.41 (br t, 1, J - 5.4), 11.00 (br s, 1). C NMR (DHS0-d6): ~ 20.66, 26.28, 29.33, 38.08, 46.36, 50.44, 55.18, 110.55, 114.03, 115.24, 121.17, 123.99, 124.61, 126.96, 128.11, 128.20, 132.26, 149.91, 152.12, 162.20, 169.12.
Anal. Calcd for C23H29N50S.HCl: C, 60.05; H, 6.57; ~, 15.22.
Found: C, 60.09; H, 6.60; N, 15.13.
CA2i 1 7434 F"XAMPT.F 44 (8) F,~ ~,tlon of (+/-)-oi~-2-(Nethoxvcsrbonvl) rArboxyll~ acid Cis-1,2-Cyrl.~ dicarboxylic anhydride (Aldrich Chemical Company) (10.0 g, 64.9 mmol) and methanol (2.76 ml, 2.18 g, 68.1 mmol, 1.05 eq) were added to a .u~.d b~L ' fl-sk equipped with a magnetic stirring bar and a reflux condenser. The reaction mixture was heated with an oil bath at lOO-C for 1 h. The reaction mixture was allowed to cool to room s , e and the excess methanol was removed in vacuo to obtain 12.0 g (lOOa) of (+/-)-Cis-2-(meLI.~ l)-l-cyrl~ rb~vylic acid as an oil which became a white solid upon standing. mp: 63-66-C. H
NMR (CDC13): ~ 1.35-1.65 (m, 4), 1.80 (m, 2), 2.03 (m, 2), 2.86 (m, 2), 3.68 (s, 3). C NNR (CDC13): ~ 23.63, 23.75, 25.96, 26,26, 42.34, 42.48, 51.71, 174.04, 179.71.
Anal. Calcd for C9H14C4: C, 58.05; H, 7.58. Found: C, 57.97; H, 7.61.
(b) Fr~nArAr;~n of (+/-)-cis-methYl 2-(l~dLUA~_ Ll.~l)-l-cvclohexane-carboxvl At~
(+/-)-cis-2-(Nethoxycarbonyl)-l-cy~ lic acid (11,7 g, 63.0 mmol) and anhydrous teL,al.~l,uf (35.0 mL) was added to a flame-dried, 250-mL, three-necked, round b,~ ~ flask equipped with a magnetic stirring bar, septum and nitrogen inlet.
The resction mixture was cooled with an ice-water bath rontA~nine rock salt. A lN solution of borane in Lei '~d,ufu,~.. (69.0 mL, 69.0 mmol, 1.1 eq) (Aldrich Chemical Company) was slowly added over a 25 min period to the cooled reaction mixture via a syringe. The stirred solution was allowed to warm to room ~ e overnight. The reaction mixture was cooled with an ice-water bath and distilled water (55.0 mL) and potassium C~2i 17434 carbonate ~17.0 g) were addet. The aqueow snd organic phases were . ~m~ The aqueous phase W8S extracted with ethyl acetste followed by ether. The organics were combined and washed with ~t~r~ted sodium chloride, dried over HgS04, filtered and ' to give 10.9 g of an oil. 7he crude material was purified by ilash .1~ with 2:1 hexanes/ethyl acetate to give 6.47 g (59~) of (+/-)-cis-Dethyl 2;(1.~d,uA~. thyl)-l-cycl~ late as a colorless oil. H NMR (CDC13): 6 1.30-1.75 (m, 7), 1.89 (m, 1), 1.97 (t, 1, J - 6.0), 2.02 (m, 1), 2.76 (m, 1), 3.63 (m, 2), 3.68 (s, 3). C NMR (CDC13): 6 23.55, 26.22, 26.34, 40.65, 42.32, 51.44, 64.27, 175.75.
Ansl. Calcd for CgH16C3: C, 62.77; H, 9.36. Found: C, 62.69 H, 9.35.
(c) F.~ 1 of methvl 2-fo~myli (+/-)-~i~-Hethyl 2-(L~d~ l)-l-cyrlr~ ' ~late (7.20 g, 41.8 mmol), anhydrous dimethylr~lfrvid~ (42.0 mL), anhydrous dirhl. L~ (200.0 mL) and trlethylsmine (29.1 mL, 21.2 g, 209 mmol, 5 eq) was added to a flsme-dried, l-L, three-necked, ,~ ' b : ' flask equipped with a magnetic stirring bar, i' L~ and nitrogen inlet. The reaction mixture was cooled in an ice-water bath and sulfur trioxide pyridine complex (Aldrich Chemical Company) (26.6 g, 167 mmol, 4.0 eq) was sdded in three equal portions at 5 min intervals. She reaction mixture vas allowed to stir for 1.5 h. Distilled water (200.0 mL) was added and the aqueous and organic phases were _ , ~ ' The aqueous phase was washed with dichloromethane, the organics were combined and ~ ~ ' to give a pale orange liquid. The product was partitioned between distilled water and ether. The organics were dried over hgS04, filtered and ~ to give 7.45 g of a light yellow oil. The crude product was puri;ied by flash cl.i~ with 12:1 hexanes/ethyl acetate as eluant to ' CA21 1 7434 give 4.98 g (70~) of methyl 2-formylbenzoate 85 a colorless liquid.
(d) F.~_ _~lon of (+/-)-cis-4A. 5. 6. 7. 8. 8A-hexahydro-1(2H)-phthslP2in~~ snt (+/-~- -4A. 5. 6. 7. 8. 8A-U~shvdro-1(2H)-~hthp1A7inAnp (+/-)-cis-Methyl 2-formylbenzoate (11.9 g, 69.8 mmol), 95~
ethanol (120 mL) ant hytrazine hytrate (Fisher Scientific) (9.0 g, 154 ~mol, 2.2 eq) as an 85~ aqueous solution was atded to a round -bottomed flask equipped with a magnetic stirring bar, reflux condenser, and nitrogen inlet. The reaction mixture was refluxet for 0.5 h, coolet to room i . ~, and in vacuo. The residue was partitioned between distillet water (100.0 mL) and ethyl acetate (300.0 mL). The organics were dried over MgS04, filteret ant c~ ' to give 7.79 g (74~) of a pale yellow oil. The crute material was used without further fi r~ti ~
(e) Pr~nsrPtir~ of (+/-)-cic-2-(4-rhlrrobutyl)-4A 5. 6. 7. 8. 8A-h~s~vdro_l(2U)_nhth~lD7in~n~ and (+/-)-trans-2-(4-rhl~robutvl) 4A. 5. 6. 7. 8. 8A-~ (2u)-~hth-lp7in~n~
Sodium hydride (Aldrich Chemical Company) (3.07 g, 103 ~mol, 2 eq) as an 80~ oil Ai . ~~ was added to a flame-dried, 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, nitrogen inlet and septum/stopper. The sodium hydride was washed with hexanes (3X) and anhydrous N,N-dimethyl~ ~A~ (30.0 mL) was added. The suspension was cooled in an ice-water bath and a (77:23) mixture of ~+/-)-cis-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-I' lP7in~ and (+/-)-trans-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-l' '-lP7inA~A
(7.79 g, 51.2 mmol) in anhydrous N, N, dimethylformamide (40.0 mL) was slowly added. After the addition of phthsls7in~A was complete, l-bromo-4-chlorobutane (Aldrich Chemical Company) (6,47 -W O 93/16073 C A 2 i i 7 4 3 4 P(~r/G B93/0028~
mL, 9.65 g, 56.3 mmol, 1.1 eq) was added dropwise. After 15 min, the excess sodium hydride was quenched with distilled water (30 mL) and the solvent was removed in vacuo. Ethyl aceea~e was added to the residue and the organics were washed with water.
The organics were dried over HgSO4, filtered and c~nr~ntr~t~d to glve 14.0 g of an orange oil. The crude material was purified by flash _1..- O ,'~ with 6:1 hexanes/ethyl acetate as eluant to give 3.02 g of ~+/-)-cis-2-(4-chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1~2H)-p~th~1O7inrn- (Rf - 0.13) as a colorless oil and 3.78 g of (+/-)-trans-2-(4-chlcrobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-phrh~lP7innre (Rf - 0.20) as a colorless oil.
cis-isomer: H NMR (CDC13): ~ 1.25-1.71 (m, 8), 1.77 (quinte~, 4, J - 3.2), 2.48 (q, 1, J - 6.4), 2.67 (m,l), 3.55 (m, 2j, 3.78 (m, 2), 7.03 (dd, 1, J - 1.0, 2.6). C NMR (CDC13): ~ 22.71, 23.25, 23.51, 24.29, 24.98, 29.15, 34.04, 37.06, 44.95, 46.10, 149.21, 167.53-Anal. Calcd for C12HlgN20Cl: C, 59.38; H, 7.89; N, 11.54. Found:C, 59.28; H, 7.91; N, 11.48.
trans-isomer: lH NMR (CDC13): ~ 1.28 (m, 4), 1.79 (m, 7), 2.10 (m, 2), 2.34 (m, 1), 3.56 (m, 2), 3.73 (m, 1), 3.84 (m, 1), 7.02 (s, 1). 13C NHR (CDC13): ~ 25.03, 25.21, 25.54, 25.66, 28.42, 29.67, 37.52, 39.92, 44.61, 47.14, 150.58, 168.66.
Anal. Calcd for C12HlgN20Cl: C, 59.38; H, 7.89; N, 11.54. Found:
C, 59.20; H, 7.85; N, 11.43.
(f) Preparation of (+/-)-cis-2-(4-(4-(1.2-hDn7i~~thiazol-3-Yl~-l-Diverazinyl)butYl)-4A. 5. 6. 7. 8. 8A-hexahydro-1(2H~-Dhrh-lD7inrno hydrrrhloride (+/-)-c s-2-(4-Chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-~' ' 107in~ .05 o7~ 4.33 mmol), 3-(1-piperazinyl)-1,2-benziso-CA2i 1 7434 thiszole (1.04 g, 4.76 mmol, 1.1 eq), triethyla~ine (0.725 mL, 0.526 g, 5.20 mmol, 1.2 eq) and acetonitrile (10.0 mL) were added to a round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The reaction mixture was allowed to reflux for 6 h. The reaction was not complete according to TLC, hence, 3-(1-piperazinyl)-1,2-benzisothiazole (0.19 g, 0.2 eq) and triethylamine (0.12 mL, 87 mg, 0.86 mmol, 0.2 eq) were added and the reaction mixture was allowed to reflux overnight. The reaction mixture was allowed to cool to room I , o and the solvent was removed in vacuo. The residue was taken up in dichlo,. ,' and washed with ~ rAt~ potassium carbonate. The organics were dried over MgS04, filtered and r~...=_..l.~t~ to give 2.54 g of an orange oil. The crude material was purified by flash ~1..~ O ,'~ with 2:1 ethyl acetate~hexa-nes followed by ethyl acetate to give 1.05 g of the free base as a yellow oil. To a solution of the free base in ethyl acetate was added HCl (2.47 mL of a lN solution in ether, 1.0 eq). The ride salt was recrystallized from ethanol to give 0.58 g (29~) of the title compound as a white solid. The hydrochloride salt contained 10~ of the trans isomer. mp: 191-193-C (dec). lH
NMR (DMS0-d6): ~ 1.32(m, 1), 1.46 (m, 3), 1.58 (m, 5), 1.73 (m, 3), 2.73 (m, 1), 3.25 (m, 4), 3.46 (br d, 2, J - 12.4), 3.55 (br d, 3, J - 14.7), 3.70 (m, 2), 4.06 (br d, 2, J - 14.2), 7.16 (d, 1, J - 1.1), 7.20 (d, 1, J - 2.6), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.60 (ddd, 1, J - 1.1, 7.0, 8.1), 8.12 (t, 2, J - 8.1), 10.83 (br s, 1). 1 C NMR(DMSO-d6): ~ 20.18, 22.76, 23.22, 23.54, 24.34, 24.87, 34.03, 37.13, 46.28 (2 carbons), 50.41, 55.12, 121.14, 123.95, 124.56, 126.91, 128.07, 149.42, 152.06, 162.16, 167~65.
Anal. Calcd for C23H31N505.HCl: C, 59.79; H, 6.98; N, 15.16.
Found: C, 59.82; H, 7.02; N, 15.08.
W O 93/16073 C ~ 2 i 1 7434 PCT/GB93/0028S
~AMPT F 45 (a) PreDaration of (+/-)-trans-2-(4-(4-(l~2-h~n7i~~rhi97nl-3-vl) Din-ro7;-~Yl)butyl)-4A. 5. 6. 7. 8. 8A-h~v~v~ro-l(2H) ~hrh~1O7;r~n~ hvdrQchloride 3-(1-Piperazinyl)-1,2 ~ '~~th;o~Ale (2.92 g, 13.3 mmol, 1.3 eq), triethylamine (2.16 ml, 1.57 g, 15.5 mmol, 1.5 eq), acetonitrile (20.0 mL) and (+/-)-trans-2-(4-chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-phtholo.i (2.49 g, 10.3 mmol) ~Example 44(e)] were added to a round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The reaction mixture was he-ted at reflux for 24 h under nitrogen. The reaction was not complete according to TLC;
therefore, -~i t; ~n,l portions of 3-(1-piperazinyl)-1,2~ rhi o~~] ~ (O . 450 g, 2.05 mmol, 0.2 eq) and triethylamine (0.72 mL, 0.52 g, 5.14 mmol, 0.5 eq) were added and the reaction mixture W85 heated at reflux for another 24 h. The reaction mixture was allowed to cool to room i . e and ethyl acetate was added. The organics were washed with satur-ted potassium carbonate, dried over MgS04, filtered, and c~ ' to give 6.2 g of an orange oil. The crude product was purified by flash cl.-~ O ,'~ with ethyl acetate as eluant to give 2.72 g of the free base as a pale yellow solid. To a solution of the free base in ethyl acetate was added HCl (6.41 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol to give 2.25 g (47~) of (+/-)-trans-2-(4-(4-(1,2-b~n7i~othl~ol-3-yl)-1-piperazinyl)butyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-I' '-1o~; hydrochloride as an off-white solid. mp:
186-188-C. H NMR (DMS0-d6): 6 1.21 (m, 4), 1.61 (br q, 2, J
6.6) 1.71 (m, 4), 1.97 (m, 2), 2.19 (m, 2) , 3.24 (m, 4), 3.47 (br t, 2, J - 13.0), 3.54 (br d, 2, J - 11.1), 3.69 (td, 2, J
2.5, 6.5), 4.06 (br d, 2, J - 13.7), 7.16 (d, 1, J - 1.1), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.60 (dtd, 1, J - 1.1, 7.0, 8.0), 8.12 (t, 2, J - 7.9), 10.8 (br s, 1). 13C N~R (DMS0-d6):
20.14, 24.45, 24.65, 24.87, 25.35, 27.59, 36.68, 38.82, 46.25, 46.30, 50.41, 55.15, 121.13, 123.95, 124.56, 126.91, 128.06, 151.05, 152.06, 162.15, 168.07.
Anal. Calcd for C23H31~50S.HCl: C, 59.79; H, 6.98; N, 15.16.
Found: C, 59.85; H, 6.97; N, 15.12.
ExA~pTF 46 (a) PrenArA~ of 2-~4-bromobutvl~-1.3(2H.4H)-iso~uinolinedione r r~'' 1i~ anhydride (Aldrich Chemical Compsny) (15 g, 92.5 mmol) and 4-amino-1-butanol (Aldrich Chemical Company) (8.54 mL, 8.26 g, 92.5 mmol, leq) were added to a three-necked, .vv~.d b_L ' flask equipped with a reflux condenser and attition funnel. The reaction mixture was heated with an oil bath at lSO-C for 2 h. The green solution was cooled to room I ~ e and ~ hv~. tribromide (6.0 mL, 17.1 g, 63 mmol) was attet dropwise. The reaction mixture was heated slowly to 170-C and 'rtsi ' at that I . e for 45 min. The hot reaction mixture was poured onto crushed ice (lS0 g). The viscous organic material w~s separated from the ice and ethanol was added. The material became a white solid upon the addition of ethanol. The solvent was removed in ~acuo to give a yellow solid. The solid was recrystallized from ethanol to give 17.1 g (62~) of 2-(4-Bromobutyl)-1,3(2H, 4H)-i~oq~;r~li ~-~ as a pale yellow solid. mp: 87-89-C. H NMR (CDC13): ~ 1.88 (m, 4), 3.43 (t, 2, J - 6.5), 4.02 (t, 4, J - 7.0), 4.03 (s, 2), 7.26 (d, 1, J
- 7.2), 7.43 (t, 1, J - 7.5), 7.58 (td, 1, J - 7.4, 1.4), 8.20 (d, 1, J - 7,8). 13C NMR (CDC13): ~ 26.26, 29.64, 32.55, 35.88, 38.66, 124.77, 126.63, 127.26, 128.66, 133.17, 133.54, 164.32, 169.44.
CA 2 i 1743¢
' 109 Anal- Calcd for C13N14N02Br: C, 52.72; H, 4.76; N, 4.73. Found C, 52.79; H, 4.80; N, 4.74 (b) P_ _on Qf 2-~4-(4-(l.2-h~n7ienth1A7~l-3-vl~-l-DiDera-71~yl~butyl~-l.3~(7u.4H~-isonllin~1in~inn~ hydr~rhloride hvdrate 2-(4-Bromobutyl)-1,3(2H, 4H)-isoqu.~.~liDedione (9.74 g, 1), 3-(1-piperazinyl)-1,2-' eothi~7Ole (7.96 g, 36.3 F ' .1 eq), triethylamine (5.52 ml, 4.G ~, 39.6 mmol, 1.2 md acetonitrile (50.0 DL) were added to a round-bottoDed .ask equipped with magnetic stirring bar, condenser and nitrogen inlet. The reaction Dixture was heated at reflux for 3.5 h. The crude mixture was absorbed onto silica gel and purified by flash ~ with 2:1 ethyl acetate/hexanes followed by ethyl acetate as eluant to give 11.9 g of the free base as an orange oil. To a solution of the free base in ethyl acetate was added HCl (27.4 DL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 6.57 g (40~) of 2-(4-(4-(1,2-b~n-ieoth1r7~1-3-yl)-l-piperazinyl)-butyl)-1,3,(2H,4H)-- I ~~~1i ' hydrochloride hydrate as an orange solid. Dp: 190-195'C. lH NMR (DMS0-d6): ~ 1.64 (m, 2), 1.75 (m, 2), 3.10-3.60 (D, 4), 3.91 (q, 2, J - 6.8), 4.05 (br d, 2, J - 13.0), 7.55 (D, 4), 8.12 (D, 4), 10.60 (br s, 1). C N~R
(D~S0-d6): ~ 20.57, 24.66, 36.02, 38.53, 46.32, 50.44, 55.12, 121.13, 123.94, 124.57, 124.84, 126.90, 127.20, 127.48, 127.93, 128.06, 133.46, 135.41, 152.06, 162.15, 164.53, 170.08.
Anal. Calcd for C24H26N402S.HClØ5H20: C, 60.05; H, 5.88; N, 11.67; H20, 1.87. Found: C, 60.30; H, 5.85; N, 11.74; H20, 1.79.
EXAMPI F. 47 (a) FL~ ~n of 2-(4-(4-(1.3-benzisothiazol-3-xl)-1-DiDera-7invl)butyl)-1.4~2H,3H)-DhthAlA7i~r~ione hvdrochloride Sodium hydride (Aldrich Chemical Company) (0.102 g, 3.39 mmol, eq) as an 80~ oil ~ n was added to a flame-dried, three-necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and nitrogen inlet. The sodium hydride was washed with hexanes (3x) and anhydrous N,N-dimethyl-formamide (10.0 mL) was added. The s~sp-nCi~r was cooled in an ice-water bath. Phthalhydrazide (0.549 g, 3.39 mmol) and 8-(1,2-benzisothiazol-3-yl)-5,8-diazaspiro(4.5)decan-5-onium bro-mide (1.2 g, 3.39 mmol, 1.0 eq) were added and the reaction was heated at reflux overnight. The reaction mixture was cooled in an ice-water bath and the excess sodium hydride was quenched with distilled water (5.0 mL). The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water, The organics were dried over MgS04, filtered and ~ d to give 0.63 g of the crude material. This crude material was combined with an n~A; t; 1 1.3 g of the crude material obtained from a previous run. The aqueous phases of both reactions were also combined and washed with dichl~.- ' . The dichl~
was dried over MgS04, filtered, and removed in vacuo to obtain an additional 0.34 g of crude material. The crude material (1.70 g total) was purified by flash ~ g ,'~ with 94:6 dichloromethane/methanol to give 0.64 g of the free base as a white solid. To a solution of the free base in chloroform was added HCl (1.47 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 0.429 g (13~) of 2-(4-(4-(1,3-benzisothia-zol-3-yl)-1-piperazinyl)butyl)-1~4(2H,3H)-I' ' ~lD7in--~ir-n- hydro-chloride as a white solid. mp: 242-245-C (dec). 1~ NMR
(DMS0-d6): ~ 1.81 (br s, 4), 3.26 (m, 4), 3.45 (br t, 2, J
12.0), 3.57 (br d, 2, J - 11.5), 4.06 (m, 4), 7.47 (ddd, 1, J
0.8, 7.2, 8.1), 7.60 (ddd, 1, J - 1.0, 7.1, 8.1), 7.90 (m, 2), 7.98 (m, 1), 8.12 (t, 2, J - 7.2), 8.25 (m, 1), 10.69 (br s, 1), 11.70 (br s, 1). 13C NMR (DMS0-d6): ~ 20.37, 25.14, 46.33, 48.32, 50.45, 55.12, 121.13, 123.93, 124.07, 124.55, 126.41, W O 93/16073 C A 2 i i 7 4 3 4 P(~r/G B93/0028s 126.90, 128.06, 128.71, 132.22, 133.03, 150.23, 152.05, 157.15, 162.15.
Anal. Calcd for C23H25N502S.HCl: C, 58.53; H, 5.55; N, 14,84.
Found: C, 58.38; H, 5.60; N, 14.76.
FY-YPJ .F. 48 (a) Pre~aration of 3.4-dihYdro-lH-2-b~ v~,~.l-l-one This compound was prepared according to a modified procedure of F. 8Onadies and R. Di Fabio (J. Ore. Chem. 1984, 49, 1647).
3,4-Dihydro-lH-2-~ " .~.. (Aldrich CheDical Company) (32.8 ml, 35.0 g, 0.261 mol), pyridinium chl~ (Aldrich Chemical Company) (56.3 g,0.261 mol, 1 eq) and anhydrous dichl~L. LL~.~
(100.0 mL) were added to a flame-dried, l-L, round-bottomed flask equipped with a cond nser, magnetic stirring bar and nitrogen inlet. The reaction mixture was heated with an oil bath at 60-70-C. Additional equiv-lents of pyridinium chlo,v~l.L~
were added at t - 2h and t - 4h and the reaction mixture was heated at reflux o~-ernight. The reaction mixture was allowed to cool to room I . e~ the solv nt was decanted from a dark 8L~ residue and the residue was washed with dichl~L. ' . The organics were combined and ~ d to give 37 g of an orange oil. The crude material was purified by flash ;: O ,'~ with 3:1 hexanes/ethyl acetate to obtain 20.2 g (52~) of 3,4-dihydro-lH-2 ~ ,~ l-one as colorless oil. 1H NMR (CDC13): 6 3.07 (t, 2, J - 6.0), 4.54 (t, 2, J
6.0), 7.27 (d, 1, J - 7.5), 7.40 (tm, 1, J - 7.6), 7.54 (td, 1, J
- 7.5, 1.3), 8.10 (dd, 1, J - 1.0, 7.8). 13C NMR (CDC13):
27.82, 67.31, 125.30, 127.24, 127.68, 130.38, 133.67, 139,55, 165.13.
Anal. Calcd for CgH802 C, 72.96; H, 5.44. Found: C, 72.88; H, 5.42.
(b) Pr~nsration of 2-(4-cblorobutvl)-2.3.4.5-~L-al.~dLv-lH-2-h~n797--nin-l-one This compound was prepared according to the method described in Example 34(c). Alkylation of 2, 3,4,5-tetrahydro-lH-2-benzaze-pin-l-on~ (0.46 g, 2.85 mmol) (prepared from 3,4-dihydro-lH-2-benzopyran-l-one according to the method of N. ~. Gllman, (Svnthetic r- . 19B2, 12, 373)) with 1-bromo-4-chlorobutane (Aldrich Chemical Company) (0.393 ml, 0.586 g, 3.42 mmol, 1.2 eq) gave 0.40 g (56 ~) of 2-(4-chlorobutyl)-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one as an orange oil.
(c) P.. _ lon of 2-(4-(4-(1.2-benzisothio~~l-3-~l)-l-DiDera-71nVl~but~yl)-2~3~4~5-t~LL~ dLv-lH-2-hon7s7on;n hydr~rhl nrid~
This compound was prepared according to the method described in Example 34(d). Alkylation of 2-(4-chlorobutyl)-2,3,4,5-tetrahy-dro-lH-2-benzazepin-1-one (0.40 g, 1.59 mmol) with 3-(1-piperazinyl)-1,2 ~ ~coth1o-nlo (0.52 g, 2.39 mmol, 1.5 eq) gave 0.45 g of the free base which was purified by flash cl.-. ~ with 2:1 ethyl acetate/hexanes/0.1% triethylamine as eluant. The hydrochloride salt was prepared, recrystallized from ethanol, and dried in a vacuum oven to give 227 mg (30~) of 2-(4-(4-(1,2-b-n~;~oth;o~~1-3-yl)-1-piperazinyl)butyl)-2,3,4,5-tetrahydro-1_-2-benzazepin-1-one hydrochloride as a beige solid.
m.p.: 215-217 ~C (dec). lH NMR (DMSO-d6): C 1.67 (m, 2), 1.81 (m, 2), 1.99 (quintet, 2, J - 6.7), 2.73 (t, 2, J - 7.0), 3.18 (t, 2, J - 6.4), 3.27 (m, 4), 3.53 (m, 6), 4.08 (br d, 2, J
13.0), 7.25 (dd, 1, J - 1.2, 7.5), 7.33 (td, 1, J - 7.5, 1.4), 7.42 (td, 1, J - 7.4, 1.6), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.51 (dd, 1, J - 1.6, 7.4), 7.60 (ddd, 1, J - 1.1, 7.0, 8.1), 8.13 (t, 2, J - 9.1), 10.92 (br s, 1). 13C NMR (DMS0-d6): ~
20.61, 25.55, 29.30, 29.58, 45.59, 45.69, 46.35, 50.46, 55.23, W O 93/16073 C A 2 i 1 7 4 3 4 PCr/GB93/00285 121.15, 123.95, 124.57, 126.59, 126.91, 127.94, 128.07, 128.24, 130.51, 136.25, 137.09, 152.06, 162.16, 169.78.
Anal. Calct for C25H30N405.HCl: C, 63.74; H, 6.63; N, 11.89.
Found: C, 63.76; H, 6.67; N, 11.87, F~yAMpT F 49 (a) PrenArAtiAn of 3-(1-(4- A~h~tvl)-4-DiDeri~inyl)-l.2 benzisothia201e Nethanol (40.0 mL) and N-(4-(4-(1,2-~ ~othiA7Al-3-yl) p~ nA)butyl)~ (6.77 g, 16.1 mmol) (Example 33) was added to a three-necked, 250-mL, round-bottomed flask equipped with a magnetic stirring bar, addition funnel, nitrogen inlet and reflux condenser. The reaction mixture was heated to reflux and hydrazine hydrate (Aldrich Chemical Company) (1.41 g of a 55 ~queous solution, 24.2 mmol, 1.5 eq) was added dropwise. The solution was refluxed for 3 h after the addition of hydrazine hydrate was complete. The reaction mixture was allowed to cool to room i ~ and a-1Aifi~d (pH - 2) with lN HCL. The , ~An was filtered and the filtrate was cooled in an ice-water bath. The pH of the cooled filtrate was adjusted to 10 by the addition of 50~ NaOH. The organics were extracted with dichlc.~ ' , dried with HgSO4, filtered and - teA to gi~e 4.22 g (91~) of 3-(1-(4-aminobutyl)-4-piperidinyl)-1,2-benz-~ 701~ as an orange oil. lH NHR (CDC13): ~ 1.57 (m, 7), 2.10 (m, 6), 2.42 (t, 2, J - 7.4), 2.74 (t, 2, J - 6.6), 3.10 (dd, 2, J - 2.0, 7.0), 7.41 (ddd, 1, J - 7.0, 8.1), 7.50 (ddd, 1, J - 1.1, 7.0, 8.0), 7.92 (dt, 1, J - 8.1, 1.0), 8.00 (dt, 1, J
8.1, 1.0).
(b) PreDaration of 2-Aminn-N-(4-(4-~1 2-h~n7icnth1A7nl 3 Diperidino)butvl)h~n7Ami~ hydrochloride This compound was prepared according to the method described in Example 36. Alkylation of isatoic anhydride (Aldrich Chemical Company) (0.68 g, 4~15 mmol) with 3-(1-(4-aminobutyl)-4-piperi-dinyl)-1,2-b-n~icothiA7nl~ (1.2 g, 4.15 mmol, 1.0 eq) gave 1.38 g of the free base which was purified by flash cl... ~ with 2:1 ethyl acetate/hexanes/0.18 triethylamine as eluant. The hydrochloride salt was prepared and recrystallized from ethsnol/water to give 1.09 g (59~) of 2-amino-N-(4-(4-(1,2-benzi-sothiazol-3-yl)piperidino)butyl)benzamide hydrochloride as a beige solid. mp: 239-240 ~C. 1~ NMR (DMS0-d6): ~ 1.58 (m, 2), 1.78 (m, 2), 2.23 (m, 4), 3.14 (m, 4), 3.27 (q, 2, J - 6.3), 3.65 (m, 3), 6.40 (br s, 2), 6.51 (ddd, 1, J - 1.3, 7.0, 8.4), 6.69 (dd, 1, J - 0.9, 8.2), 7.13 (ddd, 1, J - 1.6, 7.1, 8.7), 7.52 (m, 2), 7.63 (ddd, 1, J - 1.0, 7.0, 8.0), 8.22 (d, 1, J - 8.1), 8.27 (d, 1, J - 8.1), 8.29 (m, 1), 10.0 (br s, 1). C NMR (DMS0-d6):
20.73, 26.37, 27.71, 35.57, 37.98, 51.45, 55.67, 113.33, 114.51, 114.79, 116.28, 120.72, 123.53, 124.92, 128.06, 131.55, 133.32, 149.56, 151.95, 167.52, 168.91.
Anal. Cald. for C23H28N405.~Cl: C,62.08; H, 6/57; N,12.59. Found:
C,62.11; ~,6.61;
EXAMP!~ 50 (a) Pr~n~rAri~n of ((4-(4-~1.2-benzisothiazol-3-vl)-1-DiDera-z~nvl)butyl)~Ar~- l)DhenYl acetate 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benzisothiazole (3.0 g, 10.4 mmol) (Example 13(b)), triethylamine (1.74 mL, 1.26 g, 12.5 Cd~ j 1 7434 mmol, 1.2 eq) and dichlu-- i'~ (50.0 mL) was added to a flame-dried, 200-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and nitrogen inlet.
The reaction mixture was cooled in an ice-water bath and a solution of acetylsalicyloyl chloride (Aldrich Chemical Company) (2.06 g, 10.4 mmol, 1.0 eq) in dichlu-~ '- (20 mL) was added dropwise. The reactlon mixture was allowed to warm to room ~ , ' e and stirred for 15 min. The reaction mixture was washed with cold saturated sodium bicarbonate. The organics were dried over MgS04, filtered and ~ A to give 5.8 g of the crude material as an orange oil. The crude reaction mixture was purified by flash cl"~ with 95:5 dichlo.~ '- /metha-nol as eluant. The product (2.93 g) was obtained as a mixture of ((4-(4-(1,2-b-n7i~othis-~1-3-yl)-l-piperazinyl)butyl)carbamoyl)-phenyl acetate and ~-(4-(-(1,2-benzisothiazol-3-yl)-1-piperazin-yl)butyl)-2-1.~d. UA~ L ~ A -(b) Pr~o-Ati~~ of N-(4-~ 2-bDn7i~his7~l-3-yl~-l-oi~r zinvl)butyl~-2-l.~dLu~ de hydrochloride Methanol (30.0 mL) and a mixture (2.93 g) of N-(4-(-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)carbamoylphenyl acetate and N-(4-(-(1,2-b~n7i~othis7~1-3-yl)-l-piperazinyl)butyl)-2-hydroxy-benzamide were added to a 300-mL, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and nitrogen inlet.
A solution of sodium methoxide (Aldrich Chemical Company) (38.5 mg, 7.12 mmol, 1.1 eq) in methanol (60 mL) W8S added dropwise to the reaction mixture. The reaction mixture was allowed to stir for 1.5 h, n~vt~Ali7~(i with Dowex resin, filtered and - ~ to give 2.68 g of the free base as a viscous pale orange oil. To a solution of the free base in ethyl acetate was added HCl (6.53 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 2.32 g (50~ based on acetylsalicyloyl chloride) of N-(4-(-(1,2-b-n7i~othis~~1-3-yl)-l-piperazir.yl)but-yl)-2-h~d.~L ~ hydrochloride as an off-white solid, H
NMR (DNSO-d6): ~ 1.63 (m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.7), 3.59 (br d, 2, J - 11.3), 4.07 (br d, 2, J
13.5), 6.89 (m, 2), 7.40 (ddd, 1, J - 1.7, 7.2, 8.8), 7.47 (ddd, 1, J - 1.1, 6.9, 8.1), 7.60 (ddd, 1, J - l.l, 7.0, 8.1), 7.90 (dd, 1, J - 1.4, 7.9), 8.12 (t, 2, J - &.4), 8.98 (br t, 1, J
5.5), 10.80 (br s, 1), 12.68 (s, 1). 13C N,'-~ (DMS0-d6): ~ 20.60, 25.99, 38.38, 46.35, 50.44, 55.06, 115.07, 117.31, 118.43, 121.14, 123.95, 124.57, 126.90j 127.69, 128.07, 133.59, 152.05, 160.09, 162.16, 169.03.
Anal, Calcd for C22H26N402S.HCl: C, 59.11; H, 6.09; N, 12.53.
Found: C, 59.00; H, 6.10; N, 12.47.
(a) pL~--r~ n of N-(4-(4-(1.2-benzisothiazol-3-vl)-1-Dimera-zinyl~butvl~benzamide hvdrochloride The free base of this compound was prepared according to the method described in Example 50(a). Acylation of 3-(4-(4-amino-butyl)-l-piperszinyl)-1,2-b~n7i~or~;~771e (1.5 g, 5.17 mmol, 1.0 eq) (Example 13(b)) with benzoyl chloride (0.6 mL, 0.727 g, 5.17 mmol) over a lh periot gave 1.49 g of the free base which was purified by flash cl.-. O ,'~ with ethyl acetate/0.1%
triethylamine. To a solution of the free base in ethyl acetate was added HCl (3.8 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol to give 1.04 g (47~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl)-benzamide hydrochloride as a pale beige solid. mp: 200-201.5-C.
H NMR (DMS0-d6): ~ 1.61 (m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.6), 3.59 (br d, 2, J - 11.7), 4.08 (br d, 2, J -13.4), 7.50 (m, 4), 7.60 (t, 1, J - 7.6), 7.87 (m, 2), 8.13 (t, 2, J - 8.4), 8.58 (br t, 1, J - 5.5), 10.72 (br s, 1). 13C N.'~
(DMS0-d6): ~ 20.59, 26.25, 38.36, 46.32, 50.41, 55.09, 121.14, C~2 i i 7~34 123.95, 124.56, 126.90, 127.12, 128.07, 128.16, 131.01, 134.47, 152.05, 162.16, 166.15.
Anal. Calcd for C22H26N405.HCl: C, 61.31 H, 6.31; N, 13.00.
Found: C, 61.27; H, 6.34; N, 12.98.
pY~PJ F. 52 (a) Pr~nsration of N-(4-chlorobutvl)-N-methY1 ~
This9 compound was prepared according to the method described in Example 34(c). N-Methy~ - (Aldrich Chemical Company) (3 g, 22.2 mmol) was alkylated with 1-bromo-4-chlorobutane (Aldrich Chemical Company) (2.81 mL, 4.19 g, 24.4 mmol, 1.1 eq). The crude reaction mixture was extracted with dichl~ h9~- and purifi-d by flash cl ~ O .'~ with 2:1 ethyl acetate/hexanes to give 3.02 g (60~) of N-(4-chlorobutyl)-N-methyl benzamide as a pale yellow oil.
(b) ~ on of N-(4-(4-(1.2-h~n~i~~thiD7nl-3-Yl)-1-~inera-.1nvl~butvl-N h l)l~r~ hvdrochloride This compound was prepared according to a method analogous to that described in Example 34(d). N-Methyl-N-(4-chlorobutyl) benzamide (1.50 g, 6.65 mmol) and 3-(1-piperazinyl)-1,2-benziso-thiazole (1.60 g, 7.3 mmol, 1.1 eq) were heated at reflux overnight to give 3.64 g of the crude free base. The crude material was purified by flash .1..- g ,'~ with 2:1 ethyl acetate/hexanes/0.1~ triethylamine to give 1.40 g of the free base as a yellow oil. The hydrochloride salt was prepared and recrystallized from ethanol/ether to give 0.76 g (26~) of N-(4-(4-(1,2-' ~,~th ip7nl -3-yl)-l-piperazinyl)butyl-N-methyl)-benzamide hydrochloride as a white solid. mp: 151-154-C. lH NMR
(DMS0-d6): 6 1.57-1.83 (m, 4), 2.98 (m, 4), 3.26 (m, 4), 3.55 (m, 5), 4.07 (br d, 2, J - 12.6), 7.44 (m, 6), 7.60 (t, 1, J - 7.3), 8.13 (t, 2, J - 8.1), 11.07 (br s, 1). C NMR (D~SO-d6): 6 20.29, 23.68, 36.91, 45.74, 46.27, 50.40, 55.22, 121.14, 123.95, 124.56, 129.15, 136.70, 152.06, 162.17, 170.15.
Anal. Calcd for C23B28N40S.HCl: C, 62.08; H, 6.57; N, 12.59.
Found: C, 62.01; H, 6.56; N, 12.53.
FY~ "P! .F 53 (a) Preoaration of N-~4-(4-(l~2-han~i~nrhiA7nl-3-yl)-l-oioera zit~Yl~butYl)-4-chlu~J~ hvdrochloride hydrate 3-(4-(4-Aminobutyl)-l-piperazinyl)- 1,2-benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and dichluL- '- (10.0 mL) were added to flame-dried, 100-mL, .. ' b L ' flask equipped with a magnetic stir bar, nitrogen inlet and addition funnel. The re-ction mixture was cooled in an ice-water bath, and a solution of 4-chlorobenzoyl chloride (Aldrich Chemicsl Company) (0.61 g, 3.45 mmol, 1.0 eq) in dichlu-, '- (10.0 mL) was added dropwise. The reaction mixture was allowed to stir for 0.5 h and transferred to a , - y funnel with the aid of ethyl acetate.
The organics were washed with saturated ~Jt carbonate, dried over ngS04, filtered, and ~ ' to give a pale yellow solid (1.4 g). The crude reaction mixture was purified by flash cl... ~ with ethyl acetate/0.1~ triethyla~ine as eluant to give 0.99 g of the free base as a white solid. The free base was dissolved in ethyl acetate and dichlu.- tha~a / and 2.31 mL of lN ethereal HC1 (1.0 eq) was added. The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol/water to give 0.915 g (56~) of N-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-4-chlu.~' ,ia hydrochlor-ide hydrate as a white solid. mp: 209-210 ~C (dec). H NMR
(DMS0-d6): 6 1.60 (m, 2), 1.79 (m, 2), 3.15-3.37 (m, S), 3.45 (br t, 3, J - 12.7), 3.59 (br d, 2, J - 12.0), 4.08 (br d, 2, J
W O 93/16073 C A 2 i 1 7 4 3 4 P(~r/G B93/0028~
12.9), 7.48 (ddd, 1, J - 1.0, 7.1, 8.1), 7.55 (dm, 2, J - 8.6), 7.60 (ddd, 1, J - 1.2, 7.0, 8.2), 7.90 (dm, 2, J - 8.7), 8.13 (t, 2, J - 8.2), 8.68 (br t, 1, J - 5.5), 10.59 (br s, 1). 13C N~R
(DMS0-d6): 8 20.58, 26.17, 38.44, 46.32, 50.41, 55.08, 121.13, 123.95, 124.56, 126.91, 128.07, 128.25, 129.10, 133.18, 135.84, 152.05, 162.16, 165.09.
Anal. Calcd for C22H25N40SCl.HClØ5 H20: C, 55.69; H, 5.74; N, 11.81; H20, 1.90. Found: C, 55.58; H, 5.69; N, 11.71; H20, 2.02.
(a) P.. of N-(4-(4-(1.2-h~n~ic~thiazol-3-Yl)-l-oiDera-ziDyl)butyl)-3.4-dichlornh~n7~ ~ hydrochloride This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-L '~oth1~ol~ (i.o g, 3.45 mmoi) (Example 13(b)), triethyla~ine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and 3,4-dichlorobenzoyl chloride (Aldrich Chemical Company) (0.723 g, 3.45 mmol, 1.0 eq).
The crude reaction mixture was purified by flash ~ ,' J
with ethyl acetate/0.1~ triethylamine as eluant to give the free base (1.52 g) as a white solid. The hydrochloride salt was prepared, recrystallized from ethanol/water and dried in a vacuum ov~n to giv~ 0.88 g (51~) of N-(4-(4-(1,2-~ c~thi~7~1-3-yl)-l-piperazinyl)butyl)-3,4-dichl~.-L ~- hydrochloride as a pale beige solid. mp: 208-210 ~C (dec). H NMR (DMSO-d6): ~ 1.61 (m, 2), 1.82 (m, 2), 3.27 (m, 6), 3.52 (m, 4), 4.07 (br d, 2, J -13.4), 7.47 (t, 1, J - 7.6), 7.60 (t, 1, J - 7.5), 7.76 (d, 1, J
- 8.5), 7.88 (dd, 1, J - 2.0, 8.4), 8.12 (t, 2, J - 8.2), 8.14 (d, 1, J - 2.0), 8.86 (t, 1, J - 5.5), 11.10 (br s, 1). 13C NMR
(DMS0-d6): ~ 20.58, 26.07, 38.62, 46.33, 50.44, 55.08, 121.14, 123.95, 124.57, 126.91, 12~.52, 128.07, 129.13, 130.59, 131.16, 133.85, 134.75, 152.07, 162.17, 163.88.
CA2i 1 7434 W O 93/16073 - 120 - PCT/GB93/0028~
Anal. Calcd for C22H24N4oscl2~cl: C, 52.86; H, 5.04; N, 11-21-Found: C, 52.94; ~, 5.09; N, 11.16.
CA 2 i 1 7434 FY~''PT F 55 (a) Pron~rPtio~ of N-~4-(4-(1.2-hon~ie~thiP~nl-3-Yl~-l-DiD~ra Zi~yl)butyl~-4 thoxyhon~ 'de hvdrochloride This compound was prepared according to the method described in Example 53, by employing 3-~4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole ~1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and p-anisolyl chloride (Aldrich Chemical Company) (0.589 g, 3.45 mmol, 1.0 eq). The crude reaction mixture was purified by flash ChL~ g ,'~ with 93:7 dichl~L~ t' /methanol as eluant to give the free base as a pale beige solid (0.73 g). The hydrochloride salt was prepsred, recrystallized from ethanol, and dried in a vacuum oven to give 0.287 g (18~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) butyl) 6 , i' ~L '~o hydrochloride as a tan solid. mp: 171-173 ~C (dec). lH NLDR (DMSO-d6): ~ 1.59 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.49 (br d, 2, J - 12.1), 3.58 (br d, 2, J - 13.8), 3.81 (s, 3), 4.07 (br d, 2, J - 13.4), 7.00 (dm, 2, J - 8.9), 7.48 (ddd, 1, J - 1.2, 7.0, 8.1), 7.60 (ddd, 1, J
1.0, 7.0, 8.1), 7.86 (dm, 2, J - 8.9), 8.13 (t, 2, J - 8.3), 8.45 (t, 1, J - 5.6), 10.81 (br s, 1). C NL-DR (DMS0-d6): ~ 20.63, 26.35, 38.29, 46.35, 50.43, 55.13, 55.27, 113.35, 121.15, 123.96, 124.58, 126.69, 126.92, 128.08, 128.94, 152.07, 161.39, 162.17, 165.64.
Anal. Calcd for C23H28N4025.HCl: C, 59.92; H, 6.34; N, 12.15.
Found: C, 60.00; H, 6.39; N, 12.19.
F~AMPT~ 56 (a) P.~ n of N-(4-(4-(l~2-hon7ic~rh~ l-3-vl)-l-DiDera zinYl)butvl)-4-(trifln~romethYl)hon7 '~o hYdrochloride This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine ~0.721 mL, 0.524 g, 5.18 mmol, l.S eq) and 4-(trifluoromethyl) benzoyl chloride (Aldrich Chemical Company) (0.513 mL, 0.720 g, 3.45 mmol, 1.0 eq). After the 4-(trifl~ Ll.~l) benzoyl chloride was added, the ice-water bath was removed and the reaction mixture was stirred for l.S h. The crude reaction mixture was purified by flash ~ O a~ with 1:1 ethyl aceeate/hexanes with 0.1~ triethylamine as eluant followed by ethyl acetate/0.1~ triethylamine to give 0.57 g of the free base as a solid. The hydrochloride salt was prepared and recrystall-ized from ethanol to give 0.26 g ~lSi) of N-~4-~4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-4-(trifluoromethyl)benzamide hydrochloride as a tan solid: mp: 205-207 ~C (dec.). lH
NHR~DMS0-d6): ~ 1.62 ~m, 2), 1.83 ~m, 2), 3.15-3.40 (m, 6), 3.50 ~br t, 2, J - 13.0), 3.59 ~br d, 2, J - 11.6), 4.08 (br d, 2, J -13.3), 7.48 (ddd, 1, J - 1.0, 7.1, 8.1), 7.60 (ddd, 1, J - 1.0, 6.9, 8.1), 8.08 (d, 2, J - 8.8), 8.11 (m, 4), 8.87 (br t, 1, J
5.5), 10.95 (br s, 1). 13C N~R (D~S0-d6): ~ 20.63, 26.15, 38.50, 46.37, 50.47, 55.12, 121.18, 122.13, 123.99, 124.61, 125.23, 126.95, 128.11, 130.79, 138.25, 152.10, 162.20, 165.04.
Anal. Calcd for C23H25N405F3.HCl: C, 55.36; H, 5.25; N, 11.23.
Found: C, 55.46; H, 5.26; N, 11.18.
- ~23 -EYAMP! F. 57 . (a) Preparation of N-(4-(4-(l~2-h~n7;~~thip7nl-3-yl)-l-Din~ra-7;nvl)butyl~-4-tert-butvl'~~ ~A-~ hvdrochlor~de This compount was prepared according to the method described in Example 56, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-b~ieoth~ e (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.0 eq) snd tert-butylbenzoyl chloride (Aldrich Chemical Company) (C.674 mL, 0.679 g, 3.45 mmol, 1.0 eq). The hydrochloride salt was prepared from the free base (0.560 g) and recrystallized from ethanol to give 0.251 g (15~) of N-(4-(4-(1,2 1 ~oth;o~A1-3-yl)-1-piperazinyl)butyl)-4-tert-butylh- - ~A- L~ ride as a tan solid, mp:
220.5-222 ~C (dec.). lH NHR (DHS0-d6): 6 1.31 (s, 9), 1.60 (m, 2), 1.82 (m, 2), 3.25 (m, 6), 3.55 (m, 4), 4.08 (br d, 2, J
13.3), 7.49 (m, 3), 7.62 (t, 1, J - 7.4), 7.83 (d, 2, J - 8.4), 8.14 (m, 2), 8.55 (t, 1, J - 5.7), 11.06 (br s, 1). 13C NHR
(DHS0-d6): 6 20.82, 26.55, 31.15, 34.77, 38.53, 46.63, 50.71, 55.39, 121.51, 124.32, 124.93, 125.28, 127.28, 127.35, 128.45, 132.11, 152.45, 154.15, 162.57, 166.47.
Anal. Calcd for C26H34N40S.HCl: C, 64.11; H, 7.24; N, 11.50.
Found: C, 64.00; H, 7.25; N, 11.43.
FY~''PT F 58 (a) P.~ : ~n of N-(4-(4-(1.2-h~n-i7~thi~Al-3-yl~-l-DiDera-?;nVl~bUtVl~-4-(DhenvlD.~h~ ~A.. hvdrochloride -This compound was prepared according to the method described in _xample 53, by employLng 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ oth~ le (1.24 g, 4.27 mmol) (Example 13(b)), triethyl-amine (0.893 mL, 0.648 g, 6.41 mmol, l.S eq) and p-phenylazoben-zoyl chloride (Kodak) (1.05 g, 4.27 mmol, 1.0 eq). The reaction mixture was allowed to stir for 1 h following the addition of p-phenylazobenzoyl chloride. The free base was purified by flash CLL. ~ with 3:1 ethyl acetate/hexanes with 0.14 triethylamine followed by ethyl acetate/0.1~ triethylamine and finally ethyl acetate/0.24 triethylamine as eluant to give the 1.42 g of the compound as an orange solid. The free base was recrystallized from ethyl acetate to give 0.781 g of the pure compound as an orange solid. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 0.589 g (26~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-(phenyl-azo) benzamide hydrochloride as an orange solid. mp: 225-227 ~C.
H NMR (DMS0-d6): 6 1.67 (m, 2), 1.82 (m, 2), 3.36 (m, 8), 3.63 (br d, 2, J - 10.4), 4.11 (br d, 2, J - 11.9), 7.49 (tm, 1, J
7.6), 7.64 (m, 4), 7.98 (m, 4), 8.14 (m, 4), 8.82 (br t, 1, J
5.6), 10.50 ~br s, 1). 13C NMR (DMS0-d6): ~ 20.65, 26.22, 38.56, 46.36, 50.45, 55.12, 119.43, 119.91, 121.16, 122.30, 122.68, 123.97, 124.58, 126.91, 127.45, 127.95, 128.09, 128.50, 128.84, 129.52, 131.98, 132.61, 136.64, 151.82, 152.07, 153.15, 153.46, 155.71, 162.17, 165.18, 165.39.
Anal. Calcd for C28H30N605.HCl: C, 62.85; H, 5.84; N, 15.71.
Found: C, 62.91; H, 5.85; N, 15.63.
FY~vpJ.F 59 (a) PreDaration of 4-acetamido-N-(4-~4-(1.2-benzisothiazol-3-vl)-1-Dir~r~ yl)but~l)benzamide hvdrochloride 4~ d~h~r-~ic acid (Aldrich Chemical Company) (0.742g, 4.14 mmol), triethylamine (0.693 mL, 0.503 g, 4.97 mmol, 1.2 eq) and anhydrous tet~ d.~r~,~.. (20.0 mL) were added to a flame-dried, 100-mL, three-necked, round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet, .' and rubber septum.
The reaction mixture was cooled to -15-C with a dry ice/i~~~.~ r 1 bath. To the reaction mixture was added isobutylchloroformate (Aldrich Chemical Company) (0.537 mL, 0.565 g, 4.14 mmol, 1.0 eq~. After 5 min, a solution of 3-(4-(4-amino-butyl)-l-piperazinyl)-1,2-benzisothiazole (1.20 g, 4.14 mmol, 1.0 eq) (Example 13(b)) in anhydrous teLL~ r~- . (10.0 mL) was added dropwise. The reaction mixture was stirred at -15-C for h and then allowed to warm to room ~ . ~. After 18 h, the reaction mixture was , ' ~d to a . .~ funnel with the aid of dichl~.. ;' and washed with saturated K2C03. The organics were filtered, dried with MgS04, filtered and c~ d to give a yellow oil (1.70 g). The crude reaction mixture was purified by flash cl.-~ ~L~L~ with 9:1 ~hl. ' ~/methanol to give 0.74 g of the free base as a white foam. To a solution of the free base in ethyl acetate and ~-~hl. r~ was added 1.57 mL of lN ethereal HCl (1.0 eq).
The solvent was removed in vacuo, and the salt was recrystallized from ethanol/water to give 0.474 g (23~) of 4-acetamido-N-(4-(4-(1,2-b-~7i~oth1O~ 3-yl)-l-piperazinyl)butyl)-benzamide hydroch-loride as a pale cream solid. mp:>250 ~C. lH NMR (DMSO-d6):
1.59 (m, 2), 2.07 (s, 3), 3.25 (m, 6), 3.46 (br t, 2, J - 12.9), 3.59 (br d, 2, J - 11.4), 4.08 (br d, 2, J - 13.4), 7.48 (t, 1, 3 - 7.5), 7.60 (t, 1, J - 7.6), 7.66 (d, 2, J - 8.7), 7.82 (d, 2, J
- 8.6), 8.13 (t, 2, J - 8.3), 8.46 (br t, 1, J - 5.2), 10.23 (s, 1), 10.68 (br s, 1). 13C NMR (DMS0-d6): ~ 20.67, 24.09, 26.37, 38.34, 46.40, 50.49, 55.18, 118.01, 121.19, 124.00, 124.61, 126.95, 127.98, 128.12, 128.75, 141.84, 152.11, 162.20, 165.73, 168.66.
Anal. Calcd for C24H29N5O25.HCl: C, 59.06; H, 6.20; N, 14-35-Found: C, 58.99; H, 6.20; N, 14.43.
W O 93/16073 i ~ ~ PCT/GB93/00285 Fv~MPT.t 60 (a) PreDarAtinn of 4-((tert-butoxvcarbonYl) nn)ben-oic acid 4-' 'n~bDn~nic acid (Aldrich Chemical Company) (10.0 g, 72.9 mmol), 5~ Na2C03 (50.0 mL) and 1,4 dioxane (40.0 mL) was added to a 500-mL, round-bottomed flask equipped with a mat~,netic stir bar and addition funnel. The solution was cooled in an ice-water bath, and a solution of di-tert-butyl dicarbonate (Fluka) (23.8 g, 109 mmol, 1.5 eq) in 1,4 dioxane (40.0 mL) was added dropwise.
The ice-water bath was removed, and the reaction mixture was allowed to warm to room I , e and stir for 24h. The reaction mixture was cooled with an ice-water bath, and an additional portion of di-tert-butyl ~irArho-otD (1.0 eq) in 1,4 dioxane (20.0 mL) was added dropwise. The ice-water bath was removed, and the reaction mixture was allowed to stir at room t , e for two days. The solvent was removed in vacuo, and water (150.0 mL) was added to the resulting white solid. The pH
was adjusted to approximately 2 with lN ~Cl, and the organics were extracted with ethyl acetate, dried over MgS04, filtered, and : ' to give a white solid. The solid was triturated with hexanes and dried to give 14.80 g (86~) of the product as a white solid. lh NMR (CDC13): 6 1.50 (s, 9), 7.58 (d, 2, J
8.8), 7.86 (d, 2, J - 8.8), 9.76 (br s, 1), 12.67 (br s, 1).
(b) PrDnAration of N-(4-(4-(1.2-hDn~ienthiA7nl-3-vl)-l-DiDera z1nvl)butvl)-4-((tert-butoxvcarbonyl) nn) ben_amide hvdrnrhlnride This compound was prepared according to the method described in Fxample 59, by employing 4-((tert-~Lu~ b~ l)amino)ben~oic acid (2.05g, 8.65 mmol), triethylamine (1.45 mL, 1.05 g, 10.4 mmol, 1.2 eq), isobutylchlu.uLu (Aldrich Chemical Compsny) (1.12 mL, l.lB g, 8.65 mmol, 1.0 eq) and 3-(4-(4-aminobutyl)-1-pera_inyl)-1,2-bDn~i~othip7olD (2.51 g, 8.65 mmol, 1.0 eq) W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
(_xample 13tb)). The crude reaction mixture was purified by flash cl..l gLLyl,~ with ethyl acetate/0.1~ triethylamine as eluant to give 0.78 g of the free base as a white solid. Impure fractions were combined and purified by flash ~1... ~L~L~ with 9:1 dichluL. r' /methanol as eluant to give 0.40 g of the free base as a white solid. The free base obtained from each column was combined and dissolved in ethanol and chloroform. To a solution of the free base was added lN ethereal HCl (2.41 mL, 1.0 eq). The solvent was removed, and the hydrochloride salt was recrystallized from ethanol to give 0.644 g (14~) of N-(4-(4-b~ othio7~1-3-yl)-l-piperazinyl) butyl)-4-((tert-butoxycarbon-yl)amino)benzamide hydrochloride as a beige solid. mp: 205-208 ~C (~CC~ _ce_). lH NMR (DMS0-d6): 6 1.49 (s, 9), 1.60 (m, 2), 1.80 (m, 2), 3.10-3.54 (m, 8), 3.59 (m, 2), 4.08 (br d, 2, J
12.5), 7.55 (m, 4), 7.80 (d, 2, J - 8.8), 8.14 (m, 2), 8.45 (br t, 1, J - 5.4), 9.64 (s, 1), 10.80 (br s, 1). 13C NMR (DMS0-d6):
~ 20.64, 26.34, 28.01, 38.28, 46,36, 50.33, 55.12, 79.39, 117.00, 121.15, 123.96, 124.58, 126.92, 127.79, 127.96, 128.08, 142.11, 152.06, 152.54, 162.17, 165.70.
Anal. Calcd for C27H35N503S.HCl: C, 59.38; H, 6.64; N, 12.82.
Found: C, 59.43; H, 6.65; N, 12.92.
FY l-~PT .F. 61 (a) PreDaration of 3-~tert-butoxycarbo~yl~amino~benzoic acid This compound was prepared according to the method described in Example 60(a), by employing 3- 'n~b-~7oic acid (Aldrich Chemical Company) (5.0 g, 36.5 mmol), 5~ Na2C03 (25 mL) and di-tert-butyl ~ir-rho~Ate (Fluka) (19.9 g, 91.1 mmol, 2.5 eq). After 65 h, the reaction mixture was worked up to give 7.48 g (86~) of 3-((tert-b~u~ Lb~ l)amino)benzoic acid as a white solid. H
NMR (CDC13): ~ 1.49 (s, 9), 7.37 (t, 1, J - 7.9), 7.54 (dd, 1, J
~:A~l ~1 7~3~
W O 93/16073 PCr/GB93/00285 - 1.2, 6.5), 7.63 (dd, 1, J - 0.9, 7.9), 8.15 (s, 1), 9.56 (br s, 1), 12.92 (br s, 1).
(b) PreDaration of N-(4-(4-(1.2 _hPn7; ~nrhi 07~1- 3-vl)-1-DiDere-zinvl~butyll-3-((tert-butoxyr~rh~~vl) ~n~)benzemide h~drochloride hvdrate This compound was prepsred according to the method described in Example 59, by employing 3-((tert-b~u~ b~ l)emino)benzoic acid (2.45 g, 10.3 mmol), triethylamir.e (1.72 mL, 1.25 g, 12.4 mmol, 1.2 eq), isobutylchlu-~~ _ ~ (Aldrich Chemical Company) (1.34 mL, 1.41 g, 10.3 mmol, 1.0 eq) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-bPn~i~othio~~lP (3.0 g, 10.3 mmol, 1.0 eq) (Example 13(b)). After 20 h, the reaction mixture was ~.~.,.f~LL.d to a ~ _~ funnel with the aid of dichlorometh-ane. The organics were washed with saturated R2C03, dried over MgS04, filtered, and ~ ' to give the crude free bese.
The crude product was purified by flash cl.-. ~ O ,'~ with 95:5 dichlù.~ L' /methanol as eluant to give 2.B2 g of the free base as a white solid. To a solution of the free base ~1.0 gO, 1.96 mmol) in chloroform was added 1.96 mL of lX ethereal HCl (1.0 eq). The hydrochloride salt was recrystallized from ethanol/ether to give 0.46 g (23~) of N-(4-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)butyl)-3-((tert-butoxycarbonyl)amino)ben-zamide hydrochloride hydrate as a white solid. mp: 139-144-C
(efre.~_.ces). lH NMR (DMS0-d6): 6 1.48 (s, 9), 1.59 (m, 2), 1.80 (m, 2), 3.16-3.54 (m, 8), 3.59 (br d, 2, J - 11.8), 4.08 (br d, 2, J - 13.1), 7.32 (t, 1, J - 7.9), 7.48 (m, 3), 7.60 (ddd, 1, J
- 1.1, 6.9, 8.1), 8.00 (s, 1), 8.13 (t, 2, J - 8.1), 8.50 (br t, 1, J - 5.6), 9.49 (s, 1), lû.72 (br s, 1). C NMR (DMS0-d6):
20.84, 26.48, 29.29, 38.66, 46.62, 50.71, 55.41, 79.43, 117.68, 120.82, 121.04, 121.50, 124.31, 124.93, 127.27, 128.44, 128.72, 135.72, 139.92, 152.45, 153.12, 162.56, 166.82.
Anal- Calct for cz7H35N5o3s~Hcl 0-75 H20: C, 57.95; H, 6.75; N, 12.51; H20, 2.41 Found: C, 57.86; H, 6.74; N, 12.61; H20, 2.44.
FxAMP!F 62 (a) PrrnAration of 4-er~-ro-N-(4-(4-~1.2-hrn7i~nrh1~7nl 3 pinrrA~i~yl)butyl, :.~amide hvdrnrh1rride N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-((tert-b~LuA~hLb~ l)amiDo)benzamide (800 mg, 1.57 mmol), (Example 60(b)), anisole (Aldrich Chemical Compsny) (1.5 mL), anhydrous chloroform (15.0 mL) and trifl~ rir acid (EM Sr;rnrifir) (15.0 mL) were sdded to a 500-mL, round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was stirred for 0.5 h at room t , ~ e . The solvent was removed n vacuo to obtain an oil. The crude oil was dissolved in ethyl acetate, washed with saturated K2C03, dried over ~gS04, filtered, ~nd ~ d to give a yellow solid.
The crude amine was purified by flash cl..~ with ethyl acetate/0.2% triethylamine to give 0.37 g of the amine as an oil.
To a solution of the amine in ethyl acetate and dichloromethane was added 0.90 mL of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol/water to give 200 mg (29%) of 4-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydro-chloride as a tan solit. mp: 213.5-214.5 ~C. H NMR (DhS0-d6):
~ 1.56 (m, 2), 1.77 (m, 2), 3.27 (m, 6), 3.45 (br t, 2, J
12.5), 3.59 (br d, 2, J - 11.9), 4.08 (br d, 2, J - 13.2~, 5.61 ( br s, 2), 6.54 (d, 2, J - 8.6), 7.48 (ddd, 1, J - 1.1, 7.1, 8,1), 7.60 (m, 3), 8.12 (m, 3), 10.65 (br s, 1). 13C NMR (DMS0-d6):
20.65, 26.52, 38.11, 46.37 50.44, 55.15, 112.43, 121.16, 123.96, 124.58, 126.91, 128.08, 1 .62, 151.44, 152.06, 162.18, 166.20.
W O 93/16073 C A :2 ~ 3 4 PCT/GB93/0028S
Anal. Calcd for ~H~ OS.HCl: C, 59.25; H, 6.33; N, 15.70.
Found: C, 59.03; H, 6.32; N, 15.62.
EXA~PT F. 63 (a) PreDaration of 3-amino-N-(4-(4~ 2-benzisothi~7nl-3-vl)-l- ~
Di nvl)butyl~h~ ~- hydrochloride hvdrate This compound was prepared according to the method described in Example 62, by employing N-(4-(4-(1,2-benzisothiazol-3-yl)-1-pip-erazinyl)butyl)- 3-((tert-b~LvA~ l)amino)-benzamide (1.77 g, 3.47 mmol), (Example 61(b)), anisole (Aldrich Chemical Company) (3.0 mL), anhydrous chloroform (30.0 mL) and tr~fl ~ ''r acid (EH Sri~ntifi~) (30.0 mL). The crude amine was purified by flash cl.~ ~ v .E~ with ethyl acetate/0.1~
triethylamine followed by ethyl acetate/0.2~ triethylamine to gi~e 1.16 g of the free base as an orange oil. The hydrochloride salt was prepared and recrystallized from ethanol/ether to give 0.31g (20~) of 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydrochloride hydrate as a rust-orange solid. mp: 122-130 ~C (eife,~_sces). H NMR
(D~S0-d6): ~ 1.59 (m, 2), 1.80 (m, 2), 3.05-3.75 (m, 10), 4.08 (br d, 2, J - 13.0), 6.10 (br s, 2), 6.79 (d, 1, J - 7.4), 7.13 (m, 3), 7.48 (ddd, 1, J - 1.0, 6.9, 8.1), 7.60 (ddd, 1, J - 1.1, 6.9, 8.1), 8.13 (t, 2, J - 8.4), 8.38 (br t, 1, J - 5.5), 10.77 (br s, 1). C NHR (DhS0-d6): ~ 20.66, 26.35, 38.36, 46.40, 50.49, 55.20, 114.21, 115.93, 117.63, 121.21, 124.05, 124.64, 126.98, 128.14, 128.72, 135.61, 146.36, 152.13, 162.22, 166.77.
Anal. Calcd for C22H27N505.HClØ5 H20: C, 58.07; H, 6.42; N, 15.39; H20, 1.98. Found: C, 58.17; H, 6.41; N, 15.25; H20, 2.35.
EXA~pT.F. 64 (a) PL~_ : ~n of N-(4-(4-(l.2-bDn7;enthiD7Al-3-yl~-l-DiDera zinvl)butyl)-3-bromo-2.6-dimethoxvbenzamide hvdrochloride 3-Bromo-2,6-~ L i~ acid (1.48 g, 5.69 mmol) (obtained by b.~ ~rDtion of 2,6~ L ~,ic acid (Aldrich Chemical Company) by the method Doyle F.P.; et al J. Chem. Soc. 1963, 497.) and anhydrous toluene (50.0 mL) were adted to a flame-dried, 100-mL, three-necked, round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet, addition funnel, and 1' . Thionyl chloride (1.12 mL, 1.83 g, 15.4 mmol, 2.7 eq) was added dropwise to the reaction mixture at room i . ' e. The addition funnel was replaced with a reflux condenser and the reaction mixture was heated to 65 ~C.
Dimethyl' '~- (0.03 mL) was added to the reaction mixture, and the i . e was 'ntDin-d at 65 ~C for 2 h. The solvent was reDoved in vacuo, and the residue was taken up in chloroform (20.0 mL). To this solution was added 3-(4-~4-aminobutyl)-l-pip-erazinyl)-1,2-b-n7ie~,thiD~~l- (1.5 g, 5.17 mmol, 0.9 eq) (Example 13(b)) in chloroform (12.0 mL) and triethylamine (1.08 mL, 0.785 g, 7.76 mmol, 1.4 eq). The reaction mixture was stirred at room ~ . ' e for 0.5 h. The solvent was removed in vacuo, and the orange oil was dissolved in ethyl acetate. The organics were washed with saturated R2C03, dried over MgS04, filtered and ~ -d to give an orange oil (3.24 g). The crude material was purified by flash ch.. e .~ ~ with ethyl acetate/0.1~
triethylamine followed by ethyl acetate/0.2% triethylamine to give 1.45 g of the free base as a yellow oil. To a solution of the free base in ethyl acetate was added 2.72 mL of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 0.867 g (27S) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)but-yl)-3-bromo-2,6-dimeLI,vA~L '~ hydrochloride as a white solid. mp: 220-221 ~C (dec). H NMR (DMS0-d6): ~ 1.56 (m, 2), CA2i 1 7434 1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4), 3.78 (s, 6), 4.08 (br d, 2, J - 13.4), 6.85 (d, 1, J - 9.0), 7.48 (t, 1, J - 7.5), 7.59 (d, 1, J - 8.9), 7.60 (rm, 1, J - 8.1), 8.13 (t, 2, J - 8.9), 8.38 ( br t, 1, J - 5.6), 10.92 (br s, 1). C NMR (DMS0-d6): C
20.36, 36.23, 38.01, 46.29, 50.39, 55.07, 56.12, 61.72, 106.87, 109.21, 121.16, 123.97, 124.01, 124.59, 126.92, 128.09, 132.97, 152.06, 153.45, 156.20, 162.17, 163.33.
Anal. Calcd for C24H29N4035Br.HCl: C, S0.58; H, 5.31; N, 9.83.
Found: C, 50.69; H, 5.32; N, 9.80, EXAMPT~ 65 (a) L'L~ _ l~n of 2- ~ ~~-N-(4-(4-(1.2-benzisothiP7~l-3-Yl) Di~ ,Yl)bur~yl~h~ ~I' hYdrochloride This compound was prepared according to the method described in Example 53, by employing 2-amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-l-piperazinyl)buryl) benzamide (1.3 8, 3.17 mmol) (Example 36), triethylamine (0.66 mL, 0.48 g, 4.78 mmol, 1.5 eq) and aceryl chloride (0.226 mL, 0.25 g, 3.17 mmol, 1.0 eq). She reaction mixture was stirred in an ice-water bath for 1 h and allowed to warm to rooD I ~ e. The reaction mixture was worked up after 18 h. The free base was purified by flash ch.~ - O ,'~ with ethyl acetate/0.1~ triethylamine as eluant to give l.09 g of the free base as an oil. To a solution of the free base (1.04 8, 2.30 mmol) in ethyl acetate was added 2.30 mL
of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 0.859 g (56~) of 2-acetamido-N-(4-(4-(1,2-~ 'e~rhiD7~l-3-yl)-l-piperazinyl)buryl)benzamide hydrochloride as a beige solid.
mp: 189.5-l90.5-C. H NMR (DMSO-d6): C 1.67 (m, 2), 1.84 (m, 2), 2.10 (s, 3), 3.10-3.75 (m, 10), 4.09 (br d, 2, J - 12.9), 7.16 (r~m~ 1, J - 7.7), 7.49 (t, 2, J - 7.8), 7.62 (t, 1, J
7.4), 7.78 (dm, 1, J - 7.8), 8.13 (d, 1, J - 7.6), 8.16 (d, 1, J
W O 93/16073 ~3~ 7 4 3 4 Pcr/Gw3/0028~
- 7.8), 8.36 (t, 1, J - 8.2), 8.84 (br t, 1, J - 5.2), 10.86 (br s, 1), 11.24 (br s, 1). C NMR (D~SO-d6): ~ 20.61, 24.78, 25.99, 38.40, 46.33, 50.41, 55.08, 120.46, 121.07, 121.16, 122.49, 123.96, 124.58, 126.92, 128.09, 131.68, 138.78, 152.06, 162.17, 168.08, 161.18.
Anal. Calcd for C24H29X5025.hCl: C, 59.06; h, 6-20; N, 14-35-Found: C, 59.13; H, 6.25; N, 14.41.
FY~Mpl F 66 (a) pr~n~rAtinn Of 2-(4-(4-(l~2-h~n7i~Athi~nl-3-yl)DiDeridi butvl)-(3H)-l-isoin~l~lin~~ hydr~rhlnride 3-(4-Piperidinyl)-1,2-benzisothiazole (1.25 g, 5.73 ~ mol), 2-(4-chlorobut )-l-1eoin~ (1.54 g, 6.88 mmol, 1.2 eq) (Example 3(a)), triethylamine (2.0 mL, 1.45 g, 14.33 mmol, 2.5 eq), and acetonitrile (25.0 mL) were added to a lCO-mL, round-bottomed flask equipped with a reflux condenser, magnetic stir bar, and nitrogen inlet. The reaction mixture was heated at reflux for 2 d. The solvent was removed in vacuo, and the crude reaction mixture was purified by flash ~I.L. r,Lo~L~ with ethyl acetate/0.1~ triethylamine followed by ethyl acetate/0.2~
trlethylamine as eluant to give 1.55 g of the free base. To a solution of the free base was added lN ethereal HCl (1.0 eq).
The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 1.15 g (45~) of 2-(4-(4-(1,2-~ ~othio7~1-3-yl)piperidino)butyl)-l-isoindolinone hydro-chloride as a pale beige solid. mp: 211-214 ~C (dec). lH NMR
(D~SO-d6): ~ 1.74 (m, 4), 2.22 (m, 4), 3.13 (m, 4), 3.59 (t, 4, J
- 6.1), 3.65 (m, 1), 4.52 (s, 2), 7.51 (m, 1), 7.54 (ddd, 1, J
1.1, 7.0, 8.1), 7.63 (m, 3), 7.70 (dt, 1, J - 7.4, 1.0), 8.21 (d, 1, J - 8.1), 8.28 (d, 1, J - 8.1), 10.25 (br s, 1). 13C NMR
(DhS0-d6): ~ 20.51, 25.04, 27.63, 35.50, 40.88, 49.36, 51.42, W O 93/16073 C A 2 1 1 7 4 3 4 P(~r/GBg3/0028~
55.61, 120.66, 122.64, 123.30, 123.49, 124.86, 127.73, 127.93, 131.16, 132.31, 133.27, 141.83, 151.89, 167.33, 167.49.
Ansl. Calcd for C24H27N305.HCl: C, 65.21: H, 6.38; N, 9.51.
Found: C, 65.31; H, 6.41; N, 9.51.
FY~Pl.~ 67 and 68 (8) preDaration of N-(4-~4-(l.2-benzisothip7~l-3-yl~-l-DiDerazinyl) butyl)-3-bromo-2-hvdroxv-6-meLI.vA~l ~dP hYdrochloride and N-(4-(4-(1.2-hP~7i~Athiazol-3-yl)-l-Dir~rp7inyl)butyl)-3-brom 6-hydroxv-2 ,' jL '~e h~drochloride N-(4-(4-(1,2-BP~7icothiP7~l-3-yl)-piperazinyl)butyl)-3-bromo-2,6-~ L '~ (4.99 g, 9.35 Dmol) ((Example 64(a) and anhydrous dichlu.~ ~ (75.0 mL) were added to a flame-dried, 250 mL, .~ ' bG~ ' flask equipped with a magnetic stir bar, nitrogen inlet, and pressure :, li7in~7, addition funnel. To this solution was added HCl (9.25 mL of a lN solution in ether, 9.25 mmol, 0.99 eq) followed by the dropwise addition of boron tril ~~' (Aldrich Chemical Company) (9.35 mL of a lN solution in Airhl~ , 9.35 mmol, 1.0 eq). The reaction mixture was allowed to stir at room ~ , e for 0.5 h. The reaction mixture was cooled with an ice water bath and lN ammonium hydroxide (50 mL) was added. The solids were dissolved with the aid of dichlv.. ' and water. The phases were separated and the aqueous phase was washed with dichlv.~ -' . The organics were combined, washed with water, dried over MgS04, filtered and ~ A to give 3.61 g of the crude product as a sticky yellow residue. The crude free base was purified by flash ~1", ~ with 97:3 dichlv-~ ' /methanol as eluant to give 2.06 g (Rf-0.10) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-pip-erazinyl)bu ql)-3-bromo-2-hydroxy-6 tLVA~L ~AP as an oil and 1.32 g of a mixture of isomers. This miture was purified by flash ~L~e v .'~ with ethyl acetate as eluant to give 0.18 g W O 93/16073 - ~ 52 1 1 7 4 3 4 PCT/GB93/00285 (Rf-0.34) of the minor isomer, N-~4-(4-(1,2-benziosothiazol-3-yl)-l-piperazinyl)butyl)-3-bromo-6-hydroxy-2 r' ~L ~-, as a tan solid. The hydrochloride salts of each isomer were prepared i ~ y by dissolving the free amine in ethyl acetate and treating them with HCl (1 equivalent of a lN solution in ether).
FYAMPT F. 67 The hydrochloride salt of the major isomer was recrystallized from ethanol/water to give 1.67 g (32%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-l-P~r 'nly)butyl)-3-bromo-2-hydroxy 6 , ~ ~ hydro-chloride as a pale pink solid. mp: 191-192.5 C. H NMR (DMS0-d6): 6 1.54-1.90 (m, 4), 3.05-3.70 (m, 10), 3.94 (s, 3), 4.07 (br d, 2, J-12.8), 6.60 (d, 1, J-9.2), 7.47 (m, 1), 7.60 (m, 1), 7.66 (d, 1, J-9.0), 8.11 (d, 1, J-7.6), 8.14 (d, 1, J-7.9), 8.93 (t, 1, J-6.2), 10.75 (br s, 1), 14.87 (s, 1). 13C NHR (DMS0-d6): ~ 10.62, 25.95, 38.58, 46.35, 50.44, 55.04, 56.69, 102.30, 103.14, 104.76, 121.17, 123.99, 124.60, 126.95, 128.10, 136.07, 152.10, 158.08, 159.27, 162.21, 168.79.
Anal. Calcd for C23~27N4035Br.HCl: C, 49.69; H, 5-08; N, 10-08-Found: C, 49.79; H, 5.11; N, 9.98.
FYII"PT .F. 68 The hydrochloride salt of the minor isomer was filtered and dried under high vacuum in an abderholden apparatus to give 76 mg (2~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl-3-bromo-6-hydro-xy-2 ~ ' ~L '~ hydrochloride as a white solid. mp: 185-187 C.
H NHR (DMS0-d6): ~ 1.60 (m, 2), 1.83 (m, 2), 3.10-3.70 (m, 10), 3.79 (s, 3), 4.09 (m, 2), 6.70 (d, 1, J-8.8), 7.49 (m, 2), 7.62 (t, 1, J-7,5), 8.15 (t, 2, J-7.8), 8.47 (br t, 1, J-5.2), 10.65 (br s, 1), 10.99 (s, 1). 13C NhR (DMS0-d6): ~ 20.50, 26.17, 38.14, 46.44, 50.55, W O 93/16073 C A 2 1 1 7 4 3 4 PCr/GB93ioo28s 55.27, 61.66, 104.70, 114.00, 119.20, 121.19, 124.04, 124.63, 126.99, 128.13, 133.81, 152.13, 154.34, 156.85, 162.24, 165.15.
Anal. Calcd for C23H27N4035Br.HCl: C, 49.69; H, 5-08; N, 10-08-Found: C, 49.73; H, 5.07; N, 10.00.
EXAMPJ.~ 69 ~a) Premaration of N-(4-~4-(6-fluoro-1.2-b~n~ic~vo7ol-3-vl)viDeri ~inn~butvl~oht~l imi ~i~ hvdrochloride 6-Fluoro-3-(4-piperidinyl)-1,2-b~n7~ 7~1P (1.64 g, 7.45 mmol), N-(4-bromobutyl)p~ mi~- (Altrich Chemical Company) (2.63 g, 9.31 mmol, 1.25 eq), triethylamine (1.56 mL, 1.13 g, 11.2 mmol, 1.5 eq) and acetonitrile (30 mL) were added to a 100 mL, .~ ' b : ' flask equipped with a magnetic stirring bar. The flask was equipped with a reflux condenser and nitrogen inlet and the re-ction mixture was heated at reflux for 15 h. The oil bath was removed and the reaction mixture was allowed to cool to room , . The reaction mixture was ; ~ ~d to a ~ funnel with the aid of ethyl acetate. The organics were washed with saturated ~2C03 and the two phases were r ' ~ The aqueous phase was extracted with ethyl acetate and the organics were combined. A white solid precipitated from the solution. The ~ was placed in a freezer for 1 hr and the solid was filtered. The filtrate was ~ d to give the crude product as an orange-mustard oil/solid mixture (4.19 g). The crute material was adsorbed onto silica gel and purified by flash cl..~ with dichl~-- t' :methanol (95:5) as eluant to give the free base as a yellow solit. The free base was dissolved in dichlu-- ' , filterd, and t ' to give an oil (1.9 g) which quickly solii~fiPd to a yellow solid. Ethereal HCl (4.5 mL of lN solution, 1.0 eq) was added to a solution of the free base in ethyl acetate and tichl~.. i' . The resulting hydrochloride salt was W O 93/16073 - li7 - 4 PCT/GB93/0028~
recrystallized from ethanol and water to give 1.39 g (41%) of the title conpound as a pale beige solid. mp: 227-229~C. lH NMR
(DMS0-d6~: ~ 1.68 (m, 2), 1.78 (~, 2), 2~27 (m, 4), 3.10 (m, 4), 3.47 (m, 1), 3.62 (m, 4), 7.34 (dt, 1, J-2.0, 8.9), 7.73 (dd, 1, J-9.1, 1.8), 7.88 (m, 4), 8.20 (m, 1), 10.55 (br s, 1). 13C N~R
(DMS0-d6): ~ 20.97, 25.71, 27.16, 31.52, 37.21, 51.60, 55.78, 97.67, 98.03, 112.90, 113.24, 117.00, 123.36, 124.15, 124.30, 131.99, 134.71, 160.43, 162.40, 163.45, 163.64, 165.69, 168.32.
Anal. Calcd for C24N24N303F.HCl: C, 62.95; N, 5.50; N, 9.18.
Found: C, 63.05: H, 5.52 N, 9.14 FYI~'~PT F. 70 (a) ~~~~ ~-~n of N-(4-(4-(l.2-h-Dn~ rhip7~l-3-yl)-l-rinerazinyl) butvl~-2.2.2-trif~
3-(4-(4-~ 1)-1-piperazinyl)-1,2 ~ ~~th~ole (Example 13(b)) (6.0 g, 20.7 mmol) and anhydrous dichlc.~ ' (50.0 mL) were added to a n ame-dried, 3-necked, 250 mL, round-bottomed flask equipped with a magnetic stir bar, ~ - , addition funnel, and nitrogen inlet. The solution was cooled in an ice w-ter bath and a solution of t-ifl ,- ~r anhydride (4.40 mL, 6.53 g, 31.1 mmol, 1.5 eq) in dichl~.- ' (20.0 mL) was added dropwise over a 0.5 h period. The reaction mixture w-s allowed to stir for 2 h. S-turated K2C03 (50 mL) was slowly added to the cold reaction mixutre. The reaction mixture was transferred to a funnel and the organics were extracted with ~1~hl. ~ . The organis were dried over MgS04, filtered, and ~ l d to give 6.87 g (86~) of the title compound as an orange oil. The crude material was used without further pur~first~n lN NhR (CDC13): ~ 1.71 (br s, 4), 2.51 (br t, 2, J-6,2), 2.71 (t, 4, J-4.8), 3.41 (m, 2), 3.59 (t, 4, J-4.9), 7.36 (t, 1, J-7.9), 7.49 (t, 1, J-7.9), 7.83 (d, 1, J-8.0), 7.90 (d, 1, J-7-9)-(b) ~ of N-(4-(4-(1.2-h~n7i~nthiD~~l-3-vl~vinor~7invl) butvl-N-m-thvl-2 2 2-trifl ~O
Sodium hydride (0.587 g, 19.6 mmol) as an 80~ nn in oil was added to a flame-dried, 3-necked, 250 mL, round-bottomed flask equipped with a rubber spetum, magnetic stir bar, addition funnel, and nitrogen inlet. The sodium hydride was washed three times with hexanes and anhydrous LeLL~.~: ~' (30.0 mL) was added. The , ~ n~ was cooled in an ice water bath and a solution of N-(4-(4-(1,2-benziosthiazol-3-yl)-1-piperazinyl)but-yl)-2,2,2-trifl ~ L '~' (6.87 g, 17.8 mmol) in anhydrous LeLLI.~.' .' (30.0 mL) was slowly added over a 35 min period.
The ice water bath was removed and a solution of methyl iodide (1.1 mL, 2.53 g, 17.8 mmol) in anhydrous ~e~d,~ L~ (20 mL) w-s added dropwise. The yellow-orange solution w s allowed to warm to room t , and to stir for 4 days. The excess NaH
wa- quenched with water (15 mL) and the L_ '~I.uf~.~,, was removed i~ vacuo, The residue was partitioned between water and dichlo.~ ' . The two phases were separated and the aqueous phas- was washed two - '' t~ ~ 1 times with dichl~ ' . The organics were combined, dried over MgS04, filtered, and L - ' to give the crude product as an orange oil. The crude free base was purified by flash G O .'~ with ethyl acetate as eluant to give 4.55 g (64~) of the title compound as a white solid. ~ NMR (CDC13): ~ 1.59 (m, 2), 1.71 (m, 2), 2.47 (t, 2, J-7.0), 2.68 (m, 4), 3.04 and 3.14 (2 singlets, 3, NCa3 tautomers), 3.45 (m, 2), 3.58 (m, 4), 7.36 (t, 1, J-7.2), 7.48 (t, 1, J-7.5), 7.82 (d, 1, J-7.7), 7.91 (d, 1, J-8.0).
(c) ~ lon of 3-(4-(4-(methvl~ 'nn)but,vl)-l-pin-r~invl)-1.2-' enthi o~nle N-(4-(4-(1,2-~- 'cot~;~701 -3-yl)-1-piperazinyl)butyl)-N-methyl--2,2,2-trifl _, I '~ (2.0 g, 5.0 mmol), ~ethanol (50 mL) and 20.0 mL of R2C03 (7~ aqueous solution) were added to a 250 mL, W O 93/16073 Ç L~ i 1 7 4 3 4 P(~r/GB93/0028~
round-bottoD-d flask equipped with a magnetic stir bar. The re-ction mixture was allowed to stir at room t . . for 6 h.
The methanol was removed i~ vacuo and the organics were extracted from the aqueous phase with dichlv,. ;' . The organics were dried over MgS04, filtered and - ' to give the crude product as a yellow oil that was used without further f~ rl-ti rn (d~ Pr~~~rAtir~ of 2- '~n-N-(4-(4-(1.2-~ e~thiazol-3-Y1 Di ~nVl~bUtYl~-N-methylh~ ~~lr hydrnrh1nride 3-(4-(4-(Hethylamino)butyl-l-pipera2inyl)-1,2-ben2isothia201e (1.4 g, 4.6 mmol), isatoic anhydride (Aldrich Chemical Co~pany) (0.750 g, 4.6 mmol, 1.0 eq), and ethanol (25.0 mL) were added to a 100 mL, round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was placed under a nitrogen ~ and was allowed to stir at room for 20 h and to stand for 6 h without stirring. The reaction mixture was e ~ ' i~ vacuo to give the crude product as a bL~ _ . ,, liquid. The free base was purified by flash ~1.,. O .'~ with ethyl acetate/0.1~ triethylamine as eluant to give 1.06 g of the free base. To a solution of the free base (1.06 g, 2.50 mmol) in ethyl acetate was added 2.5 mL of 1.0 N
ethereal HCl (1.0 eq). The solvent was removed in vacuo and the solid was recrystallized from ethanol and ehter to give 0.625 g (30~) of the title compound as a tan solid. mp: 188-189 C.
NhR (DHSO-d6): 6 1.61 (br s, 4), 2.93 (s, 3), 2.95-3.72 (m, 10), 4.07 (br d, 2, 3-12.0), 5.13 (br s, 2), 6.58 (td, 1, J-7.4, 1.1), 6.73 (dd, 1, J-0.8, 8.1), 7.02 (dd, 1, J-1.4, 7.7), 7.09 (ddd, 1, J-1.7, 7.3, 8.0), 7.48 (ddd, 1, J-l.0, 7.1, 7.9), 7.60 (ddd, 1, J-l.0, 6.9, 8.0), 8.13 (t, 2, J-8.2), 10.85 (br s, 1). 13C N~R
(DHS0-d6): ~ 20.36, 24.20, 46.34, 50.40, 55.13, 115.50, 120.26, 121.16, 123.97, 124.58, 126.92, 127.36, 128.09, 129.69, 145.35, 152.06, 162.18, 169.86.
CA~l 1 7434 Anal. Calcd for C23H29N505.HCl: C, 60.05; H, 6.57; N 15 22 Found: C, 59.98; H, 6.60; N, 15.13.
pYA~'P! F 71 (a) PronAr~t;r~ of 3-hydroxY-l~2-hon7ic~yr7~le This compound was prepared, according to the method of R. Frisry snd B.R. Sunday (J. HeterocYclic. Chem. 1979, 16, 1277), by employing sslicylh~ 'r acid (47.2 g, 0.308 mol) (Aldrich Chemical Company), l,l'-csrbonylt~1imi~7ole (100.0 g, 0.617 mol, 2.0 eq) (Aldrich Chemical Company), and anhydrous tet- '~d~f~,t...
(1750 mL). Upon work up, the crude product precipitsted ss a beige solid thst W85 recrystsllized from ethyl scetste to give 15.7 g of the title compound ss sn off-white solid. A second crop yielded sn e'--t1t 1 9.4 g for a total yield of 25.1 g (60~). 1H oMR (D~SO-d6): 6 7.34 (ddd, 1, J-1.6, 6.3, 8.0), 7.61 (m, 2), 7.78 (d, 1, J-7.7), 12.39 (br s, 1).
(b) P.. _:_rn of 3-nhlnro-l.2-hon71c~-a7~le 3-Hydroxy-1,2-bon~ olo (24.8 g, 0.184 mol) and dry triethyl-amine (25.6 mL, 18.6 g, 0.184 mol, 1.0 eq) were added to a flame-dried, 300 mL, .- ' b ' flask equipped with a msgnetic stir bar. The flssk was equipped with sn sddition funnel snd nitrogen inlet snd the solution was cooled with an ice water bath. P' r' ~~ oxychloride (37.8 mL, 6Z.1 g, 0.405 mol, 2.2 eq) was added dropwise to the reaction mixture. The ice water bath was removed and the flask was equipped with a reflux condenser. The resction mixture wss hested with sn oil bsth st 150 C overnight. The oil bsth W85 removed snd the dark brown-orange liquid was allowed to cool to room ~ , e. The reaction mixture was slowly poured into a stirred solution of ice snd wster (500 mL). After wsrming to room ~ the reaction mixture was tLc.. rtr_--.d to a ~ , ~ funnel with the ~id of dichl~L. -' (250 mL). The organics were separated and the ~queous phase w-s w shed with dichlG. ~' (250 mL). The organics were combined, dried over NgS04, filtered, and c~ ' to give 28.3 g (1000) of the crude product as a dark orange liquid. The crude msteri-l was used without further pur~firs~i~n lH NNR (DNSO-d6): ~ 7.56 (tm, 1, J-7.2?, 7.85 (m, 3).
(c~ Pr~~-~ation of 1-(l~2-b~"7i~Ays7nl-3-vl)DiDerA7i~p 3-Chloro-1,2-b~ nvsz~le (28.3 g, 0.184 mol), piperazine (95.1 g, 1.10 mol, 6.0 eq) and toluene (10.0 mL) were ~dded to a 500 mL
.~ ' b_ ' fl-sk. The flask w-s equipped with a reflux condenser ~nd nitrogen inlet, ~nd the mixture was heated with an o:l b-th .s~ 155 C for 18 h. The hot, dark organge reaction .xture w.,~ poured into ice water (600 mL). The organics were ~ _ d from the ' L _O ~queous mixture with dichl__. ' . The organics were dried with MgSO4, filtered, and c --~ r~d to give 22.8 g of the product as a dark orange liquld. Ethyl ~cet-te (6.0 mL) w s ~dded to the crude product and the solution was pl-ced in a refriger-tor. The dark organge solid that formed w s filtered, crlLshed with a spatula, washed with ethyl acet-te ~nd ether, ~nd air dried to give 10.1 g of the product ~s ~ must-rd colored solid. The crude m terial was used without further p~rifir9rinn lH NNR (DNSO-d6): ~ 2.91 (m, 4), 3.42 (m, 4), 7.31 (m, 1), 7.59 (d, 2, J-3.5), 7.99 (d, 1, J-8.0).
(d) r--- -~n of N-(4-(4-(l 2-b~n~i~~vs7Al-3-vl)-l-~iDerazin bUtyl)phthAl1m~ hvdrn~hlnride 1-(1,2~ 7Ol-3-yl~pir~rp7in~ (4 0 g, 19.7 mmol), ~-(4-bro-mobutyl)phr~ mi~ (Aldrich Chemical Company) (6.66 g, 23.6 mmol, 1.2 eq), triethylamine (4.12 mL, 2.99 g, 29.6 mmol, 1.5 eq), and acetonitrile (30 _L) were added to a round-bottomed fl-sk equipped with ~ magnetic stir b-r. The fl-sk was equipped wlth a reflux condenser and nitrogen inlet. The reaceion mixture was allowed to stir at reflux for 3 h. The oil bath was removed and the dark brown solution was allowed to cool to room ~ . e. The reaction mixture was t~ LeL-~d to a S r ' ~ funnel and partitioned between saturated K2C03 and ethyl acetate (200 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (100 mL). The organics were combined and a solid precipitated from solution.
The solid was dissolved with the aid of methanol and dichluL~ tl.~ . The organics were dried over MgS04, filtered, and c- ~ t- A to give the crude free base. The free base was purified by flash ~ with ethyl acetate as eluant to give the pure compound as a viscous yellow oil. The free base (5.89 g, 14.6 mmol) was dissolved in ethyl acetate and Ai~hl~ ' and 14.6 mL of lN ethereal HCl (1.0 eq) was added. The solvent was removed n vacuo and the resulting hydrochloride salt was recrystallized from ethanol/water to give 0.71 g (8.2~) of the title compound as an off-white solid. mp:
257-259~C(dec). lH NMR (DMSO-d6): ~ 1.71 (m, 4), 3.21 (m, 4), 3.55 (m, 6), 4.14 (br d, 2, J-13.2), 7.38 (m, 1), 7.65 (d, 2, J-3.7), 7.90 (m, 4), 8.06 (br d, 1, J-8.0), 10.62 (br s, 1). 13C
NMR (DMSO-d6): ~ 21.50, 26.24, 37.84, 45.61, 50.91, 56.00, 111.17, 116.05, 123.64, 123.94, 124.01, 131.30, 132.62, 135.36, 161.01, 164.27, 168.95.
Anal. Calcd for C23H24N403.HCl: C, 62.65; H, 5.71; N, 12.71.
Found: C, 62.51; H, 5.68; N, 12.65.
_XAMPLF 72 (a) PreDaration of 3-(4-~4-aminobutvl)-1-DinDrazinvl)-1.2-hDT17i ~AV97~1~
This compound was prepared, according to the procedure described in _xample 13(b), by employing N-(4-(4-(1,2-bDn7i~ 7~1-3-yl)-l-W O 93/16073 C A ~1l137-4 3 4 P~r/GB93/00285 piperazinyl)butyl)rhthsl;mi~ (Example 71(d)) (4.04 g, 9.99 mmol), hydrazine hydrate (0.87 g of a 55~ solution, 14.99 mmol, 1.5 eq), and methanol (30 mL). The reaction mixture was heated at reflux for 2.5 h. Upon cooling, the byproduct (phthalhydrazide) failed to precipitate. An additional portion of hydrazine (0.87 g, 1.5 eq) was added and the reaction mixture heated at reflux for an adtitional 1 h period. Upon work-up, 2.1 g (77~) of the crude product was obtained as an oil that So~ fiPd upon standing. H NMR (CDC13): ~ 1.55 (m, 4), 1.72 (m, 2), 2.44 (t, 2, J-7.1), 2.65 (t, 4, J-4.9), 2.75 (t, 2, J-6.5), 3.60 (t, 4,J-5.0), 7.22 (m, 1), 7.46 (m, 2), 7.70 (d, 1, J-8.0). This material was used without further purifirAtiAn (b) r A of 2-a~ino-N-(4-(4-(l.2-hD~7iQ~vs7Al 3-yl)-l pi-~-r97i-~,vl~butyl)h- ~*D hydrnrhlAride This compound was prepared, according to the procedure described in Example 36, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ Qovs7Ale (1.0 g, 3.65 mmol), isatoic anhydride (0.656 g, 4.02 mmol, 1.1 eq), and ethanol (10 mL). After 24 h the solvent was removed in vacuo, and the crude product was purified by flash Cl.L~ with 19:1 ethyl acetate/methanol as eluant to give 1.37 g of the free base as a viscous yellow oil. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 1.08 g (60~) of the title compound as a pale tan solid. mp: 249-252~C. lH N~R
(DMSO-d6): 6 1.58 (m, 2), 1.79 (m, 2), 3.29 (m, 6), 3.56 (m, 4), 4.14 (m, 2), 6.45 (br s, 2), 6.53 (t, 1, J-7.6), 6.71 (d, 1, J-8.0), 7.15 (t, 1, J-7.7), 7.37 (m, 1), 7.52 (d, 1, J-7.2), 7.65 (d, 2, J-3.7), 8.06 (d, 1, J-8.2), 8.30 (br t, 1, J-5.4), 10.79 (br s, 1). 13C NMR (DMS0-d6): ~ 20.70, 26,34, 38.07, 44.75, 49.97, 55.23, 110.26, 114.58, 114.82, 115.13, 116.35, 122.73, 123.02, 128.10, 130.38, 131.61, 149.57, 160.11, 163.35, 168.95.
Anal. Calcd for C22H27N502.HCl: C, 61.46; H, 6.56; N, 16.29, Found: C, 61.57; H, 6.54; N, 16.34.
~XAMP7 F 73 (a) Pr~A~ration of Ethyl N-(2-~((4-(4-(1.2-hDn7~A~hiP~~1-3-vl)-l-Dir~rp7inyl~butyl) 'n~)rPrbonYl)Dhe~Yl)eA-' hYdrochloride 2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) benzamide (Example 36) (1.5 g, 3.66 mmol), triethylamine (0,638 mL, 0.463 g, 4.58 mmol, 1.25 eq) and anhydrous chlorofo D
(10 mL) were added to a flame-dried, 50-mL, round-bottomed flask.
The reaction mixture was placed under N2, cooled with an ice-water bath and a solution of ethyl chlv.ufv-~L~ (0.385 mL, 0.437 g, 4.03 mmol, 1.1 eq) (Aldrich Chemical Company) in anhydrous chlorofo D (10 mL) was added dropwise. After the addition of ethyl chi~.~ r was complete, the ice-water bath was removed and the reaction mixture was allowed to stir at room . e for 18 h. Additional portions of triethylamine (0.51 mL, 0.37 g, 3.66 mmol, 1.0 eq) and ethyl chlG.-' (0.35 mL, 0.4 g, 3.66 mmol, 1.0 eq) were added to the reaction mixtvre. The solution was allowed to stir at room i , ~ e for 4 d. The reaction mixture was ~L~.~fe--~d to a s ,- - ~
funnel, dichlu-~ L' was added, and the solution was washed with saturated NaHC03. The layers were separated and the aqueous phase was extracted with dichlv-~ r' . The organic layers were combined, dried over MgS04, filtered and c- --~ d to give 1.74 g of the crude product as an orange oil. The free base was purified by flash ,1.~ with ethyl acetate:hexanes (2:1)/0.1% triethylamine followed by ethyl acetate/0.1% triethylamine as eluant t~ give 0.49 g of the free base as an oil. HCl (0.96 mL of lN solution in ether, 1.0 eq) was added to a solution of the free base (0.46 g, 0.96 mmol) in dichlu.~ ' and ethyl acetate. The hydrochloride salt was filtered and dried in a vacuum oven to give 0.385 g (20%) of the W O 93/16073 C A 2 i ~ ~4~ 3 4 PCT/GB93/0028~
title compound as a white solid. mp: 195-195.5~C. lH NMR
(DMSO-d6): ~ 1.24 (t, 3, J - 7.2), 1.62 (m, 2), 1.83 (m, 2), 3.26 (m, 6), 3.47 (m, 2), 3.61 (m, 2), 4.07 (m, 2), 4.14 (q, 2, J
- 7.2), 7.10 (tm, 1, J - 7.7), 7.49 (m, 2), 7.60 (ddd, 1, J
1.1, 7.0, 8.1), 7.79 (dd, 1, J - 1.5, 7.9), 8.12 (tm, 2, J
8.4), 8.20 (dd, 1, J - 0.9, 8.3), 8.89 (br t, 1, J - 5.5), 10.85 (br s, 1), 10.97 (s, 1). 13C NMR (DMS0-d6): ~ 14.41, 20.68, 26.01, 38.47, 46.44, 50.53, 55.16, 60.61, 118.62, 119.59, 121.25, 121.70, 124.04, 124.67, 127.00, 128.18, 128.24, 132.18, 139.30, 152.16, 152.91, 162.24, 168.36.
Anal. Calcd for C25H31N503S.HCl: C, 57.96; H, 6.23; N, 13.52. Found:
C, 58.07; H, 6.28; N, 13.47.
EXAMPI F. 74 (a) PreDaration of N-(4-(4-(l.2-~n7i~~this7~l-3-yll-l-DiDera-7invl)butvl)-3-bromo-2. 6-dil.Yd,~ .~amide hydrochloride Thionyl chloride (1.46 mL, 2.4 g, 20 mmol, 3.8 eq), anhydrous N,N-dimethyl- '~' (0.05 mL), anhydrous toluene (15 mL) and 3-bromo-2,6-dihYd.~A~L ir acid (1.2 g, 5.15 mmol) (prepared by bL~ '~9ti~n of dil-ydL~A~L ic acid (Aldrich Chemical Company) with bromine according to the method of F. P. Doyle, et. al. (J.
Chem. Soc. 1963, 497-506)), were added to a flame-dried, 100-mL, round-bottomed flask. The solution was placed under nitrogen and heated at 60-85 C for 1 h. The solvent was removed in vacuo and anhydrous dichlo,- -' (15 mL) and triethylamine (1.08 mL, 0.782 g, 7.73 mmol) were added to the solid residue. To this . '~n was added a solution of 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-ben7i~othis7ole (1.5 g, 5.15 mmol) (Example 13(b)) in anhydrous ~irh1~ thane (15 mL) and the reaction mixture was allowed to stir at room i , ~ for 18 h. The reaction mixture was transferred to a separatory funnel, dichloromethane was added, and the solution was washed with saturated NaHC03.
The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over MgS04, filtered and c~ to give 2.94 g of the crude product as a tan-beige solid. The free base was purified by flash chromatography (2x) with dichlo.~ eh9n~
methanol (93:7) as eluant to give 0.703 g of the free base as a yellow solid. The free base ( 0.703 g, 1.39 mmol) was dissolved in dichloromethane and ethyl acetate and lN ethereal HCl (1.39 mL, 1.0 eq) was added. The hydrochloride salt was filtered, washed with ether, and dried in a vacuum oven to give 0.454 g (16~) of the title compound as an off-white solid. mp:
228-230 C (dec). lH NMR (DMS0-d6): 6 1.62 (m, 2), 1.77 (m, 2), 3.00-3.70 (m, 10), 4.05 (m, 2), 6.49 (d, 1, J - 8.8), 7.48 (tm, 1, J - 7.2), 7.48 (d, 1, J - 8.8), 7.60 (t, 1, J - 7.6), 8.13 (t, 2, J - 8.8), 9.09 (br s, 1), 10.50 (br s, 1), 11.85 (br s, 1), 14.81 (br s, 1). 13C NM~ (DMS0-d6): ~ 20.71, 26.05, 38.32, 46.47, 50.58, 55.16, 99.68, 103.61, 107.57, 121.25, 124.05, 124.68, 127.00, 128.18, 135.99, 152.15, 157.05, 159.25, 162.26, 169.57.
Anal. Calcd for C22H25BrN403S.HCl: C, 48.76; H, 4.84; N, 10.34.
Found: C, 48.67; H, 4.86; N, 10.25.
FXAMPT.~ 75 (a) PL~ , nn of 6-Fluoroisatoic anhvdride 2-Amino-6-flvv..l lc acid (3.0 g, 19.3 mmol) (Maybridge Chemical Company), trichloromethyl chloroformate (15.0 g, 75.8 mmol, 3.9 eq) (Johnson-Matthey Chemical Company) and anhydrous 1,4-dioxane (60 mL) were added to a 250-mL, round-bottomed flask equipped with a magnetic stirring bar. The solution was placed under nitrogen and heated at reflux for 6 h.
The reaction mixture was allowed to cool to room temperature and rv.... .l~m ~ to give 3.8 g of the crude product as an off-white W O 93/16073 - 147 - PCT/GB93/0028~
solid. This material was used without further purification. H
NMR ~DMSO-d6): 6 6.97 (d, 1, J - 8.2), 7.06 (dd, 1, J - 8.4, 10.7), 7.73 (m, 1), 11.90 (br s, 1).
(b) PreDaration of 2-Amir~-N-(4-(4-(l.2-benzisothiazol-3-yl) pi~ers~i~yl)butYl)-6-fluor~h~n7 'de h~ydrochloride 6-Fluoroisatoic anhydride (1.5 g, 8.28 mmol) and anhydrous teL,~.~d,uf~,~.. (40 mL) were added to a flame-dried 300-mL
round-bottomed flask. The reaction mixture was placed under N2 and a solution of 3-(4-(4-aminobutyl)-1-pi~~ nyl)-1,2-benzi-sothiazole (Example 13(b)) (2.4 g, 8.28 mmol, 1.0 eq) in anhydrous L~L~ d.~f~,~., (25 mL) was added. The reaction mixture was allowed to stir overnight at room l , aL~. The reaction mixture was ~. ' and the crude free base was purified by column _h.~ with dichloromethane:methanol (19:1) as eluant to give 2.79 g of the free base as a yellow oil.
The free base was dissolved in ethyl acetate and lN ethereal HCl (6.53 mL, 1.0 eq) was added. The 1.~. ' lori~ salt was recrystallized from ethanol/~ater to give 2.0 g (52~) of the title compound as a beige solid. mp: 218-220~C. 1H NMR
(DMSO-d6): ~ 1.57 (m, 2), 1.80 (m, 2), 3.10-3.75 (m, 10), 4.10 (br d, 2, J - 13.1), 5.89 (br s, 2), 6.34 (dd, 1, J - 8.0, 10.5), 6.53 (d, 1, J - 8.2), 7.09 (ddd, 1, J - 6.8, 8.0, 8.2), 7.49 (t, 1, J - 7.6), 7.62 (t, 1, J - 7.5), 8.15 (t, 2, J - 7.2), 8.28 (m, 1), 10.55 (br s, 1). 1 C NMR (DMS0-d6): ~ 20.75, 26.38, 38.39, 46.57, 50.66, 55.38, 101.81, 102.27, 107.65, 108.01, 111.63, 111.68, 121.49, 124.32, 124.93, 127.29, 128.44, 131.20, 131.42, 149.90, 150.03, 152.46, 158.21, 162.58, 163.05, 164.66.
Anal. Calcd for C22H26FN50S.HCl: C, 56.95; H, 5.86; N, 15.09.
Found: C, 57.06; H, 5.95; N, 14.94.
~ ~.2i 1 7434 FXAMP~F 76 (a) PreDaration of 3-fluoroisatoic anhydride and 6-fluoroisatoic ~nhvdride Anhydrous chloroform (50 mL), 3-fl~ ,' '-lir anhydride (10.0 g, 60.2 mmol~ (Fluorochem Limited), and azidotrimethylsilane (8.0 mL, 60.2 mmol, 1.0 eq) (Aldrich Chemical Company) were placed under N2 in a 250-mL, flame-dried, round-botcomed flask.
The reaction mixture was gently heated with a heat gun until evolution of gas was noted and heated at reflux for 3.5 h. The solution was allowed to cool to room ~ , e and 95~ ethanol (10 mL) was added. The milky solution was cooled with an ice/water bath and the resulting precipitate was filtered and dried in a vacuum oven to give 7.78 g (71~) of the title compounds as an off-white solid. T g rn of the lH NMR
indicated a 60:40 mixture of the 3-fluoro- and 6-fluoro-isomers, ~ ly. 3-Fluoroisatoic anhydride: lH NMR (DMSO-d6~
300 MHz): 6 7.24 (dt, 1, J-4.7, 8.1), 7.68 (ddd, 1, J-1.3, 8.2, 10.7), 7.76 (dt, 1, J-7.9, 0.9). lH NMR signals observed for 6-fluoroisatoic anhydride were identical to those observed in _xample 75(a). This mixture was used without further purification.
(b) PreDaration of 2-~minr-N-(4-(4-(l.2-hDn7i~~thiazol-3-vl) Di ~yl~but~l)-3-fl ~,.I.. ~~D hydrochloride T~L-~l-uru-~ (50 mL), 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (2.55 g, 8.80 mmol) and a 60:40 mixture of 3-fluoro- and 6-fluoroisatoic anhydride (1.59 g, 8.80 mmol, 1.0 eq) were placed in a 100-mL, round-bottomed flask. The reaction mixture was allowed to stir at room t , ~ for 10 min, and the solvent was removed with a rotary ~VD,UuLD-UL.
The resulting viscous oil was purified by flash ~IIL~ g ~
(4x) on silica gel with ethyl acetate:hexanes (2:1) and ethyl acetate (100~) as eluant to give 0.88 g of the title compound as its free base. This material was dissolved in ethyl acetate and HCl (1.89 mL of a lX solution in ether, 1.0 eq) was added. The hytrochloride salt was recrystallized twice from ethanol to give 0.36 g (lS~ based on 3-fluoroisatoic anhydride) of the title compound as tan crystals. mp: 175-176 C. H NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.80 (m, 2), 3.18-3.66 (m, 10), 4.09 (br d, 2, J - 13.3), 4.30 (br s, 2), 6.56 (dtt, 1, J - 5.1, 8.0, 8.0), 7.14 (dd, 1, J - 1.4, 8.0), 7.20 (dd, 1, J - 1.2, 8.0), 7.41 (d, 1, J - 8.0), 7.49 (tm, 1, J - 7.7), 7.62 (tm, 1, J
7.4), 8.14 (t, 2, J - 6.9), 8.48 (br t, 1, J - 5.6), 10.72 (br s, 1). C NMR (DMS0-d6, 75.43 MHz): ~ 20.68, 26.26, 38.17, 46.41, 50.49, 55.18, 113.99, 114.09, 116.63, 116.87, 117.32, 117.38, 121.24, 123.72, 123.75, 124.05, 124.67, 127.00, 128.17; 137.77, 137.95, 149.63, 152.16, 152.78, 162.27, 168.00, 168.04.
Anal. Calcd for C22H26FNOS.HCl: C, 56.95; H, 5.87; N, 15.09.
Found: C, 56.93 H, 5.95; N, 15.03.
_xAMpT F 77 (a) P-~_ :'on of 2-(~tert-bv~ l)amino)hon7ric acid 2 A ' ~ iC acid (25 g, 0.182 mol) and 1,4 dioxane (100 mL) were atted to a 2-L ~. ' ~ . ' flask snd the mixture was cooled in an ice bath. To the mixture was added 5~ aqueous Na2C03 (125 mL) followed by the slow addition of a solution of ti-tert-butyl ~ir~r~ t~ (99.5 g, 0.456 mol, 2.5 eq) (Aldrich Chemical Company) in 1,4 dioxane (120 mL). ~hen the atdition was complete, the ice bath was removed and the reaction mixture was allowed stir at room t, .~LVLC for 67 h. The reaction mixture was c~ t~d to give a viscous orange-brown solution. The solution was diluted with water (140 mL) and cooled in an ice bath. The pH of the solution was adjusted to pH - 2 by the addition of lN HCl. The reaction mixture was transferred to a CA 2 i 1 7434 ~ ~ funnel and the product was extracted with ethyl acetate, The organic phase was separated, washed with water, dried over MgS04, filtered and cu..~..LLaLud to give an off-white solid. The solid was triturated with hexanes, filtered and dried to give 38.16 g (88~) of the title compound. H NMR (CDC13): ~
1.55 (s, 9), 7.05 (tm, 1, J - 7.7), 7.58 (tm, 1, J - 7.9), 8.11 (dd, 1, J - 1.6, 8.0), 8.48 (d, 1, J - 8.6), 10.03 (s, 1), 10.84 (br s, 1).
(b) Preparation of 2-((tert-butox~carbonyl~amino)-N-(4-hvdroxy-butyl)benzamide 2-((tert-LuLuA~.bv..~l)amino)benzoic acid (37.94 g, 0.160 mol), anhydrous triethylamine (26.8 mL, 19.46 g, 0.192 mol, 1.2 eq) and anhydrous ~L '~dLufuL~.. (125 mL) were combined in a flame-dried, l-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, ;' t~r, addition funnel, and nitrogen inlet. The orange solution was cooled to -25 C with an acetone/dry ice bath and isobutylrh1~roft (20.8 mL, 21.90 g, 0.160 mol, 1.0 eq) (Aldrich Chemical Company) was added dropwise.
The - , - ~ was intnin~d between -15 and -30~C during the addition of isobutylchlu.~f . After the ~ddition of the isobutylchluLuf~ was complete, the resulting thick s ~ on was swirled for 5 min. A solution of 4-amino-1-buta-nol (14.8 mL, 14.3 g, 0.161 mol, 1.0 eq) (Aldrich Chemical Company) in anhydrous te~,~L~d-uruLn-- (50 mL) was added slowly and the reaction mixture was allowed to stir at -15 and -30~C for 50 min. The cooling bath was removed and the solution was allowed to stir at room i . ~ for 18 h. The reaction mixture was , r ~d to a . ~ ~ funnel, ethyl acetate was added, and the organic phase was washed with saturated NaHC03.
The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined, dried over MgS04, filtered and cu...~..LL~L~d to give 62.1 g of the crude product as an orange liquid. The crude product was W O 93/16073 C A 2; 1 7 4 3 4 PCT/GB93/00285 purified by flash .1..~ with ethyl acetate as eluant to give 41.34 g ~844) of the title compound as a pale-yellow oil.
H NMR (CDC13): o 1.52 (s, 9), 1.72 (m, 4), 3.48 (q, 2, J - 6.2), 3.75 (m, 2), 6.59 (br s, 1), 6.97 (tm, 1, J - 7.5), 7.42 (m, 2), 8.36 (dd, 1, J - 0.9, 8.9), 10.22 (br s, 1).
(c) Pr~~ ri~ of 2-((tert-L~ .L .1) -~)-N-(4-((methyl-5..1 f~~Yl)oxy)butyl)h' - "~
2-((tert-Butoxycarbonyl)amino)-N-(4-hJdLu~L yl)benzamide ~14.0 g, 45.3 mmol) and anhydrous pyridine (100 mL) were added to a flaDe-dried, 500-mL, round-bottomed flask and placed under N2.
The reaction mixture w s cooled with an ice-water bath and lr ~1 chloride (7.0 mL, 10.38 g, 90.6 mmol, 2.0 eq) (Aldrich Chemical Company) was added dropwise. The ice-water bath was removed and the reaction mixture was allowed to stir at room ; , ~ for 2 h. The reaction mixture was : d to give an orange oil. The oil was ~ ' ~d to a .- y funnel with the aid of ethyl acetate and r~tl.r~t~d NaHC03. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgS04, filtered and - ~ to give 18.19 g of the crude product as an orange oil. The mesylate was purified by column ~1..- ~ ,h~ with ethyl acetate:hexanes (1:1) as eluant to giYe 11.46 g (654) of the title compound as a pale-orange oil. lH NMR (CDC13): ~ 1.52 (s, 9), 1.81 (m, 4), 3.03 (s, 3), 3.49 (q, 2, J - 6.3), 4.30 (t, 2, J - 6.0), 6.27 (br s, 1), 6.99 (tm, 1, J - 8.2), 7.42 (d, 1, J - 7.9), 7.44 (m, 1), 8.36 (dm, 1, J - 8.4), 10.13 (br s, 1).
(d) PrenAr~ of 3-(~ razinyl)-l~2-benzisothi~7~le 3-Chlu.~L '~othi~ole l,l-dioxide (16.93 g, 84 mDol)(Eur. Pat.
Appl. 0196096), piperazine (43.5 g, 0.505 Dol, 6.0 eq)(Aldrich C~ 2 i i 743~
Chemical Company) and toluene (9 mL) were atded to a 500-mL, round-bottomed flask. The reaction mixture was placed under N2 and he-ted at 160-170~C for 22 h. The reaction mixture sol1dif1PA upon cooling to room i . ~. The crude product was partitioned between chloroform and water. The organic layer was . \ d, washed with water (3 x 400 mL), dried over MgSO4, filtered and - : ~ to give 7.24 g (34 ~) of the title compound as a tan solid. lH NMR (CDC13): 6 1.74 (br s , 1), 3.08 (t, 4, J - 5.1), 4.03 ( t, 4, J - 5.0), 7.68 (m, 2), 7.84 (dd, 1, J - 1.2, 6.9), 7.97 (dd, 1, J - 1.8, 6.9). This material was used without further purification.
(e) PL~ 'on of N-(4-(4-(1.2-benzisothio~~l-3-yl)-l-DiDera 7invl)butyl)-2-((tert-butoxycarbonyl)amino)hDn7 ~AP
S .S_Ai~n~iAp 3-(1-Piperazinyl)-1,2-' ~~ot~io~olP l,l-dioxide (3.2 g, 12.7 mmol), 2-((tert-L ~l)amino)-N-(4-((methylsulfonyl)oxy)-butyl)benzamide, (5.0 g, 12.9 mmol, 1.02 eq), triethylamine (2.2 mL, 1.60 g, 1.58 mmol, 1.25 eq) and anhydrous acetonitrile (75 mL) were added to a flame-dried, 500-mL, round-bottomed flask, and placed under N2. The reaction mixture was heated at reflux for 22 h. The orange solution was , ' ~d to a , ~ ~ funnel ethyl acetate was added and the solution was washed with saturated NaHC03. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, dried over MgS04, filtered and ~ d to give 6.09 g of a yellow-beige glass. The crude material was purified by flash ~ with ethyl acetate:methanol (19:1) to give 4.58 g (62~) of the title compound as a pale beige glass. lH NMR (CDC13): 6 1.52 (s, 9), 1.64 (m, 4), 2.47 (br t, 2, J - 6.5), 2.63 (br t, 4, J - 5.0), 3.48 (br q, 2, J - 6.2), 4.03 (br t, 4, J - 4.9), 6.50 (br s, 1), 6.98 (t, 1, J - 7.6), 7.41 (d, 1, J - 7.7), 7.43 (m, 1), 7.69 (m, CA 2 i i 7434 2), 7.81 (d, 1, J - 7.7), 7.96 (d, 1, J - 7.2), 8.36 (d, 1, J
8.6), 10.14 (br s, 1).
-(f) pr~nAr~rinn of 2~ N-(4-(4-(l~2-hon~;~rth1p7~l~3-yl) pir~rP7inVl~bUtyl)~ S S-~ . hvdrnrhlnride Trifluoro-cetic acid ~(40 mL) (Aldrich Chemical Company), chloroform (100 mL), anhydrous anisole (8 mL) (Aldrich Chemical Company) and N-(4-(4-(1,2-~ ~oth~P7rl-3-yl)-l-piperazinyl)but yl)-2-((tert-butoxycarbonyl)amino)benzamide S,S-dioxide (4.58 g, 7.98 mmol) were combined in a 500-mL, round-bottomed flask snd stirred at room r , - e for 0.5 h. The reaction mixture was c~ .d and the resulting orange liquid was dissolved in dichl~ ' and vashed with saturated NaHC03 The organic layer was separated and the aqueous phase was extracted twice with dichlvL- ,' . The organic layers were combined, dried over MgS04, filtered and c~ r~d to give the crude product as an orange liquid. This material was purified by column chi~ with ethyl acetate:methanol (97:3) followed by ethyl acetate:methanol (96:4) as eluant to give 3.06 g of the free base. The free base (1.95 g, 4.42 mmol) was dissolved in dichl~. ' and lN ethereal HCl (4.64 mL, 1.05 eq) was added.
The hydrochloride salt was recrystallized twice from ethanol/water to give 0.83 g (34~) of the title compound as a - pale-beige solid- mp: 259-26loc (dec), lH NNR (DMS0 d6) 1.58 (m, 2), 1.78 (m, 2), 3.00-3.80 (m, 8), 3.95 (br s, 2), 4.68 (br s, 2), 6.54 (t, 1, J - 7.4), 6.71 (d, 1, J - 8.1), 7.15 (tm, 1, J - 7.6), 7.51 (dm, 1, J - 7.4), 7.87 (m, 2), 8.09 (m, 1), 8.30 (m, 2). C NNR (DNSO-d6): ~ 20.87, 26.48, 38.22, 44.64, 50,07, 55.31, 114.94, 115.19, 116.66, 122.34, 127.14, 127.30, 128.39, 131.88, 133.55, 133.77, 144.16, 149.75, 160.56, 169.25.
IR (RBr): 1297, 1163 cm . Ion Spray MS m/z (relative intensity): 442(NH ,100).
CA 2 i i 7434 Anal. Calcd for C22H27N5035.HCl: C, 55.33; H, 5.91; N, 14.67.
Found: C, 55.08; H, 6.00; N, 14.58.
EXA~J.~ 78 (a) FL~ 'on of 1.4-dihYdro-2H-3.1-benzothiazine-2.4-dithione Isatoic anhydride (3.0 g, 18.39 mmol) (Aldrich Chemical Company), ~ psnts~lfi*s (18.0 g, 40.49 mmol, 2.2 eq) (Aldrich Chemical Company) and xylenes (100 mL) were combined in a flame-dried, 500-mL, round-bottomed flask and placed under N2.
The reaction mixture was heated at reflux for 19 h, allowed to cool to room t . e, and filtered. The filtered solids were washed with tei '~d,~f~L~-, and the combined filtrates were r... _ .1 ~ ~t- d to give the crude product as a red-brown solid. The material was purified by flash LI.L~ with hexanes:ethyl acetate (3:1) as eluant to give 2.44 g (63~) of the desired product as a purple solid. lH NMR (D~S0-d6): 6 7.43 (t, 1, J
7.4), 7.56 (d, 1, J - 8.2), 7.90 (t, 1, J - 7.7), 8.33 (d, 1, J -8.2).
(b) FL~ lnn of 2- n~ N (4-(4 (l.2-hsn7i~~this~~l-3 D~ yl)butyl)th1r~ *9 hvdznrhlnride Anhydrous Lel '~dL~' (40 mL) and 1,4-dihydro-2H-3,1-benzo-thiazine-2,4-dithione (2.9 g, 13.7 mmol) were combined in a l-L, round-bottomed flask and placed under N2. A solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (4.2 g, 14.4 mmol, 1.05 eq) (Example 13(b)) in anhydrous tetrahydrofuran (35 mL) was slowly added. The reaction mixture was allowed to stir at room t . e for 0.5 h. An additional portion of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol, 0.25 eq) (Example 13(b)) in anhydrous tetrahydrofuran (10 mL) was added and the reaction mixture was allowed to stir for 0.25 h. The , ~~ was filtered and the filtrate was ~ l . A to give 7.6 g of a red-orange oily residue. This residue was combined with an additional 0.65 g of crude material obtained from a previous ~ . ' . The coDbined material was partially purified by flash ~ .h~ (2x) with dichlo.~ methanol (97:3) as eluant. Further p~.-1fl~eti~
on a Harrison Research ~ . with a gradient eluant:
dichlu-~ th~ 00~), dichlu.~ ~' : methanol (99:1) and dichlo~- ,' :methanol (97:3), gave 0.718 g of the free base as a yellow oil. The free base (0.718 g, 1.69 mmol) was dissolved in ethyl acetate and lN ethereal HCl (1.69 mL, 1.0 eq) was added.
The solids were filtered, washed with ethyl acetate and ether, and recrystallized from ethanol to give 0.229 g (2.7~) of the title compound as a yellow solid. mp: 198-201~C. lH NMR
(DMS0-d6): 6 1.78 (m, 4), 3.05-3.80 (m, 10), 4.10 (br d, 2, J
12.7), 5.74 (br s, 2), 6.59 (t, 1, J - 7.5), 6.74 (d, 1, J
8.0), 7.08 (D, 2), 7.50 (t, 1, J - 7.7), 7.63 (t, 1, J - 7.6), 8.15 (t, 2, J - 7.2), 10.30 (D, 1), 10.83 (m, 1). 1 C NMR
(DNS0-d6): ~ 21.74, 25.35, 45.37, 47.32, 51.43, 56.10, 118.56, 118.78, 122.18, 124.98, 125.59, 127.93, 128.49, 129.11, 129.37, 130.98, 143.37, 153.08, 163.20, 197.17. CIMS m/z (relative intensity): 426 (MH+, lOO).
Anal. Calcd for C22H27N552.HCl: C, 57.19; H, 6.11; N, 15.16.
Found: C, 56.95; H, 6.17; N, 14.98.
FY~MPT F. 79 (a) F-~ - 'on of N-(4-~4-~1.2-h~n~;~~thiP7~l-3-yl)-l-Di~era 7~ yl)but~yl)-2-~(tert-butoxy~-~rbonyl~aDino~h~ S ~
3-(1-Piperazinyl)-1,2-benzisothiazole l-oxide (1.48 g, 6.29 mmol) (J, M~ Chem., 1991, 34, 3316), 2-((tert-b~ h.b~ l)aDino)-N-(4-(methylsulfonyl)ox-)butyl)benzsmide (2.52 g, 6.52 mmol, 1.04 eq) (Example 77(c)), triethylamine (1.05 mL, 0.762 g, 7.53 mmol, 1.2 eq) and acetonitrile (50 mL) were added to a W O 93/16073 - 1s6i 1 74 34 PCT/GB93/00285 250-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 24 h. The orange _ , i~n was , ~ _d to a ~ r y funnel, ethyl acetate was added and the solution was washed with saturated NaHC03. The layers were separated and the aqueous phase was ~~trD-ted twice with ethyl acetate. The organic layers were combined, washed with saturated NaCl, ~ , dried over MgS04, filtered and c-~ d to give 3.08 g of an orange-yellow residue. The crude product was purified by flash ~1.,. O ,'~ with dichluL- rhsn~:methanol (97:3) followed by dichloromethane:methanol (95:5) as eluant to give 1.9 g (57~) of the title compound as a beige glass. lH NMR
(CDC13): 6 1.51 (s, 9), 1.69 (m, 4), 2.46 (t, 2, J - 6.B), 2.61 (t, 4, J - 5.0), 3.47 (q, 2, J - 6.2), 4.00 (m, 4), 6.56 (br s, 1), 6.97 (ddd, 1, J - 1.1, 7.3, 7.8), 7.41 (d, 1, J - 7.6), 7.42 (m, 1), 7.60 (m, 2), 7.83 (dm, 1, J - 6.3), 7.99 (dm, 1, J
6.1), 8.36 (d, 1, J - 8.0), 10.11 (br s, 1).
(b) Pr~-r~ti~n of 2-~ n~-N-(4-(4-(1.2-h~n7i~~this~1-3-~l)-1-pi- ~nvl)butvl)l ~~ S-oxide hydrochloride hvdrate N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-~(tert-butoxycarbonyl)amino)benzamide S-oxide (1.9 g. 3.6 mmol), anhydrous anisole (5.0 mL) (Aldrich Chemical Company), dichlu,. tl.~"~ (68 mL) and trifl . tic acid (17.0 mL) were added to a 300-mL, 1~ ' bv; ' flask. The flask was equipped with a magnetic stirring bar and nitrogen inlet and the solution was allowed to stir at room i . - ~ for 0.5 h. The reaction mixture was s ~ ' and the crude product was dissolved in dichlu,. - . Saturated NaHC03 was added and the mixture was LL~.~f~,,.d to a - , ~ funnel. The layers were separated and the aqueous phase was extracted twice with dichlu~ rhg~g The organic layers were combined, dried over MgS04, filtered and ;d. The crude product was partially purified by flash CLL. ~ with dichlu,- ~ :methanol (97:3) and dichlu,~ :methanol (95:5) as eluant to give 2.41 g of an W 0 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
orange-brown oil. This material was purified further by flash ~LL~ with a gratient eluant of dichloromethane:methanol (98-95~ dichlo,. ' to 2-5~ Dethanol) to give 0.57 g of the free base as a white glass. The free base was dissolved in dichl~-~ Lho~c and lN ethereal HCl (1.34 mL, 1.0 eq) was added.
The hydrochloride salt was filtered and dried to give 0.47 g (27~) of the title compound as a hygroscopic off-white solid.
mp: 208-213 C (dec). lH NhR (DMSO-d6): 6 1.58 ( m, 2), 1.79 (m, 2), 3.17 (m, 2)" 3.28 (m, 2), 3.45 (m, 2), 3.58 (br s, 2), 3.73 (br s, 2), 4.67 (br s, 2), 6.54 (t, 1, J - 7.5), 6.71 (d, 1, J
8.1), 7.15 (ddd, 1, J - 1.5, 7.1, 8.4), 7.51 (d, 1, J - 8.1), 7.75 (m, 2), 8.09 (m, 1), 8.22 (m, 1), 8.32 (br t, 1, J - 5.3), 11.25 (br s, 1). 13C NMR (DMSO-d6): 6 20.65, 26.28, 38.10, 44.31, 50.17, 55.15, 116.45, 116.54, 117.52, 125.45, 126.57, 128.23, 129.84, 131.69, 131.93, 147.10, 156.75, 164.53, 168.56.
IR (RBr): 1069 cm 1, Ion Spray MS m/z (relative intensity):
426 (MH ,100).
Anal. Calcd for C22H27N5025.HCl.H20: C, SS.OS; H, 6.30; N, 14.59; H20, 3.75.
Found: C, 55.28; H, 6.21; N, 14.58; H20, 4.07.
FY~MPT.F 80 (a) Pr~n~rAt;on of N-(4-(4-(1.2-h~n71~~th;~7~1-3-Yl)-l-DiDera-7i ~yl~butyl~-2-((N-(9H-fluoren-9-Yl thoxy)carbonvl~-L-valYl) 'n~
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide (2.39 g, 5.84 mmol) (Exa~ple 36), anhydrous chloroform (60 mL) and S~ aqueous Na2C03 (60 mL) were added to a 300-mL, round-bottomed flask. To the two-phase reaction mixture was added a solution of _-((9_-fluoren-9-ylmethoxy)carbonyl)-L-valyl chloride (3.3 g, 9.22 mmol, 1.58 eq) (prepared according to the method of L.A. Carpino, et. al. (J. Ore. Chem., 1986, 51, 3734) C~2i 1~434 by employing N-((9H-fluoren-9-ylmethoxy)carbonyl)-L-valLne (BACHEM ~slif~rnip)) in chloroform (60 mL). The two-phase reaction mixture was allowed to stir for 10 min at room t . ~ e and transferred to a , .~ funnel. Chloroform was added and the organic layer was - , ~, dried over MgS04, filtered and : ~ to give 6.48 g of the crude product as a pale yellow oil. This crude material was purified by flash ~1"~ with ethyl acetate:methanol (95:5) as eluant to give 4.5 g (95%) of the title compound as a white glass. lH NMR
(CDC13): ~ 1.00 (d, 3, J - 6.9), 1.07 (d, 3, J - 6.8), 1.64 (m, 4), 2.36 (m, 3), 2.62 (m, 4), 3.38 (m, 2), 3.53 (br t, 4, J
4.8), 4.37 (m, 4), 5.55 (d, 1, J - 8.6), 6.83 (br s, 1), 7.10 (t, 1, J - 7.6), 7.30 (m, 4), 7.48 (t, 4, J - 7.1), 7.66 (t, 2, J
8.1), 7.82 (m, 4), 8.61 (d, 1, J - 8.3), 11.59 (br s, 1).
(b) Pr9~rPt~ of N-(2-(N-(4-(4-(1.2 hp~7i~thip7Al 3 yl) 1 Di ~yl~butvl)carbamoyl)phenyl)-L-v~
tri fl ~ ~ ' hYdrate N-(4-(4-(1,2-~ ~othio~l-3-yl)-l-pipera_inyl)butyl)-2-((_-(9_-fluoren-9-ylmethoxy)carbonyl)-L-valyl)amino)ben_amide (3.57 g, 4.88 mmol), chloroform (110 mL), 4-( ~ tl.~l)piperidine (50 mL) (Aldrich Chemical Company) were added to a 500-mL, round-bottomed flask. The reaction mixture was stirred under nitrogen at room L . for 0.5 h. The reaction mixture was ~ d to a r ' ~ funnel and chloroform (150 mL) was atded. The organic layer was washed with water (3 x 250 mL), , ~ ~. dried over MgS04, filtered, and : ~ ' to give 5.67 g of the crude product as a yellow oil. The free base was purified by column cl..~ on silica gel with ethyl acetate:methanol (85:15) as eluant to give 2.13 g of the free base as a viscous oil. A portion of the free base (1.17 g) was purified further by semi-preparative HPLC (Vydac C-18 column) with 0.1% CF3C02H/H20: 0.1% CF3C02H/CH3CN gradient 9:1 to 1:9.
The appropriate fractions were combined, c-~ d, dissolved W O 93/16073 C A 2 i i 7 4 3 4 159 PCT/GB93/00285 in water and methanol ant lyophilized to give 0.87 g (48%) of the title compound as a white powder. H NMR (DMS0-d6): d 1.01 (t, 6, J - 6.5), 1.60 (m, 2), 1.77 (m, 2), 2.18 (m, 1), 3.30 (m, 8), 3.61 (m, 2), 3.95 (m, 1), 4.10 (m, 2), 7.25 (t, 1, J - 7.7), 7.48 (tm, 1, J - 7.5), 7.58 (m, 2), 7.76 (d, 1, J - 7.8), 8.13 (t, 2, J - 9.0), 8.24 (d, 1, J - 8.4), 8.40 (br s, 1), 8.89 (br t, 1, J
- 4.8), 10.33 (br s, 1), 11.48 (s, 1). 13C NMR (DMSO-d6):
17.96, 18.05, 20.90. 25.92, 29.88, 46.63, 50.67, 55.31, 58.78, 121.26, 121.58, 123.01, 123.95, 124.02, 124.69, 126.97, 128.21, 128.25, 131.83, 137.09, 152.16, 157.69, 158.11, 158.54, 158.96, 162.17, 166.70, 168.00.
27H36N602S.2.35 CF3C02HØ75 H20: C 48 l9; H
5.08; N, 10.64; F, 16.95; H20, 1.71.
Found: C, 48.18; H, 5.10; N, 10.78 F, 16.90; H20, 1.79.
F.Y~''P! .F 81 (a) P-. _ lon of N-(4-~4-(1.2 ~ ~Athip~nl-3-vl~ Di~era-7i~yl)butyl)-2-((N-(9H-fluoren-9-vl thA~v)carbo~yl~-D-valyl) r.~)~ ' A-This compound was prepared according to the method described in _xample 80(-), by employing 2-amino-N-(4-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)butyl) benzamide (2.33 g, 5.7 mmol) (Example 36), _-((9_-fluoren-9-ylmethoxy)carbonyl)-_-valyl chloride (3.22 g, 9.0 mmol, 1.58 eq), anhydrous chloroform (120 mL) and 5% aqueous Na2C03 (60 mL). N-((9B-Fluoren-9-yl-methoxy)carbonyl)-D-valine was purchased from BACHEM ~.AliforniA
The crude product was purified to give 3.42 g (82%) of the title compound as a white solid. lH NMR (CDC13): 6 1.01 (d, 3, J
6.8), 1.07 (d, 3, J - 6.8), 1.64 (m, 4), 2.36 (m, 3), 2.62 (br t, 4, J - 4.5), 3.42 (m, 2), 3.53 (br t, 4, J - 4.8), 4.37 (m, 4), 5.55 (d, 1, J - 8.6), 6.80 (br s, 1), 7.10 (t, 1, J - 7.2), 7.36 CA2'i 1 7434 (tD, 4, J - 4.4), 7.48 (tD, 4, J - 7.6), 7.67 (t, 2, J - 8.2), 7.80 (m, 4), 8.62 (dm, 1, J - 8.9), 11.58 (br s, 1).
(b) PreDaration of N-~2-(N-(4-(4-(1.2-benzisothiazol-3-Yl)-l-Di n~Yl)butYl)carbaDQYl)Dhenyl)-D-valinaDide trifluoro-acetate hydrate This coDpound was prepared according to the method described in Example 80(b) by employing _-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((_-(9_-fluoren-9-ylmethoxy)carbonyl)-_-val-yl)aDino)benzaDide (3.47 g, 4.75 DDol), chloroforD (100 DL) and 4-( cl.~l)piperidine (S0 mL). The crude material was purified by column cl.~ with ethyl acetate:methanol (85:15) to give 1.99 g of the free base as a viscous oil. A
portion (0.61 g) of the free base was applied to a semi-preparative column and 0.54 g (57~) of the title compound was obtained as a white powder. lH NMR (DMS0-d6): 6 1.01 (t, 6, J - 6.5), 1.60 (m, 2), 1.78 (m, 2), 2.18 (m, 1), 3.32 (m, 8), 3.62 (m, 2), 3.95 (m, 1), 4.10 (br d, 2, J - 10.5), 4.56 (br s, 3), 7.24 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.7), 7.58 (m, 2), 7.77 (d, 1, J - 7.5), 8.13 (m, 2), 8.23 (d, 1, J - 8.1), 8.34 (br s, 3), 8.90 (br t, 1, J - 5.3), 10.54 (br s, 1), 11.49 (s, 1). C
NMR (DMSO-d6): 6 18.91, 18.97, 21.78, 26.86, 30.80, 47.52, 51.55, 56.21, 59.69, 122.18, 122.51, 123.98, 124.87, 124.95, 125.61, 127.90, 129.12, 129.20, 132.72, 138.00, 153.09, 158.68, 159.11, 159.54, 159.98, 163.12, 167.62, 168.91.
27H36N602S.2.35 CF3C02HØ75 H2O: C 48 19; H
5.08; N, 10.64; F, 16.95; H20, 1.71.
Found: C, 48.03; H, 5.06; N, 10.62; F, 16.63; H20, 1.68.
W O 93/16073 C ~ 2 i 7 4 3 4 161 - PCT/GB93/00288 FYI~MPT F. 82 (a) F.._ _. 'nn of N-(4-(4-(1.2-benzisothiazol-3-Yl)-l-Di~era-zinvl~butyl)-2-((tert-b~ aLb~ 'nr~)benzamide 2-Amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-1-piperszinyl)butyl)ben zsmite (3.3 g, 8.06 mmol) (Exsmple 36), 1,4-dioxsne (10 mL) snd 5~ squeous Ns2C03 (10 mL) were combined in a 250-mL, round-bottomed flask. The flssk was equipped with a magnetic stirring bar and an addition funnel. A solution of di-tert-butyl dicarbonste (4.41 g, 20.2 mmol, 2.5 eq) (Aldrich Chemical Company) in 1,4-dioxane (10 mL) was added dropwise and the resction mixture wss allowed to stir at room i ~ - e for 45 h. An additionsl portion of di-tert-butyl d~irArho~Atr (1.76 g, 8.06 ~mol, 1.0 eq) in 1,4-dioxane (10 mL) was added to the resction mixture and the , 'An was allowed to stir for 5 d.
The reaction mixture was filtered and the filtrate was i ~ ~d to a , - ~ funnel. Ethyl acetate and water were sdded, the organic lsyer wss sepsrsted snd the squeous phsse wss trr-t~d with ethyl gcetgte. The organic lsyers were combined, dried over HgS04, filtered snd ~ - ' to give 6.56 g of the crude product ss sn orange liquid. The crude csrbsmate wss purified by flssh cl.~ with ethyl scetste as eluant to give 3.39 g (83~) of the title compound ss a yellow oil. lH NMR
(CDC13): ~ 1.52 (s, 9), 1.71 (m, 4), 2.50 (br t, 2, J - 6.4), 2.67 (br t, 4, J - 4.9), 3.48 (m, 2), 3.55 (br t, 4, J - 4.9), 6.74 (n, 1), 6.98 (tm, 1, J - 7.6), 7.42 (m, 4), 7.82 (d, 1, J
8.0), 7.90 (d, 1, J - 8.1), 8.36 (dd, 1, J - 1.0, 9.0), 10.18 (br s, 1).
W O 93/16073 PCT/GB93/0028~
CA 2 i 17434-162 -(b) PreDaration of N-(4-~4-(l.2-bsn7icnthiazol-3-yl)-l-DiDera zinYl~butvl~-2-~(tert-butoxycsrbonyl)amino~hrn7 de Nl. S. S-trioxide A solution of 50-60~ _-chlu.~r vA~b_.L~oic acid (4.49 g, 13.0-15.6 mmol, 2.0-2.4 eq) (Aldrich Chemical Company) in dichlv.. '- (50 mL) was added to a solution of N-(4-(4-(1,2-ben~icothls~Al-3-yl)-1-piperaz$nyl)butyl)-2-((tert-b~LvA)~ l)amino)benzamide (3.32 g, 6.51 mmol) in dichluL~ ' (50 mL). The reaction mixture was allowed to stir at room ; . e for 1.5 min. The solution was ~.~.,9fe...d to a ~_r~ UL~ funnel and dichlu-~ th9nr and saturated N~HC03 were added. The organic layer was separated and the aqueous phase was extracted twice with dichlo.~ . The organic layers were combined, dried over MgS04, filtered and - ' to giYe 4.6 g of the crude product as a yellow glass. The crude product was purified by flash 'I--' v .'~
with dichlo.. ' :methanol (4:1) as eluant to gi~e 2.28 g (59~) of the title compound as a pale-yellow solid. ~ NMR
(CDC13): ~ 1.50 (s, 9), 1.84 (m, 2), 2.08 (m, 2), 3.33 (m, 6), 3.50 (m, 2), 4.48 (m, 4), 6.95 (t, 1, J - 7.7), 7.40 (tm, 1, J
8.0), 7.71 (m, 4), 7.94 (d, 1, J - 6.7), 8.20 (br s, 1), 8.32 (d, 1, J - 8.8), 10.40 (s, 1).
c) r~ of 2-~ ~nn-N-(4-~4-(1.2-benzisothis7~1-3-yl) l-Di nvl)butyl)benzamide Nl.S.S-trioxide h~drochloride N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((tert-b~LvA~c.bv.l~l)amino)benzamide Nl, S, S-trioxide (2.28 g, 3.87 mmol), anhydrous anisole (4.0 mL) (Aldrich Chemical Company) and anhydrous chloroform (50 mL) were combined in a 500-mL, round-bottomed flask and trifluoroacetic acid (5.0 mL) (EM
Science) was added. The reaction mixture was allowed to stir under a nitro~en . I' e at room , , e for 0.5 h.
Trifluoroacetic acid (15 mL) was added to the reaction mixture W O 93/16073 A 2 i i 7434 PCT/GB93/00285 ant the solution was allowet to stir for 0.5 h. Chloroform was added to the reaction mixture and a cold solution of saturatet NaHC03 was adtet slowly. The mixture was transferred to a ~ funnel ant the organic layer was s r tDd. The aqueous phase was extractet with chloroform. The organic layers were combinet, triet over MgS04, filtered ant c~ LDtet..
This material was purifiet by flash cl..~ g .'~ with tichlG.. ' :methanol (4:1) to give 0.686 g of the free base as a pale yellow glass. The free base (0.686 g, 1.55 mmol) was tissolved in tichl~.- '- ant methanol and lN ethereal HCl (1.55 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.51 g (26%) of the title compound as a beige solit. mp: 226-228 C. lH NMR
(DMS0-t~ 1.61 (m, 2), 1.91 (m, 2), 3.32 (m, 2), 3.96 (m, 8), 4.75 (br s, 2), 6.53 (ttt, 1, J - 1.1, 7.1, 8.1), 6.70 (tt, 1, J
- 1.1, 8.4), 7.15 (ddt, 1, J - 1.4, 7.1, 8.4), 7.52 (dm, 1, J
8.1), 7.87 (m, 2), 8.10 (m, 1), 8.31 (tm, 2, J - 6.2). C NMR
(DMS0-d6): ~ 19.73, 26.77, 39.00, 42.84, 61.74, 68.28, 115.50, 115.67, 117.27, 123.10, 127.85, 127.88, 129.03, 132.56, 134.23, 134.51, 144.80, 150.54, 161.17, 169.90. IR (KBr): 1311, 1162, 587 cm 1. Ion Spray MS m/z (relative intensity): 458 (MH , 80), 480 ((M+Na) , 100).
Anal. Calcd for C22H27N5045.HCl: C, 53.49; H, 5.71; N, 14.18;
Cl, 7.18.
Found: C, 53.57; H, 5.75; N, 14.14; Cl, 7.23.
F~xAMpT F 83 (a) PrDn~tiA~ of 2-Amino-N-(4-(4-tl.2-benzisothiazol-3-vl)-1-Di rlyl)butYl~hDn7 A. N1 AY;~D hvdrochloride 2-Amino-N-(4-(4-(1,2-b-n-icothi~Al-3-yl)-1-piperazinyl)butyl)ben zamite (3.28 g, 8.01 mmol) (Example 36) and anhydrous tichlu.~ t~AD (75 mL) were combined in a 250-mL, round-bottomed W O 93/16073 C A 2 i i 7 4 3-4164 - PCT/GB93/00285 flssk. The reaction mixture was allowed to stir under 8 nitrogen ~ ,' e and cooled to -78~C with a dry_ice/acetone bath. To a pear-shaped flask was added 50-60~ m-chluL~r.-uA~b_.~uic acid (2.30 g, 6.7-8.0 mmol, 0.8-1.0 eq) (Aldrich Chemical Company).
The _-chluLur~LuA~L ic acid was placed under N2, anhydrous dichluL. ' (25 mL) was added and the solution was cooled to -40~C with a dry ice/scetone bsth. A portion of the ~-chlu.ur.LuA~L ic scid was insoluble at this i , e.
The _ , C was transferred to the cold benza~ide solution with a cannu~aiOspd the remaining peracid was dissolved in anhydrow dichl~ Ll.~..c (10 mL) and cooled in an ice-water bath. The c~l,do ~olution of m-chluL-. ~Ayt_.~uic acid was LL~ CrLL_d to~ b '~D solution and the reac~ion mixture was stirred at~ ~C for 0.5 h. The reaction mixture was diluted with dichluL. ~ d to a ~ funnel and washed with satu~ed NaHC03. The layers were separated and the aqueous phase wy extracted twice with dichluL. rho~, The organic layers were combined. dried over MgS04, filtered and ' to ~ive 3.57 g of the crude product~as a beige solid. The crude free bsse was purified by flash ~LL~ LJ
with dichlu.~ rh~ methanol (17:3) as eluant to give a beige solid. The solid was partitioned between dichlu-- t~ and ssturated NaHC03. The organic layer was separated, dried over MgS04 filtered and ~ ~ ' to give 0.991 g of the free base ss a beige solid. The free bsse (0.986 g, 2.32 mmol) wss dissolved in dichlo.. Ll. .c/methsnol and lN ethereal HCl (2.32 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.470 g (13~) of the title compound as a tan solid. mp: 177.5-178.5 C (dec). H NMR
(DffS0-d6): 6 1.61 (m, 2), 1.91 (m, 2), 3.29 (br t, 2, J - 6.8), 3.66 (m, 2), 3.90 (m, 6), 4.10 (br d, 2, 3 - 13.7), 6.53 (ddd, 1, J - 1.0, 7.1, 7.6), 6.71 (dd, 1, J - 1.0, 8.4), 7.15 (ddd, 1, J -1.5, 7.1, 8.4), 7.50 (m, 1), 7.52 (dm, 1, J - 7.6), 7.63 (tm, 1, J - 7.6), 8.14 (d, 1, J - 8.0), 8.20 (d, 1, J - 8.0), 8.34 (br t, 1, J - 5.6). C NMR (DMS0-d6): 6 18.87, 26.02, 38.28, 43.90, r~'~2 i, 7~34 W O 93/16073 - 165 - PCT/GB93/0028~
61.34, 67.36, 114.88, 115.07, 116.65, 121.54, 124.32, 124.96, 127.17, 128.39, 128.47, 131.91, 149.89, 152.55, 162.12, 169,30, Ion Spray MS m/z (relative intensity): 426 tMu , 100).
Anal. Calcd for C2~u~lN~O~.HCl: C, 57.19; H, 6.11; N, 15.16.
Found: C, 57.29; H, 6.13; N, 15.10.
FXAMPT.F. 84 (a) PreDaration of 2-(2-(tert-b~uA~a-b~ l)hydrazino)benzoic acid 2-HyA~D7~ r acid hydrochloride (7.5 g, 40.0 mmol) (Aldrich Chemical Company), 1,4-dioxane (40 mL) and 5S aqueous Na2C03 (75 mL) were combined in a 500-mL, round-bottomed flask and cooled in an ice-water bath. The flask was equipped an addition funnel and a solution of di-tert-butyl ~i~Arhorst~ (9.6 g, 44.0 mmol, 1.1 eq) (Aldrich Chemical Company) in 1,4-dioxane (20 mL) was slowly added. The ice-water bath was removed and the reaction mixture was allowed to stir at room ~ for 6 h.
An additional portion of di-tert-butyl ~ bo~t~ (0.99 g, 4,54 mmol, 0.11 eq) was dissolved in 1,4-dioxane (10 mL) and slowly added to the reaction mixture. The reaction mixture was allowed to stir for an additional 26 h and ~ ' to give a red-orange residue. Water (200 mL) was added to the residue and the mixture was cooled in an ice-water bath. The pH was adjusted (pH - 1) by the addition of aqueow lN HCl and the solution was extracted with ethyl acetate. The organic layer was , - d, dried over MgS04, filtered and ' ' to give a solid. The solid was triturated with hexanes and dried in a vacuum oven to give 9.13 g (9lS) of the title compound as a tan-beige solid. H
NMR (DMS0-d6): ~ 1.43 (s, 9), 6.77 (t, 1, J - 7.5), 6.88 (d, 1, J
- 8.2), 7.45 (tm, 1, J - 7.7), 7.83 (dd, 1, J - 1.5, 7.9), 8.89 (s, 1), 9.07 (br s, 1), 12.98 (br E, 1).
(b) Pre~aration of N-(4-(4-(1.2-benzisothiD7~l-3-vl)-l-~i~era-W O 93/16073 C A 2 i 1 7 4 ~6 - PCT/GB93/00285 zinvl)but,Yl)-2-(2-(tert-butoxYcsrbonyl)hyAr,~;~~)benzamide 2-(2-(tert-E ~a.'uu..~l)hydrazino)benzoic acid (2.57 g, 10.2 mmol), anhydrous teLL~.~I.ufu.~.. (30 mL) and anhydrous triethylamine (1.70 mL, 1.23 g, 12.2 mmol, 1.2 eq) were combined in a flame-dried, 100-mL, round-bottomed flask. The orange solution was stirred under a nitrogen ~ .' e and cooled between -20 and -35~C with a dry ice/~ ol bath.
Isobutylchloroformate (1.32 mL, 1.39 g, 1.0 eq) (Aldrich Chemical Company) was added and the mixture was allowed to stir for 5 min.
A cold (-20 to -35 C) solution of 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-~ '-othiD7~1e (2.97 g, 10.2 mmol, 1.0 eq) (Lxample 13 (b)) in anhydrous teL-~.~d-uL~.~.. (30 mL) was slowly added. 'Ehe reaction mixture was allowed to stir between -15 and -30~C for 0.75 h. The cold bath was removed and the reaction mixture was allowed to stir at room r , c for 1.5 h. 'Ehe reaction mixture was i ' ~d to a - . ~ ~ funnel, dichlc.. i' was added, and the solution was washed with sDt~r~t~d NaNC03. The layers were separated and the aqueous phase was extracted with dichlu.. Ll.~..c. 'Ehe organic layers were combined, dried over NgS04, filtered and c r~ A to give 5.89 g of an orange oil. The crude product was purified by column ~1.-. ~ ,'~ with dichlu.. r~ :methanol (19:1) as eluant to give 3.01 g (56~) of the title compound as a pale-beige glass. lN NNR (CDC13): ~i 1.45 (s, 9), 1.68 (br t, 4, J - 3.0), 2.49 (br t, 2, J - 6.8), 2.67 (br t, 4, J - 4.8), 3.45 (br q, 2, J - 6.0), 3.55 (br t, 4, J - 4.8), 6.32 (br s, 1), 6.61 (m, 1), 6.78 (tm, 1, J - 7.5), 7.01 (d, 1, J - 8.2), 7.35 (m, 3), 7.47 (tm, 1, J - 7.5), 7.81 (d, 1, J - 8.0), 7.90 (d, 1, J - 8.0), 8.76 (br s, 1).
C~ 2 i 1 7434 (c) ~reDaration of N-(4-(4-(l.2-hDn7;cnt~1A7nl-3-vl)-l-DiDera zinyl)butyl)-2-hydr~7; ' ~ dihvdrochloride hydrate N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(2-(tert -butoxycarbonyl)hydrazino) benzamide (2.85 g, 5.43 mmol), anhydrous anisole (5.0 mL) (Aldrich Chemical Company) and anhydrous chloroform (75 mL) were combined in a 500-mL, ~ d flask. To the stirred pale-yellow solution was added trifluoroacetic acid (25 mL) (EM Science). The reaction mixture was allowed to stir under a nitrogen ~ for 10 min and the solution was e ~ed n vacuo. The residue was L.~f--..d to a - , ~ funnel with the aid of chloroform and washed with saturated NaNC03. The layers were separated and the aqueous phase was extracted with chloroform. The organic layers were combined, w shed with saturated NaNC03, dried over MgS04, filtered and - d to give an orange liquid. The crude product was purified by column ch.~ with a gradient eluant of 97-954 dichlo.~ th~n~ to 3-5~ methanol to give 1.54 g of the free base as a partially soli~ d yellow oil. The free base (1.41 g, 3.32 mmol) was dissolved in dichlo-~ ' and lN ethereal NCl (6.8 mL, 2.05 eq) was P.dded.
The resulting dihydrochloride salt was recrystallized from ethanol/water/ether to give 1.1 g (40~) of the title compound as a golden-yellow solid. mp: 222-226 ~C. lN NMR (DMS0-d6):
1.62 (m, 2), 1.83 (m, 2), 3.17 (m, 2), 3.29 (q, 2, J - 5.8, 6.6), 3.37 (m, 2), 3.54 (br s, 4), 4.05 (br s, 2),. 6.99 (t, 1, J
7.5), 7.12 (d, 1, J - 8.0), 7.46 (m, 2), 7.58 (t, 1, J - 7.6), 7.73 (dd, 1, J - 1.3, 7.5), 8.06 (br s, 1), 8.09 (d, 1, J - 8.2), 8.13 (d, 1, J - 8.2), 8.78 (t, 1, J - 5.6), 9.18 (s, 1), 10.27 (br s, 3), 11.18 (br s, 1). 13C NMR (DHS0-d6): ~ 20.62, 26.15, 38.25, 46.40, 50.51, 55.15, 114.43, 118.83, 120.41, 121.24, 124.07, 124.68, 127.01, 128.17, 128.36, 132.07, 145.66, 152.14, 162.30, 167.93. CIMS m/z (relative intensity): 425 (MN , 10), 291 (100).
W O 93/16073 C ~ 2 i 1 7 4 3 ~68 - PCT/GB93/0028~
Anal. Calcd for C22H28N6OS.2HClØ5H2O: C, 52.17; H, 6.17; N, 16.59; Cl, 14.00 H2O, 1.78.
Found: C, 52.23; H, 6.34; N, 16.30; Cl, 14.04; H2O, 2.05.
FY~ PT~ 85 (a) PreDaration of Hethvl 3~ h~on7A~blth~ -2-carboxvlate This compound was prepared according to the method of J. R. Beck (J. Org. Chem., 1972, 37, 3224) by employing 2-nitrobenzonitrile (50.0 g, 0.338 mol) (Aldrich Chemical Company), methyl thioglycolate (33.2 mL, 36.4 g, 0.343 mmol, 1.11 eq) (Aldrich Chemical Company), N,N-dimethy1' '~ (400 mL) and squeous KOH
(37.4 g/187 mL water) to give 36.1 g (52~) of the title compound as a pale beige solid. lH NHR (CDC13): 6 3.90 (s, 3), 5.92 (br s, 2), 7.37 (ddd, 1, J - 1.3, 7.0, 8.2), 7.48 ~ddd, 1, J - 1.5, 7.0, 8.2), 7.64 (ddd, 1, J - 0.8, 1.5, 8.0), 7.74 (ddd, 1, J
0.8, 1.2, 8.0).
(b) Freraration of benzo~blrh1- ~ 3-amine Hethyl 3- ~ ~ [b]rhil,' 2-carboxylate (32.09 g, 0.155 mol), l-methyl-2-pyrrolidinone (150.0 mL) (Aldrich Chemical Company) and l-meth91ri. ~ (43.0 mL, 38.83 g, 0.388 mol, 2.50 eq) (Aldrich Chemical Company) were combined in a 1-L, round bottomed flask snd placed under N2. The pale-orange solution was heated at 180-185~C for 3.5 h. The reaction mixture was c ' and the residue was partially purified by flush ~1,.~ O .'~ with dichl~ as elw nt to give 24.7 g of an orange liquid. Further purification by column cl.-~ ~ogrPrhy with dichlo-- ' as el w nt gave 20.1 g (87~) of the title compound as an orange liquid. H NHR (CDC13): 6 3.84 (br s, 2), 6.34 (s, 1), 7.38 (m, 2), 7.61 (m, 1), 7.80 (m, 1), W O 93/16073 C A 2 i 1 7 4 3 4 169 - PCT/GB93/002xs (c) PreDaration of 1-(benzo~blthil ' -3-vl)~i~ers71n~
Benzo[b]thio~ 3-amine (15.86 g, 0.106 mol), piperazine (21.07 g, 0.245 mol, 2.3 eq) (Aldrich Chemical Company) and l-methyl-2-pyrrolidinone (100 mL) (Aldrich Chemical Company) were combined in a 500-mL, round-bottomed flask and placed under N2.
The reaction mixture was heated st 185-190 C for 5.5 h and allowed to stand at room r , t e overnight. The reaction mixture was c~ * and the residue was purified by flush ~h.- ~ O ,'~ with dichloromethane (100~) and dichl~ methanol (85:15) as eluant to give 14.41 g (62~) of the title compound as a yellow solid. lH NMR (DMS0-d6):
2.95 (m, 8), 6.89 (s, 1), 7.38 (m, 2), 7.75 (m, 1), 7.92 (m, 1).
(d) Pr~r~r~r;~n of N-~4-(4-(~ (b)rh1~nh~n-3-yl)-l-~in~ro7inyl)-butYl~phth~ *~ hydrn~-hl~ride l-(Bell2o[b]thiophen-3-yl)p1 'n- (5.23 g, 24.0 mmol), N-(4-bromo butyl) phth~ljm~A~ (8.18 g, 29.0 mmol, 1.21 eq) (Aldrich Chemical Company), triethylamine (5.0 mL, 3.63 g, 35.9 mmol, 1.5 eq) and acetonitrile (100 mL) were combined in a 250-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 2 h. The reaction mixture was i ' ~d to a F, ' ~ funnel, dichl~L- '- was added, and the solution was washed with saturated NaHC03. The organic layer was separated and the aqueous phase was extracted with dichlo.~ -' . The organic layers were combined, washed with ~-t--r~te~ NaCl, separated, dried over NgS04, filtered and _ ~ to give 13.26 g of the crude product as an orange oil. The product was purified by flush ~ OL~ with ethyl acetate:hexanes (1:1) to give 8.5 g of the free base as a yellow solid. The free base (1.55 g, 3.69 mmol) was dissolved in ethyl acetate and lN ethereal HCl (3.70 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 1.30 g (65~) of the title compound as white solid. mp >250 C.
W O 93/16073 - 170 - ~ PCT/G893/0028~
H NMR (DMSO-d6): ~ 3.52 (br s, 4), 3.20 (m, 6), 3.61 (m, 6), 7.11 (s, 1), 7.42 (m, 2), 7.88 (m, 4), 7.89 (d, 2, J - 2.7), 10.56 (br s, 1). 13C NMR (DMSO-d6): ~ 20.62, 25.38, 36.94, 48.57, 50.98, 55.03, 108.83, 121.82, 123.08, 123.49, 123.95, 124.80, 131.69, 133.73, 134.43, 138.66, 144.78, 168.02.
Anal. Calcd for C24H25N3O25.HCl: C, 63.22; H, 5.75; N, 9.21.
Found: C, 63.19; H, 5.78; N, 9.13.
F~MP! F 86 Preoaration of 4-(4-(benzo(b)thioohen-3-yl)-l-Din~ra 71~yl)butVl~
N-(4-(4-(Benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)phth~limiA~
(3.52 g, 8.39 mmol) (Example 85(d)), 55~ hydrazine hydrate (0.75 g, 12.87 mmol, 1.53 eq) (Aldrich Chemical Company) and methanol (25 mL) were combined in a 100-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 1.75 h. The , A~ was allowed to cool to room L , ~ and water (25 mL) was added. The reaction mixture was acidified (pH - 2) by the adtition of aqueous lN HCl. The resulting solid was filtered and washed with water. The pH of the filtrate was made basic (pH - 12) by the addition of aqueous lN NaOH, ; ' ~d to a ~ funnel and extracted with dichlo.. th~n~, The organic layer was separated and the aqueous phase was extracted with dichlo.~ L'- . The organic layers were combined, dried over MgSO4, filtered, decolorized with activated carbon, filtered and c~ d to give 2.00 g (82~) of the title compound as a pale yellow oil which sol~ifi~d upon standing to give a tan-beige solid. H NMR (CDC13): 6 1.22 (br s, 2), 1.56 (m, 4), 2.46 (t, 2, J - 7.4), 2.73 (m, 6), 3.18 (br t, 4, J - 4.6), 6.62 (s, 1), 7.34 (m, 2), 7.77 (m, 2).
W O 93/16073 CA 2 i ' 743 PCT/GB93/00285 (b) PreDaration of 2-amino-N-~4-(4-(benzo(b)thioDhen-3-vl)-1-~Din~rs~71nvl)butyl)hon~ hydrnrhlnride .
4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butylamine (1.79 g, 6.18 mmol), isatoic anhydride (1.21 g, 7.42 mmol, 1.2 eq) (Aldrich Chemical Company) and etnanol (25 mL) were combined in a 100-mL, ~ ' flask. The reaction mixture was allowed to stir at room ; , under a nitrogen - r ~ for 1.5 h.
The solution was diluted with dichloromethane and washed with saturated NaHC03. The organic phase was - .-r~tPd and the aqueous phase was extracted with dichl~-- th~o, The organic layers were combined, dried over MgS04, filtered and ~
to give 3.41 g of the crude product as an orange oil. The free b-se was purified by flash ~1,.. O ,'~ with ethyl acetate as eluant to give 2.37 g of a colorless oil. The free base (2.21 g, 5.41 mmol) was dissolved in ethyl acetate and lN ethereal HCl (5.41 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 1.38 g (50~) of the title compound as an off-white solid. mp: 210-212 C. H NMR
(DMS0-d6): ~ 1.61 (m, 2), 1.82 (m, 2), 3.06-3.46 (m, 8), 3.61 (br d, 4, J - 10.7), 6.43 (br s, 2), 6.54 (t, 1, J - 7.4), 6.71 (d, 1, J - 8.0), 7.12 (s, 1), 7.16 (t, 1, J - 8.2), 7.43 (m, 2), 7,53 (d, 1, J - 7.8), 7.83 (m, 1), 7.97 (m, 1), 8.33 (br t, 1, J
5.3), 10.72 (br s, 1). 13C N~R (DMSO-d6): ~ 20.86, 26.54, 38.25, 48.78, 51.13, 55.38, 109.10, 114.86, 115.12, 116.63, 122.11, 123.77, 124.24, 125.08, 128.42, 131.88, 134.02, 138.96, 145.09, 149.90, 169.29.
Anal. Calcd for C23H28N40S.HCl: C, 62.08; H, 6.57; N, 12.59.
Found: C, 61.83 H, 6.65 N, 12.50.
~ A ~ 7 1 7 ~ 3 4 _XANPLF. 87 ~a) PreDaration of N-(4-(4-(l~2-hpn7ic~thi~7~l-3-yl)-l-Dioera ZinYl)bUtYl)-3-chloro-5-ethyl-2,6-di thoxYh~ - 'A~
hytrochloride Toluene (100 mL) and 3-chloro-5-ethyl-2,6-dimethylbenzoic acid (prepared by the method of de Paulis et ~1-. J. Ned. Chem., 29, 61-69, (1986)) (4.32 g, 17.6 mmol) were added to a 300-mL, oven-dried, round-bottomed flask. The solution was placed under N2 and thionyl chloride (Aldrich Chemical Company) (4.13 mL, 5.67 g, 47.6 mmol, 2.7 eq) was added. The light-yellow reaction mixture was heated to 75 Cand anhydrous dimethyl' A~
(0.25 mL) was added. The solution was heated at 65-75~C for 1.25 h. The solvent was removed with a rotary e... L~LuL to give the acid chloride as an orange residue. This crude acid chloride was dissolved in anhydrous chloroform (50 mL) and placed under N2. A solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzi-sothi~7~lP (5.63 g, 19.4 mmol, 1.1 eq) (Example 13(b)) in anhydrous chloroform (20 mL) was added to the acid chloride solution. Dry triethylamine (2.94 mL, 2.14 g, 2.10 mmol, 1.2 eq) was added. The reaction mixture was allowed to stir at room I , ~ for 0.75 h and the solvent was removed with a rotary e~ , ~ . The resulting viscous orange residue was dissolved in dichlu.~ ' and washed with saturated aqueous K2C03. The organic phase was dried over MgS04, filtered and ~ to give 10.03 g of an orange viscous oil. The crude material was adsorbed on silica gel and purified by flash .1.~ rh~ on silica gel with ethyl acetate/0.1~ triethylamine as eluant to give 4.78 g of a pale yellow oil. The hydrochloride salt was prepared by adding HCl (9.24 mL of a lN solution in ether, 1.0 eq) to a solution of the free base in ethanol. The salt was recrystallized from ethanol/ether and dried in a vacuum oven to give 2.96 g (30 ~) of the title compound as light tan powder.
mp: 198.5-200~C. lH NNR (DNSO-d6): ~ 1.16 (t, 3, J - 7.5), 1.60 -W O 93/16073 l73 PCT/GB93/00285 (m, 2), 1.83 (br s, 2), 2.58 (q, 2, J - 7.5), 3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br d, 2, J - 12.1), 7.38 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 8.14 (t, 2, J - 7.0), 8.50 (t, 1, J - 5.3), 10.66 (s, 1). 13C NHR (DMS0-6): ~ 14.76, 20.73, 21.80, 26.46, 46.57, 50.67, 55.39, 61.89, 62.27, 121.49, 121.76, 124.30, 124.95, 127.28, 128.45, 129.16, 130.17, 134.64, 150.88, 152.48, 153.96, 162.56, 164.26.
Anal. Calcd for C26H33N4035Cl.NCl: C, 56.41; H, 6.19; N, 10.12.
Found: C, 56.31; H, 6.18; N, 10.08.
FY~PT ~q 88 and 89 (a) P,. - :'nn of N-(4-(4-(1.2 -h~n7i cnthi ~7nl - 3-yl)-1-DiDera-71nYl~butYl)-3-nhlnro-S-ethvl-6-h,ydroxy-2-methoxyh~n~ de hYdr~~h1nride and N-(4-~4-(1.2-h~n7i~nthip7~l-3-yl~-l-DiDera 7inyl)butyl)-3-rhloro-S-ethYl-2-hydrOXy-6-me~ JL '~i~
hYdrnrhlnride hYdrate N-(4-(4-(1,2-L 'oothiP7ol-3-yl)-l-pLperazinyl)butyl-3-chloro-s-ethyl-2,6-~i L' ~L '~ (2.07 g, 4.0 mmol) (Example 87(a)) was mono dLmethylated accordLng to the method descrLbed Ln Examples 67 and 68. The two resultLng Lsomers were partially purLfLed by flash ~ on silica gel with 2:1 ethyl acetate/hexanes as eluant. Further purLfLcatLon on a Harrison Research Ch,. L ~.. wLth 1:1 and 2:1 ethyl acetate/hexanes as eluant gaYe a total of 1.07 g of the major Lsomer, N-(4-(4-(1,2-othip7ol-3-yl)-l-pLperazLnyl)butyl)-3-)chloro-s-ethyl-6-hy-droxy-2-me~ l ~A~ (Rf- 0.18 with 2:1 ethyl acetate/hexanes as eluant), and 0.27 g of the minor isomer, N-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-3-chloro- S-ethyl-2-hydroxy-6-methoxybenzamide (Rf - 0.11 with 2:1 ethyl acetate/hexanes as eluant), as li p t orange oils. The hydrochloride salts of each isomer were prepared ~ y by dissolving the free amine in ether and adding HCl (1 equivalent of a lN solution in ether), CA 2 ~ 1 7434 (r le 88) ~he hydrochloride salt of the major isomer was recrystallized from ethanol/ether and dried in a vacuum oven to gi~e 0.76 g (35%) of N-(4-(4-(1,2-' eothiD~ol-3-yl)-1-piperazinyl)butyl)-3-chloro-5-ethyl-6-hydroxy-2 ~ L ~A- hydrochloride as an off-white powder. mp: 179-181~C. lH NMR (DMS0-d6): 6 1.12 (t, 3, J - 7.3), 1.64 (m, 2), 1.81 (m, 2), 2.52 (m, 3), 3.20-3.60 (m, 9), 3.82 (s, 3), 4.06 (br d, 2, J - 12.3), 7.38 (s, 1), 7.47 (m, 1), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 6.6), 8.83 (br t, 1, J
- 5.1), 11.25 (br s, 1), 13.60 (s, 1). C NMR (DMS0-d6): 6 13.69, 20.65, 22.00, 26.04, 38.33, 46.39, 50.46, 55.15, 61.64, 110.73, 115.79, 121.24, 124.05, 124.66, 127.00, 128.16, 129.76, 132.33, 152.03, 152.16, 157.96, 162.27, 167.77.
Anal. Calcd for C25H31N403SCl.HCl: C, 55.65; H, 5.98; N, 10.38.
Found: C, 55.56; H, 5.99; N, 10.29.
(E le 89) ~he hydrochloride salt of the minor isomer was recrystallized from 95% ethanol and dried in a vacuum over to give 0.156 g (7~) of N-(4-(4-(1,2-~ ~thiD7~l-3-yl)-l-piperazinyl)butyl)-3-chlo-ro-5-ethyl-2-hydroxy-6 i ~L ~- hydrochloride hydrate as fluffy, off-white crystals. mp: 171-173~C. lH NMR (DMSO-d6): 6 1.15 (t, 3, J - 7.6), 1.62 (m, 2), 1.81 (m, 2), 2.52 (q, 2, J
7.6), 3.20-3.62 (m, 10), 3.72 (s, 3), 4.08 (br d, 2, J - 12.7), 7.40 (s, 1), 7.47 (t, 1, J - 7.6), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 8.3), 8.78 (br t, 1, J - 5.6), 10.63 (br s, 1), 12.64 (s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 15.77, 21.54, 22.13, 26.99, 39.34, 47.32, 51.40, 56.09, 63.26, 114.02, 117.53, 122.16, 124.97, 125.58, 127.93, 129.09, 129.13, 133.19, 153.08, 154.66, 155.93, 163.20, 168.18.
W O 93/16073 CA 2 1 1 7 4 3 4 PC~r/GB93/0028~
Anal Calct for C25H31N4~35Cl-HCl l-25 H2 N, 9.97; H20, 4.00.
Found: C, 53.46; H, 6.14; N, 9.99; H2O, 4.02.
FYA''PLF 90 PrD"-ration of 2- ~nn-N-~4-(4-(1.2-bDn7ien~hiP7nl-3-yl)-l-Dimera-z~nyl)butyl)-3- ~-~ y1~ ~e hyArnrl-lnride ~his compound was prepared by the method described in Example 75(b).
From 3-methoxyisatoic anhydride (3.35 g, 0.017 mol) (obtained from 2-amino-3- ' ~b_.~oic acid (Aldrich Chemical Company) by the method described in Example 99) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-ot~ nle (5.33 g, 0.017 mol, 1.0 eq) was obtained 5.41 g of the product as the free base. A portion of this material (1.94 g) was dissolved in ethanol (10 mL) and HCl (4.4 mL of a lN solution in ether, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/i r ~, 1 to give 1.93 g (65 ~) of the title compound as off-white crystals. mp: 136-138 C. lH NMR (DMSO-d6, 200 MHz):
1.59 (m, 2), 1.80 (m, 2), 3.12-3.60 (m, 6), 3.81 (s, 3), 4.09 (br d, 2, J - 12.9), 6.13 (br s, 1), 6.54 (t, 1, J - 8.0), 6.91 (d, 1, J
7.6), 7.20 (d, 1, J - 7.8), 7.49 (t, 1, J - 7.4), 7.62 (t, 1, J
7.5), 8.14 (t, 2, J - 6.8), 8.33 (br t, 1, J - 5.4), 10.89 (br s, 1).
3C NMR (DNSO-d6, 75.43 MHz): ~ 21.68, 27.29, 39.04, 47.38, 51.48, 56.20, 56.54, 112.83, 114.92, 115.40, 120.73, 122.18, 124.98, 125.59, 127.93, 129.11, 140.50, 147.88, 153.09, 163.18, 169.79. Mass Spec (CI/CH4, 50 nA/sec): h+l, base (440).
Anal. Calcd for C23H29N502S.HCl: C, 59.03; H, 6.35; N, 14.71; S, 6.74 Cl, 7.45.
Found: C, 57.94; H, 6.42; N, 14.57, S, 6.71; Cl, 7.55.
F~rAMPT.F 91 (a) PL~;rn of N-(4-(4-(1.2-h~n7;~~thi~nl-3-Yl)-l-DiDerzinyl)-butvl~-2-niL,.~ hvdrochloride This compound was prepared according to the method described in Example 53 by employing 3-(4-(4-aminobutyl)-1-piperszinyl)-1,2-b~ieothi~ole (0.99 g, 3.4 mmol) (Example 13tb)), triethylamine (0.72 mL, 0.52 g, 5.1 mmol, 1.5 eq) and 2-nitrobenzoyl chloride (Aldrich Chemical Company) (0.70 g, 3.4 mmol, 1.0 eq). The crude reaction mixt,ure was purified by flash ~hL~ with ethyl acetate/0.1~ triethylamine as eluant to give 0.94 g of the free base as a yellow solid. The hydrochloride salt was prepared, recrystallized from ethanol/ether and dried in a vacuum oven to give 0.66 g (41~) of the title compound as an off-white powder.
mp: 214-215~C. lH NMR (DMS0-d6, 200 HHz): 6 1.61 (m, 2), 1.85 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4.09 (br d, 2, J - 13.5), 7.48 (dd, 1, J - 7.2, 7.8), 7.72 (m, 4), 8.06 (d, 1, J - 8.0), 8.15 (t, 2, J - 7.0), 8.83 (br t, 1, J - 5.5), 11.29 (br s, 1). 13C
NMR (DNS0-d6, 75.43 MHz): 6 21.44, 26.95, 39.32, 47.30, 51.39, 56.06, 122.18, 124.86, 124.99, 125.59, 127.94, 129.09, 130.07, 131.63, 133.57, 134.55, 148.01, 153.09, 163.20, 166.42.
Anal. Calcd for C22H25N5035.HCl: C, 55.51; H, 5.50; N, 14.71.
Found: C, 55.56; H, 5.55; N, 14.72.
r le 92 (a) PreDaration of 2-amino-Q.~.~,-trifl-~~ro-~-toluic acid A solution of 2-nitro-o,~,~-trifluoro-p-toluic acid (Aldrich Chemical Company) (5.00 g, 21.3 mmol) in absolute ethanol (100 mL) was added to a Parr hydrogenation bottle rn~t,ining absolute ethanol (50 mL) and 5~ palladium on charcoal (100 mg).
The bottle was attached to a Parr h~dLU6-~dLUL and the solution CA2i 1 7434 was placed under a hydrogen l~ .' e at 35 psi. The reaction mixture was shaken at room t . e until consumDtion of hydrogen ceased (2h). The solution was filtered through a millipore AP filter and the filtrate was ~ ' with a rotary e~vL~LvL. The residue was dried unter vacuum to give 4.22 g (97~) of the title compound as a pale yellow solid. This material was used without further p~rifi~sti~n.
~b) PreDaration of 2-amino-N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDers7invl~butyl)-4-(trifluoromethyl)h~n~ ~ hvdrochloride Anhydrous pyridine (20 mL), 2-amino-o,o,o-trifluoro-p-toluic acid (1.33 g, 6.5 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ othiP~o~ xample 13(b)) (2.00 g, 6.5 mmol, 1.0 eq) were pl-ced in a 100-mL, round-bottomed flask. The solution was placed under N2, silicon tetrachloride (Aldrich Chemical Company) (1.48 mL, 2.19 g, 13.0 mmol, 2 eq) was slowly added with stirring, and the solution was heated at 145 C for 18 h, The re-ction mixture was allowed to cool to room I , e, poured onto crushed ice and . ~ ' in vacuo. Distilled water (200 mL) was added to the residue and the solution was - ' to dryness. Toluene (200 mL) was added to the resulting brown solid and the solvent was removed with a rotary ~ vL~Lu.. This procedure was repeated with two additional portions of toluene (200 mL). Distilled water (200 mL) was added to the residue and the solution was made basic (pH-ll) by the ~ddition of lN sodium carbonate. The aqueous solution was ~Yt-s~r~d with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over ~gS04, filtered and r--~ t~d Toluene (200 mL) was added to the residue and the solvent was re~oved with a rotary ~ tu-. This procedure was repeated with two additional portions of toluene (200 mL). The crude material was placed under high vacuum overnight and purified by flash ~h-- - ~ .'y on silica gel with a gradient eluant of ethyl acetate (100~)/methanol:ethyl acetate (l:99)/methanol:ethyl W O 93/16073 ? lJ8 - PCT/GB93/0028~
acetate (2:98) to give 1.45 g of the free amine. The product was dissolvet in ethanol and HCl (3.04 mL of a lN solution in ether~
was added. The hgdrochloride salt was recrystallized from ethanol/water to give 0.512 g (15~) of the title compound as white crystals. mp: 205-207~C. lH NMR (DMS0-d6, 200 MHz):
1.60 (m, 2), 1.80 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4.09 (d, 2, J
- 13.8), 6.74 (s, 2), 6.81 (d, 1, J - 8.3), 7.07 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 7.71 (d, 1, J - 8.3), 8.14 (m, 2), 8.57 (br t, 1, J - 5.4), 10.94 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 20.75, 26.22, 38.21, 46.45, 50.55, 55.22, 110.09, 110.13, 110.18, 110.23, 112.29, 112.35, 112.40, 112.45, 117.88, 121.24, 122.23, 124.04, 124.66, 125.84, 127.00, 128.17, 129.34, 131.38, 131.79, 149.66, 152.16, 162.24, 167.88. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (478).
Anal. Calcd for C23H26N505F3.HCl: C, 53.74; H, 5.29; N, 13.62;
S, 6.24; Cl, 6.90.
Found: C, 54.04; H, 5.38; N, 13.57; S, 6.32; Cl, 6.92.
FXAMP! F~ 93 to 98 The compounds of Examples 93 to 98 were prepared from the C~ , ''nL substituted D~thranil1~ acid y-~ , by the method described in Example 92(b). The snthrs~ilir acids employed were obtained from commercial suppliers or prepared by known methods as inAi~At~d The analytical data for these 2-amino bon7 'AD~ are shown below.
Preparation of 2-Amin~-N-(4-(4-(l~2-benzisothiA7~l-3-yl)-l-~i~era zinvl)butyl~-3-methylbenzamide hvdrochLoride St~srting material: 2-Amino-3-methylbenzoic acid (Aldrich Chemical Company). Yield: 0.806 g (54~). mp: 208-210 C. H NMR (DMS0-d6~
W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
300 MHz): 61.58 (m, 2), 1.78 (m, 2), 2.08 (s, 3), 3.31 tm, 8) 3.59 (m, 2), 4.08 (br d, 2, J - 12.1), 6.21 (br s, 2), 6.48 (t, 1, J - 7.6), 7.07 (d, 1, J - 7.1), 7.39 (d, 1, J - 7.8), 7.47 (t, 1, J - 7.5), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 8.3) , 8.30 (br t, 1, J - 5.2), 10.58 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 18.57, 21.73, 27.27, 39.08, 47.44, 51.52, 56.24, 115.39, 115.75, 122.16, 123.95, 124.97, 125.61, 126.88, 127.92, 129.11, 133.36, 148.47, 153.08, 163.18, 170.34. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (424).
Anal. Calcd for C23H29N505.HCl: C, 60.05; H, 6.57; N, 15.22; S, 6.97;
Cl, 7.71.
Found: C, 60.08; H, 6.61; N, 15.12; S, 7.06; Cl, 7.76.
FYI-~IPL.E 94 pr~nArAt~rn Of 2-pminr-N-~4-(4-(l.2-h~n7ierrh~o7rl-3-yl)-l-DiDera zinvl~but~ -3-rl~lf~ hvdrrrhlrride Starting material: 2-Amino-6-chlu-~' ir acid (Lancaster Synthesis Inc.). Yield: 0.75 g (24~). mp: 211-213~C. lH NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.82 (m, 2), 3.15-3.61 (m, 10), 4.08 (br d, 2, J - 13.5), 5.23 (br s, 2), 6.61 (d, 1, J - 7.8), 6.66 (d, 1, J
8.2), 7.05 (t, 1, J - 8.0), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J
7.5), 8.14 (t, 2, J - 7.2), 8.47 (br t, 1, J - 5.3), 10.70 (br s, 1).
13C NMR (DMS0-d6, 75.43 Mhz): ~ 21.70, 27.06, 39.18, 47.40, 51.48, 56.21, 114.59, 117.02, 122.16, 122.66, 124.98, 125.61, 127.93, 129.11, 130.98, 131.18, 148.13, 153.08, 163.18, 166.48. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (444).
Anal. Calcd for C22H26N550Cl.HCl: C, 55.00; H, 5.66; N, 14.58; S, 6.67; Cl, 14.76.
Found: C, 55.09; H, 5.66; N, 14.55; S, 6.74; Cl, 14.66.
FXAMp!F 95 PreDarstion of 2-aDino-N-(4-(4-(l.2-benzisothiazol-3-vl)-1-DiDera-zinyl)butyl-5-fluoro h-~n7'~ hydrochloride Starting material: 2-Amino-5-fluu~ acid (Riedel). Yield:
0.65 8 (22~). mp: 219-221~C. lH NMR (DMS0-d6, 300 MHz): d 1.58 (m, 2), 1.80 (m, 2), 3.29 (m, 6), 3.45 (m,2), 3.59 (br d, 2, J~ 10.9), 4.08 (br d, 2, J~ 12.6), 6.30 (br s, 2), 6.71 (dd, 1, J~ 8.9, 5.1), 7.05 (dt, 1, J- 2.7, 9.9), 7.37 (dd, 1, J~ 2.7, 10.3), 7.47 (t, 1, J
- 7.5), 7.60 (t, 1, J- 7.5), 8.12 (t, 2, J- 8.3), 8.37 (br t, 1, J-5.3), 10.65 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): d 21.72, 27.17, 39.12, 47.42, 51.51, 56.21, 114.36, 114.67, 115.39, 115.46, 118.45, 118.54, 119.82, 120.12, 122.16, 124.97, 125.61, 127.92, 129.11, 147.27, 152.10, 153.07, 155.15, 163.18, 168 80, 168.84. Mass Spec (CI/CH4, 50 DA/SeC): M~l, base (428).
Anal. Calcd for C22H26N5FOS.HCl: C, 56.95; H, 5.87; N 15 09; S
6.91; Cl, 7.64.
Found: C, 56.84; H, 5.84; N, 15.01; S, 7.01; Cl, 7.73.
PreDaration of 2-amino-N-(4-(4-(1.2-h~n~ie~thiazol-3-vl)-l-DiDera zinyl~butvl)-6-Dethvl~ hvdrochloride Starting material: 2-ADino-6-methylbenzoic acit (Aldrich Chemical Company). Yield: 1.10 g (21~). Dp: 194-196 C. H NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.80 (m, 2), 2.21 (s, 3), 3.32 ~m, 6), 3.55 (m, 4), 4.10 (m, 2), 4.93 (br s, 1), 6.44 (d, 1, J- 7.4), 6.55 (d, 1, J- 8.0), 6.96 (t, 1, J~ 7.7), 7.50 (t, 1, J~ 7.5), 7.67 (t, 1, J~
7.5), 8.15 (t, 2, J~ 7.1), 8.30 (br t, 1, J~ 5.3), 10.80 (br s, 1).
1 C NMR (DMS0-d6, 75.43 MHz): ~ 20.68, 21.73, 27.27, 39.02, 47.37, 51.44, 56.17, 113.70, 118.82, 122.18, 124.18, 124.99, 125.61, 127.93, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 129.11, 129.76, 135.30, 146.32, 153.08, 163.20, 169.29. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (424).
Anal. Calcd for C23H29N550.HCl: C, 60.05; H, 6.57; N, 15.22; S, 6.97;
Cl, 7.71.
Found: C, 59.99; H, 6.58; N, 15.17; S, 7.08; Cl, 7.64.
ExAMp!.F 97 PreDaration of 3-aminn-N-(4-~4-(1.2-h~n7i~nthiazol-3-yl)-l-DiDera-ZinV1~bUtY1)-2-naDthY1eneC~I~L 'A~ hVdrnrh1nride Stsrting material: 3-Amino-2-napthoic acid (Aldrich chemical Compang). Yield: 0.284 g (9~). mp: 216-218~C. lH NMR (DMS0-d6, 200 M~z): ~ 1.62 (m, 2), 1.84 (m, 2), 3.33 (m, 8), 3.59 (m, 2), 4.12 (br d, 2, J - 12.7), 6.11 (br s, 2), 6.98 (s, 1), 7.15 (t, 1, J
7.4), 7.36 (t, 1, J - 7.4), 7.54 (m, 3), 7.72 (d, 1, J - 8.2), 8.06 (s, 1), 8.14 (t, 2, J - 7.0), 8.68 (br t, 1, J - 5.2), 10.69 (br s, 1). 3C NMR (DMS0-d6, 50.29 MHz): ~ 20.94, 26.43, 38.47, 46.65, 50.75, 55.47, 108.56, 121.41, 121.51, 121.93, 124.32, 124.95, 125.08, 125.42, 127.28, 127.80, 128.45, 128.70, 128.90, 135.90, 146.02, 152.48, 162.58, 169.11. Mass Spec (CI/CH4, mA/sec): M+l, base (460).
Anal. Calcd for C26H29N550.HCl: C, 62.95; H, 6.10; N, 14.12; S, 6.46;
Cl, 7.15.
Found: C, 62.88 H, 6.14; N, 14.03; S, 6.53; Cl, 7.21.
F~AMP!F 98 PreDaration of 2-amino-N-(4-(4-(1.2-honi~~thi~7nl-3-yl)-l-DiDera zinvl)butvl)-5-meLLuAyL ~~ hydrochloride Starting material: 2-Amino-5-meLi.uA~L._.~ùic acid (obtained by the reduction of 2-nitro-5 ~ LLUA~b~U1C acid (Apin Chemicals Ltd.) according to the method described in Example 92 (a)). Yield: 0.313 g W O 93/16073 - 182 ~ i ~434 PCT/GB93/0028~
(104). mp: 150~C (dec.). H NMR (DMS0-d6, 200 MHz): ~ 1.60 (m, 2), 1.79 (m, 2), 3.37 (m, 12), 3.71 (s, 3), 3.88 (D, 2), 6.67 (d, 1, J
8.8), 6.86 (dd, 1, J - 2.7, 8.8), 7.10 (d, 1, J - 2.7), 7.48 (t, 1, J
- 7.5), 7.62 (t, 1, J - 7.5), 8.12 (d, 1, J - 7.5), 8.15 (d, 1, J
7.5), 8.37 (br t, 1, J _ 4,7), 1 C NMR (DMSO-d6, 75.43 MHz): C
21.84, 27.33, 39.08, 47.54, 51.60, 56.29, 56.60, 113.18, 116.18, 118.66, 120.20, 122.16, 124.97, 125.59, 127.94, 129.09, 144.58, 150.34, 153.08, 163.22, 169.58. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (440).
Anal. Calcd for C23H29N5025.HCl: C, 58.03; H, 6.35; N, 14.71; S, 6.74; Cl, 7.45.
Found: C, 58.09; H, 6.34; N, 14.62; S, 6.82; Cl, 7.39.
I'Y~MPT.F 99 (a) P~ lon of 4-fluoroi~t~ic Dnhydride 2-Amino-4-fl ,.' ic acid (0.97 g, 6.25 mmol) (obtained by the L.' L-~ of 4-fluoro-2-niL~ acid (The Sigma-Aldrich Library O~f Rare Chemicals) by the method described in Example 92 (a)), anhydrous 1,4-dioxane (20 mL), trichloromethyl rhl~ ~~f (5.0 g, 25.2 mmol, 4.0 eq) (Johnson-Matthey Chemical Company) were added to a 100-mL, round-bottomed flask.
The reaction mixture was heated at reflux for 11 h. The reaction mixture was allowed to cool and stir at room temperature overnight. The solvent was removed with a rotary evaporator to give 1.18 g (>1004 crude) of the title coDpound as an off-white solid. lH NMR (DMS0-d6, 200 MHz): ~ 6.90 ~dd, 1, J - 2.3, 9.6), 7.13 (dt, 1, J - 2.3, 7.6), 8.02 (dd, 1, J - 6.0, 8.8), 11.90 (br s, 1). This material was used without further purifi~Dti~ -(b) Preoaration of 2-Pmin~-N-(4-(4~ 2-h~n7ienthip7~l-3-vl) ~1nerazinyl~but~1)-4-fluQro benzamide hvdrochloride This compound was prepared by the method described in Lxample 75(b)- From 4-fluoroisatoic anhydride (1.18 g, 6.51 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benziso-thiazole (2.0 g, 6.51 mmol, 1.0 eq) was obtaLned 1.31 g (43~) of the tltle com~oound as a pale-yellow solid. mp: 234-236~C. lH
NMR (DMS0-d6, 300 MHz): ~ 1.53 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.53 (m, 4), 4.07 (d, 2, J - 13.4), 6.31 (dt, 1, J - 2.5, 8.5), 6.45 (dd, 1, J - 2.5, 7.2), 6.75 (br s, 2), 7.47 (t, 1, J - 7.5), 7.60 (m, 2), 8.12 (t, 2, J - 8.3), 8.32 (br t, 1, J - 5.3), 10.90 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 21.66, 27.25, 39.02, 47.37, 51.47, 56.17, 102.14, 102.33, 102.45, 102.63, 112.35, 112.37, 122.18, 124.97, 125.59, 127.93, 129.11, 131.51, 131.66, 152.97, 153.09, 153.13, 163.17, 163.66, 166.92, 169.10. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (428).
Anal. Calcd for C22H26N50FS.HCl: C, 56.95; H, 5.86; N, 15.09; S
6.91; Cl, 7.64.
Found: C, 56.89; H, 5.83; N, 15.10, S, 6.90; Cl, 7.61.
FY~MPTF. 100 (a) Pr~-ration of 3-(1-4- 'n~~tvl-4-r~;neridinyl)-6-fluoro-l.2-b~n7~ico7s7~le N-(4-(4-(6-Fluoro-1,2-b-n7ie~vP7~l-3-y)piperidino)butyl) - (1.04 g. 2.47 mmol) (Lxmaple 69), hydrazine hydrate (0.24 g 4.24 mmol, 1.67 eq) (Aldrich Chemical Company, 55 aqueous solution) and methanole (15 mL) were added to a 100-mL, round bottomed flask. The reaction mixture was headed at reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool. Distilled water (50 mL) was added to the reaction mixture and the pH of the solution wad adjusted to pH-l by the additon of lN HC1. The , ~n was filtered and the solid was washed with water. The pH of the filtrate was adjusted to pH-12 by the addition of saturated K2C03. The basic filtrate was i fe.,~d to a O_ra,~L~.~ funnel and extracted with dichloromethan (3 x 100 mL). The organic layers were combined, dried over MgS04, filtered and c~ t<A to give 0.58 g (81%) of the title compound as a pale yellow oil. lhlYMR (CDC13): 6 1.54 (m,4), 1.80 (br s,2), 2.10(m.6), 2.41 (br t, 2,J-7.2), 2.74 (br t, 2, J - 6.4) 3.08 (m, 3), 7.05 (dt, 1, J - 2.1, 8.9), 7.23 (dd, 1, J - 5.1, 8.7).
(b) ~ on of 2- ~nA-N-(4 (4-(6-fluoro-1.2-bonzi~ovs7Al -3-yl~DeDeri~ buty)' ~~o hydochloride 3-(1-(4-Aminobuty)-4-piperidiny-6-fluoro-1,2-bon7i~~Ys7nle (0.58 g, 1.99 mmol), isatoic anhydride (0.325 g 1.99 mmol, 1.0 eq) (Aldrich Chemical Company) and ethanol (12 mL) were added to a 25-mL, round bottoDed flask and stirred under N2 for 3 h. The reaction mixture was ~ ' to give a brown-orange oil which sc~ fipd upon st-nding. The crude free base was purified by flask cl.,~ with ethyl acetate/0.14 thiethylamine as eluant to give 0.69 g of the free base as an oil. The free base (0.69 g, 1.68 mmol) was dissolved in ethyl acetate and IN
ethereal HCl (1.68 mL 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.51 g (574) of the title compound as an off-white solid. mp: 242.5-245 C(dec). H
NMR (DMS0-d6): 6 1.57 (m,2), 1.78 (m,2), 2.25 (m,4), 3.12(m,4) 3.27(m,2), 3.47 (m, 1), 3.62 (br d, 2,J-12.0), 6.39 (br s,2), 6.51(tm, 1,J-7.4), 6.69 (dd, l,J -0.9, 8.1), 7.13(tm, 1, J-7.6), 7.35 (td, 1, J - 9.1, 2.1), 7.49 (dd, 1,J-1.2, 7.9), 7.74 (dd, l,J- 2.1, 9.1) 8.17 (m,l), 8.29 (m,l), 10.3(br s, 1). 1 C NMR
(DMSO-d6): 6 20.81, 26.44. 26/91, 31.26, 38.07, 51.27, 55.65, 97.72, 97.72, 112.70, 112.95, 114.59, 114.85, 115.35, 115.is, 123.88, 124.00, 128.13, 131.63, 149.63, 160.17, 162.55, 163.21, 153.35, 165.03, 168.98.
CA 2 i 1 7434 W O 93/16073 - 185 - P(~r/G B93/00285 A~nal. Calcd for c23H27N4o2F.Hcl: C~61.81; H.631; N,12-54- Fount:
C, 61.86; H, 6.33; N, 12.53.
i
0.7), 11.16 (br s, 1). 13C NMR (DMS0-d6): ~ 20.35, 25.29, 46.32, 49.43, 50.46, 55.11, 121.12, 123.94, 124.55, 125.71, 126.78, 126.91, 126.99, 128.06, 129.28, 132.00, 133.45, 138.01, 152.05, 158.36, 162.16.
Anal. Calcd for C23H25N50.HCl: C, 60.58; H, 5.75; N, 15.36.
Fount: C, 60.47 H, 5.78 N, 15.29.
EXAMPJ.F 32 (a) PreDaration of 4-methyl-1(2H~DhthA1a7innn9 2-Acetylbenzoic acid (75.0 g, 0.46 Dol) was taken up in 9S~
ethanol (800.0 mL) and a solution of 85~ hydrazine hydrate (33,0 mL, 0.57 mol) in 95~ ethsnol (50.0 mL) was added. The solution was heated at reflux for 1 h. White solids formed as the reaction yL- - '. The solution was ~ to one half of its original volume by rotary evsrorAti~n in vacuo. The solids were filtered and dried in a vacuum oven to give 68.19 e (93~) of 4-Dethgl-1(2H)rhth~1P7i as a white solid. mp: 222-224-C
[lit. Dp - 222-223-C (Hisrch, A.; Orphanos, D.G. J. Het. Chem..
1966, 3, 38)]. lH NMR (DNSO-d6): 6 2.50 (s, 3), 7.81-8.26 (m, 4), 12.40 (br s, 1).
Anal. Calcd for CgH8N20 C, 67.49; H, 5.03; N, 17.49. Found: C, 67.62; H, 5.08; N, 17.50.
(b) Pr~Daration of 2-t4-broDobutvl)-4-D~thvl-1(2H)-DhthAlP,in~n~
This compound was prepared by a method analogous to that described in ExaDple 31(a). From 4-methyl-1(2H)rhths1A7in~nP
(50.0 g, 0.31 Dol), and 1,4-dibL~ (80.33 g, 0.37 Dol) was obtained 31.05 g (34~ of 2-(4-bromobutyl)-4-Dethyl-1(2H)-phthal-azinone as orange crystals. mp: 166-172'C. lH NMR (DMSO-d6):
1.85 (D, 4), 2.56 (s, 3), 3.58 (t, 2, J - 6.2), 4.13 (t, 2, J
6.6), 7.88 (D, 1), 7.95 (m, 2), 8.29 (dD, 1, J - 8.7), (c) PreDaration of 2-(4-(4-(1.2-benzisothiP7~l-3-yl)-l-DiDera-7i~yl)butyl)-4-methvl-1(2U)-~hthA1A7in~n~ hvdrochloride hvdrate This compound was prepared according to the method outlined in Example 13(a). The crude product obtained from the reaction of 2-(4- bL~ )-4-D~thyl-l(2H)-rhth~lp7i (2.48 g, 8.4 mDol) 3 ~
and 3~ piperazinyl)-1,2 ~ 'CothlP7olp (1.93 g, 8.80 mmol, 1.05 eq) was purified by recrysrs~ tion from acetonitrile to give 2.89 g of the free base as a light orange solid. The l.~d,~ 'loride salt was prepared, recrystallized from 95~ ethanol, and dried in a vacuum oven to give 2.71 g (68~) of 2-(4-(4-tl,2-'~othio7nlP-3-yl)-l-piperazinyl)butyl)-4-Dethyl-1(2H)-phthala-zinone hydrochloride hydrate as an off-white powder. mp:
228-230'C. lH NMR (DNSO-d6): ~ 1.80 (br s, 4), 2.56 (s, 3), 3.20 (m, 4), 3.52 (m, 4), 4.04 (br d, 2, J - 13.3), 4.14 (m, 2), 7.45 (t, 1, J - 7.5), 7.59 (t, 1, J - 7.5), 7.87 (m, 1), 7.98 (d, 2, J
- 3.7), 8.11 (dd, 2, J - 7.8, 4.9), 8.29 (d, l, J - 7.7), 11.08 (br s, 1). 13C NMR (DNS0-d6): ~ 18.55, 20.37, 25.31, 46.36, 49.14, 50.51, 55.13, 121.15, 123.95, 124.57, 125.61, 126.14, 126.90, 128.08, 129.15, 131.75, 133.31, 143.46, 152.06, 158.19, 162.15.
Anal CalCd for C24H27N505 HCl ~ 25 H20 14.76. Found: C, 60.73; H, 6.11; N, 14.73.
_XAMPLF 33 (a) Preuaration of N- ~-t4-(l.2-benzisoth~ 07nl - 3-vl)riperidino)-butvl)rhthAlim~ n~drochloride hvdrate N-(4-Bromobutyl)-~ m~ (Aldrich Chemical Company) (0.956 g, 3.39 mmol), 3-(4-piperidinyl)-1,2-benzisothiazole (0.740 g, 3.39 mmol, 1.0 eq), triethylamine (0.57 mL, 0.412 g, 4.07 mmol, 1.2 eq) and acetonitrile (5.0 mL) was added to a round-bottomed flask. The resulting mixture was placed under N2 and heated at reflux overnight. The dark orange solution was allowed to cool to room I . _ and , ' ~d to a 5, ' ~ funnel with the aid of dichl~,, r' . The reaction mixture was washed with ~rll ot~ potassium carbonate. ~he organics were dried over NgS04, filtered and rP~ to give 1.65 g of a dark orange oil. This crude material was purified by flash .I.L~ ~ gL~L~
~ .7 ~ ~ ~
with ethyl acetate as eluant to give 1.30 g of N-(4-(4-(1,2-ben-zisothiazol-3-yl)piperidino) butyl) phthgl imi~' as a light orange oil which ~ ifi~d to a pale yellow solid upon standing. The free base was taken up in ethyl acetate and HCl (2.7 mL of a 1 N
solution in ether, 1.0 eq) was added. The salt was recrystalli-zed from ethanol/water to give 0.810 g (53~) of the hydrochloride salt as a white solid. Spectral and analytical data indicate one equivalent of HCL and 0.5 eq of water. mp: 220-222-C. lH NMR
(DMS0-d6): ~ 1.73 (m, 4), 2.21 (m, 4), 3.12 (br s, 4), 3.62 (m, 5), 7.54 (ddd, 1, J - 1.1, 7.0, 8.1), 7.63 (ddd, 1, J - 1.2, 6.9, 8.1), 7.88 (m, 4), 8.21 (d, 1, J - 8.1), 8.28 (d, 1, J - 8.1), 10.13 (br s, 1). C NMR (DMS0-d6): 8 20.55, 25.30, 27.63, 35.50, 36.80, 51.44, 55.48, 120.66, 122.98, 123.50, 124.86, 127.97, 131.59, 133.28, 134.33, 151.89, 167.49, 167.94.
Anal Calcd for C24H25N3025 HCl ~ 5 H20 9.04. Found: C, 61.80; H, 5.89; N, 9.05.
FY~uPJ.F 34 (a) PreDaration of ethyl N-(2-Dhenethyl)carbamate Phenethylamine (Aldrich Chemical Company) (31.1 mL, 30.0 g, 0.248 mol), triethylamine (34.6 mL, 25.1 g, 0.248 mol, 1.0 eq) and anhydrous dichluL~ ' (300.0 mL) were added to a l-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and a nitrogen inlet. The solution was cooled in an ice-water bath and a solution of ethyl chlu~ r - (Aldrich Chemical Company) (23.7 mL, 26.9 g, 0.248 mol, 1.0 eq) in dichlul~ ~'~ (25 mL) was added dropwise. The reaction mixture was stirred for 0.5 h and ether (150 mL) was added. The resulting , '~ was filtered and the filtrate was c~ A to give 46 g (96~) of an oil which soliiifi~d to a white solid upon standing. The crude material was used without further purification.
(b) P,. nn of 3.4-dihvdro-1(2H)-isoouinolinone Ethyl N-(2-phenethyl)carbamate (46.0 g, 0.238 mol) and pol~ ic acid (475.0 g) was added to a l-L, round-bottomed flask equipped with a magnetic stirring bar and reflux condenser, The mixture was heated in an oil bath at 140-160-C for 2 h. The reaction mixture was allowed to cool to room i . ~ and poured into aistilled water (2.4 L). The organics were extracted with ethyl acetate, washed with saturated NaCl, dried over MgS04, filtered and c~ r-d to give 4.36 g of an orange oil. The crude material was purified by flash ol..~ with ethyl acetate as eluant to give 1.85 g (5.1~ based on phenethylamine) of 3,4-dihydro-1(2H)-i , nnli as a light orsnge oil. lH
NMR ~CDC13): ~ 3.01 (t, 2, J - 6.6), 3.58 (dt, 2, J - 2.9, 6.6), 6.20 (br s, 1), 7.22 (dd, 1, J - 0.7, 7.4), 7.36 (ddd, 1, J
1.3, 7.6, 8.3), 7.46 (ddd, 1, J - 1.6, 7.5, 9.0), 8.07 (dd, 1, J
- 1.1, 7.7).
(c) Pre~aration of 2-(4-nhlnrobutvl~-3.4-~ih~vdro-l(2H~ ~nnlinnno Sodium hydride as an 80~ oil ~i~F-rsion (0.945 g, 31.5 mmol, 2.5 ~q) was added to a flame-dried, 100-mL, ,~.d b~ ' flask equipped with a magnetic stirring bar and nitrogen inlet. The sodium hydride was washed with hexanes (3X), and the waste hexanes were removed each time with a pipet. To the washed sodium hydride was added anhydrous N,N-dimethyl' A~ (20.0 mL) and the resulting - ~ ~or was cooled in an ice-water bath.
To the cooled reaction mixture was added a solution of 3,4-dihydro-1(2H)-isoquinolinone (1.85 g, 12.6 mmol, 1.0 eq) in anhydrous N,N-dimethyl' ~ (20.0 mL) dropwise. The cooled reaction mixture was allowed to stir for 15 min and allowed to warm to room ~ . e. After 5 min., the reaction mixture was cooled with an ice-water bath and l-bromo-4-chlorobutane (1.59 mL, 2.37 g, 13.8 mmol, 1.1 eq) was added dropwise. The reaction mixture was allowed to warm to room t . _ and stirred for ~. 1 ' ~ 7 ~ ~ ~
W O 93/16073 PCT/GB93/OOt85 0.5 h. The excess sotium hydride W85 quenched with distilled water (10 mL), the solvent was removed in vacuo, and the residue was partitioned between water and ethyl acetate. The organics were dried over MgS04, filtered, and c~ i to give 5.16 g of an orange oil. The crude material was purified by flash ~L~ e . ~ ~ with 3:2 hexanes/ethyl acetate as eluant to give 1.90 g (63t) of 2-(4-chlorobutyl)-3,4-dihydro-1(2H)-i , ~nnlin one as a colorless oil.
(d) r.._ _~'on of N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDera-zinyl~butyl)-3.4-~ihvdro-1(2H)-isoouinolin~~o hydrochloride - 2-(4-Chlorobutyl)-3,4-dihydro-1~2H)-isoquinolinone (1.90 g, 7.99 mmol), 3-(1-piperazinyl)-1,2-~ ~othio~ole (2.10 g, 9.59 mmol, 1.2 eq), triethylamine (1.56 mL, 1.13 g, 11.2 mmol, 1.4 eq) snd acetonitrile (25.0 mL) were added to a 100-mL, round-bottoDed flask equipped with a agnetic stirring bar, condenser and nitrogen inlet. The reaction mixture was heated to reflux under nitrogen for 30 h. The reaction was incomplete as indicated by TLC; therefore, ~A~iti. 1 portions of 3-(1-piperazinyl)-1,2-ben-7i~othio7ole (0.350 g, 1.60 mmol, 0.2 eq) and triethylamine (0.670 mL, 0.486 g, 4.81 mmol, 0.6 eq) were added and the reaction mixture was heated to reflux for an additional 24 h.
The solution was allowed to cool to room ~ . e and , ~ ~d to a . ~ funnel with the aid of ethyl acetate.
The solution was washed with saturated potassium carbonate. The organics were dried over MgS04, filtered and c ' to give 5.2 g of an orange oil. The crude material was purified by flash ch.. ~ ~h~ with ethyl acetate/O.l~ triethylamine as eluant to give 2.26 g of an orange oil. The free base was taken up in ethyl acetate and HCl (5.37 mL of a lN solution in ether. 1.0 eq) was added. The resulting salt was recrystallized from ethanol to give 2.0 g (55~) of a light orange solid. mp: 229-231-C. lH NMR
(DMSO-d6): 6 1.66 (m. 2). 1.78 (m, 2), 3.00 (t, 2, J - 6.6), 3.27 (m. 4), 3.52 (m, 8), 4.07(br d, 2. J - 13.0). 7.31 (d, 1, J
W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
8.0), 7.37 (dd, 1, J - 1.5, 7.4), 7.48 (dt, 2, J - 1.2, 7.5), 7.60 (dt, 1, J - 0.8, 7.5), 7.88 (dd, 1, J - 1.1, 7.5), 8.12 (t, 2, J - 7.9), 10.68 (br s, 1). 13C NMR (DMS0-d6): ~ 20.46, 24.37, 27.36, 45.36, 45.69, 46.31, 50.44, 55.22, 121.14, 123.95, 124.56, 126.60, 126.91, 127.17, 127.26, 128.06, 129.15, 131.45, 138.60, 152.05, 162.17, 163.17.
Anal. Calcd for C24H28N40S.HCl: C, 63,07; H, 6.40; N, 12.26.
Found: C, 63.04; H, 6.43; N, 12.23.
(a) Pr~nAr~ri~n of methyl 2-(N.N-dimethvl-N'-~ ~inyl)benzoate This compound was prepared according to the method described by J. T. Gupton et al. ~Tet_ ' '..~.. 1987, 43, 1747). Treatment of ' 'l;r acid (Aldrich Chemical Company) (6.0 g, 43.8 mmol) with N,N-dimethyl' ~- dimethylacetal (Aldrich Chemical Company) (15.5 mL, 13.9 g, 116.8 mmol, 2.67 eq) gave 6.2 g (69~) of methyl 2-(N,N-dimethyl-N'-' ~A;nyl)benzoate as a purple liquid.
(b) F,. _: on of 3-(4~4-(1.2-benzisothi~nl-3-yl)-l-DiDera 7;~yl)butvll-4(3Hl ~ ~r~ ;n~ hvdrochloride 3-(4-(4-~ ' ~1)-1-piperazinyl)-1,2-benzisothiazole (0.960 g, 3.31 mmol, 1.1 eq), (Example 13(b)) p-toluene sulfonic acid (0.1 g), anhydrow 1,4-dioxane (45 mL) and methyl 2-(N,N-dimethyl-N'-f~ ~;nyl)benzoate (0.621 g, 3.01 mmol, 1.0 eq) were added to a flame-dried, 250-mL, round-bottomed flask equipped with a magnetic stirring bar, condenser and nitrogen inlet. The reaction mixture was heated at reflux for 1 h, allowed to cool to rOOm ~ , ~, and c ' to give an orange oil. The oil was dissolved in a solution of ethyl acetate and dlchlur. th~ and the organics were washed with saturated W O 93/16073 921 ~ ~ 3~ PCT/GB93/00285 potassium carbonate. The organics were dried over MgS04, fLltered and o~ t-d to give 1.41 g of a tan solid. The crude material was purified by flash ~LL~ with 24:1 dichluL~ i' /methanol as eluant to give 1.02 g of a white solid. To a solution of the free base in ethyl acetate was added HCl (2.43 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/water to give 0.810 g (59~) of 3-(4-(4-(l~2-b~n7icothio7ol-3-yl)-l-piperazin yl)butyl)-4(3N)-quinazolinone hydrochloride as a white solid.
mp: 238-240-C (dec). lH NMR (DNSO-d6): 8 1.80( br s, 4), 3.28 (m, 4), 3.47 (br t, 2, J - 12.6), 3.58 (br d, 2, J - 12.0), 4.05 (br s, 3), 4.08 (m, 1), 7.47 (ddd, 1, J - 1.1, 6.9, 8.1), 7.58 (qm, 2, J - 8.4), 8.12 (t, 3, J - 8.0), 8.18 (ddd, 3, J - 0.6, 1.6, 8.0), 8.46 (s, 1), 10.86 (br s, 1). C NMR (DNSO-d6):
20.24, 25.78, 45.25, 46.31, 50.42, 54.89, 121.12, 121.48, 123.94, 124.56, 125.97, 126.90, 126.97, 127.11, 128.06, 134.22, 147.87, 147.96, 152.05, 160.17, 162.16.
Anal. Calcd for C~U 5N~.NCl: C, 60.58; H, 5.75; N, 15.36.
Found: C, 60.68; N, 5.75; N, 15.41.
EXAMP! F 36 (a) FL~ . of 2-Pmin~-N-(4-(4-(l.2-~n7ic~thi~7~l-3-yl) nin-rD7lr~Yl)but~yl)~ ' hydr~rhl-ride Isatoic anhydride (Aldrich Chemical Company) (0.894 g, 5.48 mmol), ethanol (15.0 mL) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.59 g, 5.48 mmol, l.0 eq) (Example 13(b)) were added to a round-bottom flask equipped with a magnetic stirring bar and nitrogen inlet. The reaction mixture was stirred at room ~ , ~t~Le for 22 h. The solvent was removed in vacuo to give 2.35 g of a brown oil. The crude material was purified by flash ~LL~ with 19:1 dichlui~ ' /meth-anol as eluant to give 1.28 g of an orange oil which became a W O 93/16073 ~ h ~ i ~ t P<~r/GB93/00285 pale yellow solid upon stanting. To a solution of the free base ~0.35 g, 0.855 mmol) in ethyl acetate and ethanol was added HCl (O.B55 mL of a lN solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystsllized from 95~ ethanol to give 0.230 g (60~) of 2-amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-l-piperazinyl)butyl)benzamide hydrochloride 8S a white solid, mp: 227-228-C. lH NMR (DMS0-d6): 6 1.58 (m, 2), 1.79 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.8), 3.59 (br d, 2, J - 12.4), 4.09 (br d, 2, J - 13.2), 6.41 (br s, 2), 6.51 (ddd, J - 1.1, 7.0, 8.1), 6.69 (dd, 1, J - 1.1, 8.2), 7.13 (ddd, 1, J - 1.5, 7.0, 8.4), 7.48 (m, 2), 7.60 (ddd, 1, J - 1.1, 7.0, 8.0), 8.13 (t, 2, J - 8,4), 8.29 (t, 1, J - 5.5), 10.68 (br s, 1). 13C NMR
(DMS0-d6): ~ 20.64, 26.28, 37.98, 46.35, 50.42, 55.14, 114.49, 114.75, 116.26, 121.14, 123.95, 124.57, 126.10, 126.91, 128.01, 128.07, 131.51, 149,47, 152.06, 162.16, 168.85.
Anal- Calcd for C22H27N505,HCl: C, 59.25; H, 6.33; N, 15.70.
Found: C, 59.18; H, 6.35; N, 15.68.
~XAMP!~ 37 (a) P.._ _~'on of 3-(4-(4-(1.2-hDn~i~Athio~ 3-yl)-l-DiDera zi nyl )butYl)-1.2.3 _h on7 ~triazin-4(3H)-one hydrochloride 2-Amino-N-(4-(4-(1,2 ~ ~orhiD~ol-3-yl)-l-piperazinyl)butyl)be-nzamide (0.960 g, 2.34 mmol) (Example 36(a)), distilled water (11.0 mL) and conc. HCl (1.06 mL) were added to a round-bottomed flask equipped with a magnetic stirring bar, nitrogen inlet and adtition funnel. The reaction mixture was cooled in an ice-water bath and a solution of sodium nitrite (0.186 g, 2.70 mmol, 1.15 eq) in distilled water (2.58 mL) was added dropwise. The reaction mixture was stirred for 2 h and treated with 1.2 mL of 10 N sodium hydroxide. After 1 h, the pH was adjusted to 6-7 by the addition of acetic acid and ~ ly to a pH of 10 with 10 N sotium hydroxide. The organics were extracted with ethyl ~ 2 1 7 ~7 ~ 3 ~
acetate, dried over MgS04, filtered and e ~ ' to give 0.900 g of an orange oil. The crude material was purified by flash ~ . g ,'~ with 2:1 ethyl acetate/hexanes to give 0.630 g of a white solid. The free base was dissolved in ethyl acetate and to this solution was added HCl ~1.5 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/water to give 0.490 g (464) of 3-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2,3 benzotriazin-4t3H)-one hydrochloride as a white solid. mp:
242-243.5-C. H NMR (DHS0-d6): 6 1.89 ~m, 4), 3.24 (m, 4), 3.43 (br t, 2, J - 11.9), 3.59 (br t, 2, J - 11.1), 4.07 (br d, 2, J -11.4), 4.46 (t, 2, J - 6.5), 7.47 (tm, 1, J - 7.5), 7.60 (tm, 1, J - 7.5), 7.96 (ddd, 1, J - 1.3, 7.2, 7.9), 8.12 (m, 3), 8.24 (dd, 1, J - 0.7, 8.1), 8.29 (ddd, 1, J - 0.5, 1.4, 7.9), 10.5 (br s, 1). 13C NMR (DMS0-d6): ~ 20.36, 25.52, 46.33, 48.50, 50.49, 55.02, 119.24, 121.15, 123.96, 124.54, 124.57, 126.91, 127.94, 128.08, 132.89, 135.35, 143.66, 152.06, 154.78, 162.16.
Anal. Calcd for C22H24N605.HCl: C, 57.82; H, 5.51; N, 18.39.
Found: C, 57.92; H, 5.53; N, 18.45.
FY~ PT.~ 38 (a) PreDaration of N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDerazinYl) butyl)-3-~hlnro-5-ethyl-2.6-~ hvdrochloride Anhydrous toluene (100.0 mL) and 3-chloro-5-ethyl-2,6-dimethoxy-benzoic acid (4.32 g, 0.0176 mol) (obtained in three steps from 2,4-dimethylacetophenone (Aldrich Chemical Company) by the method of de Paulis et al. J.Med.Chem. 1985, 28 (9), 1263-1269 J.Med.Chem. 1986, 29(1), 61-69) were added to a oven-dried, 300 mL, round-bottomed flask. The solution was placed under a nitrogen ~- .' e and thionyl chloride (4.13 mL, 0.0476 mol, 2.7 eq) was added. The light yellow solution was heated to is~c and anhydrous dimethyl' ~ (0.25 mL) was added. The reaction mixture was heated at 65-75 C for 1.25 h and the solvent was removed with a rotary e~y~L~LuL. The resulting orange residue was taken up in anhydrous chlorofo D (50 mL) and placed under nitrogen. 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benziso-thiazole (Example 13(b)) (5.63 g, 0.0194 mol, 1.1 eg) in chlorofo D (20.0 mL) followed by anhydrous trithylamine (2.94 mL, 0.021 mol, 1.2 eq) was added to this crude acid chloride. The resulting clear orange mixture was allowed to a stir at room ~ , ~ for 0.75 h. The solvent was removed with a roeary e~ L~toI and the viscous orange oil was taken up in dichluL. Ll.~... and washed with saturated K2C03. The organics were dried over MgS04, filtered and r. .._....Ar/d to give 10.03 g of a viscous orange oil. This crude material was purified by flash ~1.,l ~ .'~ with ethyl acetate as eluant followed by ethyl acetate/0.1~ triethylamine as eluant to give 4.78 g of the free base as a pale yellow oil. The free base was dissolved in ethanol and HCl (9.24 mL of a lN solution in ether) was added.
The solution was heated and fil~ ~ed hot. Ether was added to the ethanolic solution and the mix~ure was allowed to cool. The solids that fo Ded upon cooling were filtered, washed with ether and dried in a vacuum oven to give 2.96 g (30~) of the title compound as a light tan powder. mp: 198.5-200~C. lH NMR
(DMS0-d6): ~ 1.16 (6, 3, J - 7.5), 1.60 (m, 2), 1.83 (br s, 2), 2.58 (q, 2, J - 7.5), 3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br d, 2, J - 12.1), 7.38 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 8.14 (t, 2, J - 7.0), 8.50 (t, 1, J - 5.3), 10.66 (br s, 1). 13C NMR (DMS0-d6): ~ 14.76, 20.73, 21.80, 26.46, 46.57, 50.67, 55.39, 61.89, 62.27, 121.49, 121.76, 124.30, 124.95, 127.28, 128.45, 129.16, 130.17, 134.64, 150.88, 152.48, 153.96, 162.56, 164.26.
Anal. Calcd for C26H33N4035Cl.HCl: C, 56.41; N, 6.19; N, 10.12.
Found: C, 56.31; H, 6.18; N, 10.08.
CA 2 i 1 7434 EXA~pJ.F 39 (a) PreDaration of ethYl 2.3-Aihvdro-3-oxo-lH-indazole-l-carboxylate Starting materials: 3 T~A~7~ (Aldrich Chemical Company), Ethyl Chl~L~f~ (Aldrich Chemical Company). This compound was prepared according to the method described by S. D. Wyrick et al. (J. Med. Chem. 1984, 27, 768). mp:l93-195-C. H NMR
(DMS0-d6): 6 1.37 (t, 3, J - 7.1), 4.41 (q, 2, J - 7.1), 7.34 (ddd, 1, J - 0.8, 7.1, 8.0), 7.61 (ddd, 1, J - 1.2, 7.2, 8.4), 7.75 (dt, 1, J - 7.8, 1.0), 8.04 (d, 1, J - 8.4), 12.13 (br s, 1). 13C NMR (DMSO-d6): ~ 14.14, 62.84, 114.09, 117.16, 120.43, 123.36, 130.00, 140.28, 150.04, 158.50.
CloHloN203: C, 58.25; H, 4.89; N, 13 59 Found C, 58.30; H, 4.93; N, 13.61.
(b) P~ _ on of Ethyl 2-(4-chlorobutyl)-z~3-~ih~ydro-3-oxo-lH-indazole-l-carboxvlate and Ethyi 2-(4-bromobutyl)-2.3-dihydro-3-oxo-lH-indazole-l-carboxYlate Sodium hgdride (1.51 g, 50.3 mmol, 1.2 eq) as an 80~ oil dispersion was added to a flame-dried, 250-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The sodium hydride was washed with hexanes (3X). To the washed sodium hydride was added anhydrous N,N-dimethyl~ ~A~ (50,0 mL) and the resulting grey r~ ~n was cooled in an ice-water bath. Ethyl 2,3-dihydro-3-oxo-lH-indazole-l-carboxylate (8.65 g, 41.9 mmol) was added slowly with a spatula to the cooled reaction mixture. To the cooled reaction mixture was added l-bromo-4-chlorobutane (Aldrich Chemical Company) (5.31 mL, 7.91 g, 46.1 mmol, 1.1 eq). The reaction mixture was slowly warmed to 65-C and stirred overnight at 65-C. The reaction mixture was allowed to cool and the excess sodium hydride was quenched with distilled water (2 mL). The W O 93/16073 ~ A 2 1 1 7 ~ J ~ , PCT/GB93/0028~
ma~ority of the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and distilled water. The organics were driet over MgS04, filtered, and c~ ..LLeted to give 12.2 g of an orange oil. lH NMR of this crude material indicated that both N-alkylated and O-alkylated products were forDed. Fu~ i' e, these alkylated products were obtained as mixtures of their C~LL~_r ng chlorides and bromides. The crude oil was purified by flash ~ with 3:1 hexanes/ethyl acetate as eluant to give 2.00 g of Ethyl 2-(4-chlorobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate and Ethyl 2-(4-bromobutyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxy-late as a 60:40 mixture of the chloride and bromide. The chloride/bromide ratio was determined by int-gr~tion of their ..llng methylene triplets at 3.39 and 3.52 ppm, ~ ti~_ly. This material was used as a mixture without further isolation of each halide.
(c) ~ l~n of ethyl 2-(4-(4-(1.2-h~n~ie~th~7~l-3-vl)-l-DiDera-7i~yl~butyl)-2.3-iih~dro-3-oxo-lU-in~i~7~le-l-carbox~late hydrnrhl nride A 60:40 mixture of ethyl 2-(4-chlorobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate and ethyl 2-(4-bromobutyl)-2,3-dihydro-3-oxo-lH-indazole l-carboxylate (3.13 g, 9.68 mmol), 3-(1-pipera-zinyl)-1,2-ben~iF7thi~77l~ (3.84 g, 17.5 mmol, 1.8 eq), triethyl-amine (2.44 DL, 1.77 g, 17.5 mmol, 1.8 eq), and acetonitrile (30.0 mL) was added to a 50-mL, round-bottomed flask equipped with a magnetic stirring bar, condenser and nitrogen inlet . The reaction mixture was heated at reflux under nitrogen overnight.
The reaction mixture was allowed to cool to rooD ~ ~ e and partitioned between ethyl acetate and saturated potassium carbonate. The organics were dried over MgS04, filtered and e ~ ' to give 7.18 g of a oily tan solid. The crude material was purified by flash cl.,~ ~ gL~L~ with 2:1 ethyl acetate/hexanes followed by ethyl acetate to give 2.97 g of the CA 2 i 1 7434 free base as B yellow oil. To a solution of the free base in ethyl acetate was added HCl (6.2 mL of a lN solution in ether, 1.0 eq~. The resulting hydrochloride salt was recrystallized from ethanol to give 0.52 6 (8~) of ethyl 2-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxylate hydrochloride as beige solid. mp: 189-l90-C. H
NMR (DMS0-d6): 6 1.41 (t, 2, J - 7.1), 1.66 (br s, 3), 3.23 (m, 6), 3.42 (br t, 2, J - 12.1), 3.53 (br d, 2, J - 12.0), 4.05 (br d, 2, J - 13.2), 4.15 (m, 2), 4.44 (q, 2, J - 7.1), 7.46 (m, 2), 7.60 (ddd, 1, J - 0.9, 7.1, 8.0), 7.78 (ddd, 1, J - 1.3, 7.2, 8.5), 7.84 (ddd, 1, J - 0.8, 1.3, 7.7), 7.94 (d, 1, J - 8,4), 8.12 (t, 2, J - 6.9), 10.53 (br s, 1). 3C NMR (DMSO-d6). 6 14.05, 20.36, 24.51, 45.78, 46.27, 50.41, 54.90, 64.10, 115.39, 117.86, 121.14, 123.37, 123.95, 124.57, 124.90, 126.91, 128.07, 133.88, 142.68, 150.63, 152.05, 162.15, 163.75.
Anal. Calcd for C25H29N5035.HCl: C, 58.19: H, 5.86; N, 13.57.
Found: C, 58.06; H, 5.89; N, 13.51.
FY IluPLF 40 (a) Preoaration of 2-(4-(4-(l.2-ben7i~~thiA7nl-3-vl)-l-DiDerA7in~yl) butvl~-1.2-dihydro-3H-indazol-3-one hvdrochloride hydrate Ethyl 2-(4-(4-(1,2 ~ ~othiA-ol-3-yl)-1-piperazinyl)butyl)-2,3-dihydro-3-oxo-lH-indazole-l-carboxylate (1.88 g, 3.92 mmol) (Example 39(c)) and potassium hydroxide (23.7 mL of a 0.67 M
solution in ethanol) were added to a 300-mL, round-bottomed flask equipped with a Dagnetic stirring bar, nitrogen inlet and condenser, The reaction mixture was refluxed under nitrogen for 2 h. The reaction mixture was allowed to cool to room t . e and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated potassium carbonate. The organics were dried over MgSO4, filtered and ' to give 1.37 g of the crude product as an orange W O 93/16073 C k ? i91 7 4 3 4 PCT/GB93/00285 oil. The crude material was purified by flash .1.-~ DLp~
with 92:8 dichloromethane/methanol as eluant to give 1.03 g of the free base as a light yellow solid. To a solution of the free base in ethyl acetate and dichlo-- t~- was added HCl (2.53 mL
of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol/ether to give 0.36 g (20~) of 2-(4-(4-~1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,2-dihyd-ro-3H-indazol-3-one b~IL~ 'loride hydrate as a white solid. mp:
80-90-C (softens, shrinks), 125-145-C (effervesces). lH NMR
(DMS0-d6): C 1.77 (m, 4?~ 3.25 (m, 4), 3.44 (m, 2), 3.56 (br d, 2, J - 11.4), 3.87 (t, 2, J - 6.0), 4.06 (br d, 2, 3 - 13.3), 7.11 (ddd, 1, J - 0.8, 7.1, 8.0), 7.28 (dt, 1, J - 8.3, 0.8), 7.47 (ddd, 1, J - 1.1, 6.4, 8.2), 7.52 (ddd, 1, J - 1.2, 6.5, 8.3), 7.60 (ddd, 1, J - 1.1, 7.0, 8.2), 7.65 (dt, 1, J - 7.9, 1.1), 8.12 (t, 2, J - 7.8), 10.4 (br s, 1), 10.7 (br s, 1). 13C
NMR (DMS0-d6): C 20.31, 25.04, 42.41, 46.33, 50.49, 54.94, 112.12, 117.20, 120.80, 121.15, 122.87, 123.96, 124.58, 126.91, 128.08, 131.20, 145.91, 152.06, 160.58, 162~16.
Anal. Calcd for C22H25N50S.HClØ75 H20: C, 57.76; H, 6.06; N, lS.31; H20, 2.95. Found: C, 57.71; H, 6.10; N, 15.20; H20, 2.73.
F~AMPJ.F 41 (a) PrPnAration of 2- 'n~-N-(4-(4-(l.2-benzisothi~7~l-3 ~ in"r~ yl ) butyl ) - S - chlor~hPn7 ~ AP hydr~lrhl oride This compound was prepared according to the method described in Example 36, by employing S-chloroisatoic anhydride (Aldrich Chemical Company) (1.02 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (l.S g, 5.17 mmol, 1.0 eq, (Example 13(b)). The free base was purified by flash cl..~ with 1:1 ethyl acetate/hexanes as eluant. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 1.61 g (65~) of 2-amino-N-(4-(4-(1,2-benzi-CA 2 i i 7434 W O 93/t6073 PCT/GB93/00285 sothiazol-3-yl)-1-piperazinyl)butyl)-5-chlu--L '~le hydrochloride as a white solid. mp: 173-176-C. H NMR (DMS0-d6):
~ 1.57 (m, 2), 1.78 (m, 2), 3.10-3.68 (m, 12), 4.08 (br d, 2, J -13.1), 6.74 (d, 1, J - 8.9), 7.18 (dd, 1, J - 2.4, 8.8), 7.48 (tm, 1, J- 7.2), 7.57 (d, 1, J- 2.4), 7.60 (tm, 1, J- 7.2), 8.13 (t, 2, J- 8.6), 8.45 (t, 1, J- 5.3), 10.70 (br s, 1). 13C
NMR(DMS0-d6): 6 20.64, 26.19, 38.20, 46.35, 50.44, 55.16, 116.75, 118.78, 119.04, 121.18, 124.00, 124.61, 126.95, 127.44, 128.12, 131.37, 146.88, 152.11, 162.21, 167.41.
Anal. Calcd for C22H26N505Cl.HCl: C, SS.00; H, 5.66; N, 14.58.
Found: C, 54.91; H, 5.69; N, 14.51.
FXAMPT.F 42 (a) PreDaration of 2- 'r~-N-(4-(4-(l~2--h~n7ienthip7~l-3 ,DirAr~7ir,~Yl)butyl)-s-nitr-' ~' hYdrnrhlnride The compound was prepared according to the method described in ExamDle 36, by employing 5-nitroisatoic anhydride (Trans Uorld Chemicals) (1.08 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-ben2isothia2O1e (l.S g, 5.17 mmol, 1.0 eq) (Example 13(b)). The free base was purified by flash cl.-~ -ogr~Ahy with ethyl acetate as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 1.10 g (43~) of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl)-S-niL-o~~ hydrochloride as a yellow solid. mp: 224-230'C (dec).H NHR(DMSO-d6): ~ 1.61 (m, 2), 1.80 (m, 2), 3.28 (m, 4), 3.46 (br t, 4, J- 12.1), 3.59 (br d, 2, J- 10.2), 4.08 (br d, 2,J- 12.8), 6.82 (d, 1, J- 9.3), 7.48 (t, 1, J- 7.6), 7.60 (t, 1, J- 7.2), 7.80 (br s, 2), 8.03 (dd, 1, J- 2.5, 9.1), 8.13 (t, 2, J- 8.3), 8.52 (d, 1, J -2.5), 8.80 (t, 1, J- 5.3), 10.72 (br s, 1). C NMR (DMsO-d6j:
~ 20.72, 26.17, 38.34, 46.38, 50.48, 55.20, 112.87, 115.85, CA 2 i i 7434 W O 93/16073 P(~r/GB93/0028~
121.18, 123.99, 124.61, 125.71, 126.95, 127.35, 128.11, 134.86, 152.11, 155.31, 162.21, 167.21.
.
Anal. Calcd for C22H26N6035.HCl: C, 53.B2; H, 5.54; N, 17.12.
Found: C, 53.95; H, 5.57; N, 17.05.
_XAMPLF 43 (a) PreDaration of N-(4-(4-(l.2-h~7i~~thio7~l-3-vl)-l-oi~era 71~yl~butvl~-2-(methylamino)~ hydrochloride This compound was prepared according to the method described in Fxample 36, by employing N-Dethylisatoic anhydride (Aldrich Chemical Comp-ny) (0.92 g, 5.17 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.5 g, 5.17 mmol, 1.0 eq) (_xample 13(b)). The free base was purified by flash h~ with ethyl acetate as eluant. The hydrochloride salt was prepared, recrystallized from ethanol/ether, and dried in a vacuum oven to give 1.22 g (51~) of N-(4-(4-(1,2-benzisoth-iazol-3-yl)-1-piperazinyl)butyl)-2-(methylamino)benzamide hydro-chloride as a pale beige solid. mp: 169-173'C. lH NMR
(DMS0-d6): ~ 1.58 (m, 2), 1.81 (m, 2), 2.77 (s, 3), 3.30 (m, 4), 3.48 (br d, 3, 3 - 13.8), 3.58 (br d, 3, J - 12.9), 4.07 (br d, 2, J - 14.8), 6.56 (t, 1, J - 7.4), 6.63 ( d, 1, J - 8.3), 7.29 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.5), 7.57 (d, 1, J - 7.2), 7.61 (d, 1, J - 7.4), 7.64 (br s, 1), 8.13 (t, 2, J - 8.3), 8.41 (br t, 1, J - 5.4), 11.00 (br s, 1). C NMR (DHS0-d6): ~ 20.66, 26.28, 29.33, 38.08, 46.36, 50.44, 55.18, 110.55, 114.03, 115.24, 121.17, 123.99, 124.61, 126.96, 128.11, 128.20, 132.26, 149.91, 152.12, 162.20, 169.12.
Anal. Calcd for C23H29N50S.HCl: C, 60.05; H, 6.57; ~, 15.22.
Found: C, 60.09; H, 6.60; N, 15.13.
CA2i 1 7434 F"XAMPT.F 44 (8) F,~ ~,tlon of (+/-)-oi~-2-(Nethoxvcsrbonvl) rArboxyll~ acid Cis-1,2-Cyrl.~ dicarboxylic anhydride (Aldrich Chemical Company) (10.0 g, 64.9 mmol) and methanol (2.76 ml, 2.18 g, 68.1 mmol, 1.05 eq) were added to a .u~.d b~L ' fl-sk equipped with a magnetic stirring bar and a reflux condenser. The reaction mixture was heated with an oil bath at lOO-C for 1 h. The reaction mixture was allowed to cool to room s , e and the excess methanol was removed in vacuo to obtain 12.0 g (lOOa) of (+/-)-Cis-2-(meLI.~ l)-l-cyrl~ rb~vylic acid as an oil which became a white solid upon standing. mp: 63-66-C. H
NMR (CDC13): ~ 1.35-1.65 (m, 4), 1.80 (m, 2), 2.03 (m, 2), 2.86 (m, 2), 3.68 (s, 3). C NNR (CDC13): ~ 23.63, 23.75, 25.96, 26,26, 42.34, 42.48, 51.71, 174.04, 179.71.
Anal. Calcd for C9H14C4: C, 58.05; H, 7.58. Found: C, 57.97; H, 7.61.
(b) Fr~nArAr;~n of (+/-)-cis-methYl 2-(l~dLUA~_ Ll.~l)-l-cvclohexane-carboxvl At~
(+/-)-cis-2-(Nethoxycarbonyl)-l-cy~ lic acid (11,7 g, 63.0 mmol) and anhydrous teL,al.~l,uf (35.0 mL) was added to a flame-dried, 250-mL, three-necked, round b,~ ~ flask equipped with a magnetic stirring bar, septum and nitrogen inlet.
The resction mixture was cooled with an ice-water bath rontA~nine rock salt. A lN solution of borane in Lei '~d,ufu,~.. (69.0 mL, 69.0 mmol, 1.1 eq) (Aldrich Chemical Company) was slowly added over a 25 min period to the cooled reaction mixture via a syringe. The stirred solution was allowed to warm to room ~ e overnight. The reaction mixture was cooled with an ice-water bath and distilled water (55.0 mL) and potassium C~2i 17434 carbonate ~17.0 g) were addet. The aqueow snd organic phases were . ~m~ The aqueous phase W8S extracted with ethyl acetste followed by ether. The organics were combined and washed with ~t~r~ted sodium chloride, dried over HgS04, filtered and ' to give 10.9 g of an oil. 7he crude material was purified by ilash .1~ with 2:1 hexanes/ethyl acetate to give 6.47 g (59~) of (+/-)-cis-Dethyl 2;(1.~d,uA~. thyl)-l-cycl~ late as a colorless oil. H NMR (CDC13): 6 1.30-1.75 (m, 7), 1.89 (m, 1), 1.97 (t, 1, J - 6.0), 2.02 (m, 1), 2.76 (m, 1), 3.63 (m, 2), 3.68 (s, 3). C NMR (CDC13): 6 23.55, 26.22, 26.34, 40.65, 42.32, 51.44, 64.27, 175.75.
Ansl. Calcd for CgH16C3: C, 62.77; H, 9.36. Found: C, 62.69 H, 9.35.
(c) F.~ 1 of methvl 2-fo~myli (+/-)-~i~-Hethyl 2-(L~d~ l)-l-cyrlr~ ' ~late (7.20 g, 41.8 mmol), anhydrous dimethylr~lfrvid~ (42.0 mL), anhydrous dirhl. L~ (200.0 mL) and trlethylsmine (29.1 mL, 21.2 g, 209 mmol, 5 eq) was added to a flsme-dried, l-L, three-necked, ,~ ' b : ' flask equipped with a magnetic stirring bar, i' L~ and nitrogen inlet. The reaction mixture was cooled in an ice-water bath and sulfur trioxide pyridine complex (Aldrich Chemical Company) (26.6 g, 167 mmol, 4.0 eq) was sdded in three equal portions at 5 min intervals. She reaction mixture vas allowed to stir for 1.5 h. Distilled water (200.0 mL) was added and the aqueous and organic phases were _ , ~ ' The aqueous phase was washed with dichloromethane, the organics were combined and ~ ~ ' to give a pale orange liquid. The product was partitioned between distilled water and ether. The organics were dried over hgS04, filtered and ~ to give 7.45 g of a light yellow oil. The crude product was puri;ied by flash cl.i~ with 12:1 hexanes/ethyl acetate as eluant to ' CA21 1 7434 give 4.98 g (70~) of methyl 2-formylbenzoate 85 a colorless liquid.
(d) F.~_ _~lon of (+/-)-cis-4A. 5. 6. 7. 8. 8A-hexahydro-1(2H)-phthslP2in~~ snt (+/-~- -4A. 5. 6. 7. 8. 8A-U~shvdro-1(2H)-~hthp1A7inAnp (+/-)-cis-Methyl 2-formylbenzoate (11.9 g, 69.8 mmol), 95~
ethanol (120 mL) ant hytrazine hytrate (Fisher Scientific) (9.0 g, 154 ~mol, 2.2 eq) as an 85~ aqueous solution was atded to a round -bottomed flask equipped with a magnetic stirring bar, reflux condenser, and nitrogen inlet. The reaction mixture was refluxet for 0.5 h, coolet to room i . ~, and in vacuo. The residue was partitioned between distillet water (100.0 mL) and ethyl acetate (300.0 mL). The organics were dried over MgS04, filteret ant c~ ' to give 7.79 g (74~) of a pale yellow oil. The crute material was used without further fi r~ti ~
(e) Pr~nsrPtir~ of (+/-)-cic-2-(4-rhlrrobutyl)-4A 5. 6. 7. 8. 8A-h~s~vdro_l(2U)_nhth~lD7in~n~ and (+/-)-trans-2-(4-rhl~robutvl) 4A. 5. 6. 7. 8. 8A-~ (2u)-~hth-lp7in~n~
Sodium hydride (Aldrich Chemical Company) (3.07 g, 103 ~mol, 2 eq) as an 80~ oil Ai . ~~ was added to a flame-dried, 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, nitrogen inlet and septum/stopper. The sodium hydride was washed with hexanes (3X) and anhydrous N,N-dimethyl~ ~A~ (30.0 mL) was added. The suspension was cooled in an ice-water bath and a (77:23) mixture of ~+/-)-cis-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-I' lP7in~ and (+/-)-trans-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-l' '-lP7inA~A
(7.79 g, 51.2 mmol) in anhydrous N, N, dimethylformamide (40.0 mL) was slowly added. After the addition of phthsls7in~A was complete, l-bromo-4-chlorobutane (Aldrich Chemical Company) (6,47 -W O 93/16073 C A 2 i i 7 4 3 4 P(~r/G B93/0028~
mL, 9.65 g, 56.3 mmol, 1.1 eq) was added dropwise. After 15 min, the excess sodium hydride was quenched with distilled water (30 mL) and the solvent was removed in vacuo. Ethyl aceea~e was added to the residue and the organics were washed with water.
The organics were dried over HgSO4, filtered and c~nr~ntr~t~d to glve 14.0 g of an orange oil. The crude material was purified by flash _1..- O ,'~ with 6:1 hexanes/ethyl acetate as eluant to give 3.02 g of ~+/-)-cis-2-(4-chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1~2H)-p~th~1O7inrn- (Rf - 0.13) as a colorless oil and 3.78 g of (+/-)-trans-2-(4-chlcrobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-phrh~lP7innre (Rf - 0.20) as a colorless oil.
cis-isomer: H NMR (CDC13): ~ 1.25-1.71 (m, 8), 1.77 (quinte~, 4, J - 3.2), 2.48 (q, 1, J - 6.4), 2.67 (m,l), 3.55 (m, 2j, 3.78 (m, 2), 7.03 (dd, 1, J - 1.0, 2.6). C NMR (CDC13): ~ 22.71, 23.25, 23.51, 24.29, 24.98, 29.15, 34.04, 37.06, 44.95, 46.10, 149.21, 167.53-Anal. Calcd for C12HlgN20Cl: C, 59.38; H, 7.89; N, 11.54. Found:C, 59.28; H, 7.91; N, 11.48.
trans-isomer: lH NMR (CDC13): ~ 1.28 (m, 4), 1.79 (m, 7), 2.10 (m, 2), 2.34 (m, 1), 3.56 (m, 2), 3.73 (m, 1), 3.84 (m, 1), 7.02 (s, 1). 13C NHR (CDC13): ~ 25.03, 25.21, 25.54, 25.66, 28.42, 29.67, 37.52, 39.92, 44.61, 47.14, 150.58, 168.66.
Anal. Calcd for C12HlgN20Cl: C, 59.38; H, 7.89; N, 11.54. Found:
C, 59.20; H, 7.85; N, 11.43.
(f) Preparation of (+/-)-cis-2-(4-(4-(1.2-hDn7i~~thiazol-3-Yl~-l-Diverazinyl)butYl)-4A. 5. 6. 7. 8. 8A-hexahydro-1(2H~-Dhrh-lD7inrno hydrrrhloride (+/-)-c s-2-(4-Chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-~' ' 107in~ .05 o7~ 4.33 mmol), 3-(1-piperazinyl)-1,2-benziso-CA2i 1 7434 thiszole (1.04 g, 4.76 mmol, 1.1 eq), triethyla~ine (0.725 mL, 0.526 g, 5.20 mmol, 1.2 eq) and acetonitrile (10.0 mL) were added to a round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The reaction mixture was allowed to reflux for 6 h. The reaction was not complete according to TLC, hence, 3-(1-piperazinyl)-1,2-benzisothiazole (0.19 g, 0.2 eq) and triethylamine (0.12 mL, 87 mg, 0.86 mmol, 0.2 eq) were added and the reaction mixture was allowed to reflux overnight. The reaction mixture was allowed to cool to room I , o and the solvent was removed in vacuo. The residue was taken up in dichlo,. ,' and washed with ~ rAt~ potassium carbonate. The organics were dried over MgS04, filtered and r~...=_..l.~t~ to give 2.54 g of an orange oil. The crude material was purified by flash ~1..~ O ,'~ with 2:1 ethyl acetate~hexa-nes followed by ethyl acetate to give 1.05 g of the free base as a yellow oil. To a solution of the free base in ethyl acetate was added HCl (2.47 mL of a lN solution in ether, 1.0 eq). The ride salt was recrystallized from ethanol to give 0.58 g (29~) of the title compound as a white solid. The hydrochloride salt contained 10~ of the trans isomer. mp: 191-193-C (dec). lH
NMR (DMS0-d6): ~ 1.32(m, 1), 1.46 (m, 3), 1.58 (m, 5), 1.73 (m, 3), 2.73 (m, 1), 3.25 (m, 4), 3.46 (br d, 2, J - 12.4), 3.55 (br d, 3, J - 14.7), 3.70 (m, 2), 4.06 (br d, 2, J - 14.2), 7.16 (d, 1, J - 1.1), 7.20 (d, 1, J - 2.6), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.60 (ddd, 1, J - 1.1, 7.0, 8.1), 8.12 (t, 2, J - 8.1), 10.83 (br s, 1). 1 C NMR(DMSO-d6): ~ 20.18, 22.76, 23.22, 23.54, 24.34, 24.87, 34.03, 37.13, 46.28 (2 carbons), 50.41, 55.12, 121.14, 123.95, 124.56, 126.91, 128.07, 149.42, 152.06, 162.16, 167~65.
Anal. Calcd for C23H31N505.HCl: C, 59.79; H, 6.98; N, 15.16.
Found: C, 59.82; H, 7.02; N, 15.08.
W O 93/16073 C ~ 2 i 1 7434 PCT/GB93/0028S
~AMPT F 45 (a) PreDaration of (+/-)-trans-2-(4-(4-(l~2-h~n7i~~rhi97nl-3-vl) Din-ro7;-~Yl)butyl)-4A. 5. 6. 7. 8. 8A-h~v~v~ro-l(2H) ~hrh~1O7;r~n~ hvdrQchloride 3-(1-Piperazinyl)-1,2 ~ '~~th;o~Ale (2.92 g, 13.3 mmol, 1.3 eq), triethylamine (2.16 ml, 1.57 g, 15.5 mmol, 1.5 eq), acetonitrile (20.0 mL) and (+/-)-trans-2-(4-chlorobutyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-phtholo.i (2.49 g, 10.3 mmol) ~Example 44(e)] were added to a round-bottomed flask equipped with a magnetic stirring bar, reflux condenser and nitrogen inlet. The reaction mixture was he-ted at reflux for 24 h under nitrogen. The reaction was not complete according to TLC;
therefore, -~i t; ~n,l portions of 3-(1-piperazinyl)-1,2~ rhi o~~] ~ (O . 450 g, 2.05 mmol, 0.2 eq) and triethylamine (0.72 mL, 0.52 g, 5.14 mmol, 0.5 eq) were added and the reaction mixture W85 heated at reflux for another 24 h. The reaction mixture was allowed to cool to room i . e and ethyl acetate was added. The organics were washed with satur-ted potassium carbonate, dried over MgS04, filtered, and c~ ' to give 6.2 g of an orange oil. The crude product was purified by flash cl.-~ O ,'~ with ethyl acetate as eluant to give 2.72 g of the free base as a pale yellow solid. To a solution of the free base in ethyl acetate was added HCl (6.41 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol to give 2.25 g (47~) of (+/-)-trans-2-(4-(4-(1,2-b~n7i~othl~ol-3-yl)-1-piperazinyl)butyl)-4A, 5, 6, 7, 8, 8A-hexahydro-1(2H)-I' '-1o~; hydrochloride as an off-white solid. mp:
186-188-C. H NMR (DMS0-d6): 6 1.21 (m, 4), 1.61 (br q, 2, J
6.6) 1.71 (m, 4), 1.97 (m, 2), 2.19 (m, 2) , 3.24 (m, 4), 3.47 (br t, 2, J - 13.0), 3.54 (br d, 2, J - 11.1), 3.69 (td, 2, J
2.5, 6.5), 4.06 (br d, 2, J - 13.7), 7.16 (d, 1, J - 1.1), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.60 (dtd, 1, J - 1.1, 7.0, 8.0), 8.12 (t, 2, J - 7.9), 10.8 (br s, 1). 13C N~R (DMS0-d6):
20.14, 24.45, 24.65, 24.87, 25.35, 27.59, 36.68, 38.82, 46.25, 46.30, 50.41, 55.15, 121.13, 123.95, 124.56, 126.91, 128.06, 151.05, 152.06, 162.15, 168.07.
Anal. Calcd for C23H31~50S.HCl: C, 59.79; H, 6.98; N, 15.16.
Found: C, 59.85; H, 6.97; N, 15.12.
ExA~pTF 46 (a) PrenArA~ of 2-~4-bromobutvl~-1.3(2H.4H)-iso~uinolinedione r r~'' 1i~ anhydride (Aldrich Chemical Compsny) (15 g, 92.5 mmol) and 4-amino-1-butanol (Aldrich Chemical Company) (8.54 mL, 8.26 g, 92.5 mmol, leq) were added to a three-necked, .vv~.d b_L ' flask equipped with a reflux condenser and attition funnel. The reaction mixture was heated with an oil bath at lSO-C for 2 h. The green solution was cooled to room I ~ e and ~ hv~. tribromide (6.0 mL, 17.1 g, 63 mmol) was attet dropwise. The reaction mixture was heated slowly to 170-C and 'rtsi ' at that I . e for 45 min. The hot reaction mixture was poured onto crushed ice (lS0 g). The viscous organic material w~s separated from the ice and ethanol was added. The material became a white solid upon the addition of ethanol. The solvent was removed in ~acuo to give a yellow solid. The solid was recrystallized from ethanol to give 17.1 g (62~) of 2-(4-Bromobutyl)-1,3(2H, 4H)-i~oq~;r~li ~-~ as a pale yellow solid. mp: 87-89-C. H NMR (CDC13): ~ 1.88 (m, 4), 3.43 (t, 2, J - 6.5), 4.02 (t, 4, J - 7.0), 4.03 (s, 2), 7.26 (d, 1, J
- 7.2), 7.43 (t, 1, J - 7.5), 7.58 (td, 1, J - 7.4, 1.4), 8.20 (d, 1, J - 7,8). 13C NMR (CDC13): ~ 26.26, 29.64, 32.55, 35.88, 38.66, 124.77, 126.63, 127.26, 128.66, 133.17, 133.54, 164.32, 169.44.
CA 2 i 1743¢
' 109 Anal- Calcd for C13N14N02Br: C, 52.72; H, 4.76; N, 4.73. Found C, 52.79; H, 4.80; N, 4.74 (b) P_ _on Qf 2-~4-(4-(l.2-h~n7ienth1A7~l-3-vl~-l-DiDera-71~yl~butyl~-l.3~(7u.4H~-isonllin~1in~inn~ hydr~rhloride hvdrate 2-(4-Bromobutyl)-1,3(2H, 4H)-isoqu.~.~liDedione (9.74 g, 1), 3-(1-piperazinyl)-1,2-' eothi~7Ole (7.96 g, 36.3 F ' .1 eq), triethylamine (5.52 ml, 4.G ~, 39.6 mmol, 1.2 md acetonitrile (50.0 DL) were added to a round-bottoDed .ask equipped with magnetic stirring bar, condenser and nitrogen inlet. The reaction Dixture was heated at reflux for 3.5 h. The crude mixture was absorbed onto silica gel and purified by flash ~ with 2:1 ethyl acetate/hexanes followed by ethyl acetate as eluant to give 11.9 g of the free base as an orange oil. To a solution of the free base in ethyl acetate was added HCl (27.4 DL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 6.57 g (40~) of 2-(4-(4-(1,2-b~n-ieoth1r7~1-3-yl)-l-piperazinyl)-butyl)-1,3,(2H,4H)-- I ~~~1i ' hydrochloride hydrate as an orange solid. Dp: 190-195'C. lH NMR (DMS0-d6): ~ 1.64 (m, 2), 1.75 (m, 2), 3.10-3.60 (D, 4), 3.91 (q, 2, J - 6.8), 4.05 (br d, 2, J - 13.0), 7.55 (D, 4), 8.12 (D, 4), 10.60 (br s, 1). C N~R
(D~S0-d6): ~ 20.57, 24.66, 36.02, 38.53, 46.32, 50.44, 55.12, 121.13, 123.94, 124.57, 124.84, 126.90, 127.20, 127.48, 127.93, 128.06, 133.46, 135.41, 152.06, 162.15, 164.53, 170.08.
Anal. Calcd for C24H26N402S.HClØ5H20: C, 60.05; H, 5.88; N, 11.67; H20, 1.87. Found: C, 60.30; H, 5.85; N, 11.74; H20, 1.79.
EXAMPI F. 47 (a) FL~ ~n of 2-(4-(4-(1.3-benzisothiazol-3-xl)-1-DiDera-7invl)butyl)-1.4~2H,3H)-DhthAlA7i~r~ione hvdrochloride Sodium hydride (Aldrich Chemical Company) (0.102 g, 3.39 mmol, eq) as an 80~ oil ~ n was added to a flame-dried, three-necked, round-bottomed flask equipped with a magnetic stirring bar, reflux condenser, and nitrogen inlet. The sodium hydride was washed with hexanes (3x) and anhydrous N,N-dimethyl-formamide (10.0 mL) was added. The s~sp-nCi~r was cooled in an ice-water bath. Phthalhydrazide (0.549 g, 3.39 mmol) and 8-(1,2-benzisothiazol-3-yl)-5,8-diazaspiro(4.5)decan-5-onium bro-mide (1.2 g, 3.39 mmol, 1.0 eq) were added and the reaction was heated at reflux overnight. The reaction mixture was cooled in an ice-water bath and the excess sodium hydride was quenched with distilled water (5.0 mL). The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water, The organics were dried over MgS04, filtered and ~ d to give 0.63 g of the crude material. This crude material was combined with an n~A; t; 1 1.3 g of the crude material obtained from a previous run. The aqueous phases of both reactions were also combined and washed with dichl~.- ' . The dichl~
was dried over MgS04, filtered, and removed in vacuo to obtain an additional 0.34 g of crude material. The crude material (1.70 g total) was purified by flash ~ g ,'~ with 94:6 dichloromethane/methanol to give 0.64 g of the free base as a white solid. To a solution of the free base in chloroform was added HCl (1.47 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 0.429 g (13~) of 2-(4-(4-(1,3-benzisothia-zol-3-yl)-1-piperazinyl)butyl)-1~4(2H,3H)-I' ' ~lD7in--~ir-n- hydro-chloride as a white solid. mp: 242-245-C (dec). 1~ NMR
(DMS0-d6): ~ 1.81 (br s, 4), 3.26 (m, 4), 3.45 (br t, 2, J
12.0), 3.57 (br d, 2, J - 11.5), 4.06 (m, 4), 7.47 (ddd, 1, J
0.8, 7.2, 8.1), 7.60 (ddd, 1, J - 1.0, 7.1, 8.1), 7.90 (m, 2), 7.98 (m, 1), 8.12 (t, 2, J - 7.2), 8.25 (m, 1), 10.69 (br s, 1), 11.70 (br s, 1). 13C NMR (DMS0-d6): ~ 20.37, 25.14, 46.33, 48.32, 50.45, 55.12, 121.13, 123.93, 124.07, 124.55, 126.41, W O 93/16073 C A 2 i i 7 4 3 4 P(~r/G B93/0028s 126.90, 128.06, 128.71, 132.22, 133.03, 150.23, 152.05, 157.15, 162.15.
Anal. Calcd for C23H25N502S.HCl: C, 58.53; H, 5.55; N, 14,84.
Found: C, 58.38; H, 5.60; N, 14.76.
FY-YPJ .F. 48 (a) Pre~aration of 3.4-dihYdro-lH-2-b~ v~,~.l-l-one This compound was prepared according to a modified procedure of F. 8Onadies and R. Di Fabio (J. Ore. Chem. 1984, 49, 1647).
3,4-Dihydro-lH-2-~ " .~.. (Aldrich CheDical Company) (32.8 ml, 35.0 g, 0.261 mol), pyridinium chl~ (Aldrich Chemical Company) (56.3 g,0.261 mol, 1 eq) and anhydrous dichl~L. LL~.~
(100.0 mL) were added to a flame-dried, l-L, round-bottomed flask equipped with a cond nser, magnetic stirring bar and nitrogen inlet. The reaction mixture was heated with an oil bath at 60-70-C. Additional equiv-lents of pyridinium chlo,v~l.L~
were added at t - 2h and t - 4h and the reaction mixture was heated at reflux o~-ernight. The reaction mixture was allowed to cool to room I . e~ the solv nt was decanted from a dark 8L~ residue and the residue was washed with dichl~L. ' . The organics were combined and ~ d to give 37 g of an orange oil. The crude material was purified by flash ;: O ,'~ with 3:1 hexanes/ethyl acetate to obtain 20.2 g (52~) of 3,4-dihydro-lH-2 ~ ,~ l-one as colorless oil. 1H NMR (CDC13): 6 3.07 (t, 2, J - 6.0), 4.54 (t, 2, J
6.0), 7.27 (d, 1, J - 7.5), 7.40 (tm, 1, J - 7.6), 7.54 (td, 1, J
- 7.5, 1.3), 8.10 (dd, 1, J - 1.0, 7.8). 13C NMR (CDC13):
27.82, 67.31, 125.30, 127.24, 127.68, 130.38, 133.67, 139,55, 165.13.
Anal. Calcd for CgH802 C, 72.96; H, 5.44. Found: C, 72.88; H, 5.42.
(b) Pr~nsration of 2-(4-cblorobutvl)-2.3.4.5-~L-al.~dLv-lH-2-h~n797--nin-l-one This compound was prepared according to the method described in Example 34(c). Alkylation of 2, 3,4,5-tetrahydro-lH-2-benzaze-pin-l-on~ (0.46 g, 2.85 mmol) (prepared from 3,4-dihydro-lH-2-benzopyran-l-one according to the method of N. ~. Gllman, (Svnthetic r- . 19B2, 12, 373)) with 1-bromo-4-chlorobutane (Aldrich Chemical Company) (0.393 ml, 0.586 g, 3.42 mmol, 1.2 eq) gave 0.40 g (56 ~) of 2-(4-chlorobutyl)-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one as an orange oil.
(c) P.. _ lon of 2-(4-(4-(1.2-benzisothio~~l-3-~l)-l-DiDera-71nVl~but~yl)-2~3~4~5-t~LL~ dLv-lH-2-hon7s7on;n hydr~rhl nrid~
This compound was prepared according to the method described in Example 34(d). Alkylation of 2-(4-chlorobutyl)-2,3,4,5-tetrahy-dro-lH-2-benzazepin-1-one (0.40 g, 1.59 mmol) with 3-(1-piperazinyl)-1,2 ~ ~coth1o-nlo (0.52 g, 2.39 mmol, 1.5 eq) gave 0.45 g of the free base which was purified by flash cl.-. ~ with 2:1 ethyl acetate/hexanes/0.1% triethylamine as eluant. The hydrochloride salt was prepared, recrystallized from ethanol, and dried in a vacuum oven to give 227 mg (30~) of 2-(4-(4-(1,2-b-n~;~oth;o~~1-3-yl)-1-piperazinyl)butyl)-2,3,4,5-tetrahydro-1_-2-benzazepin-1-one hydrochloride as a beige solid.
m.p.: 215-217 ~C (dec). lH NMR (DMSO-d6): C 1.67 (m, 2), 1.81 (m, 2), 1.99 (quintet, 2, J - 6.7), 2.73 (t, 2, J - 7.0), 3.18 (t, 2, J - 6.4), 3.27 (m, 4), 3.53 (m, 6), 4.08 (br d, 2, J
13.0), 7.25 (dd, 1, J - 1.2, 7.5), 7.33 (td, 1, J - 7.5, 1.4), 7.42 (td, 1, J - 7.4, 1.6), 7.48 (ddd, 1, J - 1.1, 7.0, 8.1), 7.51 (dd, 1, J - 1.6, 7.4), 7.60 (ddd, 1, J - 1.1, 7.0, 8.1), 8.13 (t, 2, J - 9.1), 10.92 (br s, 1). 13C NMR (DMS0-d6): ~
20.61, 25.55, 29.30, 29.58, 45.59, 45.69, 46.35, 50.46, 55.23, W O 93/16073 C A 2 i 1 7 4 3 4 PCr/GB93/00285 121.15, 123.95, 124.57, 126.59, 126.91, 127.94, 128.07, 128.24, 130.51, 136.25, 137.09, 152.06, 162.16, 169.78.
Anal. Calct for C25H30N405.HCl: C, 63.74; H, 6.63; N, 11.89.
Found: C, 63.76; H, 6.67; N, 11.87, F~yAMpT F 49 (a) PrenArAtiAn of 3-(1-(4- A~h~tvl)-4-DiDeri~inyl)-l.2 benzisothia201e Nethanol (40.0 mL) and N-(4-(4-(1,2-~ ~othiA7Al-3-yl) p~ nA)butyl)~ (6.77 g, 16.1 mmol) (Example 33) was added to a three-necked, 250-mL, round-bottomed flask equipped with a magnetic stirring bar, addition funnel, nitrogen inlet and reflux condenser. The reaction mixture was heated to reflux and hydrazine hydrate (Aldrich Chemical Company) (1.41 g of a 55 ~queous solution, 24.2 mmol, 1.5 eq) was added dropwise. The solution was refluxed for 3 h after the addition of hydrazine hydrate was complete. The reaction mixture was allowed to cool to room i ~ and a-1Aifi~d (pH - 2) with lN HCL. The , ~An was filtered and the filtrate was cooled in an ice-water bath. The pH of the cooled filtrate was adjusted to 10 by the addition of 50~ NaOH. The organics were extracted with dichlc.~ ' , dried with HgSO4, filtered and - teA to gi~e 4.22 g (91~) of 3-(1-(4-aminobutyl)-4-piperidinyl)-1,2-benz-~ 701~ as an orange oil. lH NHR (CDC13): ~ 1.57 (m, 7), 2.10 (m, 6), 2.42 (t, 2, J - 7.4), 2.74 (t, 2, J - 6.6), 3.10 (dd, 2, J - 2.0, 7.0), 7.41 (ddd, 1, J - 7.0, 8.1), 7.50 (ddd, 1, J - 1.1, 7.0, 8.0), 7.92 (dt, 1, J - 8.1, 1.0), 8.00 (dt, 1, J
8.1, 1.0).
(b) PreDaration of 2-Aminn-N-(4-(4-~1 2-h~n7icnth1A7nl 3 Diperidino)butvl)h~n7Ami~ hydrochloride This compound was prepared according to the method described in Example 36. Alkylation of isatoic anhydride (Aldrich Chemical Company) (0.68 g, 4~15 mmol) with 3-(1-(4-aminobutyl)-4-piperi-dinyl)-1,2-b-n~icothiA7nl~ (1.2 g, 4.15 mmol, 1.0 eq) gave 1.38 g of the free base which was purified by flash cl... ~ with 2:1 ethyl acetate/hexanes/0.18 triethylamine as eluant. The hydrochloride salt was prepared and recrystallized from ethsnol/water to give 1.09 g (59~) of 2-amino-N-(4-(4-(1,2-benzi-sothiazol-3-yl)piperidino)butyl)benzamide hydrochloride as a beige solid. mp: 239-240 ~C. 1~ NMR (DMS0-d6): ~ 1.58 (m, 2), 1.78 (m, 2), 2.23 (m, 4), 3.14 (m, 4), 3.27 (q, 2, J - 6.3), 3.65 (m, 3), 6.40 (br s, 2), 6.51 (ddd, 1, J - 1.3, 7.0, 8.4), 6.69 (dd, 1, J - 0.9, 8.2), 7.13 (ddd, 1, J - 1.6, 7.1, 8.7), 7.52 (m, 2), 7.63 (ddd, 1, J - 1.0, 7.0, 8.0), 8.22 (d, 1, J - 8.1), 8.27 (d, 1, J - 8.1), 8.29 (m, 1), 10.0 (br s, 1). C NMR (DMS0-d6):
20.73, 26.37, 27.71, 35.57, 37.98, 51.45, 55.67, 113.33, 114.51, 114.79, 116.28, 120.72, 123.53, 124.92, 128.06, 131.55, 133.32, 149.56, 151.95, 167.52, 168.91.
Anal. Cald. for C23H28N405.~Cl: C,62.08; H, 6/57; N,12.59. Found:
C,62.11; ~,6.61;
EXAMP!~ 50 (a) Pr~n~rAri~n of ((4-(4-~1.2-benzisothiazol-3-vl)-1-DiDera-z~nvl)butyl)~Ar~- l)DhenYl acetate 3-(4-(4-Aminobutyl)-l-piperazinyl)-1,2-benzisothiazole (3.0 g, 10.4 mmol) (Example 13(b)), triethylamine (1.74 mL, 1.26 g, 12.5 Cd~ j 1 7434 mmol, 1.2 eq) and dichlu-- i'~ (50.0 mL) was added to a flame-dried, 200-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and nitrogen inlet.
The reaction mixture was cooled in an ice-water bath and a solution of acetylsalicyloyl chloride (Aldrich Chemical Company) (2.06 g, 10.4 mmol, 1.0 eq) in dichlu-~ '- (20 mL) was added dropwise. The reactlon mixture was allowed to warm to room ~ , ' e and stirred for 15 min. The reaction mixture was washed with cold saturated sodium bicarbonate. The organics were dried over MgS04, filtered and ~ A to give 5.8 g of the crude material as an orange oil. The crude reaction mixture was purified by flash cl"~ with 95:5 dichlo.~ '- /metha-nol as eluant. The product (2.93 g) was obtained as a mixture of ((4-(4-(1,2-b-n7i~othis-~1-3-yl)-l-piperazinyl)butyl)carbamoyl)-phenyl acetate and ~-(4-(-(1,2-benzisothiazol-3-yl)-1-piperazin-yl)butyl)-2-1.~d. UA~ L ~ A -(b) Pr~o-Ati~~ of N-(4-~ 2-bDn7i~his7~l-3-yl~-l-oi~r zinvl)butyl~-2-l.~dLu~ de hydrochloride Methanol (30.0 mL) and a mixture (2.93 g) of N-(4-(-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)carbamoylphenyl acetate and N-(4-(-(1,2-b~n7i~othis7~1-3-yl)-l-piperazinyl)butyl)-2-hydroxy-benzamide were added to a 300-mL, round-bottomed flask equipped with a magnetic stirring bar, addition funnel and nitrogen inlet.
A solution of sodium methoxide (Aldrich Chemical Company) (38.5 mg, 7.12 mmol, 1.1 eq) in methanol (60 mL) W8S added dropwise to the reaction mixture. The reaction mixture was allowed to stir for 1.5 h, n~vt~Ali7~(i with Dowex resin, filtered and - ~ to give 2.68 g of the free base as a viscous pale orange oil. To a solution of the free base in ethyl acetate was added HCl (6.53 mL of a 1 N solution in ether, 1.0 eq). The resulting hydrochloride salt was recrystallized from ethanol/water to give 2.32 g (50~ based on acetylsalicyloyl chloride) of N-(4-(-(1,2-b-n7i~othis~~1-3-yl)-l-piperazir.yl)but-yl)-2-h~d.~L ~ hydrochloride as an off-white solid, H
NMR (DNSO-d6): ~ 1.63 (m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.7), 3.59 (br d, 2, J - 11.3), 4.07 (br d, 2, J
13.5), 6.89 (m, 2), 7.40 (ddd, 1, J - 1.7, 7.2, 8.8), 7.47 (ddd, 1, J - 1.1, 6.9, 8.1), 7.60 (ddd, 1, J - l.l, 7.0, 8.1), 7.90 (dd, 1, J - 1.4, 7.9), 8.12 (t, 2, J - &.4), 8.98 (br t, 1, J
5.5), 10.80 (br s, 1), 12.68 (s, 1). 13C N,'-~ (DMS0-d6): ~ 20.60, 25.99, 38.38, 46.35, 50.44, 55.06, 115.07, 117.31, 118.43, 121.14, 123.95, 124.57, 126.90j 127.69, 128.07, 133.59, 152.05, 160.09, 162.16, 169.03.
Anal, Calcd for C22H26N402S.HCl: C, 59.11; H, 6.09; N, 12.53.
Found: C, 59.00; H, 6.10; N, 12.47.
(a) pL~--r~ n of N-(4-(4-(1.2-benzisothiazol-3-vl)-1-Dimera-zinyl~butvl~benzamide hvdrochloride The free base of this compound was prepared according to the method described in Example 50(a). Acylation of 3-(4-(4-amino-butyl)-l-piperszinyl)-1,2-b~n7i~or~;~771e (1.5 g, 5.17 mmol, 1.0 eq) (Example 13(b)) with benzoyl chloride (0.6 mL, 0.727 g, 5.17 mmol) over a lh periot gave 1.49 g of the free base which was purified by flash cl.-. O ,'~ with ethyl acetate/0.1%
triethylamine. To a solution of the free base in ethyl acetate was added HCl (3.8 mL of a lN solution in ether, 1.0 eq). The hydrochloride salt was recrystallized from ethanol to give 1.04 g (47~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl)butyl)-benzamide hydrochloride as a pale beige solid. mp: 200-201.5-C.
H NMR (DMS0-d6): ~ 1.61 (m, 2), 1.80 (m, 2), 3.27 (m, 6), 3.47 (br t, 2, J - 12.6), 3.59 (br d, 2, J - 11.7), 4.08 (br d, 2, J -13.4), 7.50 (m, 4), 7.60 (t, 1, J - 7.6), 7.87 (m, 2), 8.13 (t, 2, J - 8.4), 8.58 (br t, 1, J - 5.5), 10.72 (br s, 1). 13C N.'~
(DMS0-d6): ~ 20.59, 26.25, 38.36, 46.32, 50.41, 55.09, 121.14, C~2 i i 7~34 123.95, 124.56, 126.90, 127.12, 128.07, 128.16, 131.01, 134.47, 152.05, 162.16, 166.15.
Anal. Calcd for C22H26N405.HCl: C, 61.31 H, 6.31; N, 13.00.
Found: C, 61.27; H, 6.34; N, 12.98.
pY~PJ F. 52 (a) Pr~nsration of N-(4-chlorobutvl)-N-methY1 ~
This9 compound was prepared according to the method described in Example 34(c). N-Methy~ - (Aldrich Chemical Company) (3 g, 22.2 mmol) was alkylated with 1-bromo-4-chlorobutane (Aldrich Chemical Company) (2.81 mL, 4.19 g, 24.4 mmol, 1.1 eq). The crude reaction mixture was extracted with dichl~ h9~- and purifi-d by flash cl ~ O .'~ with 2:1 ethyl acetate/hexanes to give 3.02 g (60~) of N-(4-chlorobutyl)-N-methyl benzamide as a pale yellow oil.
(b) ~ on of N-(4-(4-(1.2-h~n~i~~thiD7nl-3-Yl)-1-~inera-.1nvl~butvl-N h l)l~r~ hvdrochloride This compound was prepared according to a method analogous to that described in Example 34(d). N-Methyl-N-(4-chlorobutyl) benzamide (1.50 g, 6.65 mmol) and 3-(1-piperazinyl)-1,2-benziso-thiazole (1.60 g, 7.3 mmol, 1.1 eq) were heated at reflux overnight to give 3.64 g of the crude free base. The crude material was purified by flash .1..- g ,'~ with 2:1 ethyl acetate/hexanes/0.1~ triethylamine to give 1.40 g of the free base as a yellow oil. The hydrochloride salt was prepared and recrystallized from ethanol/ether to give 0.76 g (26~) of N-(4-(4-(1,2-' ~,~th ip7nl -3-yl)-l-piperazinyl)butyl-N-methyl)-benzamide hydrochloride as a white solid. mp: 151-154-C. lH NMR
(DMS0-d6): 6 1.57-1.83 (m, 4), 2.98 (m, 4), 3.26 (m, 4), 3.55 (m, 5), 4.07 (br d, 2, J - 12.6), 7.44 (m, 6), 7.60 (t, 1, J - 7.3), 8.13 (t, 2, J - 8.1), 11.07 (br s, 1). C NMR (D~SO-d6): 6 20.29, 23.68, 36.91, 45.74, 46.27, 50.40, 55.22, 121.14, 123.95, 124.56, 129.15, 136.70, 152.06, 162.17, 170.15.
Anal. Calcd for C23B28N40S.HCl: C, 62.08; H, 6.57; N, 12.59.
Found: C, 62.01; H, 6.56; N, 12.53.
FY~ "P! .F 53 (a) Preoaration of N-~4-(4-(l~2-han~i~nrhiA7nl-3-yl)-l-oioera zit~Yl~butYl)-4-chlu~J~ hvdrochloride hydrate 3-(4-(4-Aminobutyl)-l-piperazinyl)- 1,2-benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and dichluL- '- (10.0 mL) were added to flame-dried, 100-mL, .. ' b L ' flask equipped with a magnetic stir bar, nitrogen inlet and addition funnel. The re-ction mixture was cooled in an ice-water bath, and a solution of 4-chlorobenzoyl chloride (Aldrich Chemicsl Company) (0.61 g, 3.45 mmol, 1.0 eq) in dichlu-, '- (10.0 mL) was added dropwise. The reaction mixture was allowed to stir for 0.5 h and transferred to a , - y funnel with the aid of ethyl acetate.
The organics were washed with saturated ~Jt carbonate, dried over ngS04, filtered, and ~ ' to give a pale yellow solid (1.4 g). The crude reaction mixture was purified by flash cl... ~ with ethyl acetate/0.1~ triethyla~ine as eluant to give 0.99 g of the free base as a white solid. The free base was dissolved in ethyl acetate and dichlu.- tha~a / and 2.31 mL of lN ethereal HC1 (1.0 eq) was added. The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol/water to give 0.915 g (56~) of N-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-4-chlu.~' ,ia hydrochlor-ide hydrate as a white solid. mp: 209-210 ~C (dec). H NMR
(DMS0-d6): 6 1.60 (m, 2), 1.79 (m, 2), 3.15-3.37 (m, S), 3.45 (br t, 3, J - 12.7), 3.59 (br d, 2, J - 12.0), 4.08 (br d, 2, J
W O 93/16073 C A 2 i 1 7 4 3 4 P(~r/G B93/0028~
12.9), 7.48 (ddd, 1, J - 1.0, 7.1, 8.1), 7.55 (dm, 2, J - 8.6), 7.60 (ddd, 1, J - 1.2, 7.0, 8.2), 7.90 (dm, 2, J - 8.7), 8.13 (t, 2, J - 8.2), 8.68 (br t, 1, J - 5.5), 10.59 (br s, 1). 13C N~R
(DMS0-d6): 8 20.58, 26.17, 38.44, 46.32, 50.41, 55.08, 121.13, 123.95, 124.56, 126.91, 128.07, 128.25, 129.10, 133.18, 135.84, 152.05, 162.16, 165.09.
Anal. Calcd for C22H25N40SCl.HClØ5 H20: C, 55.69; H, 5.74; N, 11.81; H20, 1.90. Found: C, 55.58; H, 5.69; N, 11.71; H20, 2.02.
(a) P.. of N-(4-(4-(1.2-h~n~ic~thiazol-3-Yl)-l-oiDera-ziDyl)butyl)-3.4-dichlornh~n7~ ~ hydrochloride This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-L '~oth1~ol~ (i.o g, 3.45 mmoi) (Example 13(b)), triethyla~ine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and 3,4-dichlorobenzoyl chloride (Aldrich Chemical Company) (0.723 g, 3.45 mmol, 1.0 eq).
The crude reaction mixture was purified by flash ~ ,' J
with ethyl acetate/0.1~ triethylamine as eluant to give the free base (1.52 g) as a white solid. The hydrochloride salt was prepared, recrystallized from ethanol/water and dried in a vacuum ov~n to giv~ 0.88 g (51~) of N-(4-(4-(1,2-~ c~thi~7~1-3-yl)-l-piperazinyl)butyl)-3,4-dichl~.-L ~- hydrochloride as a pale beige solid. mp: 208-210 ~C (dec). H NMR (DMSO-d6): ~ 1.61 (m, 2), 1.82 (m, 2), 3.27 (m, 6), 3.52 (m, 4), 4.07 (br d, 2, J -13.4), 7.47 (t, 1, J - 7.6), 7.60 (t, 1, J - 7.5), 7.76 (d, 1, J
- 8.5), 7.88 (dd, 1, J - 2.0, 8.4), 8.12 (t, 2, J - 8.2), 8.14 (d, 1, J - 2.0), 8.86 (t, 1, J - 5.5), 11.10 (br s, 1). 13C NMR
(DMS0-d6): ~ 20.58, 26.07, 38.62, 46.33, 50.44, 55.08, 121.14, 123.95, 124.57, 126.91, 12~.52, 128.07, 129.13, 130.59, 131.16, 133.85, 134.75, 152.07, 162.17, 163.88.
CA2i 1 7434 W O 93/16073 - 120 - PCT/GB93/0028~
Anal. Calcd for C22H24N4oscl2~cl: C, 52.86; H, 5.04; N, 11-21-Found: C, 52.94; ~, 5.09; N, 11.16.
CA 2 i 1 7434 FY~''PT F 55 (a) Pron~rPtio~ of N-~4-(4-(1.2-hon~ie~thiP~nl-3-Yl~-l-DiD~ra Zi~yl)butyl~-4 thoxyhon~ 'de hvdrochloride This compound was prepared according to the method described in Example 53, by employing 3-~4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole ~1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.5 eq) and p-anisolyl chloride (Aldrich Chemical Company) (0.589 g, 3.45 mmol, 1.0 eq). The crude reaction mixture was purified by flash ChL~ g ,'~ with 93:7 dichl~L~ t' /methanol as eluant to give the free base as a pale beige solid (0.73 g). The hydrochloride salt was prepsred, recrystallized from ethanol, and dried in a vacuum oven to give 0.287 g (18~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl) butyl) 6 , i' ~L '~o hydrochloride as a tan solid. mp: 171-173 ~C (dec). lH NLDR (DMSO-d6): ~ 1.59 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.49 (br d, 2, J - 12.1), 3.58 (br d, 2, J - 13.8), 3.81 (s, 3), 4.07 (br d, 2, J - 13.4), 7.00 (dm, 2, J - 8.9), 7.48 (ddd, 1, J - 1.2, 7.0, 8.1), 7.60 (ddd, 1, J
1.0, 7.0, 8.1), 7.86 (dm, 2, J - 8.9), 8.13 (t, 2, J - 8.3), 8.45 (t, 1, J - 5.6), 10.81 (br s, 1). C NL-DR (DMS0-d6): ~ 20.63, 26.35, 38.29, 46.35, 50.43, 55.13, 55.27, 113.35, 121.15, 123.96, 124.58, 126.69, 126.92, 128.08, 128.94, 152.07, 161.39, 162.17, 165.64.
Anal. Calcd for C23H28N4025.HCl: C, 59.92; H, 6.34; N, 12.15.
Found: C, 60.00; H, 6.39; N, 12.19.
F~AMPT~ 56 (a) P.~ n of N-(4-(4-(l~2-hon7ic~rh~ l-3-vl)-l-DiDera zinYl)butvl)-4-(trifln~romethYl)hon7 '~o hYdrochloride This compound was prepared according to the method described in Example 53, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine ~0.721 mL, 0.524 g, 5.18 mmol, l.S eq) and 4-(trifluoromethyl) benzoyl chloride (Aldrich Chemical Company) (0.513 mL, 0.720 g, 3.45 mmol, 1.0 eq). After the 4-(trifl~ Ll.~l) benzoyl chloride was added, the ice-water bath was removed and the reaction mixture was stirred for l.S h. The crude reaction mixture was purified by flash ~ O a~ with 1:1 ethyl aceeate/hexanes with 0.1~ triethylamine as eluant followed by ethyl acetate/0.1~ triethylamine to give 0.57 g of the free base as a solid. The hydrochloride salt was prepared and recrystall-ized from ethanol to give 0.26 g ~lSi) of N-~4-~4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-4-(trifluoromethyl)benzamide hydrochloride as a tan solid: mp: 205-207 ~C (dec.). lH
NHR~DMS0-d6): ~ 1.62 ~m, 2), 1.83 ~m, 2), 3.15-3.40 (m, 6), 3.50 ~br t, 2, J - 13.0), 3.59 ~br d, 2, J - 11.6), 4.08 (br d, 2, J -13.3), 7.48 (ddd, 1, J - 1.0, 7.1, 8.1), 7.60 (ddd, 1, J - 1.0, 6.9, 8.1), 8.08 (d, 2, J - 8.8), 8.11 (m, 4), 8.87 (br t, 1, J
5.5), 10.95 (br s, 1). 13C N~R (D~S0-d6): ~ 20.63, 26.15, 38.50, 46.37, 50.47, 55.12, 121.18, 122.13, 123.99, 124.61, 125.23, 126.95, 128.11, 130.79, 138.25, 152.10, 162.20, 165.04.
Anal. Calcd for C23H25N405F3.HCl: C, 55.36; H, 5.25; N, 11.23.
Found: C, 55.46; H, 5.26; N, 11.18.
- ~23 -EYAMP! F. 57 . (a) Preparation of N-(4-(4-(l~2-h~n7;~~thip7nl-3-yl)-l-Din~ra-7;nvl)butyl~-4-tert-butvl'~~ ~A-~ hvdrochlor~de This compount was prepared according to the method described in Example 56, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-b~ieoth~ e (1.0 g, 3.45 mmol) (Example 13(b)), triethylamine (0.721 mL, 0.524 g, 5.18 mmol, 1.0 eq) snd tert-butylbenzoyl chloride (Aldrich Chemical Company) (C.674 mL, 0.679 g, 3.45 mmol, 1.0 eq). The hydrochloride salt was prepared from the free base (0.560 g) and recrystallized from ethanol to give 0.251 g (15~) of N-(4-(4-(1,2 1 ~oth;o~A1-3-yl)-1-piperazinyl)butyl)-4-tert-butylh- - ~A- L~ ride as a tan solid, mp:
220.5-222 ~C (dec.). lH NHR (DHS0-d6): 6 1.31 (s, 9), 1.60 (m, 2), 1.82 (m, 2), 3.25 (m, 6), 3.55 (m, 4), 4.08 (br d, 2, J
13.3), 7.49 (m, 3), 7.62 (t, 1, J - 7.4), 7.83 (d, 2, J - 8.4), 8.14 (m, 2), 8.55 (t, 1, J - 5.7), 11.06 (br s, 1). 13C NHR
(DHS0-d6): 6 20.82, 26.55, 31.15, 34.77, 38.53, 46.63, 50.71, 55.39, 121.51, 124.32, 124.93, 125.28, 127.28, 127.35, 128.45, 132.11, 152.45, 154.15, 162.57, 166.47.
Anal. Calcd for C26H34N40S.HCl: C, 64.11; H, 7.24; N, 11.50.
Found: C, 64.00; H, 7.25; N, 11.43.
FY~''PT F 58 (a) P.~ : ~n of N-(4-(4-(1.2-h~n-i7~thi~Al-3-yl~-l-DiDera-?;nVl~bUtVl~-4-(DhenvlD.~h~ ~A.. hvdrochloride -This compound was prepared according to the method described in _xample 53, by employLng 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ oth~ le (1.24 g, 4.27 mmol) (Example 13(b)), triethyl-amine (0.893 mL, 0.648 g, 6.41 mmol, l.S eq) and p-phenylazoben-zoyl chloride (Kodak) (1.05 g, 4.27 mmol, 1.0 eq). The reaction mixture was allowed to stir for 1 h following the addition of p-phenylazobenzoyl chloride. The free base was purified by flash CLL. ~ with 3:1 ethyl acetate/hexanes with 0.14 triethylamine followed by ethyl acetate/0.1~ triethylamine and finally ethyl acetate/0.24 triethylamine as eluant to give the 1.42 g of the compound as an orange solid. The free base was recrystallized from ethyl acetate to give 0.781 g of the pure compound as an orange solid. The hydrochloride salt was prepared and recrystallized from ethanol/water to give 0.589 g (26~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-(phenyl-azo) benzamide hydrochloride as an orange solid. mp: 225-227 ~C.
H NMR (DMS0-d6): 6 1.67 (m, 2), 1.82 (m, 2), 3.36 (m, 8), 3.63 (br d, 2, J - 10.4), 4.11 (br d, 2, J - 11.9), 7.49 (tm, 1, J
7.6), 7.64 (m, 4), 7.98 (m, 4), 8.14 (m, 4), 8.82 (br t, 1, J
5.6), 10.50 ~br s, 1). 13C NMR (DMS0-d6): ~ 20.65, 26.22, 38.56, 46.36, 50.45, 55.12, 119.43, 119.91, 121.16, 122.30, 122.68, 123.97, 124.58, 126.91, 127.45, 127.95, 128.09, 128.50, 128.84, 129.52, 131.98, 132.61, 136.64, 151.82, 152.07, 153.15, 153.46, 155.71, 162.17, 165.18, 165.39.
Anal. Calcd for C28H30N605.HCl: C, 62.85; H, 5.84; N, 15.71.
Found: C, 62.91; H, 5.85; N, 15.63.
FY~vpJ.F 59 (a) PreDaration of 4-acetamido-N-(4-~4-(1.2-benzisothiazol-3-vl)-1-Dir~r~ yl)but~l)benzamide hvdrochloride 4~ d~h~r-~ic acid (Aldrich Chemical Company) (0.742g, 4.14 mmol), triethylamine (0.693 mL, 0.503 g, 4.97 mmol, 1.2 eq) and anhydrous tet~ d.~r~,~.. (20.0 mL) were added to a flame-dried, 100-mL, three-necked, round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet, .' and rubber septum.
The reaction mixture was cooled to -15-C with a dry ice/i~~~.~ r 1 bath. To the reaction mixture was added isobutylchloroformate (Aldrich Chemical Company) (0.537 mL, 0.565 g, 4.14 mmol, 1.0 eq~. After 5 min, a solution of 3-(4-(4-amino-butyl)-l-piperazinyl)-1,2-benzisothiazole (1.20 g, 4.14 mmol, 1.0 eq) (Example 13(b)) in anhydrous teLL~ r~- . (10.0 mL) was added dropwise. The reaction mixture was stirred at -15-C for h and then allowed to warm to room ~ . ~. After 18 h, the reaction mixture was , ' ~d to a . .~ funnel with the aid of dichl~.. ;' and washed with saturated K2C03. The organics were filtered, dried with MgS04, filtered and c~ d to give a yellow oil (1.70 g). The crude reaction mixture was purified by flash cl.-~ ~L~L~ with 9:1 ~hl. ' ~/methanol to give 0.74 g of the free base as a white foam. To a solution of the free base in ethyl acetate and ~-~hl. r~ was added 1.57 mL of lN ethereal HCl (1.0 eq).
The solvent was removed in vacuo, and the salt was recrystallized from ethanol/water to give 0.474 g (23~) of 4-acetamido-N-(4-(4-(1,2-b-~7i~oth1O~ 3-yl)-l-piperazinyl)butyl)-benzamide hydroch-loride as a pale cream solid. mp:>250 ~C. lH NMR (DMSO-d6):
1.59 (m, 2), 2.07 (s, 3), 3.25 (m, 6), 3.46 (br t, 2, J - 12.9), 3.59 (br d, 2, J - 11.4), 4.08 (br d, 2, J - 13.4), 7.48 (t, 1, 3 - 7.5), 7.60 (t, 1, J - 7.6), 7.66 (d, 2, J - 8.7), 7.82 (d, 2, J
- 8.6), 8.13 (t, 2, J - 8.3), 8.46 (br t, 1, J - 5.2), 10.23 (s, 1), 10.68 (br s, 1). 13C NMR (DMS0-d6): ~ 20.67, 24.09, 26.37, 38.34, 46.40, 50.49, 55.18, 118.01, 121.19, 124.00, 124.61, 126.95, 127.98, 128.12, 128.75, 141.84, 152.11, 162.20, 165.73, 168.66.
Anal. Calcd for C24H29N5O25.HCl: C, 59.06; H, 6.20; N, 14-35-Found: C, 58.99; H, 6.20; N, 14.43.
W O 93/16073 i ~ ~ PCT/GB93/00285 Fv~MPT.t 60 (a) PreDarAtinn of 4-((tert-butoxvcarbonYl) nn)ben-oic acid 4-' 'n~bDn~nic acid (Aldrich Chemical Company) (10.0 g, 72.9 mmol), 5~ Na2C03 (50.0 mL) and 1,4 dioxane (40.0 mL) was added to a 500-mL, round-bottomed flask equipped with a mat~,netic stir bar and addition funnel. The solution was cooled in an ice-water bath, and a solution of di-tert-butyl dicarbonate (Fluka) (23.8 g, 109 mmol, 1.5 eq) in 1,4 dioxane (40.0 mL) was added dropwise.
The ice-water bath was removed, and the reaction mixture was allowed to warm to room I , e and stir for 24h. The reaction mixture was cooled with an ice-water bath, and an additional portion of di-tert-butyl ~irArho-otD (1.0 eq) in 1,4 dioxane (20.0 mL) was added dropwise. The ice-water bath was removed, and the reaction mixture was allowed to stir at room t , e for two days. The solvent was removed in vacuo, and water (150.0 mL) was added to the resulting white solid. The pH
was adjusted to approximately 2 with lN ~Cl, and the organics were extracted with ethyl acetate, dried over MgS04, filtered, and : ' to give a white solid. The solid was triturated with hexanes and dried to give 14.80 g (86~) of the product as a white solid. lh NMR (CDC13): 6 1.50 (s, 9), 7.58 (d, 2, J
8.8), 7.86 (d, 2, J - 8.8), 9.76 (br s, 1), 12.67 (br s, 1).
(b) PrDnAration of N-(4-(4-(1.2-hDn~ienthiA7nl-3-vl)-l-DiDera z1nvl)butvl)-4-((tert-butoxvcarbonyl) nn) ben_amide hvdrnrhlnride This compound was prepared according to the method described in Fxample 59, by employing 4-((tert-~Lu~ b~ l)amino)ben~oic acid (2.05g, 8.65 mmol), triethylamine (1.45 mL, 1.05 g, 10.4 mmol, 1.2 eq), isobutylchlu.uLu (Aldrich Chemical Compsny) (1.12 mL, l.lB g, 8.65 mmol, 1.0 eq) and 3-(4-(4-aminobutyl)-1-pera_inyl)-1,2-bDn~i~othip7olD (2.51 g, 8.65 mmol, 1.0 eq) W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
(_xample 13tb)). The crude reaction mixture was purified by flash cl..l gLLyl,~ with ethyl acetate/0.1~ triethylamine as eluant to give 0.78 g of the free base as a white solid. Impure fractions were combined and purified by flash ~1... ~L~L~ with 9:1 dichluL. r' /methanol as eluant to give 0.40 g of the free base as a white solid. The free base obtained from each column was combined and dissolved in ethanol and chloroform. To a solution of the free base was added lN ethereal HCl (2.41 mL, 1.0 eq). The solvent was removed, and the hydrochloride salt was recrystallized from ethanol to give 0.644 g (14~) of N-(4-(4-b~ othio7~1-3-yl)-l-piperazinyl) butyl)-4-((tert-butoxycarbon-yl)amino)benzamide hydrochloride as a beige solid. mp: 205-208 ~C (~CC~ _ce_). lH NMR (DMS0-d6): 6 1.49 (s, 9), 1.60 (m, 2), 1.80 (m, 2), 3.10-3.54 (m, 8), 3.59 (m, 2), 4.08 (br d, 2, J
12.5), 7.55 (m, 4), 7.80 (d, 2, J - 8.8), 8.14 (m, 2), 8.45 (br t, 1, J - 5.4), 9.64 (s, 1), 10.80 (br s, 1). 13C NMR (DMS0-d6):
~ 20.64, 26.34, 28.01, 38.28, 46,36, 50.33, 55.12, 79.39, 117.00, 121.15, 123.96, 124.58, 126.92, 127.79, 127.96, 128.08, 142.11, 152.06, 152.54, 162.17, 165.70.
Anal. Calcd for C27H35N503S.HCl: C, 59.38; H, 6.64; N, 12.82.
Found: C, 59.43; H, 6.65; N, 12.92.
FY l-~PT .F. 61 (a) PreDaration of 3-~tert-butoxycarbo~yl~amino~benzoic acid This compound was prepared according to the method described in Example 60(a), by employing 3- 'n~b-~7oic acid (Aldrich Chemical Company) (5.0 g, 36.5 mmol), 5~ Na2C03 (25 mL) and di-tert-butyl ~ir-rho~Ate (Fluka) (19.9 g, 91.1 mmol, 2.5 eq). After 65 h, the reaction mixture was worked up to give 7.48 g (86~) of 3-((tert-b~u~ Lb~ l)amino)benzoic acid as a white solid. H
NMR (CDC13): ~ 1.49 (s, 9), 7.37 (t, 1, J - 7.9), 7.54 (dd, 1, J
~:A~l ~1 7~3~
W O 93/16073 PCr/GB93/00285 - 1.2, 6.5), 7.63 (dd, 1, J - 0.9, 7.9), 8.15 (s, 1), 9.56 (br s, 1), 12.92 (br s, 1).
(b) PreDaration of N-(4-(4-(1.2 _hPn7; ~nrhi 07~1- 3-vl)-1-DiDere-zinvl~butyll-3-((tert-butoxyr~rh~~vl) ~n~)benzemide h~drochloride hvdrate This compound was prepsred according to the method described in Example 59, by employing 3-((tert-b~u~ b~ l)emino)benzoic acid (2.45 g, 10.3 mmol), triethylamir.e (1.72 mL, 1.25 g, 12.4 mmol, 1.2 eq), isobutylchlu-~~ _ ~ (Aldrich Chemical Company) (1.34 mL, 1.41 g, 10.3 mmol, 1.0 eq) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-bPn~i~othio~~lP (3.0 g, 10.3 mmol, 1.0 eq) (Example 13(b)). After 20 h, the reaction mixture was ~.~.,.f~LL.d to a ~ _~ funnel with the aid of dichlorometh-ane. The organics were washed with saturated R2C03, dried over MgS04, filtered, and ~ ' to give the crude free bese.
The crude product was purified by flash cl.-. ~ O ,'~ with 95:5 dichlù.~ L' /methanol as eluant to give 2.B2 g of the free base as a white solid. To a solution of the free base ~1.0 gO, 1.96 mmol) in chloroform was added 1.96 mL of lX ethereal HCl (1.0 eq). The hydrochloride salt was recrystallized from ethanol/ether to give 0.46 g (23~) of N-(4-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)butyl)-3-((tert-butoxycarbonyl)amino)ben-zamide hydrochloride hydrate as a white solid. mp: 139-144-C
(efre.~_.ces). lH NMR (DMS0-d6): 6 1.48 (s, 9), 1.59 (m, 2), 1.80 (m, 2), 3.16-3.54 (m, 8), 3.59 (br d, 2, J - 11.8), 4.08 (br d, 2, J - 13.1), 7.32 (t, 1, J - 7.9), 7.48 (m, 3), 7.60 (ddd, 1, J
- 1.1, 6.9, 8.1), 8.00 (s, 1), 8.13 (t, 2, J - 8.1), 8.50 (br t, 1, J - 5.6), 9.49 (s, 1), lû.72 (br s, 1). C NMR (DMS0-d6):
20.84, 26.48, 29.29, 38.66, 46.62, 50.71, 55.41, 79.43, 117.68, 120.82, 121.04, 121.50, 124.31, 124.93, 127.27, 128.44, 128.72, 135.72, 139.92, 152.45, 153.12, 162.56, 166.82.
Anal- Calct for cz7H35N5o3s~Hcl 0-75 H20: C, 57.95; H, 6.75; N, 12.51; H20, 2.41 Found: C, 57.86; H, 6.74; N, 12.61; H20, 2.44.
FxAMP!F 62 (a) PrrnAration of 4-er~-ro-N-(4-(4-~1.2-hrn7i~nrh1~7nl 3 pinrrA~i~yl)butyl, :.~amide hvdrnrh1rride N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-((tert-b~LuA~hLb~ l)amiDo)benzamide (800 mg, 1.57 mmol), (Example 60(b)), anisole (Aldrich Chemical Compsny) (1.5 mL), anhydrous chloroform (15.0 mL) and trifl~ rir acid (EM Sr;rnrifir) (15.0 mL) were sdded to a 500-mL, round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was stirred for 0.5 h at room t , ~ e . The solvent was removed n vacuo to obtain an oil. The crude oil was dissolved in ethyl acetate, washed with saturated K2C03, dried over ~gS04, filtered, ~nd ~ d to give a yellow solid.
The crude amine was purified by flash cl..~ with ethyl acetate/0.2% triethylamine to give 0.37 g of the amine as an oil.
To a solution of the amine in ethyl acetate and dichloromethane was added 0.90 mL of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol/water to give 200 mg (29%) of 4-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydro-chloride as a tan solit. mp: 213.5-214.5 ~C. H NMR (DhS0-d6):
~ 1.56 (m, 2), 1.77 (m, 2), 3.27 (m, 6), 3.45 (br t, 2, J
12.5), 3.59 (br d, 2, J - 11.9), 4.08 (br d, 2, J - 13.2~, 5.61 ( br s, 2), 6.54 (d, 2, J - 8.6), 7.48 (ddd, 1, J - 1.1, 7.1, 8,1), 7.60 (m, 3), 8.12 (m, 3), 10.65 (br s, 1). 13C NMR (DMS0-d6):
20.65, 26.52, 38.11, 46.37 50.44, 55.15, 112.43, 121.16, 123.96, 124.58, 126.91, 128.08, 1 .62, 151.44, 152.06, 162.18, 166.20.
W O 93/16073 C A :2 ~ 3 4 PCT/GB93/0028S
Anal. Calcd for ~H~ OS.HCl: C, 59.25; H, 6.33; N, 15.70.
Found: C, 59.03; H, 6.32; N, 15.62.
EXA~PT F. 63 (a) PreDaration of 3-amino-N-(4-(4~ 2-benzisothi~7nl-3-vl)-l- ~
Di nvl)butyl~h~ ~- hydrochloride hvdrate This compound was prepared according to the method described in Example 62, by employing N-(4-(4-(1,2-benzisothiazol-3-yl)-1-pip-erazinyl)butyl)- 3-((tert-b~LvA~ l)amino)-benzamide (1.77 g, 3.47 mmol), (Example 61(b)), anisole (Aldrich Chemical Company) (3.0 mL), anhydrous chloroform (30.0 mL) and tr~fl ~ ''r acid (EH Sri~ntifi~) (30.0 mL). The crude amine was purified by flash cl.~ ~ v .E~ with ethyl acetate/0.1~
triethylamine followed by ethyl acetate/0.2~ triethylamine to gi~e 1.16 g of the free base as an orange oil. The hydrochloride salt was prepared and recrystallized from ethanol/ether to give 0.31g (20~) of 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide hydrochloride hydrate as a rust-orange solid. mp: 122-130 ~C (eife,~_sces). H NMR
(D~S0-d6): ~ 1.59 (m, 2), 1.80 (m, 2), 3.05-3.75 (m, 10), 4.08 (br d, 2, J - 13.0), 6.10 (br s, 2), 6.79 (d, 1, J - 7.4), 7.13 (m, 3), 7.48 (ddd, 1, J - 1.0, 6.9, 8.1), 7.60 (ddd, 1, J - 1.1, 6.9, 8.1), 8.13 (t, 2, J - 8.4), 8.38 (br t, 1, J - 5.5), 10.77 (br s, 1). C NHR (DhS0-d6): ~ 20.66, 26.35, 38.36, 46.40, 50.49, 55.20, 114.21, 115.93, 117.63, 121.21, 124.05, 124.64, 126.98, 128.14, 128.72, 135.61, 146.36, 152.13, 162.22, 166.77.
Anal. Calcd for C22H27N505.HClØ5 H20: C, 58.07; H, 6.42; N, 15.39; H20, 1.98. Found: C, 58.17; H, 6.41; N, 15.25; H20, 2.35.
EXA~pT.F. 64 (a) PL~_ : ~n of N-(4-(4-(l.2-bDn7;enthiD7Al-3-yl~-l-DiDera zinvl)butyl)-3-bromo-2.6-dimethoxvbenzamide hvdrochloride 3-Bromo-2,6-~ L i~ acid (1.48 g, 5.69 mmol) (obtained by b.~ ~rDtion of 2,6~ L ~,ic acid (Aldrich Chemical Company) by the method Doyle F.P.; et al J. Chem. Soc. 1963, 497.) and anhydrous toluene (50.0 mL) were adted to a flame-dried, 100-mL, three-necked, round-bottomed flask equipped with a magnetic stir bar, nitrogen inlet, addition funnel, and 1' . Thionyl chloride (1.12 mL, 1.83 g, 15.4 mmol, 2.7 eq) was added dropwise to the reaction mixture at room i . ' e. The addition funnel was replaced with a reflux condenser and the reaction mixture was heated to 65 ~C.
Dimethyl' '~- (0.03 mL) was added to the reaction mixture, and the i . e was 'ntDin-d at 65 ~C for 2 h. The solvent was reDoved in vacuo, and the residue was taken up in chloroform (20.0 mL). To this solution was added 3-(4-~4-aminobutyl)-l-pip-erazinyl)-1,2-b-n7ie~,thiD~~l- (1.5 g, 5.17 mmol, 0.9 eq) (Example 13(b)) in chloroform (12.0 mL) and triethylamine (1.08 mL, 0.785 g, 7.76 mmol, 1.4 eq). The reaction mixture was stirred at room ~ . ' e for 0.5 h. The solvent was removed in vacuo, and the orange oil was dissolved in ethyl acetate. The organics were washed with saturated R2C03, dried over MgS04, filtered and ~ -d to give an orange oil (3.24 g). The crude material was purified by flash ch.. e .~ ~ with ethyl acetate/0.1~
triethylamine followed by ethyl acetate/0.2% triethylamine to give 1.45 g of the free base as a yellow oil. To a solution of the free base in ethyl acetate was added 2.72 mL of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 0.867 g (27S) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)but-yl)-3-bromo-2,6-dimeLI,vA~L '~ hydrochloride as a white solid. mp: 220-221 ~C (dec). H NMR (DMS0-d6): ~ 1.56 (m, 2), CA2i 1 7434 1.83 (m, 2), 3.24 (m, 6), 3.54 (m, 4), 3.78 (s, 6), 4.08 (br d, 2, J - 13.4), 6.85 (d, 1, J - 9.0), 7.48 (t, 1, J - 7.5), 7.59 (d, 1, J - 8.9), 7.60 (rm, 1, J - 8.1), 8.13 (t, 2, J - 8.9), 8.38 ( br t, 1, J - 5.6), 10.92 (br s, 1). C NMR (DMS0-d6): C
20.36, 36.23, 38.01, 46.29, 50.39, 55.07, 56.12, 61.72, 106.87, 109.21, 121.16, 123.97, 124.01, 124.59, 126.92, 128.09, 132.97, 152.06, 153.45, 156.20, 162.17, 163.33.
Anal. Calcd for C24H29N4035Br.HCl: C, S0.58; H, 5.31; N, 9.83.
Found: C, 50.69; H, 5.32; N, 9.80, EXAMPT~ 65 (a) L'L~ _ l~n of 2- ~ ~~-N-(4-(4-(1.2-benzisothiP7~l-3-Yl) Di~ ,Yl)bur~yl~h~ ~I' hYdrochloride This compound was prepared according to the method described in Example 53, by employing 2-amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-l-piperazinyl)buryl) benzamide (1.3 8, 3.17 mmol) (Example 36), triethylamine (0.66 mL, 0.48 g, 4.78 mmol, 1.5 eq) and aceryl chloride (0.226 mL, 0.25 g, 3.17 mmol, 1.0 eq). She reaction mixture was stirred in an ice-water bath for 1 h and allowed to warm to rooD I ~ e. The reaction mixture was worked up after 18 h. The free base was purified by flash ch.~ - O ,'~ with ethyl acetate/0.1~ triethylamine as eluant to give l.09 g of the free base as an oil. To a solution of the free base (1.04 8, 2.30 mmol) in ethyl acetate was added 2.30 mL
of lN ethereal HCl (1.0 eq). The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 0.859 g (56~) of 2-acetamido-N-(4-(4-(1,2-~ 'e~rhiD7~l-3-yl)-l-piperazinyl)buryl)benzamide hydrochloride as a beige solid.
mp: 189.5-l90.5-C. H NMR (DMSO-d6): C 1.67 (m, 2), 1.84 (m, 2), 2.10 (s, 3), 3.10-3.75 (m, 10), 4.09 (br d, 2, J - 12.9), 7.16 (r~m~ 1, J - 7.7), 7.49 (t, 2, J - 7.8), 7.62 (t, 1, J
7.4), 7.78 (dm, 1, J - 7.8), 8.13 (d, 1, J - 7.6), 8.16 (d, 1, J
W O 93/16073 ~3~ 7 4 3 4 Pcr/Gw3/0028~
- 7.8), 8.36 (t, 1, J - 8.2), 8.84 (br t, 1, J - 5.2), 10.86 (br s, 1), 11.24 (br s, 1). C NMR (D~SO-d6): ~ 20.61, 24.78, 25.99, 38.40, 46.33, 50.41, 55.08, 120.46, 121.07, 121.16, 122.49, 123.96, 124.58, 126.92, 128.09, 131.68, 138.78, 152.06, 162.17, 168.08, 161.18.
Anal. Calcd for C24H29X5025.hCl: C, 59.06; h, 6-20; N, 14-35-Found: C, 59.13; H, 6.25; N, 14.41.
FY~Mpl F 66 (a) pr~n~rAtinn Of 2-(4-(4-(l~2-h~n7i~Athi~nl-3-yl)DiDeridi butvl)-(3H)-l-isoin~l~lin~~ hydr~rhlnride 3-(4-Piperidinyl)-1,2-benzisothiazole (1.25 g, 5.73 ~ mol), 2-(4-chlorobut )-l-1eoin~ (1.54 g, 6.88 mmol, 1.2 eq) (Example 3(a)), triethylamine (2.0 mL, 1.45 g, 14.33 mmol, 2.5 eq), and acetonitrile (25.0 mL) were added to a lCO-mL, round-bottomed flask equipped with a reflux condenser, magnetic stir bar, and nitrogen inlet. The reaction mixture was heated at reflux for 2 d. The solvent was removed in vacuo, and the crude reaction mixture was purified by flash ~I.L. r,Lo~L~ with ethyl acetate/0.1~ triethylamine followed by ethyl acetate/0.2~
trlethylamine as eluant to give 1.55 g of the free base. To a solution of the free base was added lN ethereal HCl (1.0 eq).
The solvent was removed in vacuo, and the hydrochloride salt was recrystallized from ethanol to give 1.15 g (45~) of 2-(4-(4-(1,2-~ ~othio7~1-3-yl)piperidino)butyl)-l-isoindolinone hydro-chloride as a pale beige solid. mp: 211-214 ~C (dec). lH NMR
(D~SO-d6): ~ 1.74 (m, 4), 2.22 (m, 4), 3.13 (m, 4), 3.59 (t, 4, J
- 6.1), 3.65 (m, 1), 4.52 (s, 2), 7.51 (m, 1), 7.54 (ddd, 1, J
1.1, 7.0, 8.1), 7.63 (m, 3), 7.70 (dt, 1, J - 7.4, 1.0), 8.21 (d, 1, J - 8.1), 8.28 (d, 1, J - 8.1), 10.25 (br s, 1). 13C NMR
(DhS0-d6): ~ 20.51, 25.04, 27.63, 35.50, 40.88, 49.36, 51.42, W O 93/16073 C A 2 1 1 7 4 3 4 P(~r/GBg3/0028~
55.61, 120.66, 122.64, 123.30, 123.49, 124.86, 127.73, 127.93, 131.16, 132.31, 133.27, 141.83, 151.89, 167.33, 167.49.
Ansl. Calcd for C24H27N305.HCl: C, 65.21: H, 6.38; N, 9.51.
Found: C, 65.31; H, 6.41; N, 9.51.
FY~Pl.~ 67 and 68 (8) preDaration of N-(4-~4-(l.2-benzisothip7~l-3-yl~-l-DiDerazinyl) butyl)-3-bromo-2-hvdroxv-6-meLI.vA~l ~dP hYdrochloride and N-(4-(4-(1.2-hP~7i~Athiazol-3-yl)-l-Dir~rp7inyl)butyl)-3-brom 6-hydroxv-2 ,' jL '~e h~drochloride N-(4-(4-(1,2-BP~7icothiP7~l-3-yl)-piperazinyl)butyl)-3-bromo-2,6-~ L '~ (4.99 g, 9.35 Dmol) ((Example 64(a) and anhydrous dichlu.~ ~ (75.0 mL) were added to a flame-dried, 250 mL, .~ ' bG~ ' flask equipped with a magnetic stir bar, nitrogen inlet, and pressure :, li7in~7, addition funnel. To this solution was added HCl (9.25 mL of a lN solution in ether, 9.25 mmol, 0.99 eq) followed by the dropwise addition of boron tril ~~' (Aldrich Chemical Company) (9.35 mL of a lN solution in Airhl~ , 9.35 mmol, 1.0 eq). The reaction mixture was allowed to stir at room ~ , e for 0.5 h. The reaction mixture was cooled with an ice water bath and lN ammonium hydroxide (50 mL) was added. The solids were dissolved with the aid of dichlv.. ' and water. The phases were separated and the aqueous phase was washed with dichlv.~ -' . The organics were combined, washed with water, dried over MgS04, filtered and ~ A to give 3.61 g of the crude product as a sticky yellow residue. The crude free base was purified by flash ~1", ~ with 97:3 dichlv-~ ' /methanol as eluant to give 2.06 g (Rf-0.10) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-pip-erazinyl)bu ql)-3-bromo-2-hydroxy-6 tLVA~L ~AP as an oil and 1.32 g of a mixture of isomers. This miture was purified by flash ~L~e v .'~ with ethyl acetate as eluant to give 0.18 g W O 93/16073 - ~ 52 1 1 7 4 3 4 PCT/GB93/00285 (Rf-0.34) of the minor isomer, N-~4-(4-(1,2-benziosothiazol-3-yl)-l-piperazinyl)butyl)-3-bromo-6-hydroxy-2 r' ~L ~-, as a tan solid. The hydrochloride salts of each isomer were prepared i ~ y by dissolving the free amine in ethyl acetate and treating them with HCl (1 equivalent of a lN solution in ether).
FYAMPT F. 67 The hydrochloride salt of the major isomer was recrystallized from ethanol/water to give 1.67 g (32%) of N-(4-(4-(1,2-benzisothiazol-3-yl)-l-P~r 'nly)butyl)-3-bromo-2-hydroxy 6 , ~ ~ hydro-chloride as a pale pink solid. mp: 191-192.5 C. H NMR (DMS0-d6): 6 1.54-1.90 (m, 4), 3.05-3.70 (m, 10), 3.94 (s, 3), 4.07 (br d, 2, J-12.8), 6.60 (d, 1, J-9.2), 7.47 (m, 1), 7.60 (m, 1), 7.66 (d, 1, J-9.0), 8.11 (d, 1, J-7.6), 8.14 (d, 1, J-7.9), 8.93 (t, 1, J-6.2), 10.75 (br s, 1), 14.87 (s, 1). 13C NHR (DMS0-d6): ~ 10.62, 25.95, 38.58, 46.35, 50.44, 55.04, 56.69, 102.30, 103.14, 104.76, 121.17, 123.99, 124.60, 126.95, 128.10, 136.07, 152.10, 158.08, 159.27, 162.21, 168.79.
Anal. Calcd for C23~27N4035Br.HCl: C, 49.69; H, 5-08; N, 10-08-Found: C, 49.79; H, 5.11; N, 9.98.
FYII"PT .F. 68 The hydrochloride salt of the minor isomer was filtered and dried under high vacuum in an abderholden apparatus to give 76 mg (2~) of N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl-3-bromo-6-hydro-xy-2 ~ ' ~L '~ hydrochloride as a white solid. mp: 185-187 C.
H NHR (DMS0-d6): ~ 1.60 (m, 2), 1.83 (m, 2), 3.10-3.70 (m, 10), 3.79 (s, 3), 4.09 (m, 2), 6.70 (d, 1, J-8.8), 7.49 (m, 2), 7.62 (t, 1, J-7,5), 8.15 (t, 2, J-7.8), 8.47 (br t, 1, J-5.2), 10.65 (br s, 1), 10.99 (s, 1). 13C NhR (DMS0-d6): ~ 20.50, 26.17, 38.14, 46.44, 50.55, W O 93/16073 C A 2 1 1 7 4 3 4 PCr/GB93ioo28s 55.27, 61.66, 104.70, 114.00, 119.20, 121.19, 124.04, 124.63, 126.99, 128.13, 133.81, 152.13, 154.34, 156.85, 162.24, 165.15.
Anal. Calcd for C23H27N4035Br.HCl: C, 49.69; H, 5-08; N, 10-08-Found: C, 49.73; H, 5.07; N, 10.00.
EXAMPJ.~ 69 ~a) Premaration of N-(4-~4-(6-fluoro-1.2-b~n~ic~vo7ol-3-vl)viDeri ~inn~butvl~oht~l imi ~i~ hvdrochloride 6-Fluoro-3-(4-piperidinyl)-1,2-b~n7~ 7~1P (1.64 g, 7.45 mmol), N-(4-bromobutyl)p~ mi~- (Altrich Chemical Company) (2.63 g, 9.31 mmol, 1.25 eq), triethylamine (1.56 mL, 1.13 g, 11.2 mmol, 1.5 eq) and acetonitrile (30 mL) were added to a 100 mL, .~ ' b : ' flask equipped with a magnetic stirring bar. The flask was equipped with a reflux condenser and nitrogen inlet and the re-ction mixture was heated at reflux for 15 h. The oil bath was removed and the reaction mixture was allowed to cool to room , . The reaction mixture was ; ~ ~d to a ~ funnel with the aid of ethyl acetate. The organics were washed with saturated ~2C03 and the two phases were r ' ~ The aqueous phase was extracted with ethyl acetate and the organics were combined. A white solid precipitated from the solution. The ~ was placed in a freezer for 1 hr and the solid was filtered. The filtrate was ~ d to give the crude product as an orange-mustard oil/solid mixture (4.19 g). The crute material was adsorbed onto silica gel and purified by flash cl..~ with dichl~-- t' :methanol (95:5) as eluant to give the free base as a yellow solit. The free base was dissolved in dichlu-- ' , filterd, and t ' to give an oil (1.9 g) which quickly solii~fiPd to a yellow solid. Ethereal HCl (4.5 mL of lN solution, 1.0 eq) was added to a solution of the free base in ethyl acetate and tichl~.. i' . The resulting hydrochloride salt was W O 93/16073 - li7 - 4 PCT/GB93/0028~
recrystallized from ethanol and water to give 1.39 g (41%) of the title conpound as a pale beige solid. mp: 227-229~C. lH NMR
(DMS0-d6~: ~ 1.68 (m, 2), 1.78 (~, 2), 2~27 (m, 4), 3.10 (m, 4), 3.47 (m, 1), 3.62 (m, 4), 7.34 (dt, 1, J-2.0, 8.9), 7.73 (dd, 1, J-9.1, 1.8), 7.88 (m, 4), 8.20 (m, 1), 10.55 (br s, 1). 13C N~R
(DMS0-d6): ~ 20.97, 25.71, 27.16, 31.52, 37.21, 51.60, 55.78, 97.67, 98.03, 112.90, 113.24, 117.00, 123.36, 124.15, 124.30, 131.99, 134.71, 160.43, 162.40, 163.45, 163.64, 165.69, 168.32.
Anal. Calcd for C24N24N303F.HCl: C, 62.95; N, 5.50; N, 9.18.
Found: C, 63.05: H, 5.52 N, 9.14 FYI~'~PT F. 70 (a) ~~~~ ~-~n of N-(4-(4-(l.2-h-Dn~ rhip7~l-3-yl)-l-rinerazinyl) butvl~-2.2.2-trif~
3-(4-(4-~ 1)-1-piperazinyl)-1,2 ~ ~~th~ole (Example 13(b)) (6.0 g, 20.7 mmol) and anhydrous dichlc.~ ' (50.0 mL) were added to a n ame-dried, 3-necked, 250 mL, round-bottomed flask equipped with a magnetic stir bar, ~ - , addition funnel, and nitrogen inlet. The solution was cooled in an ice w-ter bath and a solution of t-ifl ,- ~r anhydride (4.40 mL, 6.53 g, 31.1 mmol, 1.5 eq) in dichl~.- ' (20.0 mL) was added dropwise over a 0.5 h period. The reaction mixture w-s allowed to stir for 2 h. S-turated K2C03 (50 mL) was slowly added to the cold reaction mixutre. The reaction mixture was transferred to a funnel and the organics were extracted with ~1~hl. ~ . The organis were dried over MgS04, filtered, and ~ l d to give 6.87 g (86~) of the title compound as an orange oil. The crude material was used without further pur~first~n lN NhR (CDC13): ~ 1.71 (br s, 4), 2.51 (br t, 2, J-6,2), 2.71 (t, 4, J-4.8), 3.41 (m, 2), 3.59 (t, 4, J-4.9), 7.36 (t, 1, J-7.9), 7.49 (t, 1, J-7.9), 7.83 (d, 1, J-8.0), 7.90 (d, 1, J-7-9)-(b) ~ of N-(4-(4-(1.2-h~n7i~nthiD~~l-3-vl~vinor~7invl) butvl-N-m-thvl-2 2 2-trifl ~O
Sodium hydride (0.587 g, 19.6 mmol) as an 80~ nn in oil was added to a flame-dried, 3-necked, 250 mL, round-bottomed flask equipped with a rubber spetum, magnetic stir bar, addition funnel, and nitrogen inlet. The sodium hydride was washed three times with hexanes and anhydrous LeLL~.~: ~' (30.0 mL) was added. The , ~ n~ was cooled in an ice water bath and a solution of N-(4-(4-(1,2-benziosthiazol-3-yl)-1-piperazinyl)but-yl)-2,2,2-trifl ~ L '~' (6.87 g, 17.8 mmol) in anhydrous LeLLI.~.' .' (30.0 mL) was slowly added over a 35 min period.
The ice water bath was removed and a solution of methyl iodide (1.1 mL, 2.53 g, 17.8 mmol) in anhydrous ~e~d,~ L~ (20 mL) w-s added dropwise. The yellow-orange solution w s allowed to warm to room t , and to stir for 4 days. The excess NaH
wa- quenched with water (15 mL) and the L_ '~I.uf~.~,, was removed i~ vacuo, The residue was partitioned between water and dichlo.~ ' . The two phases were separated and the aqueous phas- was washed two - '' t~ ~ 1 times with dichl~ ' . The organics were combined, dried over MgS04, filtered, and L - ' to give the crude product as an orange oil. The crude free base was purified by flash G O .'~ with ethyl acetate as eluant to give 4.55 g (64~) of the title compound as a white solid. ~ NMR (CDC13): ~ 1.59 (m, 2), 1.71 (m, 2), 2.47 (t, 2, J-7.0), 2.68 (m, 4), 3.04 and 3.14 (2 singlets, 3, NCa3 tautomers), 3.45 (m, 2), 3.58 (m, 4), 7.36 (t, 1, J-7.2), 7.48 (t, 1, J-7.5), 7.82 (d, 1, J-7.7), 7.91 (d, 1, J-8.0).
(c) ~ lon of 3-(4-(4-(methvl~ 'nn)but,vl)-l-pin-r~invl)-1.2-' enthi o~nle N-(4-(4-(1,2-~- 'cot~;~701 -3-yl)-1-piperazinyl)butyl)-N-methyl--2,2,2-trifl _, I '~ (2.0 g, 5.0 mmol), ~ethanol (50 mL) and 20.0 mL of R2C03 (7~ aqueous solution) were added to a 250 mL, W O 93/16073 Ç L~ i 1 7 4 3 4 P(~r/GB93/0028~
round-bottoD-d flask equipped with a magnetic stir bar. The re-ction mixture was allowed to stir at room t . . for 6 h.
The methanol was removed i~ vacuo and the organics were extracted from the aqueous phase with dichlv,. ;' . The organics were dried over MgS04, filtered and - ' to give the crude product as a yellow oil that was used without further f~ rl-ti rn (d~ Pr~~~rAtir~ of 2- '~n-N-(4-(4-(1.2-~ e~thiazol-3-Y1 Di ~nVl~bUtYl~-N-methylh~ ~~lr hydrnrh1nride 3-(4-(4-(Hethylamino)butyl-l-pipera2inyl)-1,2-ben2isothia201e (1.4 g, 4.6 mmol), isatoic anhydride (Aldrich Chemical Co~pany) (0.750 g, 4.6 mmol, 1.0 eq), and ethanol (25.0 mL) were added to a 100 mL, round-bottomed flask equipped with a magnetic stir bar and nitrogen inlet. The reaction mixture was placed under a nitrogen ~ and was allowed to stir at room for 20 h and to stand for 6 h without stirring. The reaction mixture was e ~ ' i~ vacuo to give the crude product as a bL~ _ . ,, liquid. The free base was purified by flash ~1.,. O .'~ with ethyl acetate/0.1~ triethylamine as eluant to give 1.06 g of the free base. To a solution of the free base (1.06 g, 2.50 mmol) in ethyl acetate was added 2.5 mL of 1.0 N
ethereal HCl (1.0 eq). The solvent was removed in vacuo and the solid was recrystallized from ethanol and ehter to give 0.625 g (30~) of the title compound as a tan solid. mp: 188-189 C.
NhR (DHSO-d6): 6 1.61 (br s, 4), 2.93 (s, 3), 2.95-3.72 (m, 10), 4.07 (br d, 2, 3-12.0), 5.13 (br s, 2), 6.58 (td, 1, J-7.4, 1.1), 6.73 (dd, 1, J-0.8, 8.1), 7.02 (dd, 1, J-1.4, 7.7), 7.09 (ddd, 1, J-1.7, 7.3, 8.0), 7.48 (ddd, 1, J-l.0, 7.1, 7.9), 7.60 (ddd, 1, J-l.0, 6.9, 8.0), 8.13 (t, 2, J-8.2), 10.85 (br s, 1). 13C N~R
(DHS0-d6): ~ 20.36, 24.20, 46.34, 50.40, 55.13, 115.50, 120.26, 121.16, 123.97, 124.58, 126.92, 127.36, 128.09, 129.69, 145.35, 152.06, 162.18, 169.86.
CA~l 1 7434 Anal. Calcd for C23H29N505.HCl: C, 60.05; H, 6.57; N 15 22 Found: C, 59.98; H, 6.60; N, 15.13.
pYA~'P! F 71 (a) PronAr~t;r~ of 3-hydroxY-l~2-hon7ic~yr7~le This compound was prepared, according to the method of R. Frisry snd B.R. Sunday (J. HeterocYclic. Chem. 1979, 16, 1277), by employing sslicylh~ 'r acid (47.2 g, 0.308 mol) (Aldrich Chemical Company), l,l'-csrbonylt~1imi~7ole (100.0 g, 0.617 mol, 2.0 eq) (Aldrich Chemical Company), and anhydrous tet- '~d~f~,t...
(1750 mL). Upon work up, the crude product precipitsted ss a beige solid thst W85 recrystsllized from ethyl scetste to give 15.7 g of the title compound ss sn off-white solid. A second crop yielded sn e'--t1t 1 9.4 g for a total yield of 25.1 g (60~). 1H oMR (D~SO-d6): 6 7.34 (ddd, 1, J-1.6, 6.3, 8.0), 7.61 (m, 2), 7.78 (d, 1, J-7.7), 12.39 (br s, 1).
(b) P.. _:_rn of 3-nhlnro-l.2-hon71c~-a7~le 3-Hydroxy-1,2-bon~ olo (24.8 g, 0.184 mol) and dry triethyl-amine (25.6 mL, 18.6 g, 0.184 mol, 1.0 eq) were added to a flame-dried, 300 mL, .- ' b ' flask equipped with a msgnetic stir bar. The flssk was equipped with sn sddition funnel snd nitrogen inlet snd the solution was cooled with an ice water bath. P' r' ~~ oxychloride (37.8 mL, 6Z.1 g, 0.405 mol, 2.2 eq) was added dropwise to the reaction mixture. The ice water bath was removed and the flask was equipped with a reflux condenser. The resction mixture wss hested with sn oil bsth st 150 C overnight. The oil bsth W85 removed snd the dark brown-orange liquid was allowed to cool to room ~ , e. The reaction mixture was slowly poured into a stirred solution of ice snd wster (500 mL). After wsrming to room ~ the reaction mixture was tLc.. rtr_--.d to a ~ , ~ funnel with the ~id of dichl~L. -' (250 mL). The organics were separated and the ~queous phase w-s w shed with dichlG. ~' (250 mL). The organics were combined, dried over NgS04, filtered, and c~ ' to give 28.3 g (1000) of the crude product as a dark orange liquid. The crude msteri-l was used without further pur~firs~i~n lH NNR (DNSO-d6): ~ 7.56 (tm, 1, J-7.2?, 7.85 (m, 3).
(c~ Pr~~-~ation of 1-(l~2-b~"7i~Ays7nl-3-vl)DiDerA7i~p 3-Chloro-1,2-b~ nvsz~le (28.3 g, 0.184 mol), piperazine (95.1 g, 1.10 mol, 6.0 eq) and toluene (10.0 mL) were ~dded to a 500 mL
.~ ' b_ ' fl-sk. The flask w-s equipped with a reflux condenser ~nd nitrogen inlet, ~nd the mixture was heated with an o:l b-th .s~ 155 C for 18 h. The hot, dark organge reaction .xture w.,~ poured into ice water (600 mL). The organics were ~ _ d from the ' L _O ~queous mixture with dichl__. ' . The organics were dried with MgSO4, filtered, and c --~ r~d to give 22.8 g of the product as a dark orange liquld. Ethyl ~cet-te (6.0 mL) w s ~dded to the crude product and the solution was pl-ced in a refriger-tor. The dark organge solid that formed w s filtered, crlLshed with a spatula, washed with ethyl acet-te ~nd ether, ~nd air dried to give 10.1 g of the product ~s ~ must-rd colored solid. The crude m terial was used without further p~rifir9rinn lH NNR (DNSO-d6): ~ 2.91 (m, 4), 3.42 (m, 4), 7.31 (m, 1), 7.59 (d, 2, J-3.5), 7.99 (d, 1, J-8.0).
(d) r--- -~n of N-(4-(4-(l 2-b~n~i~~vs7Al-3-vl)-l-~iDerazin bUtyl)phthAl1m~ hvdrn~hlnride 1-(1,2~ 7Ol-3-yl~pir~rp7in~ (4 0 g, 19.7 mmol), ~-(4-bro-mobutyl)phr~ mi~ (Aldrich Chemical Company) (6.66 g, 23.6 mmol, 1.2 eq), triethylamine (4.12 mL, 2.99 g, 29.6 mmol, 1.5 eq), and acetonitrile (30 _L) were added to a round-bottomed fl-sk equipped with ~ magnetic stir b-r. The fl-sk was equipped wlth a reflux condenser and nitrogen inlet. The reaceion mixture was allowed to stir at reflux for 3 h. The oil bath was removed and the dark brown solution was allowed to cool to room ~ . e. The reaction mixture was t~ LeL-~d to a S r ' ~ funnel and partitioned between saturated K2C03 and ethyl acetate (200 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (100 mL). The organics were combined and a solid precipitated from solution.
The solid was dissolved with the aid of methanol and dichluL~ tl.~ . The organics were dried over MgS04, filtered, and c- ~ t- A to give the crude free base. The free base was purified by flash ~ with ethyl acetate as eluant to give the pure compound as a viscous yellow oil. The free base (5.89 g, 14.6 mmol) was dissolved in ethyl acetate and Ai~hl~ ' and 14.6 mL of lN ethereal HCl (1.0 eq) was added. The solvent was removed n vacuo and the resulting hydrochloride salt was recrystallized from ethanol/water to give 0.71 g (8.2~) of the title compound as an off-white solid. mp:
257-259~C(dec). lH NMR (DMSO-d6): ~ 1.71 (m, 4), 3.21 (m, 4), 3.55 (m, 6), 4.14 (br d, 2, J-13.2), 7.38 (m, 1), 7.65 (d, 2, J-3.7), 7.90 (m, 4), 8.06 (br d, 1, J-8.0), 10.62 (br s, 1). 13C
NMR (DMSO-d6): ~ 21.50, 26.24, 37.84, 45.61, 50.91, 56.00, 111.17, 116.05, 123.64, 123.94, 124.01, 131.30, 132.62, 135.36, 161.01, 164.27, 168.95.
Anal. Calcd for C23H24N403.HCl: C, 62.65; H, 5.71; N, 12.71.
Found: C, 62.51; H, 5.68; N, 12.65.
_XAMPLF 72 (a) PreDaration of 3-(4-~4-aminobutvl)-1-DinDrazinvl)-1.2-hDT17i ~AV97~1~
This compound was prepared, according to the procedure described in _xample 13(b), by employing N-(4-(4-(1,2-bDn7i~ 7~1-3-yl)-l-W O 93/16073 C A ~1l137-4 3 4 P~r/GB93/00285 piperazinyl)butyl)rhthsl;mi~ (Example 71(d)) (4.04 g, 9.99 mmol), hydrazine hydrate (0.87 g of a 55~ solution, 14.99 mmol, 1.5 eq), and methanol (30 mL). The reaction mixture was heated at reflux for 2.5 h. Upon cooling, the byproduct (phthalhydrazide) failed to precipitate. An additional portion of hydrazine (0.87 g, 1.5 eq) was added and the reaction mixture heated at reflux for an adtitional 1 h period. Upon work-up, 2.1 g (77~) of the crude product was obtained as an oil that So~ fiPd upon standing. H NMR (CDC13): ~ 1.55 (m, 4), 1.72 (m, 2), 2.44 (t, 2, J-7.1), 2.65 (t, 4, J-4.9), 2.75 (t, 2, J-6.5), 3.60 (t, 4,J-5.0), 7.22 (m, 1), 7.46 (m, 2), 7.70 (d, 1, J-8.0). This material was used without further purifirAtiAn (b) r A of 2-a~ino-N-(4-(4-(l.2-hD~7iQ~vs7Al 3-yl)-l pi-~-r97i-~,vl~butyl)h- ~*D hydrnrhlAride This compound was prepared, according to the procedure described in Example 36, by employing 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ Qovs7Ale (1.0 g, 3.65 mmol), isatoic anhydride (0.656 g, 4.02 mmol, 1.1 eq), and ethanol (10 mL). After 24 h the solvent was removed in vacuo, and the crude product was purified by flash Cl.L~ with 19:1 ethyl acetate/methanol as eluant to give 1.37 g of the free base as a viscous yellow oil. The hydrochloride salt was prepared, recrystallized from ethanol/water, and dried in a vacuum oven to give 1.08 g (60~) of the title compound as a pale tan solid. mp: 249-252~C. lH N~R
(DMSO-d6): 6 1.58 (m, 2), 1.79 (m, 2), 3.29 (m, 6), 3.56 (m, 4), 4.14 (m, 2), 6.45 (br s, 2), 6.53 (t, 1, J-7.6), 6.71 (d, 1, J-8.0), 7.15 (t, 1, J-7.7), 7.37 (m, 1), 7.52 (d, 1, J-7.2), 7.65 (d, 2, J-3.7), 8.06 (d, 1, J-8.2), 8.30 (br t, 1, J-5.4), 10.79 (br s, 1). 13C NMR (DMS0-d6): ~ 20.70, 26,34, 38.07, 44.75, 49.97, 55.23, 110.26, 114.58, 114.82, 115.13, 116.35, 122.73, 123.02, 128.10, 130.38, 131.61, 149.57, 160.11, 163.35, 168.95.
Anal. Calcd for C22H27N502.HCl: C, 61.46; H, 6.56; N, 16.29, Found: C, 61.57; H, 6.54; N, 16.34.
~XAMP7 F 73 (a) Pr~A~ration of Ethyl N-(2-~((4-(4-(1.2-hDn7~A~hiP~~1-3-vl)-l-Dir~rp7inyl~butyl) 'n~)rPrbonYl)Dhe~Yl)eA-' hYdrochloride 2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) benzamide (Example 36) (1.5 g, 3.66 mmol), triethylamine (0,638 mL, 0.463 g, 4.58 mmol, 1.25 eq) and anhydrous chlorofo D
(10 mL) were added to a flame-dried, 50-mL, round-bottomed flask.
The reaction mixture was placed under N2, cooled with an ice-water bath and a solution of ethyl chlv.ufv-~L~ (0.385 mL, 0.437 g, 4.03 mmol, 1.1 eq) (Aldrich Chemical Company) in anhydrous chlorofo D (10 mL) was added dropwise. After the addition of ethyl chi~.~ r was complete, the ice-water bath was removed and the reaction mixture was allowed to stir at room . e for 18 h. Additional portions of triethylamine (0.51 mL, 0.37 g, 3.66 mmol, 1.0 eq) and ethyl chlG.-' (0.35 mL, 0.4 g, 3.66 mmol, 1.0 eq) were added to the reaction mixtvre. The solution was allowed to stir at room i , ~ e for 4 d. The reaction mixture was ~L~.~fe--~d to a s ,- - ~
funnel, dichlu-~ L' was added, and the solution was washed with saturated NaHC03. The layers were separated and the aqueous phase was extracted with dichlv-~ r' . The organic layers were combined, dried over MgS04, filtered and c- --~ d to give 1.74 g of the crude product as an orange oil. The free base was purified by flash ,1.~ with ethyl acetate:hexanes (2:1)/0.1% triethylamine followed by ethyl acetate/0.1% triethylamine as eluant t~ give 0.49 g of the free base as an oil. HCl (0.96 mL of lN solution in ether, 1.0 eq) was added to a solution of the free base (0.46 g, 0.96 mmol) in dichlu.~ ' and ethyl acetate. The hydrochloride salt was filtered and dried in a vacuum oven to give 0.385 g (20%) of the W O 93/16073 C A 2 i ~ ~4~ 3 4 PCT/GB93/0028~
title compound as a white solid. mp: 195-195.5~C. lH NMR
(DMSO-d6): ~ 1.24 (t, 3, J - 7.2), 1.62 (m, 2), 1.83 (m, 2), 3.26 (m, 6), 3.47 (m, 2), 3.61 (m, 2), 4.07 (m, 2), 4.14 (q, 2, J
- 7.2), 7.10 (tm, 1, J - 7.7), 7.49 (m, 2), 7.60 (ddd, 1, J
1.1, 7.0, 8.1), 7.79 (dd, 1, J - 1.5, 7.9), 8.12 (tm, 2, J
8.4), 8.20 (dd, 1, J - 0.9, 8.3), 8.89 (br t, 1, J - 5.5), 10.85 (br s, 1), 10.97 (s, 1). 13C NMR (DMS0-d6): ~ 14.41, 20.68, 26.01, 38.47, 46.44, 50.53, 55.16, 60.61, 118.62, 119.59, 121.25, 121.70, 124.04, 124.67, 127.00, 128.18, 128.24, 132.18, 139.30, 152.16, 152.91, 162.24, 168.36.
Anal. Calcd for C25H31N503S.HCl: C, 57.96; H, 6.23; N, 13.52. Found:
C, 58.07; H, 6.28; N, 13.47.
EXAMPI F. 74 (a) PreDaration of N-(4-(4-(l.2-~n7i~~this7~l-3-yll-l-DiDera-7invl)butvl)-3-bromo-2. 6-dil.Yd,~ .~amide hydrochloride Thionyl chloride (1.46 mL, 2.4 g, 20 mmol, 3.8 eq), anhydrous N,N-dimethyl- '~' (0.05 mL), anhydrous toluene (15 mL) and 3-bromo-2,6-dihYd.~A~L ir acid (1.2 g, 5.15 mmol) (prepared by bL~ '~9ti~n of dil-ydL~A~L ic acid (Aldrich Chemical Company) with bromine according to the method of F. P. Doyle, et. al. (J.
Chem. Soc. 1963, 497-506)), were added to a flame-dried, 100-mL, round-bottomed flask. The solution was placed under nitrogen and heated at 60-85 C for 1 h. The solvent was removed in vacuo and anhydrous dichlo,- -' (15 mL) and triethylamine (1.08 mL, 0.782 g, 7.73 mmol) were added to the solid residue. To this . '~n was added a solution of 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-ben7i~othis7ole (1.5 g, 5.15 mmol) (Example 13(b)) in anhydrous ~irh1~ thane (15 mL) and the reaction mixture was allowed to stir at room i , ~ for 18 h. The reaction mixture was transferred to a separatory funnel, dichloromethane was added, and the solution was washed with saturated NaHC03.
The organic phase was separated and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over MgS04, filtered and c~ to give 2.94 g of the crude product as a tan-beige solid. The free base was purified by flash chromatography (2x) with dichlo.~ eh9n~
methanol (93:7) as eluant to give 0.703 g of the free base as a yellow solid. The free base ( 0.703 g, 1.39 mmol) was dissolved in dichloromethane and ethyl acetate and lN ethereal HCl (1.39 mL, 1.0 eq) was added. The hydrochloride salt was filtered, washed with ether, and dried in a vacuum oven to give 0.454 g (16~) of the title compound as an off-white solid. mp:
228-230 C (dec). lH NMR (DMS0-d6): 6 1.62 (m, 2), 1.77 (m, 2), 3.00-3.70 (m, 10), 4.05 (m, 2), 6.49 (d, 1, J - 8.8), 7.48 (tm, 1, J - 7.2), 7.48 (d, 1, J - 8.8), 7.60 (t, 1, J - 7.6), 8.13 (t, 2, J - 8.8), 9.09 (br s, 1), 10.50 (br s, 1), 11.85 (br s, 1), 14.81 (br s, 1). 13C NM~ (DMS0-d6): ~ 20.71, 26.05, 38.32, 46.47, 50.58, 55.16, 99.68, 103.61, 107.57, 121.25, 124.05, 124.68, 127.00, 128.18, 135.99, 152.15, 157.05, 159.25, 162.26, 169.57.
Anal. Calcd for C22H25BrN403S.HCl: C, 48.76; H, 4.84; N, 10.34.
Found: C, 48.67; H, 4.86; N, 10.25.
FXAMPT.~ 75 (a) PL~ , nn of 6-Fluoroisatoic anhvdride 2-Amino-6-flvv..l lc acid (3.0 g, 19.3 mmol) (Maybridge Chemical Company), trichloromethyl chloroformate (15.0 g, 75.8 mmol, 3.9 eq) (Johnson-Matthey Chemical Company) and anhydrous 1,4-dioxane (60 mL) were added to a 250-mL, round-bottomed flask equipped with a magnetic stirring bar. The solution was placed under nitrogen and heated at reflux for 6 h.
The reaction mixture was allowed to cool to room temperature and rv.... .l~m ~ to give 3.8 g of the crude product as an off-white W O 93/16073 - 147 - PCT/GB93/0028~
solid. This material was used without further purification. H
NMR ~DMSO-d6): 6 6.97 (d, 1, J - 8.2), 7.06 (dd, 1, J - 8.4, 10.7), 7.73 (m, 1), 11.90 (br s, 1).
(b) PreDaration of 2-Amir~-N-(4-(4-(l.2-benzisothiazol-3-yl) pi~ers~i~yl)butYl)-6-fluor~h~n7 'de h~ydrochloride 6-Fluoroisatoic anhydride (1.5 g, 8.28 mmol) and anhydrous teL,~.~d,uf~,~.. (40 mL) were added to a flame-dried 300-mL
round-bottomed flask. The reaction mixture was placed under N2 and a solution of 3-(4-(4-aminobutyl)-1-pi~~ nyl)-1,2-benzi-sothiazole (Example 13(b)) (2.4 g, 8.28 mmol, 1.0 eq) in anhydrous L~L~ d.~f~,~., (25 mL) was added. The reaction mixture was allowed to stir overnight at room l , aL~. The reaction mixture was ~. ' and the crude free base was purified by column _h.~ with dichloromethane:methanol (19:1) as eluant to give 2.79 g of the free base as a yellow oil.
The free base was dissolved in ethyl acetate and lN ethereal HCl (6.53 mL, 1.0 eq) was added. The 1.~. ' lori~ salt was recrystallized from ethanol/~ater to give 2.0 g (52~) of the title compound as a beige solid. mp: 218-220~C. 1H NMR
(DMSO-d6): ~ 1.57 (m, 2), 1.80 (m, 2), 3.10-3.75 (m, 10), 4.10 (br d, 2, J - 13.1), 5.89 (br s, 2), 6.34 (dd, 1, J - 8.0, 10.5), 6.53 (d, 1, J - 8.2), 7.09 (ddd, 1, J - 6.8, 8.0, 8.2), 7.49 (t, 1, J - 7.6), 7.62 (t, 1, J - 7.5), 8.15 (t, 2, J - 7.2), 8.28 (m, 1), 10.55 (br s, 1). 1 C NMR (DMS0-d6): ~ 20.75, 26.38, 38.39, 46.57, 50.66, 55.38, 101.81, 102.27, 107.65, 108.01, 111.63, 111.68, 121.49, 124.32, 124.93, 127.29, 128.44, 131.20, 131.42, 149.90, 150.03, 152.46, 158.21, 162.58, 163.05, 164.66.
Anal. Calcd for C22H26FN50S.HCl: C, 56.95; H, 5.86; N, 15.09.
Found: C, 57.06; H, 5.95; N, 14.94.
~ ~.2i 1 7434 FXAMP~F 76 (a) PreDaration of 3-fluoroisatoic anhydride and 6-fluoroisatoic ~nhvdride Anhydrous chloroform (50 mL), 3-fl~ ,' '-lir anhydride (10.0 g, 60.2 mmol~ (Fluorochem Limited), and azidotrimethylsilane (8.0 mL, 60.2 mmol, 1.0 eq) (Aldrich Chemical Company) were placed under N2 in a 250-mL, flame-dried, round-botcomed flask.
The reaction mixture was gently heated with a heat gun until evolution of gas was noted and heated at reflux for 3.5 h. The solution was allowed to cool to room ~ , e and 95~ ethanol (10 mL) was added. The milky solution was cooled with an ice/water bath and the resulting precipitate was filtered and dried in a vacuum oven to give 7.78 g (71~) of the title compounds as an off-white solid. T g rn of the lH NMR
indicated a 60:40 mixture of the 3-fluoro- and 6-fluoro-isomers, ~ ly. 3-Fluoroisatoic anhydride: lH NMR (DMSO-d6~
300 MHz): 6 7.24 (dt, 1, J-4.7, 8.1), 7.68 (ddd, 1, J-1.3, 8.2, 10.7), 7.76 (dt, 1, J-7.9, 0.9). lH NMR signals observed for 6-fluoroisatoic anhydride were identical to those observed in _xample 75(a). This mixture was used without further purification.
(b) PreDaration of 2-~minr-N-(4-(4-(l.2-hDn7i~~thiazol-3-vl) Di ~yl~but~l)-3-fl ~,.I.. ~~D hydrochloride T~L-~l-uru-~ (50 mL), 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (2.55 g, 8.80 mmol) and a 60:40 mixture of 3-fluoro- and 6-fluoroisatoic anhydride (1.59 g, 8.80 mmol, 1.0 eq) were placed in a 100-mL, round-bottomed flask. The reaction mixture was allowed to stir at room t , ~ for 10 min, and the solvent was removed with a rotary ~VD,UuLD-UL.
The resulting viscous oil was purified by flash ~IIL~ g ~
(4x) on silica gel with ethyl acetate:hexanes (2:1) and ethyl acetate (100~) as eluant to give 0.88 g of the title compound as its free base. This material was dissolved in ethyl acetate and HCl (1.89 mL of a lX solution in ether, 1.0 eq) was added. The hytrochloride salt was recrystallized twice from ethanol to give 0.36 g (lS~ based on 3-fluoroisatoic anhydride) of the title compound as tan crystals. mp: 175-176 C. H NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.80 (m, 2), 3.18-3.66 (m, 10), 4.09 (br d, 2, J - 13.3), 4.30 (br s, 2), 6.56 (dtt, 1, J - 5.1, 8.0, 8.0), 7.14 (dd, 1, J - 1.4, 8.0), 7.20 (dd, 1, J - 1.2, 8.0), 7.41 (d, 1, J - 8.0), 7.49 (tm, 1, J - 7.7), 7.62 (tm, 1, J
7.4), 8.14 (t, 2, J - 6.9), 8.48 (br t, 1, J - 5.6), 10.72 (br s, 1). C NMR (DMS0-d6, 75.43 MHz): ~ 20.68, 26.26, 38.17, 46.41, 50.49, 55.18, 113.99, 114.09, 116.63, 116.87, 117.32, 117.38, 121.24, 123.72, 123.75, 124.05, 124.67, 127.00, 128.17; 137.77, 137.95, 149.63, 152.16, 152.78, 162.27, 168.00, 168.04.
Anal. Calcd for C22H26FNOS.HCl: C, 56.95; H, 5.87; N, 15.09.
Found: C, 56.93 H, 5.95; N, 15.03.
_xAMpT F 77 (a) P-~_ :'on of 2-(~tert-bv~ l)amino)hon7ric acid 2 A ' ~ iC acid (25 g, 0.182 mol) and 1,4 dioxane (100 mL) were atted to a 2-L ~. ' ~ . ' flask snd the mixture was cooled in an ice bath. To the mixture was added 5~ aqueous Na2C03 (125 mL) followed by the slow addition of a solution of ti-tert-butyl ~ir~r~ t~ (99.5 g, 0.456 mol, 2.5 eq) (Aldrich Chemical Company) in 1,4 dioxane (120 mL). ~hen the atdition was complete, the ice bath was removed and the reaction mixture was allowed stir at room t, .~LVLC for 67 h. The reaction mixture was c~ t~d to give a viscous orange-brown solution. The solution was diluted with water (140 mL) and cooled in an ice bath. The pH of the solution was adjusted to pH - 2 by the addition of lN HCl. The reaction mixture was transferred to a CA 2 i 1 7434 ~ ~ funnel and the product was extracted with ethyl acetate, The organic phase was separated, washed with water, dried over MgS04, filtered and cu..~..LLaLud to give an off-white solid. The solid was triturated with hexanes, filtered and dried to give 38.16 g (88~) of the title compound. H NMR (CDC13): ~
1.55 (s, 9), 7.05 (tm, 1, J - 7.7), 7.58 (tm, 1, J - 7.9), 8.11 (dd, 1, J - 1.6, 8.0), 8.48 (d, 1, J - 8.6), 10.03 (s, 1), 10.84 (br s, 1).
(b) Preparation of 2-((tert-butox~carbonyl~amino)-N-(4-hvdroxy-butyl)benzamide 2-((tert-LuLuA~.bv..~l)amino)benzoic acid (37.94 g, 0.160 mol), anhydrous triethylamine (26.8 mL, 19.46 g, 0.192 mol, 1.2 eq) and anhydrous ~L '~dLufuL~.. (125 mL) were combined in a flame-dried, l-L, three-necked, round-bottomed flask equipped with a magnetic stirring bar, ;' t~r, addition funnel, and nitrogen inlet. The orange solution was cooled to -25 C with an acetone/dry ice bath and isobutylrh1~roft (20.8 mL, 21.90 g, 0.160 mol, 1.0 eq) (Aldrich Chemical Company) was added dropwise.
The - , - ~ was intnin~d between -15 and -30~C during the addition of isobutylchlu.~f . After the ~ddition of the isobutylchluLuf~ was complete, the resulting thick s ~ on was swirled for 5 min. A solution of 4-amino-1-buta-nol (14.8 mL, 14.3 g, 0.161 mol, 1.0 eq) (Aldrich Chemical Company) in anhydrous te~,~L~d-uruLn-- (50 mL) was added slowly and the reaction mixture was allowed to stir at -15 and -30~C for 50 min. The cooling bath was removed and the solution was allowed to stir at room i . ~ for 18 h. The reaction mixture was , r ~d to a . ~ ~ funnel, ethyl acetate was added, and the organic phase was washed with saturated NaHC03.
The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined, dried over MgS04, filtered and cu...~..LL~L~d to give 62.1 g of the crude product as an orange liquid. The crude product was W O 93/16073 C A 2; 1 7 4 3 4 PCT/GB93/00285 purified by flash .1..~ with ethyl acetate as eluant to give 41.34 g ~844) of the title compound as a pale-yellow oil.
H NMR (CDC13): o 1.52 (s, 9), 1.72 (m, 4), 3.48 (q, 2, J - 6.2), 3.75 (m, 2), 6.59 (br s, 1), 6.97 (tm, 1, J - 7.5), 7.42 (m, 2), 8.36 (dd, 1, J - 0.9, 8.9), 10.22 (br s, 1).
(c) Pr~~ ri~ of 2-((tert-L~ .L .1) -~)-N-(4-((methyl-5..1 f~~Yl)oxy)butyl)h' - "~
2-((tert-Butoxycarbonyl)amino)-N-(4-hJdLu~L yl)benzamide ~14.0 g, 45.3 mmol) and anhydrous pyridine (100 mL) were added to a flaDe-dried, 500-mL, round-bottomed flask and placed under N2.
The reaction mixture w s cooled with an ice-water bath and lr ~1 chloride (7.0 mL, 10.38 g, 90.6 mmol, 2.0 eq) (Aldrich Chemical Company) was added dropwise. The ice-water bath was removed and the reaction mixture was allowed to stir at room ; , ~ for 2 h. The reaction mixture was : d to give an orange oil. The oil was ~ ' ~d to a .- y funnel with the aid of ethyl acetate and r~tl.r~t~d NaHC03. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over MgS04, filtered and - ~ to give 18.19 g of the crude product as an orange oil. The mesylate was purified by column ~1..- ~ ,h~ with ethyl acetate:hexanes (1:1) as eluant to giYe 11.46 g (654) of the title compound as a pale-orange oil. lH NMR (CDC13): ~ 1.52 (s, 9), 1.81 (m, 4), 3.03 (s, 3), 3.49 (q, 2, J - 6.3), 4.30 (t, 2, J - 6.0), 6.27 (br s, 1), 6.99 (tm, 1, J - 8.2), 7.42 (d, 1, J - 7.9), 7.44 (m, 1), 8.36 (dm, 1, J - 8.4), 10.13 (br s, 1).
(d) PrenAr~ of 3-(~ razinyl)-l~2-benzisothi~7~le 3-Chlu.~L '~othi~ole l,l-dioxide (16.93 g, 84 mDol)(Eur. Pat.
Appl. 0196096), piperazine (43.5 g, 0.505 Dol, 6.0 eq)(Aldrich C~ 2 i i 743~
Chemical Company) and toluene (9 mL) were atded to a 500-mL, round-bottomed flask. The reaction mixture was placed under N2 and he-ted at 160-170~C for 22 h. The reaction mixture sol1dif1PA upon cooling to room i . ~. The crude product was partitioned between chloroform and water. The organic layer was . \ d, washed with water (3 x 400 mL), dried over MgSO4, filtered and - : ~ to give 7.24 g (34 ~) of the title compound as a tan solid. lH NMR (CDC13): 6 1.74 (br s , 1), 3.08 (t, 4, J - 5.1), 4.03 ( t, 4, J - 5.0), 7.68 (m, 2), 7.84 (dd, 1, J - 1.2, 6.9), 7.97 (dd, 1, J - 1.8, 6.9). This material was used without further purification.
(e) PL~ 'on of N-(4-(4-(1.2-benzisothio~~l-3-yl)-l-DiDera 7invl)butyl)-2-((tert-butoxycarbonyl)amino)hDn7 ~AP
S .S_Ai~n~iAp 3-(1-Piperazinyl)-1,2-' ~~ot~io~olP l,l-dioxide (3.2 g, 12.7 mmol), 2-((tert-L ~l)amino)-N-(4-((methylsulfonyl)oxy)-butyl)benzamide, (5.0 g, 12.9 mmol, 1.02 eq), triethylamine (2.2 mL, 1.60 g, 1.58 mmol, 1.25 eq) and anhydrous acetonitrile (75 mL) were added to a flame-dried, 500-mL, round-bottomed flask, and placed under N2. The reaction mixture was heated at reflux for 22 h. The orange solution was , ' ~d to a , ~ ~ funnel ethyl acetate was added and the solution was washed with saturated NaHC03. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, dried over MgS04, filtered and ~ d to give 6.09 g of a yellow-beige glass. The crude material was purified by flash ~ with ethyl acetate:methanol (19:1) to give 4.58 g (62~) of the title compound as a pale beige glass. lH NMR (CDC13): 6 1.52 (s, 9), 1.64 (m, 4), 2.47 (br t, 2, J - 6.5), 2.63 (br t, 4, J - 5.0), 3.48 (br q, 2, J - 6.2), 4.03 (br t, 4, J - 4.9), 6.50 (br s, 1), 6.98 (t, 1, J - 7.6), 7.41 (d, 1, J - 7.7), 7.43 (m, 1), 7.69 (m, CA 2 i i 7434 2), 7.81 (d, 1, J - 7.7), 7.96 (d, 1, J - 7.2), 8.36 (d, 1, J
8.6), 10.14 (br s, 1).
-(f) pr~nAr~rinn of 2~ N-(4-(4-(l~2-hon~;~rth1p7~l~3-yl) pir~rP7inVl~bUtyl)~ S S-~ . hvdrnrhlnride Trifluoro-cetic acid ~(40 mL) (Aldrich Chemical Company), chloroform (100 mL), anhydrous anisole (8 mL) (Aldrich Chemical Company) and N-(4-(4-(1,2-~ ~oth~P7rl-3-yl)-l-piperazinyl)but yl)-2-((tert-butoxycarbonyl)amino)benzamide S,S-dioxide (4.58 g, 7.98 mmol) were combined in a 500-mL, round-bottomed flask snd stirred at room r , - e for 0.5 h. The reaction mixture was c~ .d and the resulting orange liquid was dissolved in dichl~ ' and vashed with saturated NaHC03 The organic layer was separated and the aqueous phase was extracted twice with dichlvL- ,' . The organic layers were combined, dried over MgS04, filtered and c~ r~d to give the crude product as an orange liquid. This material was purified by column chi~ with ethyl acetate:methanol (97:3) followed by ethyl acetate:methanol (96:4) as eluant to give 3.06 g of the free base. The free base (1.95 g, 4.42 mmol) was dissolved in dichl~. ' and lN ethereal HCl (4.64 mL, 1.05 eq) was added.
The hydrochloride salt was recrystallized twice from ethanol/water to give 0.83 g (34~) of the title compound as a - pale-beige solid- mp: 259-26loc (dec), lH NNR (DMS0 d6) 1.58 (m, 2), 1.78 (m, 2), 3.00-3.80 (m, 8), 3.95 (br s, 2), 4.68 (br s, 2), 6.54 (t, 1, J - 7.4), 6.71 (d, 1, J - 8.1), 7.15 (tm, 1, J - 7.6), 7.51 (dm, 1, J - 7.4), 7.87 (m, 2), 8.09 (m, 1), 8.30 (m, 2). C NNR (DNSO-d6): ~ 20.87, 26.48, 38.22, 44.64, 50,07, 55.31, 114.94, 115.19, 116.66, 122.34, 127.14, 127.30, 128.39, 131.88, 133.55, 133.77, 144.16, 149.75, 160.56, 169.25.
IR (RBr): 1297, 1163 cm . Ion Spray MS m/z (relative intensity): 442(NH ,100).
CA 2 i i 7434 Anal. Calcd for C22H27N5035.HCl: C, 55.33; H, 5.91; N, 14.67.
Found: C, 55.08; H, 6.00; N, 14.58.
EXA~J.~ 78 (a) FL~ 'on of 1.4-dihYdro-2H-3.1-benzothiazine-2.4-dithione Isatoic anhydride (3.0 g, 18.39 mmol) (Aldrich Chemical Company), ~ psnts~lfi*s (18.0 g, 40.49 mmol, 2.2 eq) (Aldrich Chemical Company) and xylenes (100 mL) were combined in a flame-dried, 500-mL, round-bottomed flask and placed under N2.
The reaction mixture was heated at reflux for 19 h, allowed to cool to room t . e, and filtered. The filtered solids were washed with tei '~d,~f~L~-, and the combined filtrates were r... _ .1 ~ ~t- d to give the crude product as a red-brown solid. The material was purified by flash LI.L~ with hexanes:ethyl acetate (3:1) as eluant to give 2.44 g (63~) of the desired product as a purple solid. lH NMR (D~S0-d6): 6 7.43 (t, 1, J
7.4), 7.56 (d, 1, J - 8.2), 7.90 (t, 1, J - 7.7), 8.33 (d, 1, J -8.2).
(b) FL~ lnn of 2- n~ N (4-(4 (l.2-hsn7i~~this~~l-3 D~ yl)butyl)th1r~ *9 hvdznrhlnride Anhydrous Lel '~dL~' (40 mL) and 1,4-dihydro-2H-3,1-benzo-thiazine-2,4-dithione (2.9 g, 13.7 mmol) were combined in a l-L, round-bottomed flask and placed under N2. A solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (4.2 g, 14.4 mmol, 1.05 eq) (Example 13(b)) in anhydrous tetrahydrofuran (35 mL) was slowly added. The reaction mixture was allowed to stir at room t . e for 0.5 h. An additional portion of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzisothiazole (1.0 g, 3.45 mmol, 0.25 eq) (Example 13(b)) in anhydrous tetrahydrofuran (10 mL) was added and the reaction mixture was allowed to stir for 0.25 h. The , ~~ was filtered and the filtrate was ~ l . A to give 7.6 g of a red-orange oily residue. This residue was combined with an additional 0.65 g of crude material obtained from a previous ~ . ' . The coDbined material was partially purified by flash ~ .h~ (2x) with dichlo.~ methanol (97:3) as eluant. Further p~.-1fl~eti~
on a Harrison Research ~ . with a gradient eluant:
dichlu-~ th~ 00~), dichlu.~ ~' : methanol (99:1) and dichlo~- ,' :methanol (97:3), gave 0.718 g of the free base as a yellow oil. The free base (0.718 g, 1.69 mmol) was dissolved in ethyl acetate and lN ethereal HCl (1.69 mL, 1.0 eq) was added.
The solids were filtered, washed with ethyl acetate and ether, and recrystallized from ethanol to give 0.229 g (2.7~) of the title compound as a yellow solid. mp: 198-201~C. lH NMR
(DMS0-d6): 6 1.78 (m, 4), 3.05-3.80 (m, 10), 4.10 (br d, 2, J
12.7), 5.74 (br s, 2), 6.59 (t, 1, J - 7.5), 6.74 (d, 1, J
8.0), 7.08 (D, 2), 7.50 (t, 1, J - 7.7), 7.63 (t, 1, J - 7.6), 8.15 (t, 2, J - 7.2), 10.30 (D, 1), 10.83 (m, 1). 1 C NMR
(DNS0-d6): ~ 21.74, 25.35, 45.37, 47.32, 51.43, 56.10, 118.56, 118.78, 122.18, 124.98, 125.59, 127.93, 128.49, 129.11, 129.37, 130.98, 143.37, 153.08, 163.20, 197.17. CIMS m/z (relative intensity): 426 (MH+, lOO).
Anal. Calcd for C22H27N552.HCl: C, 57.19; H, 6.11; N, 15.16.
Found: C, 56.95; H, 6.17; N, 14.98.
FY~MPT F. 79 (a) F-~ - 'on of N-(4-~4-~1.2-h~n~;~~thiP7~l-3-yl)-l-Di~era 7~ yl)but~yl)-2-~(tert-butoxy~-~rbonyl~aDino~h~ S ~
3-(1-Piperazinyl)-1,2-benzisothiazole l-oxide (1.48 g, 6.29 mmol) (J, M~ Chem., 1991, 34, 3316), 2-((tert-b~ h.b~ l)aDino)-N-(4-(methylsulfonyl)ox-)butyl)benzsmide (2.52 g, 6.52 mmol, 1.04 eq) (Example 77(c)), triethylamine (1.05 mL, 0.762 g, 7.53 mmol, 1.2 eq) and acetonitrile (50 mL) were added to a W O 93/16073 - 1s6i 1 74 34 PCT/GB93/00285 250-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 24 h. The orange _ , i~n was , ~ _d to a ~ r y funnel, ethyl acetate was added and the solution was washed with saturated NaHC03. The layers were separated and the aqueous phase was ~~trD-ted twice with ethyl acetate. The organic layers were combined, washed with saturated NaCl, ~ , dried over MgS04, filtered and c-~ d to give 3.08 g of an orange-yellow residue. The crude product was purified by flash ~1.,. O ,'~ with dichluL- rhsn~:methanol (97:3) followed by dichloromethane:methanol (95:5) as eluant to give 1.9 g (57~) of the title compound as a beige glass. lH NMR
(CDC13): 6 1.51 (s, 9), 1.69 (m, 4), 2.46 (t, 2, J - 6.B), 2.61 (t, 4, J - 5.0), 3.47 (q, 2, J - 6.2), 4.00 (m, 4), 6.56 (br s, 1), 6.97 (ddd, 1, J - 1.1, 7.3, 7.8), 7.41 (d, 1, J - 7.6), 7.42 (m, 1), 7.60 (m, 2), 7.83 (dm, 1, J - 6.3), 7.99 (dm, 1, J
6.1), 8.36 (d, 1, J - 8.0), 10.11 (br s, 1).
(b) Pr~-r~ti~n of 2-~ n~-N-(4-(4-(1.2-h~n7i~~this~1-3-~l)-1-pi- ~nvl)butvl)l ~~ S-oxide hydrochloride hvdrate N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-~(tert-butoxycarbonyl)amino)benzamide S-oxide (1.9 g. 3.6 mmol), anhydrous anisole (5.0 mL) (Aldrich Chemical Company), dichlu,. tl.~"~ (68 mL) and trifl . tic acid (17.0 mL) were added to a 300-mL, 1~ ' bv; ' flask. The flask was equipped with a magnetic stirring bar and nitrogen inlet and the solution was allowed to stir at room i . - ~ for 0.5 h. The reaction mixture was s ~ ' and the crude product was dissolved in dichlu,. - . Saturated NaHC03 was added and the mixture was LL~.~f~,,.d to a - , ~ funnel. The layers were separated and the aqueous phase was extracted twice with dichlu~ rhg~g The organic layers were combined, dried over MgS04, filtered and ;d. The crude product was partially purified by flash CLL. ~ with dichlu,- ~ :methanol (97:3) and dichlu,~ :methanol (95:5) as eluant to give 2.41 g of an W 0 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/0028~
orange-brown oil. This material was purified further by flash ~LL~ with a gratient eluant of dichloromethane:methanol (98-95~ dichlo,. ' to 2-5~ Dethanol) to give 0.57 g of the free base as a white glass. The free base was dissolved in dichl~-~ Lho~c and lN ethereal HCl (1.34 mL, 1.0 eq) was added.
The hydrochloride salt was filtered and dried to give 0.47 g (27~) of the title compound as a hygroscopic off-white solid.
mp: 208-213 C (dec). lH NhR (DMSO-d6): 6 1.58 ( m, 2), 1.79 (m, 2), 3.17 (m, 2)" 3.28 (m, 2), 3.45 (m, 2), 3.58 (br s, 2), 3.73 (br s, 2), 4.67 (br s, 2), 6.54 (t, 1, J - 7.5), 6.71 (d, 1, J
8.1), 7.15 (ddd, 1, J - 1.5, 7.1, 8.4), 7.51 (d, 1, J - 8.1), 7.75 (m, 2), 8.09 (m, 1), 8.22 (m, 1), 8.32 (br t, 1, J - 5.3), 11.25 (br s, 1). 13C NMR (DMSO-d6): 6 20.65, 26.28, 38.10, 44.31, 50.17, 55.15, 116.45, 116.54, 117.52, 125.45, 126.57, 128.23, 129.84, 131.69, 131.93, 147.10, 156.75, 164.53, 168.56.
IR (RBr): 1069 cm 1, Ion Spray MS m/z (relative intensity):
426 (MH ,100).
Anal. Calcd for C22H27N5025.HCl.H20: C, SS.OS; H, 6.30; N, 14.59; H20, 3.75.
Found: C, 55.28; H, 6.21; N, 14.58; H20, 4.07.
FY~MPT.F 80 (a) Pr~n~rAt;on of N-(4-(4-(1.2-h~n71~~th;~7~1-3-Yl)-l-DiDera-7i ~yl~butyl~-2-((N-(9H-fluoren-9-Yl thoxy)carbonvl~-L-valYl) 'n~
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)ben zamide (2.39 g, 5.84 mmol) (Exa~ple 36), anhydrous chloroform (60 mL) and S~ aqueous Na2C03 (60 mL) were added to a 300-mL, round-bottomed flask. To the two-phase reaction mixture was added a solution of _-((9_-fluoren-9-ylmethoxy)carbonyl)-L-valyl chloride (3.3 g, 9.22 mmol, 1.58 eq) (prepared according to the method of L.A. Carpino, et. al. (J. Ore. Chem., 1986, 51, 3734) C~2i 1~434 by employing N-((9H-fluoren-9-ylmethoxy)carbonyl)-L-valLne (BACHEM ~slif~rnip)) in chloroform (60 mL). The two-phase reaction mixture was allowed to stir for 10 min at room t . ~ e and transferred to a , .~ funnel. Chloroform was added and the organic layer was - , ~, dried over MgS04, filtered and : ~ to give 6.48 g of the crude product as a pale yellow oil. This crude material was purified by flash ~1"~ with ethyl acetate:methanol (95:5) as eluant to give 4.5 g (95%) of the title compound as a white glass. lH NMR
(CDC13): ~ 1.00 (d, 3, J - 6.9), 1.07 (d, 3, J - 6.8), 1.64 (m, 4), 2.36 (m, 3), 2.62 (m, 4), 3.38 (m, 2), 3.53 (br t, 4, J
4.8), 4.37 (m, 4), 5.55 (d, 1, J - 8.6), 6.83 (br s, 1), 7.10 (t, 1, J - 7.6), 7.30 (m, 4), 7.48 (t, 4, J - 7.1), 7.66 (t, 2, J
8.1), 7.82 (m, 4), 8.61 (d, 1, J - 8.3), 11.59 (br s, 1).
(b) Pr9~rPt~ of N-(2-(N-(4-(4-(1.2 hp~7i~thip7Al 3 yl) 1 Di ~yl~butvl)carbamoyl)phenyl)-L-v~
tri fl ~ ~ ' hYdrate N-(4-(4-(1,2-~ ~othio~l-3-yl)-l-pipera_inyl)butyl)-2-((_-(9_-fluoren-9-ylmethoxy)carbonyl)-L-valyl)amino)ben_amide (3.57 g, 4.88 mmol), chloroform (110 mL), 4-( ~ tl.~l)piperidine (50 mL) (Aldrich Chemical Company) were added to a 500-mL, round-bottomed flask. The reaction mixture was stirred under nitrogen at room L . for 0.5 h. The reaction mixture was ~ d to a r ' ~ funnel and chloroform (150 mL) was atded. The organic layer was washed with water (3 x 250 mL), , ~ ~. dried over MgS04, filtered, and : ~ ' to give 5.67 g of the crude product as a yellow oil. The free base was purified by column cl..~ on silica gel with ethyl acetate:methanol (85:15) as eluant to give 2.13 g of the free base as a viscous oil. A portion of the free base (1.17 g) was purified further by semi-preparative HPLC (Vydac C-18 column) with 0.1% CF3C02H/H20: 0.1% CF3C02H/CH3CN gradient 9:1 to 1:9.
The appropriate fractions were combined, c-~ d, dissolved W O 93/16073 C A 2 i i 7 4 3 4 159 PCT/GB93/00285 in water and methanol ant lyophilized to give 0.87 g (48%) of the title compound as a white powder. H NMR (DMS0-d6): d 1.01 (t, 6, J - 6.5), 1.60 (m, 2), 1.77 (m, 2), 2.18 (m, 1), 3.30 (m, 8), 3.61 (m, 2), 3.95 (m, 1), 4.10 (m, 2), 7.25 (t, 1, J - 7.7), 7.48 (tm, 1, J - 7.5), 7.58 (m, 2), 7.76 (d, 1, J - 7.8), 8.13 (t, 2, J - 9.0), 8.24 (d, 1, J - 8.4), 8.40 (br s, 1), 8.89 (br t, 1, J
- 4.8), 10.33 (br s, 1), 11.48 (s, 1). 13C NMR (DMSO-d6):
17.96, 18.05, 20.90. 25.92, 29.88, 46.63, 50.67, 55.31, 58.78, 121.26, 121.58, 123.01, 123.95, 124.02, 124.69, 126.97, 128.21, 128.25, 131.83, 137.09, 152.16, 157.69, 158.11, 158.54, 158.96, 162.17, 166.70, 168.00.
27H36N602S.2.35 CF3C02HØ75 H20: C 48 l9; H
5.08; N, 10.64; F, 16.95; H20, 1.71.
Found: C, 48.18; H, 5.10; N, 10.78 F, 16.90; H20, 1.79.
F.Y~''P! .F 81 (a) P-. _ lon of N-(4-~4-(1.2 ~ ~Athip~nl-3-vl~ Di~era-7i~yl)butyl)-2-((N-(9H-fluoren-9-vl thA~v)carbo~yl~-D-valyl) r.~)~ ' A-This compound was prepared according to the method described in _xample 80(-), by employing 2-amino-N-(4-(4-(1,2-benzisothia-zol-3-yl)-1-piperazinyl)butyl) benzamide (2.33 g, 5.7 mmol) (Example 36), _-((9_-fluoren-9-ylmethoxy)carbonyl)-_-valyl chloride (3.22 g, 9.0 mmol, 1.58 eq), anhydrous chloroform (120 mL) and 5% aqueous Na2C03 (60 mL). N-((9B-Fluoren-9-yl-methoxy)carbonyl)-D-valine was purchased from BACHEM ~.AliforniA
The crude product was purified to give 3.42 g (82%) of the title compound as a white solid. lH NMR (CDC13): 6 1.01 (d, 3, J
6.8), 1.07 (d, 3, J - 6.8), 1.64 (m, 4), 2.36 (m, 3), 2.62 (br t, 4, J - 4.5), 3.42 (m, 2), 3.53 (br t, 4, J - 4.8), 4.37 (m, 4), 5.55 (d, 1, J - 8.6), 6.80 (br s, 1), 7.10 (t, 1, J - 7.2), 7.36 CA2'i 1 7434 (tD, 4, J - 4.4), 7.48 (tD, 4, J - 7.6), 7.67 (t, 2, J - 8.2), 7.80 (m, 4), 8.62 (dm, 1, J - 8.9), 11.58 (br s, 1).
(b) PreDaration of N-~2-(N-(4-(4-(1.2-benzisothiazol-3-Yl)-l-Di n~Yl)butYl)carbaDQYl)Dhenyl)-D-valinaDide trifluoro-acetate hydrate This coDpound was prepared according to the method described in Example 80(b) by employing _-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((_-(9_-fluoren-9-ylmethoxy)carbonyl)-_-val-yl)aDino)benzaDide (3.47 g, 4.75 DDol), chloroforD (100 DL) and 4-( cl.~l)piperidine (S0 mL). The crude material was purified by column cl.~ with ethyl acetate:methanol (85:15) to give 1.99 g of the free base as a viscous oil. A
portion (0.61 g) of the free base was applied to a semi-preparative column and 0.54 g (57~) of the title compound was obtained as a white powder. lH NMR (DMS0-d6): 6 1.01 (t, 6, J - 6.5), 1.60 (m, 2), 1.78 (m, 2), 2.18 (m, 1), 3.32 (m, 8), 3.62 (m, 2), 3.95 (m, 1), 4.10 (br d, 2, J - 10.5), 4.56 (br s, 3), 7.24 (t, 1, J - 7.7), 7.48 (t, 1, J - 7.7), 7.58 (m, 2), 7.77 (d, 1, J - 7.5), 8.13 (m, 2), 8.23 (d, 1, J - 8.1), 8.34 (br s, 3), 8.90 (br t, 1, J - 5.3), 10.54 (br s, 1), 11.49 (s, 1). C
NMR (DMSO-d6): 6 18.91, 18.97, 21.78, 26.86, 30.80, 47.52, 51.55, 56.21, 59.69, 122.18, 122.51, 123.98, 124.87, 124.95, 125.61, 127.90, 129.12, 129.20, 132.72, 138.00, 153.09, 158.68, 159.11, 159.54, 159.98, 163.12, 167.62, 168.91.
27H36N602S.2.35 CF3C02HØ75 H2O: C 48 19; H
5.08; N, 10.64; F, 16.95; H20, 1.71.
Found: C, 48.03; H, 5.06; N, 10.62; F, 16.63; H20, 1.68.
W O 93/16073 C ~ 2 i 7 4 3 4 161 - PCT/GB93/00288 FYI~MPT F. 82 (a) F.._ _. 'nn of N-(4-(4-(1.2-benzisothiazol-3-Yl)-l-Di~era-zinvl~butyl)-2-((tert-b~ aLb~ 'nr~)benzamide 2-Amino-N-(4-(4-(1,2-benzisothiszol-3-yl)-1-piperszinyl)butyl)ben zsmite (3.3 g, 8.06 mmol) (Exsmple 36), 1,4-dioxsne (10 mL) snd 5~ squeous Ns2C03 (10 mL) were combined in a 250-mL, round-bottomed flask. The flssk was equipped with a magnetic stirring bar and an addition funnel. A solution of di-tert-butyl dicarbonste (4.41 g, 20.2 mmol, 2.5 eq) (Aldrich Chemical Company) in 1,4-dioxane (10 mL) was added dropwise and the resction mixture wss allowed to stir at room i ~ - e for 45 h. An additionsl portion of di-tert-butyl d~irArho~Atr (1.76 g, 8.06 ~mol, 1.0 eq) in 1,4-dioxane (10 mL) was added to the resction mixture and the , 'An was allowed to stir for 5 d.
The reaction mixture was filtered and the filtrate was i ~ ~d to a , - ~ funnel. Ethyl acetate and water were sdded, the organic lsyer wss sepsrsted snd the squeous phsse wss trr-t~d with ethyl gcetgte. The organic lsyers were combined, dried over HgS04, filtered snd ~ - ' to give 6.56 g of the crude product ss sn orange liquid. The crude csrbsmate wss purified by flssh cl.~ with ethyl scetste as eluant to give 3.39 g (83~) of the title compound ss a yellow oil. lH NMR
(CDC13): ~ 1.52 (s, 9), 1.71 (m, 4), 2.50 (br t, 2, J - 6.4), 2.67 (br t, 4, J - 4.9), 3.48 (m, 2), 3.55 (br t, 4, J - 4.9), 6.74 (n, 1), 6.98 (tm, 1, J - 7.6), 7.42 (m, 4), 7.82 (d, 1, J
8.0), 7.90 (d, 1, J - 8.1), 8.36 (dd, 1, J - 1.0, 9.0), 10.18 (br s, 1).
W O 93/16073 PCT/GB93/0028~
CA 2 i 17434-162 -(b) PreDaration of N-(4-~4-(l.2-bsn7icnthiazol-3-yl)-l-DiDera zinYl~butvl~-2-~(tert-butoxycsrbonyl)amino~hrn7 de Nl. S. S-trioxide A solution of 50-60~ _-chlu.~r vA~b_.L~oic acid (4.49 g, 13.0-15.6 mmol, 2.0-2.4 eq) (Aldrich Chemical Company) in dichlv.. '- (50 mL) was added to a solution of N-(4-(4-(1,2-ben~icothls~Al-3-yl)-1-piperaz$nyl)butyl)-2-((tert-b~LvA)~ l)amino)benzamide (3.32 g, 6.51 mmol) in dichluL~ ' (50 mL). The reaction mixture was allowed to stir at room ; . e for 1.5 min. The solution was ~.~.,9fe...d to a ~_r~ UL~ funnel and dichlu-~ th9nr and saturated N~HC03 were added. The organic layer was separated and the aqueous phase was extracted twice with dichlo.~ . The organic layers were combined, dried over MgS04, filtered and - ' to giYe 4.6 g of the crude product as a yellow glass. The crude product was purified by flash 'I--' v .'~
with dichlo.. ' :methanol (4:1) as eluant to gi~e 2.28 g (59~) of the title compound as a pale-yellow solid. ~ NMR
(CDC13): ~ 1.50 (s, 9), 1.84 (m, 2), 2.08 (m, 2), 3.33 (m, 6), 3.50 (m, 2), 4.48 (m, 4), 6.95 (t, 1, J - 7.7), 7.40 (tm, 1, J
8.0), 7.71 (m, 4), 7.94 (d, 1, J - 6.7), 8.20 (br s, 1), 8.32 (d, 1, J - 8.8), 10.40 (s, 1).
c) r~ of 2-~ ~nn-N-(4-~4-(1.2-benzisothis7~1-3-yl) l-Di nvl)butyl)benzamide Nl.S.S-trioxide h~drochloride N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-((tert-b~LvA~c.bv.l~l)amino)benzamide Nl, S, S-trioxide (2.28 g, 3.87 mmol), anhydrous anisole (4.0 mL) (Aldrich Chemical Company) and anhydrous chloroform (50 mL) were combined in a 500-mL, round-bottomed flask and trifluoroacetic acid (5.0 mL) (EM
Science) was added. The reaction mixture was allowed to stir under a nitro~en . I' e at room , , e for 0.5 h.
Trifluoroacetic acid (15 mL) was added to the reaction mixture W O 93/16073 A 2 i i 7434 PCT/GB93/00285 ant the solution was allowet to stir for 0.5 h. Chloroform was added to the reaction mixture and a cold solution of saturatet NaHC03 was adtet slowly. The mixture was transferred to a ~ funnel ant the organic layer was s r tDd. The aqueous phase was extractet with chloroform. The organic layers were combinet, triet over MgS04, filtered ant c~ LDtet..
This material was purifiet by flash cl..~ g .'~ with tichlG.. ' :methanol (4:1) to give 0.686 g of the free base as a pale yellow glass. The free base (0.686 g, 1.55 mmol) was tissolved in tichl~.- '- ant methanol and lN ethereal HCl (1.55 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.51 g (26%) of the title compound as a beige solit. mp: 226-228 C. lH NMR
(DMS0-t~ 1.61 (m, 2), 1.91 (m, 2), 3.32 (m, 2), 3.96 (m, 8), 4.75 (br s, 2), 6.53 (ttt, 1, J - 1.1, 7.1, 8.1), 6.70 (tt, 1, J
- 1.1, 8.4), 7.15 (ddt, 1, J - 1.4, 7.1, 8.4), 7.52 (dm, 1, J
8.1), 7.87 (m, 2), 8.10 (m, 1), 8.31 (tm, 2, J - 6.2). C NMR
(DMS0-d6): ~ 19.73, 26.77, 39.00, 42.84, 61.74, 68.28, 115.50, 115.67, 117.27, 123.10, 127.85, 127.88, 129.03, 132.56, 134.23, 134.51, 144.80, 150.54, 161.17, 169.90. IR (KBr): 1311, 1162, 587 cm 1. Ion Spray MS m/z (relative intensity): 458 (MH , 80), 480 ((M+Na) , 100).
Anal. Calcd for C22H27N5045.HCl: C, 53.49; H, 5.71; N, 14.18;
Cl, 7.18.
Found: C, 53.57; H, 5.75; N, 14.14; Cl, 7.23.
F~xAMpT F 83 (a) PrDn~tiA~ of 2-Amino-N-(4-(4-tl.2-benzisothiazol-3-vl)-1-Di rlyl)butYl~hDn7 A. N1 AY;~D hvdrochloride 2-Amino-N-(4-(4-(1,2-b-n-icothi~Al-3-yl)-1-piperazinyl)butyl)ben zamite (3.28 g, 8.01 mmol) (Example 36) and anhydrous tichlu.~ t~AD (75 mL) were combined in a 250-mL, round-bottomed W O 93/16073 C A 2 i i 7 4 3-4164 - PCT/GB93/00285 flssk. The reaction mixture was allowed to stir under 8 nitrogen ~ ,' e and cooled to -78~C with a dry_ice/acetone bath. To a pear-shaped flask was added 50-60~ m-chluL~r.-uA~b_.~uic acid (2.30 g, 6.7-8.0 mmol, 0.8-1.0 eq) (Aldrich Chemical Company).
The _-chluLur~LuA~L ic acid was placed under N2, anhydrous dichluL. ' (25 mL) was added and the solution was cooled to -40~C with a dry ice/scetone bsth. A portion of the ~-chlu.ur.LuA~L ic scid was insoluble at this i , e.
The _ , C was transferred to the cold benza~ide solution with a cannu~aiOspd the remaining peracid was dissolved in anhydrow dichl~ Ll.~..c (10 mL) and cooled in an ice-water bath. The c~l,do ~olution of m-chluL-. ~Ayt_.~uic acid was LL~ CrLL_d to~ b '~D solution and the reac~ion mixture was stirred at~ ~C for 0.5 h. The reaction mixture was diluted with dichluL. ~ d to a ~ funnel and washed with satu~ed NaHC03. The layers were separated and the aqueous phase wy extracted twice with dichluL. rho~, The organic layers were combined. dried over MgS04, filtered and ' to ~ive 3.57 g of the crude product~as a beige solid. The crude free bsse was purified by flash ~LL~ LJ
with dichlu.~ rh~ methanol (17:3) as eluant to give a beige solid. The solid was partitioned between dichlu-- t~ and ssturated NaHC03. The organic layer was separated, dried over MgS04 filtered and ~ ~ ' to give 0.991 g of the free base ss a beige solid. The free bsse (0.986 g, 2.32 mmol) wss dissolved in dichlo.. Ll. .c/methsnol and lN ethereal HCl (2.32 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.470 g (13~) of the title compound as a tan solid. mp: 177.5-178.5 C (dec). H NMR
(DffS0-d6): 6 1.61 (m, 2), 1.91 (m, 2), 3.29 (br t, 2, J - 6.8), 3.66 (m, 2), 3.90 (m, 6), 4.10 (br d, 2, 3 - 13.7), 6.53 (ddd, 1, J - 1.0, 7.1, 7.6), 6.71 (dd, 1, J - 1.0, 8.4), 7.15 (ddd, 1, J -1.5, 7.1, 8.4), 7.50 (m, 1), 7.52 (dm, 1, J - 7.6), 7.63 (tm, 1, J - 7.6), 8.14 (d, 1, J - 8.0), 8.20 (d, 1, J - 8.0), 8.34 (br t, 1, J - 5.6). C NMR (DMS0-d6): 6 18.87, 26.02, 38.28, 43.90, r~'~2 i, 7~34 W O 93/16073 - 165 - PCT/GB93/0028~
61.34, 67.36, 114.88, 115.07, 116.65, 121.54, 124.32, 124.96, 127.17, 128.39, 128.47, 131.91, 149.89, 152.55, 162.12, 169,30, Ion Spray MS m/z (relative intensity): 426 tMu , 100).
Anal. Calcd for C2~u~lN~O~.HCl: C, 57.19; H, 6.11; N, 15.16.
Found: C, 57.29; H, 6.13; N, 15.10.
FXAMPT.F. 84 (a) PreDaration of 2-(2-(tert-b~uA~a-b~ l)hydrazino)benzoic acid 2-HyA~D7~ r acid hydrochloride (7.5 g, 40.0 mmol) (Aldrich Chemical Company), 1,4-dioxane (40 mL) and 5S aqueous Na2C03 (75 mL) were combined in a 500-mL, round-bottomed flask and cooled in an ice-water bath. The flask was equipped an addition funnel and a solution of di-tert-butyl ~i~Arhorst~ (9.6 g, 44.0 mmol, 1.1 eq) (Aldrich Chemical Company) in 1,4-dioxane (20 mL) was slowly added. The ice-water bath was removed and the reaction mixture was allowed to stir at room ~ for 6 h.
An additional portion of di-tert-butyl ~ bo~t~ (0.99 g, 4,54 mmol, 0.11 eq) was dissolved in 1,4-dioxane (10 mL) and slowly added to the reaction mixture. The reaction mixture was allowed to stir for an additional 26 h and ~ ' to give a red-orange residue. Water (200 mL) was added to the residue and the mixture was cooled in an ice-water bath. The pH was adjusted (pH - 1) by the addition of aqueow lN HCl and the solution was extracted with ethyl acetate. The organic layer was , - d, dried over MgS04, filtered and ' ' to give a solid. The solid was triturated with hexanes and dried in a vacuum oven to give 9.13 g (9lS) of the title compound as a tan-beige solid. H
NMR (DMS0-d6): ~ 1.43 (s, 9), 6.77 (t, 1, J - 7.5), 6.88 (d, 1, J
- 8.2), 7.45 (tm, 1, J - 7.7), 7.83 (dd, 1, J - 1.5, 7.9), 8.89 (s, 1), 9.07 (br s, 1), 12.98 (br E, 1).
(b) Pre~aration of N-(4-(4-(1.2-benzisothiD7~l-3-vl)-l-~i~era-W O 93/16073 C A 2 i 1 7 4 ~6 - PCT/GB93/00285 zinvl)but,Yl)-2-(2-(tert-butoxYcsrbonyl)hyAr,~;~~)benzamide 2-(2-(tert-E ~a.'uu..~l)hydrazino)benzoic acid (2.57 g, 10.2 mmol), anhydrous teLL~.~I.ufu.~.. (30 mL) and anhydrous triethylamine (1.70 mL, 1.23 g, 12.2 mmol, 1.2 eq) were combined in a flame-dried, 100-mL, round-bottomed flask. The orange solution was stirred under a nitrogen ~ .' e and cooled between -20 and -35~C with a dry ice/~ ol bath.
Isobutylchloroformate (1.32 mL, 1.39 g, 1.0 eq) (Aldrich Chemical Company) was added and the mixture was allowed to stir for 5 min.
A cold (-20 to -35 C) solution of 3-(4-(4-aminobutyl)-1-pipera-zinyl)-1,2-~ '-othiD7~1e (2.97 g, 10.2 mmol, 1.0 eq) (Lxample 13 (b)) in anhydrous teL-~.~d-uL~.~.. (30 mL) was slowly added. 'Ehe reaction mixture was allowed to stir between -15 and -30~C for 0.75 h. The cold bath was removed and the reaction mixture was allowed to stir at room r , c for 1.5 h. 'Ehe reaction mixture was i ' ~d to a - . ~ ~ funnel, dichlc.. i' was added, and the solution was washed with sDt~r~t~d NaNC03. The layers were separated and the aqueous phase was extracted with dichlu.. Ll.~..c. 'Ehe organic layers were combined, dried over NgS04, filtered and c r~ A to give 5.89 g of an orange oil. The crude product was purified by column ~1.-. ~ ,'~ with dichlu.. r~ :methanol (19:1) as eluant to give 3.01 g (56~) of the title compound as a pale-beige glass. lN NNR (CDC13): ~i 1.45 (s, 9), 1.68 (br t, 4, J - 3.0), 2.49 (br t, 2, J - 6.8), 2.67 (br t, 4, J - 4.8), 3.45 (br q, 2, J - 6.0), 3.55 (br t, 4, J - 4.8), 6.32 (br s, 1), 6.61 (m, 1), 6.78 (tm, 1, J - 7.5), 7.01 (d, 1, J - 8.2), 7.35 (m, 3), 7.47 (tm, 1, J - 7.5), 7.81 (d, 1, J - 8.0), 7.90 (d, 1, J - 8.0), 8.76 (br s, 1).
C~ 2 i 1 7434 (c) ~reDaration of N-(4-(4-(l.2-hDn7;cnt~1A7nl-3-vl)-l-DiDera zinyl)butyl)-2-hydr~7; ' ~ dihvdrochloride hydrate N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(2-(tert -butoxycarbonyl)hydrazino) benzamide (2.85 g, 5.43 mmol), anhydrous anisole (5.0 mL) (Aldrich Chemical Company) and anhydrous chloroform (75 mL) were combined in a 500-mL, ~ d flask. To the stirred pale-yellow solution was added trifluoroacetic acid (25 mL) (EM Science). The reaction mixture was allowed to stir under a nitrogen ~ for 10 min and the solution was e ~ed n vacuo. The residue was L.~f--..d to a - , ~ funnel with the aid of chloroform and washed with saturated NaNC03. The layers were separated and the aqueous phase was extracted with chloroform. The organic layers were combined, w shed with saturated NaNC03, dried over MgS04, filtered and - d to give an orange liquid. The crude product was purified by column ch.~ with a gradient eluant of 97-954 dichlo.~ th~n~ to 3-5~ methanol to give 1.54 g of the free base as a partially soli~ d yellow oil. The free base (1.41 g, 3.32 mmol) was dissolved in dichlo-~ ' and lN ethereal NCl (6.8 mL, 2.05 eq) was P.dded.
The resulting dihydrochloride salt was recrystallized from ethanol/water/ether to give 1.1 g (40~) of the title compound as a golden-yellow solid. mp: 222-226 ~C. lN NMR (DMS0-d6):
1.62 (m, 2), 1.83 (m, 2), 3.17 (m, 2), 3.29 (q, 2, J - 5.8, 6.6), 3.37 (m, 2), 3.54 (br s, 4), 4.05 (br s, 2),. 6.99 (t, 1, J
7.5), 7.12 (d, 1, J - 8.0), 7.46 (m, 2), 7.58 (t, 1, J - 7.6), 7.73 (dd, 1, J - 1.3, 7.5), 8.06 (br s, 1), 8.09 (d, 1, J - 8.2), 8.13 (d, 1, J - 8.2), 8.78 (t, 1, J - 5.6), 9.18 (s, 1), 10.27 (br s, 3), 11.18 (br s, 1). 13C NMR (DHS0-d6): ~ 20.62, 26.15, 38.25, 46.40, 50.51, 55.15, 114.43, 118.83, 120.41, 121.24, 124.07, 124.68, 127.01, 128.17, 128.36, 132.07, 145.66, 152.14, 162.30, 167.93. CIMS m/z (relative intensity): 425 (MN , 10), 291 (100).
W O 93/16073 C ~ 2 i 1 7 4 3 ~68 - PCT/GB93/0028~
Anal. Calcd for C22H28N6OS.2HClØ5H2O: C, 52.17; H, 6.17; N, 16.59; Cl, 14.00 H2O, 1.78.
Found: C, 52.23; H, 6.34; N, 16.30; Cl, 14.04; H2O, 2.05.
FY~ PT~ 85 (a) PreDaration of Hethvl 3~ h~on7A~blth~ -2-carboxvlate This compound was prepared according to the method of J. R. Beck (J. Org. Chem., 1972, 37, 3224) by employing 2-nitrobenzonitrile (50.0 g, 0.338 mol) (Aldrich Chemical Company), methyl thioglycolate (33.2 mL, 36.4 g, 0.343 mmol, 1.11 eq) (Aldrich Chemical Company), N,N-dimethy1' '~ (400 mL) and squeous KOH
(37.4 g/187 mL water) to give 36.1 g (52~) of the title compound as a pale beige solid. lH NHR (CDC13): 6 3.90 (s, 3), 5.92 (br s, 2), 7.37 (ddd, 1, J - 1.3, 7.0, 8.2), 7.48 ~ddd, 1, J - 1.5, 7.0, 8.2), 7.64 (ddd, 1, J - 0.8, 1.5, 8.0), 7.74 (ddd, 1, J
0.8, 1.2, 8.0).
(b) Freraration of benzo~blrh1- ~ 3-amine Hethyl 3- ~ ~ [b]rhil,' 2-carboxylate (32.09 g, 0.155 mol), l-methyl-2-pyrrolidinone (150.0 mL) (Aldrich Chemical Company) and l-meth91ri. ~ (43.0 mL, 38.83 g, 0.388 mol, 2.50 eq) (Aldrich Chemical Company) were combined in a 1-L, round bottomed flask snd placed under N2. The pale-orange solution was heated at 180-185~C for 3.5 h. The reaction mixture was c ' and the residue was partially purified by flush ~1,.~ O .'~ with dichl~ as elw nt to give 24.7 g of an orange liquid. Further purification by column cl.-~ ~ogrPrhy with dichlo-- ' as el w nt gave 20.1 g (87~) of the title compound as an orange liquid. H NHR (CDC13): 6 3.84 (br s, 2), 6.34 (s, 1), 7.38 (m, 2), 7.61 (m, 1), 7.80 (m, 1), W O 93/16073 C A 2 i 1 7 4 3 4 169 - PCT/GB93/002xs (c) PreDaration of 1-(benzo~blthil ' -3-vl)~i~ers71n~
Benzo[b]thio~ 3-amine (15.86 g, 0.106 mol), piperazine (21.07 g, 0.245 mol, 2.3 eq) (Aldrich Chemical Company) and l-methyl-2-pyrrolidinone (100 mL) (Aldrich Chemical Company) were combined in a 500-mL, round-bottomed flask and placed under N2.
The reaction mixture was heated st 185-190 C for 5.5 h and allowed to stand at room r , t e overnight. The reaction mixture was c~ * and the residue was purified by flush ~h.- ~ O ,'~ with dichloromethane (100~) and dichl~ methanol (85:15) as eluant to give 14.41 g (62~) of the title compound as a yellow solid. lH NMR (DMS0-d6):
2.95 (m, 8), 6.89 (s, 1), 7.38 (m, 2), 7.75 (m, 1), 7.92 (m, 1).
(d) Pr~r~r~r;~n of N-~4-(4-(~ (b)rh1~nh~n-3-yl)-l-~in~ro7inyl)-butYl~phth~ *~ hydrn~-hl~ride l-(Bell2o[b]thiophen-3-yl)p1 'n- (5.23 g, 24.0 mmol), N-(4-bromo butyl) phth~ljm~A~ (8.18 g, 29.0 mmol, 1.21 eq) (Aldrich Chemical Company), triethylamine (5.0 mL, 3.63 g, 35.9 mmol, 1.5 eq) and acetonitrile (100 mL) were combined in a 250-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 2 h. The reaction mixture was i ' ~d to a F, ' ~ funnel, dichl~L- '- was added, and the solution was washed with saturated NaHC03. The organic layer was separated and the aqueous phase was extracted with dichlo.~ -' . The organic layers were combined, washed with ~-t--r~te~ NaCl, separated, dried over NgS04, filtered and _ ~ to give 13.26 g of the crude product as an orange oil. The product was purified by flush ~ OL~ with ethyl acetate:hexanes (1:1) to give 8.5 g of the free base as a yellow solid. The free base (1.55 g, 3.69 mmol) was dissolved in ethyl acetate and lN ethereal HCl (3.70 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 1.30 g (65~) of the title compound as white solid. mp >250 C.
W O 93/16073 - 170 - ~ PCT/G893/0028~
H NMR (DMSO-d6): ~ 3.52 (br s, 4), 3.20 (m, 6), 3.61 (m, 6), 7.11 (s, 1), 7.42 (m, 2), 7.88 (m, 4), 7.89 (d, 2, J - 2.7), 10.56 (br s, 1). 13C NMR (DMSO-d6): ~ 20.62, 25.38, 36.94, 48.57, 50.98, 55.03, 108.83, 121.82, 123.08, 123.49, 123.95, 124.80, 131.69, 133.73, 134.43, 138.66, 144.78, 168.02.
Anal. Calcd for C24H25N3O25.HCl: C, 63.22; H, 5.75; N, 9.21.
Found: C, 63.19; H, 5.78; N, 9.13.
F~MP! F 86 Preoaration of 4-(4-(benzo(b)thioohen-3-yl)-l-Din~ra 71~yl)butVl~
N-(4-(4-(Benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)phth~limiA~
(3.52 g, 8.39 mmol) (Example 85(d)), 55~ hydrazine hydrate (0.75 g, 12.87 mmol, 1.53 eq) (Aldrich Chemical Company) and methanol (25 mL) were combined in a 100-mL, round-bottomed flask and placed under N2. The reaction mixture was heated at reflux for 1.75 h. The , A~ was allowed to cool to room L , ~ and water (25 mL) was added. The reaction mixture was acidified (pH - 2) by the adtition of aqueous lN HCl. The resulting solid was filtered and washed with water. The pH of the filtrate was made basic (pH - 12) by the addition of aqueous lN NaOH, ; ' ~d to a ~ funnel and extracted with dichlo.. th~n~, The organic layer was separated and the aqueous phase was extracted with dichlo.~ L'- . The organic layers were combined, dried over MgSO4, filtered, decolorized with activated carbon, filtered and c~ d to give 2.00 g (82~) of the title compound as a pale yellow oil which sol~ifi~d upon standing to give a tan-beige solid. H NMR (CDC13): 6 1.22 (br s, 2), 1.56 (m, 4), 2.46 (t, 2, J - 7.4), 2.73 (m, 6), 3.18 (br t, 4, J - 4.6), 6.62 (s, 1), 7.34 (m, 2), 7.77 (m, 2).
W O 93/16073 CA 2 i ' 743 PCT/GB93/00285 (b) PreDaration of 2-amino-N-~4-(4-(benzo(b)thioDhen-3-vl)-1-~Din~rs~71nvl)butyl)hon~ hydrnrhlnride .
4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butylamine (1.79 g, 6.18 mmol), isatoic anhydride (1.21 g, 7.42 mmol, 1.2 eq) (Aldrich Chemical Company) and etnanol (25 mL) were combined in a 100-mL, ~ ' flask. The reaction mixture was allowed to stir at room ; , under a nitrogen - r ~ for 1.5 h.
The solution was diluted with dichloromethane and washed with saturated NaHC03. The organic phase was - .-r~tPd and the aqueous phase was extracted with dichl~-- th~o, The organic layers were combined, dried over MgS04, filtered and ~
to give 3.41 g of the crude product as an orange oil. The free b-se was purified by flash ~1,.. O ,'~ with ethyl acetate as eluant to give 2.37 g of a colorless oil. The free base (2.21 g, 5.41 mmol) was dissolved in ethyl acetate and lN ethereal HCl (5.41 mL, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 1.38 g (50~) of the title compound as an off-white solid. mp: 210-212 C. H NMR
(DMS0-d6): ~ 1.61 (m, 2), 1.82 (m, 2), 3.06-3.46 (m, 8), 3.61 (br d, 4, J - 10.7), 6.43 (br s, 2), 6.54 (t, 1, J - 7.4), 6.71 (d, 1, J - 8.0), 7.12 (s, 1), 7.16 (t, 1, J - 8.2), 7.43 (m, 2), 7,53 (d, 1, J - 7.8), 7.83 (m, 1), 7.97 (m, 1), 8.33 (br t, 1, J
5.3), 10.72 (br s, 1). 13C N~R (DMSO-d6): ~ 20.86, 26.54, 38.25, 48.78, 51.13, 55.38, 109.10, 114.86, 115.12, 116.63, 122.11, 123.77, 124.24, 125.08, 128.42, 131.88, 134.02, 138.96, 145.09, 149.90, 169.29.
Anal. Calcd for C23H28N40S.HCl: C, 62.08; H, 6.57; N, 12.59.
Found: C, 61.83 H, 6.65 N, 12.50.
~ A ~ 7 1 7 ~ 3 4 _XANPLF. 87 ~a) PreDaration of N-(4-(4-(l~2-hpn7ic~thi~7~l-3-yl)-l-Dioera ZinYl)bUtYl)-3-chloro-5-ethyl-2,6-di thoxYh~ - 'A~
hytrochloride Toluene (100 mL) and 3-chloro-5-ethyl-2,6-dimethylbenzoic acid (prepared by the method of de Paulis et ~1-. J. Ned. Chem., 29, 61-69, (1986)) (4.32 g, 17.6 mmol) were added to a 300-mL, oven-dried, round-bottomed flask. The solution was placed under N2 and thionyl chloride (Aldrich Chemical Company) (4.13 mL, 5.67 g, 47.6 mmol, 2.7 eq) was added. The light-yellow reaction mixture was heated to 75 Cand anhydrous dimethyl' A~
(0.25 mL) was added. The solution was heated at 65-75~C for 1.25 h. The solvent was removed with a rotary e... L~LuL to give the acid chloride as an orange residue. This crude acid chloride was dissolved in anhydrous chloroform (50 mL) and placed under N2. A solution of 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benzi-sothi~7~lP (5.63 g, 19.4 mmol, 1.1 eq) (Example 13(b)) in anhydrous chloroform (20 mL) was added to the acid chloride solution. Dry triethylamine (2.94 mL, 2.14 g, 2.10 mmol, 1.2 eq) was added. The reaction mixture was allowed to stir at room I , ~ for 0.75 h and the solvent was removed with a rotary e~ , ~ . The resulting viscous orange residue was dissolved in dichlu.~ ' and washed with saturated aqueous K2C03. The organic phase was dried over MgS04, filtered and ~ to give 10.03 g of an orange viscous oil. The crude material was adsorbed on silica gel and purified by flash .1.~ rh~ on silica gel with ethyl acetate/0.1~ triethylamine as eluant to give 4.78 g of a pale yellow oil. The hydrochloride salt was prepared by adding HCl (9.24 mL of a lN solution in ether, 1.0 eq) to a solution of the free base in ethanol. The salt was recrystallized from ethanol/ether and dried in a vacuum oven to give 2.96 g (30 ~) of the title compound as light tan powder.
mp: 198.5-200~C. lH NNR (DNSO-d6): ~ 1.16 (t, 3, J - 7.5), 1.60 -W O 93/16073 l73 PCT/GB93/00285 (m, 2), 1.83 (br s, 2), 2.58 (q, 2, J - 7.5), 3.20-3.63 (m, 10), 3.74 (s, 3), 3.78 (s, 3), 4.10 (br d, 2, J - 12.1), 7.38 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 8.14 (t, 2, J - 7.0), 8.50 (t, 1, J - 5.3), 10.66 (s, 1). 13C NHR (DMS0-6): ~ 14.76, 20.73, 21.80, 26.46, 46.57, 50.67, 55.39, 61.89, 62.27, 121.49, 121.76, 124.30, 124.95, 127.28, 128.45, 129.16, 130.17, 134.64, 150.88, 152.48, 153.96, 162.56, 164.26.
Anal. Calcd for C26H33N4035Cl.NCl: C, 56.41; H, 6.19; N, 10.12.
Found: C, 56.31; H, 6.18; N, 10.08.
FY~PT ~q 88 and 89 (a) P,. - :'nn of N-(4-(4-(1.2 -h~n7i cnthi ~7nl - 3-yl)-1-DiDera-71nYl~butYl)-3-nhlnro-S-ethvl-6-h,ydroxy-2-methoxyh~n~ de hYdr~~h1nride and N-(4-~4-(1.2-h~n7i~nthip7~l-3-yl~-l-DiDera 7inyl)butyl)-3-rhloro-S-ethYl-2-hydrOXy-6-me~ JL '~i~
hYdrnrhlnride hYdrate N-(4-(4-(1,2-L 'oothiP7ol-3-yl)-l-pLperazinyl)butyl-3-chloro-s-ethyl-2,6-~i L' ~L '~ (2.07 g, 4.0 mmol) (Example 87(a)) was mono dLmethylated accordLng to the method descrLbed Ln Examples 67 and 68. The two resultLng Lsomers were partially purLfLed by flash ~ on silica gel with 2:1 ethyl acetate/hexanes as eluant. Further purLfLcatLon on a Harrison Research Ch,. L ~.. wLth 1:1 and 2:1 ethyl acetate/hexanes as eluant gaYe a total of 1.07 g of the major Lsomer, N-(4-(4-(1,2-othip7ol-3-yl)-l-pLperazLnyl)butyl)-3-)chloro-s-ethyl-6-hy-droxy-2-me~ l ~A~ (Rf- 0.18 with 2:1 ethyl acetate/hexanes as eluant), and 0.27 g of the minor isomer, N-(4-(4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl)butyl)-3-chloro- S-ethyl-2-hydroxy-6-methoxybenzamide (Rf - 0.11 with 2:1 ethyl acetate/hexanes as eluant), as li p t orange oils. The hydrochloride salts of each isomer were prepared ~ y by dissolving the free amine in ether and adding HCl (1 equivalent of a lN solution in ether), CA 2 ~ 1 7434 (r le 88) ~he hydrochloride salt of the major isomer was recrystallized from ethanol/ether and dried in a vacuum oven to gi~e 0.76 g (35%) of N-(4-(4-(1,2-' eothiD~ol-3-yl)-1-piperazinyl)butyl)-3-chloro-5-ethyl-6-hydroxy-2 ~ L ~A- hydrochloride as an off-white powder. mp: 179-181~C. lH NMR (DMS0-d6): 6 1.12 (t, 3, J - 7.3), 1.64 (m, 2), 1.81 (m, 2), 2.52 (m, 3), 3.20-3.60 (m, 9), 3.82 (s, 3), 4.06 (br d, 2, J - 12.3), 7.38 (s, 1), 7.47 (m, 1), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 6.6), 8.83 (br t, 1, J
- 5.1), 11.25 (br s, 1), 13.60 (s, 1). C NMR (DMS0-d6): 6 13.69, 20.65, 22.00, 26.04, 38.33, 46.39, 50.46, 55.15, 61.64, 110.73, 115.79, 121.24, 124.05, 124.66, 127.00, 128.16, 129.76, 132.33, 152.03, 152.16, 157.96, 162.27, 167.77.
Anal. Calcd for C25H31N403SCl.HCl: C, 55.65; H, 5.98; N, 10.38.
Found: C, 55.56; H, 5.99; N, 10.29.
(E le 89) ~he hydrochloride salt of the minor isomer was recrystallized from 95% ethanol and dried in a vacuum over to give 0.156 g (7~) of N-(4-(4-(1,2-~ ~thiD7~l-3-yl)-l-piperazinyl)butyl)-3-chlo-ro-5-ethyl-2-hydroxy-6 i ~L ~- hydrochloride hydrate as fluffy, off-white crystals. mp: 171-173~C. lH NMR (DMSO-d6): 6 1.15 (t, 3, J - 7.6), 1.62 (m, 2), 1.81 (m, 2), 2.52 (q, 2, J
7.6), 3.20-3.62 (m, 10), 3.72 (s, 3), 4.08 (br d, 2, J - 12.7), 7.40 (s, 1), 7.47 (t, 1, J - 7.6), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 8.3), 8.78 (br t, 1, J - 5.6), 10.63 (br s, 1), 12.64 (s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 15.77, 21.54, 22.13, 26.99, 39.34, 47.32, 51.40, 56.09, 63.26, 114.02, 117.53, 122.16, 124.97, 125.58, 127.93, 129.09, 129.13, 133.19, 153.08, 154.66, 155.93, 163.20, 168.18.
W O 93/16073 CA 2 1 1 7 4 3 4 PC~r/GB93/0028~
Anal Calct for C25H31N4~35Cl-HCl l-25 H2 N, 9.97; H20, 4.00.
Found: C, 53.46; H, 6.14; N, 9.99; H2O, 4.02.
FYA''PLF 90 PrD"-ration of 2- ~nn-N-~4-(4-(1.2-bDn7ien~hiP7nl-3-yl)-l-Dimera-z~nyl)butyl)-3- ~-~ y1~ ~e hyArnrl-lnride ~his compound was prepared by the method described in Example 75(b).
From 3-methoxyisatoic anhydride (3.35 g, 0.017 mol) (obtained from 2-amino-3- ' ~b_.~oic acid (Aldrich Chemical Company) by the method described in Example 99) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-ot~ nle (5.33 g, 0.017 mol, 1.0 eq) was obtained 5.41 g of the product as the free base. A portion of this material (1.94 g) was dissolved in ethanol (10 mL) and HCl (4.4 mL of a lN solution in ether, 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/i r ~, 1 to give 1.93 g (65 ~) of the title compound as off-white crystals. mp: 136-138 C. lH NMR (DMSO-d6, 200 MHz):
1.59 (m, 2), 1.80 (m, 2), 3.12-3.60 (m, 6), 3.81 (s, 3), 4.09 (br d, 2, J - 12.9), 6.13 (br s, 1), 6.54 (t, 1, J - 8.0), 6.91 (d, 1, J
7.6), 7.20 (d, 1, J - 7.8), 7.49 (t, 1, J - 7.4), 7.62 (t, 1, J
7.5), 8.14 (t, 2, J - 6.8), 8.33 (br t, 1, J - 5.4), 10.89 (br s, 1).
3C NMR (DNSO-d6, 75.43 MHz): ~ 21.68, 27.29, 39.04, 47.38, 51.48, 56.20, 56.54, 112.83, 114.92, 115.40, 120.73, 122.18, 124.98, 125.59, 127.93, 129.11, 140.50, 147.88, 153.09, 163.18, 169.79. Mass Spec (CI/CH4, 50 nA/sec): h+l, base (440).
Anal. Calcd for C23H29N502S.HCl: C, 59.03; H, 6.35; N, 14.71; S, 6.74 Cl, 7.45.
Found: C, 57.94; H, 6.42; N, 14.57, S, 6.71; Cl, 7.55.
F~rAMPT.F 91 (a) PL~;rn of N-(4-(4-(1.2-h~n7;~~thi~nl-3-Yl)-l-DiDerzinyl)-butvl~-2-niL,.~ hvdrochloride This compound was prepared according to the method described in Example 53 by employing 3-(4-(4-aminobutyl)-1-piperszinyl)-1,2-b~ieothi~ole (0.99 g, 3.4 mmol) (Example 13tb)), triethylamine (0.72 mL, 0.52 g, 5.1 mmol, 1.5 eq) and 2-nitrobenzoyl chloride (Aldrich Chemical Company) (0.70 g, 3.4 mmol, 1.0 eq). The crude reaction mixt,ure was purified by flash ~hL~ with ethyl acetate/0.1~ triethylamine as eluant to give 0.94 g of the free base as a yellow solid. The hydrochloride salt was prepared, recrystallized from ethanol/ether and dried in a vacuum oven to give 0.66 g (41~) of the title compound as an off-white powder.
mp: 214-215~C. lH NMR (DMS0-d6, 200 HHz): 6 1.61 (m, 2), 1.85 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4.09 (br d, 2, J - 13.5), 7.48 (dd, 1, J - 7.2, 7.8), 7.72 (m, 4), 8.06 (d, 1, J - 8.0), 8.15 (t, 2, J - 7.0), 8.83 (br t, 1, J - 5.5), 11.29 (br s, 1). 13C
NMR (DNS0-d6, 75.43 MHz): 6 21.44, 26.95, 39.32, 47.30, 51.39, 56.06, 122.18, 124.86, 124.99, 125.59, 127.94, 129.09, 130.07, 131.63, 133.57, 134.55, 148.01, 153.09, 163.20, 166.42.
Anal. Calcd for C22H25N5035.HCl: C, 55.51; H, 5.50; N, 14.71.
Found: C, 55.56; H, 5.55; N, 14.72.
r le 92 (a) PreDaration of 2-amino-Q.~.~,-trifl-~~ro-~-toluic acid A solution of 2-nitro-o,~,~-trifluoro-p-toluic acid (Aldrich Chemical Company) (5.00 g, 21.3 mmol) in absolute ethanol (100 mL) was added to a Parr hydrogenation bottle rn~t,ining absolute ethanol (50 mL) and 5~ palladium on charcoal (100 mg).
The bottle was attached to a Parr h~dLU6-~dLUL and the solution CA2i 1 7434 was placed under a hydrogen l~ .' e at 35 psi. The reaction mixture was shaken at room t . e until consumDtion of hydrogen ceased (2h). The solution was filtered through a millipore AP filter and the filtrate was ~ ' with a rotary e~vL~LvL. The residue was dried unter vacuum to give 4.22 g (97~) of the title compound as a pale yellow solid. This material was used without further p~rifi~sti~n.
~b) PreDaration of 2-amino-N-(4-(4-(1.2-benzisothiazol-3-yl)-1-DiDers7invl~butyl)-4-(trifluoromethyl)h~n~ ~ hvdrochloride Anhydrous pyridine (20 mL), 2-amino-o,o,o-trifluoro-p-toluic acid (1.33 g, 6.5 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-~ othiP~o~ xample 13(b)) (2.00 g, 6.5 mmol, 1.0 eq) were pl-ced in a 100-mL, round-bottomed flask. The solution was placed under N2, silicon tetrachloride (Aldrich Chemical Company) (1.48 mL, 2.19 g, 13.0 mmol, 2 eq) was slowly added with stirring, and the solution was heated at 145 C for 18 h, The re-ction mixture was allowed to cool to room I , e, poured onto crushed ice and . ~ ' in vacuo. Distilled water (200 mL) was added to the residue and the solution was - ' to dryness. Toluene (200 mL) was added to the resulting brown solid and the solvent was removed with a rotary ~ vL~Lu.. This procedure was repeated with two additional portions of toluene (200 mL). Distilled water (200 mL) was added to the residue and the solution was made basic (pH-ll) by the ~ddition of lN sodium carbonate. The aqueous solution was ~Yt-s~r~d with ethyl acetate (3 x 200 mL). The organic layers were combined, dried over ~gS04, filtered and r--~ t~d Toluene (200 mL) was added to the residue and the solvent was re~oved with a rotary ~ tu-. This procedure was repeated with two additional portions of toluene (200 mL). The crude material was placed under high vacuum overnight and purified by flash ~h-- - ~ .'y on silica gel with a gradient eluant of ethyl acetate (100~)/methanol:ethyl acetate (l:99)/methanol:ethyl W O 93/16073 ? lJ8 - PCT/GB93/0028~
acetate (2:98) to give 1.45 g of the free amine. The product was dissolvet in ethanol and HCl (3.04 mL of a lN solution in ether~
was added. The hgdrochloride salt was recrystallized from ethanol/water to give 0.512 g (15~) of the title compound as white crystals. mp: 205-207~C. lH NMR (DMS0-d6, 200 MHz):
1.60 (m, 2), 1.80 (m, 2), 3.28 (m, 6), 3.56 (m, 4), 4.09 (d, 2, J
- 13.8), 6.74 (s, 2), 6.81 (d, 1, J - 8.3), 7.07 (s, 1), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J - 7.5), 7.71 (d, 1, J - 8.3), 8.14 (m, 2), 8.57 (br t, 1, J - 5.4), 10.94 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 20.75, 26.22, 38.21, 46.45, 50.55, 55.22, 110.09, 110.13, 110.18, 110.23, 112.29, 112.35, 112.40, 112.45, 117.88, 121.24, 122.23, 124.04, 124.66, 125.84, 127.00, 128.17, 129.34, 131.38, 131.79, 149.66, 152.16, 162.24, 167.88. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (478).
Anal. Calcd for C23H26N505F3.HCl: C, 53.74; H, 5.29; N, 13.62;
S, 6.24; Cl, 6.90.
Found: C, 54.04; H, 5.38; N, 13.57; S, 6.32; Cl, 6.92.
FXAMP! F~ 93 to 98 The compounds of Examples 93 to 98 were prepared from the C~ , ''nL substituted D~thranil1~ acid y-~ , by the method described in Example 92(b). The snthrs~ilir acids employed were obtained from commercial suppliers or prepared by known methods as inAi~At~d The analytical data for these 2-amino bon7 'AD~ are shown below.
Preparation of 2-Amin~-N-(4-(4-(l~2-benzisothiA7~l-3-yl)-l-~i~era zinvl)butyl~-3-methylbenzamide hvdrochLoride St~srting material: 2-Amino-3-methylbenzoic acid (Aldrich Chemical Company). Yield: 0.806 g (54~). mp: 208-210 C. H NMR (DMS0-d6~
W O 93/16073 C A 2 1 1 7 4 3 4 PCT/GB93/0028~
300 MHz): 61.58 (m, 2), 1.78 (m, 2), 2.08 (s, 3), 3.31 tm, 8) 3.59 (m, 2), 4.08 (br d, 2, J - 12.1), 6.21 (br s, 2), 6.48 (t, 1, J - 7.6), 7.07 (d, 1, J - 7.1), 7.39 (d, 1, J - 7.8), 7.47 (t, 1, J - 7.5), 7.60 (t, 1, J - 7.5), 8.12 (t, 2, J - 8.3) , 8.30 (br t, 1, J - 5.2), 10.58 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 18.57, 21.73, 27.27, 39.08, 47.44, 51.52, 56.24, 115.39, 115.75, 122.16, 123.95, 124.97, 125.61, 126.88, 127.92, 129.11, 133.36, 148.47, 153.08, 163.18, 170.34. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (424).
Anal. Calcd for C23H29N505.HCl: C, 60.05; H, 6.57; N, 15.22; S, 6.97;
Cl, 7.71.
Found: C, 60.08; H, 6.61; N, 15.12; S, 7.06; Cl, 7.76.
FYI-~IPL.E 94 pr~nArAt~rn Of 2-pminr-N-~4-(4-(l.2-h~n7ierrh~o7rl-3-yl)-l-DiDera zinvl~but~ -3-rl~lf~ hvdrrrhlrride Starting material: 2-Amino-6-chlu-~' ir acid (Lancaster Synthesis Inc.). Yield: 0.75 g (24~). mp: 211-213~C. lH NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.82 (m, 2), 3.15-3.61 (m, 10), 4.08 (br d, 2, J - 13.5), 5.23 (br s, 2), 6.61 (d, 1, J - 7.8), 6.66 (d, 1, J
8.2), 7.05 (t, 1, J - 8.0), 7.49 (t, 1, J - 7.5), 7.62 (t, 1, J
7.5), 8.14 (t, 2, J - 7.2), 8.47 (br t, 1, J - 5.3), 10.70 (br s, 1).
13C NMR (DMS0-d6, 75.43 Mhz): ~ 21.70, 27.06, 39.18, 47.40, 51.48, 56.21, 114.59, 117.02, 122.16, 122.66, 124.98, 125.61, 127.93, 129.11, 130.98, 131.18, 148.13, 153.08, 163.18, 166.48. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (444).
Anal. Calcd for C22H26N550Cl.HCl: C, 55.00; H, 5.66; N, 14.58; S, 6.67; Cl, 14.76.
Found: C, 55.09; H, 5.66; N, 14.55; S, 6.74; Cl, 14.66.
FXAMp!F 95 PreDarstion of 2-aDino-N-(4-(4-(l.2-benzisothiazol-3-vl)-1-DiDera-zinyl)butyl-5-fluoro h-~n7'~ hydrochloride Starting material: 2-Amino-5-fluu~ acid (Riedel). Yield:
0.65 8 (22~). mp: 219-221~C. lH NMR (DMS0-d6, 300 MHz): d 1.58 (m, 2), 1.80 (m, 2), 3.29 (m, 6), 3.45 (m,2), 3.59 (br d, 2, J~ 10.9), 4.08 (br d, 2, J~ 12.6), 6.30 (br s, 2), 6.71 (dd, 1, J~ 8.9, 5.1), 7.05 (dt, 1, J- 2.7, 9.9), 7.37 (dd, 1, J~ 2.7, 10.3), 7.47 (t, 1, J
- 7.5), 7.60 (t, 1, J- 7.5), 8.12 (t, 2, J- 8.3), 8.37 (br t, 1, J-5.3), 10.65 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): d 21.72, 27.17, 39.12, 47.42, 51.51, 56.21, 114.36, 114.67, 115.39, 115.46, 118.45, 118.54, 119.82, 120.12, 122.16, 124.97, 125.61, 127.92, 129.11, 147.27, 152.10, 153.07, 155.15, 163.18, 168 80, 168.84. Mass Spec (CI/CH4, 50 DA/SeC): M~l, base (428).
Anal. Calcd for C22H26N5FOS.HCl: C, 56.95; H, 5.87; N 15 09; S
6.91; Cl, 7.64.
Found: C, 56.84; H, 5.84; N, 15.01; S, 7.01; Cl, 7.73.
PreDaration of 2-amino-N-(4-(4-(1.2-h~n~ie~thiazol-3-vl)-l-DiDera zinyl~butvl)-6-Dethvl~ hvdrochloride Starting material: 2-ADino-6-methylbenzoic acit (Aldrich Chemical Company). Yield: 1.10 g (21~). Dp: 194-196 C. H NMR (DMS0-d6, 200 MHz): ~ 1.59 (m, 2), 1.80 (m, 2), 2.21 (s, 3), 3.32 ~m, 6), 3.55 (m, 4), 4.10 (m, 2), 4.93 (br s, 1), 6.44 (d, 1, J- 7.4), 6.55 (d, 1, J- 8.0), 6.96 (t, 1, J~ 7.7), 7.50 (t, 1, J~ 7.5), 7.67 (t, 1, J~
7.5), 8.15 (t, 2, J~ 7.1), 8.30 (br t, 1, J~ 5.3), 10.80 (br s, 1).
1 C NMR (DMS0-d6, 75.43 MHz): ~ 20.68, 21.73, 27.27, 39.02, 47.37, 51.44, 56.17, 113.70, 118.82, 122.18, 124.18, 124.99, 125.61, 127.93, W O 93/16073 C A 2 i 1 7 4 3 4 PCT/GB93/00285 129.11, 129.76, 135.30, 146.32, 153.08, 163.20, 169.29. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (424).
Anal. Calcd for C23H29N550.HCl: C, 60.05; H, 6.57; N, 15.22; S, 6.97;
Cl, 7.71.
Found: C, 59.99; H, 6.58; N, 15.17; S, 7.08; Cl, 7.64.
ExAMp!.F 97 PreDaration of 3-aminn-N-(4-~4-(1.2-h~n7i~nthiazol-3-yl)-l-DiDera-ZinV1~bUtY1)-2-naDthY1eneC~I~L 'A~ hVdrnrh1nride Stsrting material: 3-Amino-2-napthoic acid (Aldrich chemical Compang). Yield: 0.284 g (9~). mp: 216-218~C. lH NMR (DMS0-d6, 200 M~z): ~ 1.62 (m, 2), 1.84 (m, 2), 3.33 (m, 8), 3.59 (m, 2), 4.12 (br d, 2, J - 12.7), 6.11 (br s, 2), 6.98 (s, 1), 7.15 (t, 1, J
7.4), 7.36 (t, 1, J - 7.4), 7.54 (m, 3), 7.72 (d, 1, J - 8.2), 8.06 (s, 1), 8.14 (t, 2, J - 7.0), 8.68 (br t, 1, J - 5.2), 10.69 (br s, 1). 3C NMR (DMS0-d6, 50.29 MHz): ~ 20.94, 26.43, 38.47, 46.65, 50.75, 55.47, 108.56, 121.41, 121.51, 121.93, 124.32, 124.95, 125.08, 125.42, 127.28, 127.80, 128.45, 128.70, 128.90, 135.90, 146.02, 152.48, 162.58, 169.11. Mass Spec (CI/CH4, mA/sec): M+l, base (460).
Anal. Calcd for C26H29N550.HCl: C, 62.95; H, 6.10; N, 14.12; S, 6.46;
Cl, 7.15.
Found: C, 62.88 H, 6.14; N, 14.03; S, 6.53; Cl, 7.21.
F~AMP!F 98 PreDaration of 2-amino-N-(4-(4-(1.2-honi~~thi~7nl-3-yl)-l-DiDera zinvl)butvl)-5-meLLuAyL ~~ hydrochloride Starting material: 2-Amino-5-meLi.uA~L._.~ùic acid (obtained by the reduction of 2-nitro-5 ~ LLUA~b~U1C acid (Apin Chemicals Ltd.) according to the method described in Example 92 (a)). Yield: 0.313 g W O 93/16073 - 182 ~ i ~434 PCT/GB93/0028~
(104). mp: 150~C (dec.). H NMR (DMS0-d6, 200 MHz): ~ 1.60 (m, 2), 1.79 (m, 2), 3.37 (m, 12), 3.71 (s, 3), 3.88 (D, 2), 6.67 (d, 1, J
8.8), 6.86 (dd, 1, J - 2.7, 8.8), 7.10 (d, 1, J - 2.7), 7.48 (t, 1, J
- 7.5), 7.62 (t, 1, J - 7.5), 8.12 (d, 1, J - 7.5), 8.15 (d, 1, J
7.5), 8.37 (br t, 1, J _ 4,7), 1 C NMR (DMSO-d6, 75.43 MHz): C
21.84, 27.33, 39.08, 47.54, 51.60, 56.29, 56.60, 113.18, 116.18, 118.66, 120.20, 122.16, 124.97, 125.59, 127.94, 129.09, 144.58, 150.34, 153.08, 163.22, 169.58. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (440).
Anal. Calcd for C23H29N5025.HCl: C, 58.03; H, 6.35; N, 14.71; S, 6.74; Cl, 7.45.
Found: C, 58.09; H, 6.34; N, 14.62; S, 6.82; Cl, 7.39.
I'Y~MPT.F 99 (a) P~ lon of 4-fluoroi~t~ic Dnhydride 2-Amino-4-fl ,.' ic acid (0.97 g, 6.25 mmol) (obtained by the L.' L-~ of 4-fluoro-2-niL~ acid (The Sigma-Aldrich Library O~f Rare Chemicals) by the method described in Example 92 (a)), anhydrous 1,4-dioxane (20 mL), trichloromethyl rhl~ ~~f (5.0 g, 25.2 mmol, 4.0 eq) (Johnson-Matthey Chemical Company) were added to a 100-mL, round-bottomed flask.
The reaction mixture was heated at reflux for 11 h. The reaction mixture was allowed to cool and stir at room temperature overnight. The solvent was removed with a rotary evaporator to give 1.18 g (>1004 crude) of the title coDpound as an off-white solid. lH NMR (DMS0-d6, 200 MHz): ~ 6.90 ~dd, 1, J - 2.3, 9.6), 7.13 (dt, 1, J - 2.3, 7.6), 8.02 (dd, 1, J - 6.0, 8.8), 11.90 (br s, 1). This material was used without further purifi~Dti~ -(b) Preoaration of 2-Pmin~-N-(4-(4~ 2-h~n7ienthip7~l-3-vl) ~1nerazinyl~but~1)-4-fluQro benzamide hvdrochloride This compound was prepared by the method described in Lxample 75(b)- From 4-fluoroisatoic anhydride (1.18 g, 6.51 mmol) and 3-(4-(4-aminobutyl)-1-piperazinyl)-1,2-benziso-thiazole (2.0 g, 6.51 mmol, 1.0 eq) was obtaLned 1.31 g (43~) of the tltle com~oound as a pale-yellow solid. mp: 234-236~C. lH
NMR (DMS0-d6, 300 MHz): ~ 1.53 (m, 2), 1.78 (m, 2), 3.26 (m, 6), 3.53 (m, 4), 4.07 (d, 2, J - 13.4), 6.31 (dt, 1, J - 2.5, 8.5), 6.45 (dd, 1, J - 2.5, 7.2), 6.75 (br s, 2), 7.47 (t, 1, J - 7.5), 7.60 (m, 2), 8.12 (t, 2, J - 8.3), 8.32 (br t, 1, J - 5.3), 10.90 (br s, 1). 13C NMR (DMS0-d6, 75.43 MHz): ~ 21.66, 27.25, 39.02, 47.37, 51.47, 56.17, 102.14, 102.33, 102.45, 102.63, 112.35, 112.37, 122.18, 124.97, 125.59, 127.93, 129.11, 131.51, 131.66, 152.97, 153.09, 153.13, 163.17, 163.66, 166.92, 169.10. Mass Spec (CI/CH4, 50 mA/sec): M+l, base (428).
Anal. Calcd for C22H26N50FS.HCl: C, 56.95; H, 5.86; N, 15.09; S
6.91; Cl, 7.64.
Found: C, 56.89; H, 5.83; N, 15.10, S, 6.90; Cl, 7.61.
FY~MPTF. 100 (a) Pr~-ration of 3-(1-4- 'n~~tvl-4-r~;neridinyl)-6-fluoro-l.2-b~n7~ico7s7~le N-(4-(4-(6-Fluoro-1,2-b-n7ie~vP7~l-3-y)piperidino)butyl) - (1.04 g. 2.47 mmol) (Lxmaple 69), hydrazine hydrate (0.24 g 4.24 mmol, 1.67 eq) (Aldrich Chemical Company, 55 aqueous solution) and methanole (15 mL) were added to a 100-mL, round bottomed flask. The reaction mixture was headed at reflux for 2 h. The oil bath was removed and the reaction mixture was allowed to cool. Distilled water (50 mL) was added to the reaction mixture and the pH of the solution wad adjusted to pH-l by the additon of lN HC1. The , ~n was filtered and the solid was washed with water. The pH of the filtrate was adjusted to pH-12 by the addition of saturated K2C03. The basic filtrate was i fe.,~d to a O_ra,~L~.~ funnel and extracted with dichloromethan (3 x 100 mL). The organic layers were combined, dried over MgS04, filtered and c~ t<A to give 0.58 g (81%) of the title compound as a pale yellow oil. lhlYMR (CDC13): 6 1.54 (m,4), 1.80 (br s,2), 2.10(m.6), 2.41 (br t, 2,J-7.2), 2.74 (br t, 2, J - 6.4) 3.08 (m, 3), 7.05 (dt, 1, J - 2.1, 8.9), 7.23 (dd, 1, J - 5.1, 8.7).
(b) ~ on of 2- ~nA-N-(4 (4-(6-fluoro-1.2-bonzi~ovs7Al -3-yl~DeDeri~ buty)' ~~o hydochloride 3-(1-(4-Aminobuty)-4-piperidiny-6-fluoro-1,2-bon7i~~Ys7nle (0.58 g, 1.99 mmol), isatoic anhydride (0.325 g 1.99 mmol, 1.0 eq) (Aldrich Chemical Company) and ethanol (12 mL) were added to a 25-mL, round bottoDed flask and stirred under N2 for 3 h. The reaction mixture was ~ ' to give a brown-orange oil which sc~ fipd upon st-nding. The crude free base was purified by flask cl.,~ with ethyl acetate/0.14 thiethylamine as eluant to give 0.69 g of the free base as an oil. The free base (0.69 g, 1.68 mmol) was dissolved in ethyl acetate and IN
ethereal HCl (1.68 mL 1.0 eq) was added. The hydrochloride salt was recrystallized from ethanol/water to give 0.51 g (574) of the title compound as an off-white solid. mp: 242.5-245 C(dec). H
NMR (DMS0-d6): 6 1.57 (m,2), 1.78 (m,2), 2.25 (m,4), 3.12(m,4) 3.27(m,2), 3.47 (m, 1), 3.62 (br d, 2,J-12.0), 6.39 (br s,2), 6.51(tm, 1,J-7.4), 6.69 (dd, l,J -0.9, 8.1), 7.13(tm, 1, J-7.6), 7.35 (td, 1, J - 9.1, 2.1), 7.49 (dd, 1,J-1.2, 7.9), 7.74 (dd, l,J- 2.1, 9.1) 8.17 (m,l), 8.29 (m,l), 10.3(br s, 1). 1 C NMR
(DMSO-d6): 6 20.81, 26.44. 26/91, 31.26, 38.07, 51.27, 55.65, 97.72, 97.72, 112.70, 112.95, 114.59, 114.85, 115.35, 115.is, 123.88, 124.00, 128.13, 131.63, 149.63, 160.17, 162.55, 163.21, 153.35, 165.03, 168.98.
CA 2 i 1 7434 W O 93/16073 - 185 - P(~r/G B93/00285 A~nal. Calcd for c23H27N4o2F.Hcl: C~61.81; H.631; N,12-54- Fount:
C, 61.86; H, 6.33; N, 12.53.
i
Claims (27)
1. A compound of formula (I), or a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof or a physiologically functional derivative or N-oxide thereof;
wherein Y represents a group of the formula (a), (b) or (c):
wherein a single line accompanying a broken line (~~~~) represents a single bond or a double bond, wherein R1 represents one or more ring substituents comprising hydrogen, halogen, hydroxy, -N(R4)2, nitro, S(O)nR4 where n is 0, 1 or 2, C-N, CON(R4)2, COR4, CO2R4, CC-aryl, azido, benzyloxy, - NR4N (R4)2, -NR4N-C(R4)2, - NR4(C-O)CH(N(R4)2)R4, NR4CO2R4 and -NR4(C-O)R4 , C1-6alkyl optionally substituted with one or more halogens and C1-6alkoxy optionally substituted with one or more halogens, R2 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -N-N- or - (C-O)NR4;
R3 represents hydrogen, C1-6 alkyl, or C1-6alkoxycarbonyl;
R4 represents hydrogen or C1-6alkyl:
R5 represents -N-C- or -C-N-;
R6 represents hydrogen or C1-6 alkyl;
R7, R8, R9, R10 and R11, which are the same or different each represent hydrogen, halogen. nitro, , hydroxy, S(O)nR4 where n is 0, 1 or 2, C-N, CON(R4)2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -N(R4)2, NR4N(R4)2, -NHR4-C(R4)2, -NR4(C-O)CH(N(R4)2)R4, -NR4(C-O)R4, NR4CO2R4, C1-6alkoxycarbonylamino, PhN-N, C1-6alkyl optionally substituted with one or more halogens or C1-6alkoxy optionally substituted with one or more halogens, or when considered in pairwise combination, R7 and R8 or R8 and R9 or R9 and R10 or R10 and R11 represent V represents O or S:
Z represents C4-8alkylene, optionally interrupted by -S(O)n -where n is 0, 1 or 2, C4-8alkenylene or C4-8alkynylene;
X represents N or C:
W represents a group of formula (d) where A represents CR4 or N; B represents oxygen, NR4 or S(O)n , where n=0, 1 or 2 and R12 represents hydrogen or halogen.
wherein Y represents a group of the formula (a), (b) or (c):
wherein a single line accompanying a broken line (~~~~) represents a single bond or a double bond, wherein R1 represents one or more ring substituents comprising hydrogen, halogen, hydroxy, -N(R4)2, nitro, S(O)nR4 where n is 0, 1 or 2, C-N, CON(R4)2, COR4, CO2R4, CC-aryl, azido, benzyloxy, - NR4N (R4)2, -NR4N-C(R4)2, - NR4(C-O)CH(N(R4)2)R4, NR4CO2R4 and -NR4(C-O)R4 , C1-6alkyl optionally substituted with one or more halogens and C1-6alkoxy optionally substituted with one or more halogens, R2 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -N-N- or - (C-O)NR4;
R3 represents hydrogen, C1-6 alkyl, or C1-6alkoxycarbonyl;
R4 represents hydrogen or C1-6alkyl:
R5 represents -N-C- or -C-N-;
R6 represents hydrogen or C1-6 alkyl;
R7, R8, R9, R10 and R11, which are the same or different each represent hydrogen, halogen. nitro, , hydroxy, S(O)nR4 where n is 0, 1 or 2, C-N, CON(R4)2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -N(R4)2, NR4N(R4)2, -NHR4-C(R4)2, -NR4(C-O)CH(N(R4)2)R4, -NR4(C-O)R4, NR4CO2R4, C1-6alkoxycarbonylamino, PhN-N, C1-6alkyl optionally substituted with one or more halogens or C1-6alkoxy optionally substituted with one or more halogens, or when considered in pairwise combination, R7 and R8 or R8 and R9 or R9 and R10 or R10 and R11 represent V represents O or S:
Z represents C4-8alkylene, optionally interrupted by -S(O)n -where n is 0, 1 or 2, C4-8alkenylene or C4-8alkynylene;
X represents N or C:
W represents a group of formula (d) where A represents CR4 or N; B represents oxygen, NR4 or S(O)n , where n=0, 1 or 2 and R12 represents hydrogen or halogen.
2. A compound, salt, solvate or derivative according to claim 1, wherein the nitrogen of formula (I) which is adjacent to Z and which is part of the monocyclic six-membered ring is in its oxidised form as N-oxide.
3. A compound, salt, solvate or derivative according to either claim 1 or claim 2, wherein Y is a group of formula (a) and R1 is H or Cl;
R2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -(C-O)NH- or -N-N-; and ~~~~ represents a double bond in each case;
R3 is -CO2Et or H; and R4 is H or Me.
R2 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -(C-O)NH- or -N-N-; and ~~~~ represents a double bond in each case;
R3 is -CO2Et or H; and R4 is H or Me.
4. A compound, salt, solvate or derivative according to claim 3, wherein R1 is H, R2 is -CH2-, -CH2CH2-, -CH2CH2CH2- or -N-N-; and R3 and R4 are H.
5. A compound, salt, solvate or derivative according to claim 4, wherein R2 is -CH2-, -CH2CH2- or -N-N-,
6. A compound, salt, solvate or derivative according to either claim 1 or claim 2, wherein Y is a group of formula (b) and R1 is H, Cl, F, Me, OH, OMe, NO2 or di-Cl; and R5 is -C-N-.
7. A compound, salt, solvate or derivative according to claim 6, wherein R1 is H, Me, F, NO2 or OMe.
8. A compound, salt, solvate or derivative according to claim 7, wherein R1 is H or NO2.
9. A compound, salt, solvate or derivative according to either claim 1 or claim 2, wherein Y is a group of formula (c) and R6 is H or Me;
R7 is H, NH2, NHMe, OH, OMe or NHAc;
R8 is Cl, NHCO2~-Bu, Br or NH2;
R9 is H, OMe, CF3, ~-Bu, N-N-Ph, NHAc, NHCO2~-Bu, Br or NH2;
R10 is H, NO2, Br or Cl; and R11 is H, OMe or OH.
R7 is H, NH2, NHMe, OH, OMe or NHAc;
R8 is Cl, NHCO2~-Bu, Br or NH2;
R9 is H, OMe, CF3, ~-Bu, N-N-Ph, NHAc, NHCO2~-Bu, Br or NH2;
R10 is H, NO2, Br or Cl; and R11 is H, OMe or OH.
10. A compound, salt, solvate or derivative according to claim 9, wherein R6 is H; R7 is NH2, OMe, NHAc or NHMe; R8 is H or Br; R9 is H or Br; R10 is H or Br and R11 is OMe or OH.
11. A compound, salt, solvate or derivative according to claim 10, wherein R8, R9 and R10 are H; R11 is OH and R7 is NH2 or NHMe; or R7 is OMe, R8 is H, R9 is Br, R10 is H and R11 is OH.
12. A compound, salt, solvate or derivative according to any of claims 1 to 11, wherein Z is C4-6 alkylene.
13. A compound, salt, solvate or derivative according to any of claims 1 to 12, wherein W is a group of formula (d) and B is -S- or -O- and R12 is H or F.
14. A compound, salt, solvate or derivative according to claim 13 wherein B is -S- and R12 is H
15. The compounds 2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-1-isoindolinone;
N-(4-(4-(1,2,benzisothiazol-3-yl)-1-piperazinyl)butyl)-3,4-dihy-dro-1(2H)-isoquinolinone;
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)piperidino)butyl)benzamide;
6-(4-(4-(1,2-benzisothazol-3-yl)-1-piperazinyl)butyl)-6,7-dihy-dro-5H-pyrrolo(3,4-B)pyridine-5,7-dione;
N-(4-(4-(1,2-benzisothiazol-3-yl)piperidino)butyl)phthalimide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(methyl-amino)-benzamide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide.
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-benzamide;
(+/-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1-(2H)-phthalazinone;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenzamide;
2-Amino-N-(4-(4-(1,2-benzisoxazol-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
and physiologically acceptable salts and solvates and physiologically functional derivatives and N-oxides thereof.
N-(4-(4-(1,2,benzisothiazol-3-yl)-1-piperazinyl)butyl)-3,4-dihy-dro-1(2H)-isoquinolinone;
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)piperidino)butyl)benzamide;
6-(4-(4-(1,2-benzisothazol-3-yl)-1-piperazinyl)butyl)-6,7-dihy-dro-5H-pyrrolo(3,4-B)pyridine-5,7-dione;
N-(4-(4-(1,2-benzisothiazol-3-yl)piperidino)butyl)phthalimide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-(methyl-amino)-benzamide;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)benzamide.
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-benzamide;
(+/-)-cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1-(2H)-phthalazinone;
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenzamide;
2-Amino-N-(4-(4-(1,2-benzisoxazol-3-yl)-1-piperazinyl)butyl)benzamide;
2-Amino-N-(4-(4-benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)benzamide;
and physiologically acceptable salts and solvates and physiologically functional derivatives and N-oxides thereof.
16. N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenzamide;
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-benzamide;
2-Amino-N-(4-(4-(1,2-benzisoxazol-3-yl)-1-piperazinyl)butyl)-benzamide;
2-Amino-N-(4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)-benzamide:
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenzamide;
and physiologically acceptable salts and solvates and N-oxides and physiologically functional derivatives thereof.
2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-benzamide;
2-Amino-N-(4-(4-(1,2-benzisoxazol-3-yl)-1-piperazinyl)butyl)-benzamide;
2-Amino-N-(4-(4-(benzo(b)thiophen-3-yl)-1-piperazinyl)butyl)-benzamide:
N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-3-bromo-2-hydroxy-6-methoxybenzamide;
and physiologically acceptable salts and solvates and N-oxides and physiologically functional derivatives thereof.
17. 2-Amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-benzamide hydrochloride;
18. The following compounds;
N-(4-(4-(1,2-Benzisothiazol-3-yl)piperidino)butyl)phthalimide;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)-butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-pnhthalazinone;
N-(4-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine)butyl)-phthalimide.
N-(4-(4-(1,2-Benzisothiazol-3-yl)piperidino)butyl)phthalimide;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)-butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-pnhthalazinone;
N-(4-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine)butyl)-phthalimide.
19. A compound of formula (I) as defined in either claim 1 or claim 2, or a pnysiologically acceptable salt or solvate or N-oxide or physiologically functional derivative thereof, for use in therapy.
20. The use of any of the following compounds, or a physiologically acceptable salt, solvate or N-oxide thereof or physiologically functional derivative thereof; in therapy;
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-Nitro-phthalimide;
3-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4(3H)-quinazolinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1(2H)-phhthalazinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,3(2H,4H)-isoquinolinedione;
N-(4-(4-(1,2-Benzisothiazol-3-yl)piperidino)butyl)phthalimide;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)-butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
N-(4-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino)butyl)-phthalimide.
N-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4-Nitro-phthalimide;
3-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-4(3H)-quinazolinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1(2H)-phhthalazinone;
2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)butyl)-1,3(2H,4H)-isoquinolinedione;
N-(4-(4-(1,2-Benzisothiazol-3-yl)piperidino)butyl)phthalimide;
(+-)-Cis-2-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
(+-)-Trans-2-(4-(4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl)-butyl)-4A,5,6,7,8,8A-hexahydro-1(2H)-phthalazinone;
N-(4-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino)butyl)-phthalimide.
21. A pharmaceutical composition comprising a compound of formula (I) (as defined in either claim 1 or claim 2), or a physiologically acceptable salt or solvate or N-oxide or physiologically functional derivative thereof.
22. A pharmaceutical composition comprising any one of the compounds described in claim 20 or a salt, solvate, N-oxide or derivative thereof.
23. The use of a compound of formula (I) (as defined in claim 1 or 2), or a physiologically acceptable salt or solvate or N-oxide or physiologically functional derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of a disorder selected from the following:
anxiety, muscle spasm, depression, aggression associated with senile dementia, borderline personality disorders. emesis and psychosis.
anxiety, muscle spasm, depression, aggression associated with senile dementia, borderline personality disorders. emesis and psychosis.
24. The use according to claim 23 of a compound of formula (I) (as defined in either claim 1 or 2), or a physiologically acceptable salt or solvate or N-oxide or physiologically functional derivative thereof, wherein the disorder is a psychotic disorder.
25. The use according to claim 24 of a compound of formula (I) (as defined in either claim 1 or claim 2), or a physiologically acceptable salt or solvate or N-oxide or physiologically functional derivative thereof, wherein the disorder is schizophrenia.
26. The use of any of the compounds described in claim 20 or a salt, solvate, N-oxide or derivative thereof, in the preparation of a medicament for use in the treatment of any of the disorders described in claim 23.
27. A process of preparing a compound of formula (I) wherein, Y represents a group of the formula (a), (b) or (c):
wherein a single line accompanying a broken line (~) represents a single bond or a double bond, wherein R1 represents one or more ring substituents selected from the group comprising hydrogen, halogen, C1-6alkyl optionally substituted with one or more halogens, C1-6alkoxy optionally substituted with one or more halogens, hydroxy, -N(R4)2, or nitro, S(O)nR4 where n is 0, 1 or 2, C=N, CONR4 2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -NR4N(R4)2, -NR4N=C(R4)2, -NR4(C=O)CH(NR4)2R4, NR4CO2R4 and -NR4(C=O)R4;
R2 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -N=N-, or -(C=O)NR4-;
R3 represents hydrogen, C1-6alkyl, or C1-6alkoxycarbonyl;
R4 represents hydrogen or C1-6alkyl;
R5 represents -N=C- or -C=N-;
R6 represents hydrogen or C1-6alkyl;
R7, R8, R9, R10 and R11, which are the same or different, each represent hydrogen, halogen, nitro, C1-6alkyl optionally substituted with one or more halogen, C1-6alkoxy optionally substituted with one or more halogen, hydroxy, S(O)nR4 where n is 0, 1 or 2, C=N, CONR4 2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -N(R4)2, -NHN-C(R4)2, -NR4(C=O)CH(N(R4)2)R4, -NR4(C=O)R4, NR4N(R4)2, NR4CO2R4, C1-6alkoxycarbonylamino or PhN=N, or when considered in pairwise combination, R7 and R8 or R8 and R9 or R9 and R10 or R10 and R11 represent V represents O or S, Z represents C1-8alkylene, optionally interrupted by - S(O)n- wherein n is 0, 1 or 2, C4-8alkenylene or C4-8alkynylene;
X represents N or C;
W represents a group of the formula (d) wherein B represents oxygen, NR4 or S(O)n, where n-0, 1 or 2 and R12 represents hydrogen or halogen, comprising the reaction of a compound of formula (II) YH (II) with a compound of formula (III) wherein L is a leaving group, or by reaction of a compound of formula (II) with a compound of formula (IV) wherein A is a suitable anion, and R13 is -(CH2)4- or -(CH2)5 or by reaction of a compound of formula (V) Y~Z~L (V) wherein L is a leaving group, with a compound of formula (VI) or by reaction of a compound of formula (VII) with a compound of formula (VIII) L~W (VIII) wherein L is a leaving group, or when Y is a group of formula (a) in which R2 is -CH2- or -N=N-where a single line accompanying a broken line (~) represents a double bond and V represents oxygen, by cyclisation of a compound of formula (IX) wherein B14 is -CH2OH or -NH2, or by reaction of a compound of formula (X) or (X1) wherein B15 is -CH2-, or -N(R4)(C=V)- and R16 is R5 or -C=C- wherein R17 is R7, -S-L2- or CH2-L2 and L1 is Cl, Br, Ohe or OH, L2 is Cl, Br, Ohs or OTs and with a compound of formula (XI) or when Y represents a group of formula (c) and R7 represents -N(R4)2, by the treatment of a compound of formula X1, where L2 represents hydroxy, V represents oxygen and R16 represents -N(R4)2, with a compound of formula (XI) or when Y is a group of formula (a),(b) or (c) and R1, R7, R8, R9, R10, or R11 is OH, by treatment of the corresponding methoxy derivatives.
or when Y is a group of formula (a), (b) or (c) ant R1, R7, R8, R9, R10, or R11 is N(R4)2 or NR4N(R4)2, by hydrolysis of the corresponding alkoxycarbonylamino derivatives, or when Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10 or R11 is N(R4)2, by reduction of the corresponding nitro derivatives, or when Y is a group of formula (c) and R6 is C1-6 alkyl, by alkylation of the corresponding secondary amide, or when Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10 or R11 is NR4N=C(R4), by reaction of the corresponding hydrazine derivatives with the appropriate ketone and optionally reducing a compound of formula (I) in which Z is C4-8 alkenylene or C4-8 alkenylene to produce another compound of formula (I) in which Z is C4-8 alkylene, and optionally treating a compound of formula (I) where Y is a group of formula (c) and V represents O with a sulfonating reagent to produce another compound of formula (I) where Y is a group of formula (c) and V represents S, and optionally oxidising a compound of formula (I) to produce another compound of formula (I) in which the nitrogen is oxidised to the N-oxide.
wherein a single line accompanying a broken line (~) represents a single bond or a double bond, wherein R1 represents one or more ring substituents selected from the group comprising hydrogen, halogen, C1-6alkyl optionally substituted with one or more halogens, C1-6alkoxy optionally substituted with one or more halogens, hydroxy, -N(R4)2, or nitro, S(O)nR4 where n is 0, 1 or 2, C=N, CONR4 2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -NR4N(R4)2, -NR4N=C(R4)2, -NR4(C=O)CH(NR4)2R4, NR4CO2R4 and -NR4(C=O)R4;
R2 represents -CH2-, -CH2CH2-, -CH2CH2CH2-, -S-, -NR3-, -N=N-, or -(C=O)NR4-;
R3 represents hydrogen, C1-6alkyl, or C1-6alkoxycarbonyl;
R4 represents hydrogen or C1-6alkyl;
R5 represents -N=C- or -C=N-;
R6 represents hydrogen or C1-6alkyl;
R7, R8, R9, R10 and R11, which are the same or different, each represent hydrogen, halogen, nitro, C1-6alkyl optionally substituted with one or more halogen, C1-6alkoxy optionally substituted with one or more halogen, hydroxy, S(O)nR4 where n is 0, 1 or 2, C=N, CONR4 2, COR4, CO2R4, CO-aryl, azido, benzyloxy, -N(R4)2, -NHN-C(R4)2, -NR4(C=O)CH(N(R4)2)R4, -NR4(C=O)R4, NR4N(R4)2, NR4CO2R4, C1-6alkoxycarbonylamino or PhN=N, or when considered in pairwise combination, R7 and R8 or R8 and R9 or R9 and R10 or R10 and R11 represent V represents O or S, Z represents C1-8alkylene, optionally interrupted by - S(O)n- wherein n is 0, 1 or 2, C4-8alkenylene or C4-8alkynylene;
X represents N or C;
W represents a group of the formula (d) wherein B represents oxygen, NR4 or S(O)n, where n-0, 1 or 2 and R12 represents hydrogen or halogen, comprising the reaction of a compound of formula (II) YH (II) with a compound of formula (III) wherein L is a leaving group, or by reaction of a compound of formula (II) with a compound of formula (IV) wherein A is a suitable anion, and R13 is -(CH2)4- or -(CH2)5 or by reaction of a compound of formula (V) Y~Z~L (V) wherein L is a leaving group, with a compound of formula (VI) or by reaction of a compound of formula (VII) with a compound of formula (VIII) L~W (VIII) wherein L is a leaving group, or when Y is a group of formula (a) in which R2 is -CH2- or -N=N-where a single line accompanying a broken line (~) represents a double bond and V represents oxygen, by cyclisation of a compound of formula (IX) wherein B14 is -CH2OH or -NH2, or by reaction of a compound of formula (X) or (X1) wherein B15 is -CH2-, or -N(R4)(C=V)- and R16 is R5 or -C=C- wherein R17 is R7, -S-L2- or CH2-L2 and L1 is Cl, Br, Ohe or OH, L2 is Cl, Br, Ohs or OTs and with a compound of formula (XI) or when Y represents a group of formula (c) and R7 represents -N(R4)2, by the treatment of a compound of formula X1, where L2 represents hydroxy, V represents oxygen and R16 represents -N(R4)2, with a compound of formula (XI) or when Y is a group of formula (a),(b) or (c) and R1, R7, R8, R9, R10, or R11 is OH, by treatment of the corresponding methoxy derivatives.
or when Y is a group of formula (a), (b) or (c) ant R1, R7, R8, R9, R10, or R11 is N(R4)2 or NR4N(R4)2, by hydrolysis of the corresponding alkoxycarbonylamino derivatives, or when Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10 or R11 is N(R4)2, by reduction of the corresponding nitro derivatives, or when Y is a group of formula (c) and R6 is C1-6 alkyl, by alkylation of the corresponding secondary amide, or when Y is a group of formula (a), (b) or (c) and R1, R7, R8, R9, R10 or R11 is NR4N=C(R4), by reaction of the corresponding hydrazine derivatives with the appropriate ketone and optionally reducing a compound of formula (I) in which Z is C4-8 alkenylene or C4-8 alkenylene to produce another compound of formula (I) in which Z is C4-8 alkylene, and optionally treating a compound of formula (I) where Y is a group of formula (c) and V represents O with a sulfonating reagent to produce another compound of formula (I) where Y is a group of formula (c) and V represents S, and optionally oxidising a compound of formula (I) to produce another compound of formula (I) in which the nitrogen is oxidised to the N-oxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9202915.6 | 1992-02-12 | ||
| GB929202915A GB9202915D0 (en) | 1992-02-12 | 1992-02-12 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2117434A1 true CA2117434A1 (en) | 1993-08-19 |
Family
ID=10710223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117434A Abandoned CA2117434A1 (en) | 1992-02-12 | 1993-02-11 | Piperazine and piperidine derivatives, and their use as antipsychotics |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0625978A1 (en) |
| JP (1) | JPH07503723A (en) |
| KR (1) | KR950700290A (en) |
| AU (1) | AU3460393A (en) |
| CA (1) | CA2117434A1 (en) |
| CZ (1) | CZ194994A3 (en) |
| FI (1) | FI943718A0 (en) |
| GB (1) | GB9202915D0 (en) |
| HU (1) | HUT72309A (en) |
| IL (1) | IL104690A0 (en) |
| MX (1) | MX9300786A (en) |
| NO (1) | NO942977L (en) |
| RU (1) | RU94038064A (en) |
| SK (1) | SK96494A3 (en) |
| WO (1) | WO1993016073A1 (en) |
| ZA (1) | ZA93958B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5776963A (en) * | 1989-05-19 | 1998-07-07 | Hoechst Marion Roussel, Inc. | 3-(heteroaryl)-1- (2,3-dihydro-1h-isoindol-2-yl)alkyl!pyrrolidines and 3-(heteroaryl)-1- (2,3-dihydro-1h-indol-1-yl)alkyl!pyrrolidines and related compounds and their therapeutic untility |
| US5364866A (en) * | 1989-05-19 | 1994-11-15 | Hoechst-Roussel Pharmaceuticals, Inc. | Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analetics |
| RU2118322C1 (en) * | 1993-07-05 | 1998-08-27 | Дюфар Интернэшнл Рисерч Б.В. | 2,3-dihydro-1,4-benzodioxine-5-yl-pyrerazine derivatives and salts thereof |
| ATE246682T1 (en) * | 1993-12-24 | 2003-08-15 | Daiichi Suntory Pharma Co Ltd | BENZOTHIAZINE DERIVATIVES |
| US5874429A (en) * | 1993-12-24 | 1999-02-23 | Suntory Limited | Benzothiazine derivative |
| JPH0912562A (en) * | 1995-06-22 | 1997-01-14 | Suntory Ltd | Substituted benzothiazine derivative |
| US6001827A (en) * | 1993-12-24 | 1999-12-14 | Suntory Limited | Benzothiazine derivative |
| JP3948744B2 (en) * | 1994-11-04 | 2007-07-25 | 大日本住友製薬株式会社 | Novel lactam derivatives |
| EP0732332B1 (en) * | 1995-03-17 | 2001-12-19 | Aventis Pharmaceuticals Inc. | Substituted benzothienylpiperazines, their use as medicaments, and processes for their preparation |
| US6087364A (en) * | 1998-01-29 | 2000-07-11 | Warner-Lambert Company | Dopamine D4 receptor antagonists |
| DE19814084B4 (en) | 1998-03-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | D2 agonist-containing transdermal therapeutic system for the treatment of Parkinson's syndrome and process for its preparation |
| US7030142B1 (en) | 1999-04-06 | 2006-04-18 | Sepracor Inc. | Methods for the treatment of neuroleptic and related disorders using ziprasidone metabolites |
| EP1165083A2 (en) * | 1999-04-06 | 2002-01-02 | Sepracor Inc. | Methods and compositions for the treatment of psychotic and related disorders using ziprasidone metabolites |
| AR028685A1 (en) | 2000-06-14 | 2003-05-21 | Lundbeck & Co As H | INDOL DERIVATIVES |
| US8246979B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system for the administration of rotigotine |
| DE10234673B4 (en) | 2002-07-30 | 2007-08-16 | Schwarz Pharma Ag | Hot-melt TTS for the administration of rotigotine and process for its preparation, and use of rotigotine in the manufacture of a hot-melt TTS |
| US8246980B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
| DE60327634D1 (en) | 2002-08-22 | 2009-06-25 | Dainippon Sumitomo Pharma Co | MEANS FOR TREATING THE INTEGRATION DYSFUNCTION SYNDROME |
| DE10261696A1 (en) | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Device for the transdermal administration of rotigotine base |
| EP1637530A4 (en) * | 2003-06-23 | 2009-04-01 | Dainippon Sumitomo Pharma Co | Therapeutic agent for senile dementia |
| DE10334188B4 (en) | 2003-07-26 | 2007-07-05 | Schwarz Pharma Ag | Use of rotigotine to treat depression |
| EP1726952A4 (en) | 2004-02-20 | 2008-06-18 | Dainippon Sumitomo Pharma Co | Method of in vivo screening of therapeutic agent for memory/learning dysfunction by schizophrenia |
| EA200900937A1 (en) * | 2007-01-03 | 2009-12-30 | Кортекс Фармасеутикалс, Инк. | COMPOUNDS OF 3-SUBSTITUTED- [1,2,3] BENZOTRIAZINONE FOR STRENGTHENING GLUTAMATERGIC SYNAPTIC RESPONSES |
| US8258139B2 (en) | 2010-11-08 | 2012-09-04 | Dainippon Sumitomo Pharma Co., Ltd. | Method of treatment for mental disorders |
| GB201102248D0 (en) | 2011-02-09 | 2011-03-23 | Isis Innovation | Treatment of bipolar disorder |
| EP2736905A4 (en) * | 2011-07-28 | 2015-07-29 | Mapi Pharma Ltd | Intermediate compounds and process for the preparation of lurasidone and salts thereof |
| WO2015014442A1 (en) * | 2013-07-31 | 2015-02-05 | Merck Patent Gmbh | Oxoquinazolinyl-butanamide derivatives |
| CN105669665A (en) * | 2016-03-15 | 2016-06-15 | 烟台贝森医药科技有限公司 | Preparation method of perospirone |
| US11246905B2 (en) | 2016-08-15 | 2022-02-15 | President And Fellows Of Harvard College | Treating infections using IdsD from Proteus mirabilis |
| CN115124464B (en) * | 2022-07-04 | 2023-06-06 | 新乡学院 | Quinoline diketone sulfonyl piperazine hybrid, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2258843B1 (en) * | 1974-01-30 | 1977-09-09 | Roussel Uclaf | |
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
| JPH0625181B2 (en) * | 1985-03-27 | 1994-04-06 | 住友製薬株式会社 | New imide derivative |
| JP2660407B2 (en) * | 1986-09-26 | 1997-10-08 | 住友製薬株式会社 | New imide derivatives |
| CA1335289C (en) * | 1987-10-26 | 1995-04-18 | Fujio Antoku | Piperidinyl benzisoxazole derivatives, their production and pharmaceutical use |
| US5001130A (en) * | 1988-02-18 | 1991-03-19 | Bristol-Myers Company | Psychotropic heterobicycloalkylpiperazine derivatives |
| US4780466A (en) * | 1988-03-17 | 1988-10-25 | Hoechst-Roussel Pharmaceuticals, Inc. | Arylpiperazinylalkoxy derivatives of cyclic imides |
| NZ230045A (en) * | 1988-08-05 | 1990-11-27 | Janssen Pharmaceutica Nv | 3-piperazinylbenzazole derivatives and pharmaceutical compositions |
| US4968792A (en) * | 1989-09-25 | 1990-11-06 | American Home Products Corporation | Psychotropic benzisothiazole derivatives |
| JP2800953B2 (en) * | 1990-07-06 | 1998-09-21 | 住友製薬株式会社 | New imide derivatives |
-
1992
- 1992-02-12 GB GB929202915A patent/GB9202915D0/en active Pending
-
1993
- 1993-02-11 HU HU9402343A patent/HUT72309A/en unknown
- 1993-02-11 EP EP93903266A patent/EP0625978A1/en not_active Withdrawn
- 1993-02-11 SK SK964-94A patent/SK96494A3/en unknown
- 1993-02-11 WO PCT/GB1993/000285 patent/WO1993016073A1/en not_active Application Discontinuation
- 1993-02-11 CZ CZ941949A patent/CZ194994A3/en unknown
- 1993-02-11 ZA ZA93958A patent/ZA93958B/en unknown
- 1993-02-11 CA CA002117434A patent/CA2117434A1/en not_active Abandoned
- 1993-02-11 JP JP5513907A patent/JPH07503723A/en active Pending
- 1993-02-11 AU AU34603/93A patent/AU3460393A/en not_active Abandoned
- 1993-02-11 IL IL104690A patent/IL104690A0/en unknown
- 1993-02-11 RU RU94038064/04A patent/RU94038064A/en unknown
- 1993-02-12 MX MX9300786A patent/MX9300786A/en unknown
-
1994
- 1994-08-11 NO NO942977A patent/NO942977L/en unknown
- 1994-08-11 FI FI943718A patent/FI943718A0/en unknown
- 1994-08-12 KR KR1019940702790A patent/KR950700290A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA93958B (en) | 1994-08-11 |
| AU3460393A (en) | 1993-09-03 |
| EP0625978A1 (en) | 1994-11-30 |
| NO942977L (en) | 1994-10-10 |
| KR950700290A (en) | 1995-01-16 |
| SK96494A3 (en) | 1995-07-11 |
| FI943718A (en) | 1994-08-11 |
| NO942977D0 (en) | 1994-08-11 |
| MX9300786A (en) | 1994-03-31 |
| CZ194994A3 (en) | 1995-09-13 |
| GB9202915D0 (en) | 1992-03-25 |
| FI943718A0 (en) | 1994-08-11 |
| WO1993016073A1 (en) | 1993-08-19 |
| HU9402343D0 (en) | 1994-10-28 |
| IL104690A0 (en) | 1993-06-10 |
| HUT72309A (en) | 1996-04-29 |
| JPH07503723A (en) | 1995-04-20 |
| RU94038064A (en) | 1997-05-27 |
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