WO2000043383A1 - Piperidinylquinolines utilisees comme inhibiteurs de la proteine tyrosine kinase - Google Patents

Piperidinylquinolines utilisees comme inhibiteurs de la proteine tyrosine kinase Download PDF

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Publication number
WO2000043383A1
WO2000043383A1 PCT/EP2000/000350 EP0000350W WO0043383A1 WO 2000043383 A1 WO2000043383 A1 WO 2000043383A1 EP 0000350 W EP0000350 W EP 0000350W WO 0043383 A1 WO0043383 A1 WO 0043383A1
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alkyl
hydroxy
formula
compound
optionally substituted
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PCT/EP2000/000350
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English (en)
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David Thomas Davies
Caroline Joan Henry
Neil David Pearson
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Smithkline Beecham P.L.C.
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Priority claimed from GBGB9901236.1A external-priority patent/GB9901236D0/en
Priority claimed from GBGB9923936.0A external-priority patent/GB9923936D0/en
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to JP2000594799A priority Critical patent/JP2002535323A/ja
Priority to EP00902605A priority patent/EP1144404A1/fr
Priority to AU24379/00A priority patent/AU2437900A/en
Publication of WO2000043383A1 publication Critical patent/WO2000043383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to novel medicaments, being novel antibacterial compounds and compositions.
  • WO9217475, WO9802438, WO9703069 and WO9639145 disclose certain bicyclic heteroaromatic compounds having cholinesterase inhibitor, protein tyrosine kinase inhibitor, cell proliferation inhibitor and human epidermal growth factor receptor type 2 inhibitor activity.
  • This invention provides a method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment of an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof:
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is N or CR l a and the remainder are CH;
  • R! is selected from hydroxy; (C . ⁇ ) alkoxy optionally substituted by (C ⁇ _6)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C ⁇ _ 6)alkyl, acyl or (C ⁇ _6)alkylsulphonyl groups, NH2CO, hydroxy, thiol, (C ⁇ _6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (Ci .
  • R ⁇ a is selected from hydrogen and the groups listed above for R* ;
  • R3 is in the 2- or 3-position and is: carboxy; (Cj_6)alkoxycarbonyl; aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C ⁇ _6)alkyl, hydroxy(C ⁇ _6)alkyl, (C2- g)alkenyl, (C ⁇ _6)alkylsulphonyl, trifluoromethylsulphonyl, (C ⁇ _6)alkenylsulphonyl, (Ci .
  • R 4 is a group -CH2-R ⁇ in which R ⁇ is selected from:
  • n 0, 1 or 2;
  • A-B is NHC(O)NH or NHC(O)O, or
  • A is NR 1 1, O, S(O) x or CR 6 R 7 and B is NR 1 1, O, S(O) x or CR 8 R 9 where x is 0, 1 or 2 and wherein: each of R ⁇ and R 7 R 8 and R 9 is independently selected from: H; thiol; (C ⁇ _6)alkylthio; halo; trifluoromethyl; azido; (C ⁇ ..6)alkyl; (C2-6)alkenyl; (C ⁇ _6)alkoxycarbonyl; (C ⁇ _
  • a and B cannot both be selected from NR ⁇ A O and S(O) x and when one of A and B is CO the other is not CO, O or S(O) x .
  • the invention provides a method according to the invention wherein in compounds of formula (I) Rl and R ⁇ a are selected from the groups listed above other than trifluoromethyl.
  • the invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for use in the treatment of bacterial infections in mammals.
  • the invention also provides a pharmaceutical composition for use in the treatment of bacterial infections in mammals comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment of bacterial infections in mammals comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
  • Z 5 is CH or N and Z -Z 4 are each CH.
  • R! or R a is substituted alkoxy it is preferably C2-6 alkoxy substitituted by optionally N-substituted amino, guanidino or amidino, or C ⁇ _6alkoxy substituted by piperidyl.
  • R* alkoxy examples include methoxy, n-propyloxy, i-butyloxy, aminoethyloxy, aminopropyloxy, aminopentyloxy, guanidinopropyloxy, piperidin-4- ylmethyloxy, phthalimido pentyloxy or 2-aminocarbonylprop-2-oxy.
  • R* is methoxy, amino- or guanidino-(C3_5)alkyloxy, guanidino(C3_5)alkyloxy, pi ⁇ eridyl(C3_ 5)alkyloxy, nitro or fluoro, most preferably methoxy.
  • R a is preferably hydrogen.
  • R3 preferably contains carboxy, cyano or 2-oxo-oxazolidinyl optionally substituted by R 10 .
  • R 3 is substituted alkyl is it preferably substituted methyl.
  • R 3 include CO 2 H, CH 2 CO H, (CH 2 )2CO 2 H, (CH 2 )2CN, CONH 2 ,
  • R 3 is preferably in the 3-position. R 3 is most preferably CH2CO2H or 2-oxo-oxazolidinyl.
  • A is NH, NCH3, O, CH , CHOH, CH(NH 2 ), C(Me)(OH) or CH(Me).
  • B is CH 2 , CHOH or CO.
  • n is 0 or 1. More preferably: when A is NH, B is CO and n is 1 or 0; when A is O, B is CH2 and n is 1 or 0; when A is CH2 or CH2OH, B is CH2, and n is 1 or 0; when A is NCH3, CH(NH 2 ), C(Me)(OH) or CH(Me), B is CH 2 and n is 1; when A is CR 6 R 7 and B CR 8 R 9 and R 6 and R 8 together represent -O- and R 7 and R 9 are both hydrogen and n is 1.
  • AB(CH2) n is most preferably (CH2>3.
  • Suitable groups R 4 include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, methoxybutyl, phenylethyl, phenylpropyl or 3-phenyl-prop-2-en-yl optionally substituted on the phenyl ring, 3-benzoylpropyl, 4-benzoylbutyl, 3-pyridylmethyl, 3-(4- fluorobenzoyl)propyl, cyclohexylmethyl, cyclobutylmethyl, t- butoxycarbonylaminomethyl and phenoxyethyl.
  • R 4 is (C5_ ⁇ o)alkyl, unsubstituted phenyl(C2-3)alkyl or unsubstituted phenyl(C3_4)alkenyl, more preferably hexyl, heptyl, 5-methylhexyl, 6-methyl heptyl, 3- phenyl-prop-2-en-yl or 3-phenylpropyl, most preferably n-heptyl.
  • R ⁇ is unbranched at the ⁇ and, where appropriate, ⁇ positions.
  • Halo or halogen includes fluoro, chloro, bromo and iodo.
  • heterocyclic ' as used herein includes aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from optionally substituted amino, halogen, (C ⁇ _ 6>alkyl, (C ⁇ _6)alkoxy, halo(C ⁇ _6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C ⁇ _6)alkoxycarbonyl, (C ⁇ -6)alkoxycarbonyl(C ⁇ _6)alkyl, aryl, and oxo groups.
  • Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
  • a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
  • Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
  • suitable optional substituents in such substituted amino groups include (C ⁇ _6)alkyl optionally substituted by hydroxy, (C ⁇ _6)alkoxy, thiol, (C . 6)alkylthio, halo or trifluoromethyl, and amino-protecting groups such as acyl or (C ⁇ _ 6)alkylsulphonyl groups.
  • lieteroaryr includes the aromatic heterocyclic groups referred to above.
  • heteroaryl groups include pyridyl, triazolyl, tetrazolyl, indolyl, thienyl, isoimidazolyl, thiazolyl, fi ⁇ ranyl,quinolinyl, imidazolidinyl and benzothienyl.
  • the term 'aryl' includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C ⁇ _6)alkyl, phenyl, (C ⁇ _g)alkoxy, hydroxy(C ⁇ _6)alkyl, mercapto (C ⁇ _6)alkyl, halo(C ⁇ _6)alkyl, hydroxy, optionally substituted amino, nitro, carboxy, (Cj. 6)alkylcarbonyloxy, (C ⁇ _6)alkoxycarbonyl, formyl, or (C ⁇ _6)alkylcarbonyl groups.
  • acyl' includes (C ⁇ _6)alkoxycarbonyl, formyl or (Ci -. ⁇ ) alkylcarbonyl group.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (IA), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
  • Some of the compounds of this invention may be crystallised or recrystallised from solvents such as organic solvents. In such cases solvates may be formed.
  • This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis).
  • Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 59% of a compound of the formula (I) or salt thereof.
  • compositions of the above-mentioned compounds of formula (I) include the free base form or their acid addition or quaternary ammonium salts, for example their salts with mineral acids e.g. hydrochloric, hydrobromic, sulphuric nitric or phosphoric acids, or organic acids, e.g. acetic, fumaric, succinic, maleic, citric, benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acid or tartaric acids.
  • Compounds of formula (I) may also be prepared as the N-oxide.
  • Compounds of formula (I) having a free carboxy group may also be prepared as an in vivo hydrolysable ester. The invention extends to all such derivatives.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester- forming groups include those forming esters which break down readily in the human body to leave the parent acid or its salt. Suitable groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
  • R a is hydrogen, (C ⁇ _6) alkyl, (C3.7) cycloalkyl, methyl, or phenyl
  • R ⁇ is (Cj.g) alkyl, (C g) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3-.7) cycloalkyloxy, (C ⁇ _6) alkyl (C3.7) cycloalkyl, 1-amino (C . ) alkyl, or l-(C ⁇ _6 alkyl)amino (C ⁇ . ) alkyl; or R a and R D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R c represents ( .
  • alkylene optionally substituted with a methyl or ethyl group and R ⁇ and R e independently represent (C ⁇ . ) alkyl;
  • R ⁇ represents (C . ) alkyl;
  • RS represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C ⁇ ) alkyl, or (C ⁇ . ) alkoxy;
  • Q is oxygen or NH;
  • R* 1 is hydrogen or (C _£) alkyl;
  • R 1 is hydrogen, (C g) alkyl optionally substituted by halogen, (C2-6) alkenyl, (C .
  • R* 1 and R 1 together form (Cj.g) alkylene;
  • R) represents hydrogen, (C ⁇ . ) alkyl or (C . ) alkoxycarbonyl; and
  • R ⁇ represents (C ⁇ .g) alkyl, (C ⁇ . ⁇ ) alkoxy, (C ⁇ . ) alkoxy(C ⁇ _6)alkoxy or aryl.
  • Suitable in vivo hydrolysable ester groups include, for example, acyloxy(C ⁇ _6)alkyl groups such as acetoxymethyl, pivaloyloxymethyl, ⁇ -acetoxyethyl, ⁇ -pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l-yl, and (l-aminoethyl)carbonyloxymethyl; (Cj.6)alkoxycarbonyloxy(C ⁇ _6)alkyl groups, such as ethoxycarbonyloxymethyl, ⁇ -ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; di(C ⁇ _6) a ⁇ yla ⁇ ino(C ⁇ _6)alkyl especially di(C ⁇ _4)alkylamino(C ⁇ _4)alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethy
  • a further suitable pharmaceutically acceptable in vivo hydrolysable ester-forming group is that of the formula:
  • R ⁇ is hydrogen, C ⁇ . alkyl or phenyl.
  • R is preferably hydrogen.
  • Certain of the above-mentioned compounds of formula (I) may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the invention includes compound in which an A-B group CH(OH)-CH2 is in either isomeric configuration, the R-isomer is preferred.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • TT-T? are Z ⁇ -Z ⁇ or groups convertible thereto
  • R ⁇ , R* , R , R 3 ' and R 4 ' are R! 1, Rl, R 2 , R 3 and R 4 or groups convertible thereto, and thereafter optionally or as necessary converting R 1 *', R 1 ' , R 2 ', R 3 ' and R 4 ' to R 1 1 R 1 , R 2 , R 3 and R 4 , converting Z 1 -Z 5 ' to Z!-Z 5 , converting A-B to other A-B, interconverting R 1 A R , R 2 , R 3 and/or R 4 and forming a pharmaceutically acceptable derivative thereof.
  • Process variant (a)(iii) and (c) in other aspects initially produces compounds of formula (I) wherein A-B is CH 2 CHOH or CHOHCH 2 .
  • Process variant (a)(iv) initially produces compounds of formula (I) wherein A-B is CH 2 CHOH. .
  • Process variant (a)(x) initially produces compounds of formula (I) wherein A-B is CONHRl l or NHRl lCO.
  • Process variant (a)(xi) initially produces compounds of formula (I) wherein one of A and B is CH2 and the other is NHR 1 1 , O or S.
  • Process variant (a)(xiii) initially produces compounds of formula (I) wherein A-B is OCH 2 or CH O.
  • Process variant (a)(xiv) initially produces compounds of formula (I) where A-B is NHC(O)NH or NHC(O)O.
  • Process variant (b) initially produces compounds of formula (I) wherein A is CH2 and B is NHR 1 1 or O.
  • M is preferably an alkali metal, more preferably Li.
  • the reaction is conducted in an aprotic solvent preferably THF, ether or benzene at -78 to 25°C.
  • An analogous route is described in G. Grethe et al (1972) Helv. Chimica.Acta., 55, 1044.
  • the process is two step: firstly a condensation using a base, preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide, preferably in an aprotic solvent e.g. ether, THF or benzene; secondly, hydrolysis using an inorganic acid, preferably HC1 in aqueous organic solvent at 0- 100°C.
  • a base preferably sodium hydride or alkoxide, sodamide, alkyl lithium or lithium dialkylamide
  • an aprotic solvent e.g. ether, THF or benzene
  • hydrolysis using an inorganic acid preferably HC1 in aqueous organic solvent at 0- 100°C.
  • a base is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide e.g.di- isopropylamide.
  • an analogous method is described in US 3989691 and in Taylor et al. (1972) JACS 94, 6218)
  • the reaction is carried out in the presence of a base, preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt, preferably in an aprotic solvent, preferably THF, ether or benzene at -78 to 25°C (analogous process in Gutswiller et al. (1978) JACS 100, 576).
  • a base preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt
  • an aprotic solvent preferably THF, ether or benzene
  • reaction is carried out in the presence of a base, preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt, preferably in an aprotic solvent, preferably THF, ether or benzene at -78 to 25°C.
  • a base preferably organometallic or metal hydride e.g. NaH, lithium diisopropylamide or NaOEt
  • an aprotic solvent preferably THF, ether or benzene at -78 to 25°C.
  • process variant (a)(vi) a similar Claisen methodology to that described for (a)(ii) is used, analogous to that described in Soszko et. al., Pr. Kom.Mat. Przyr.Poznan.Tow.Przyj.Nauk., (1962), 10, 15.
  • a base it is preferably NaH, KH, an alkyl lithium e.g. BuLi, a metal alkoxide e.g. NaOEt, sodamide or lithium dialkylamide e.g.di- isopropylamide.
  • An analogous method is described in US 3989691 and M. Gates et. al.
  • reaction is carried out using palladium catalysis.
  • the palladium catalyst is preferably palladium acetate in the presence of trialkyl or triaryl phosphine and a trialkylamine e.g. triphenyl phosphine and tributylamine.
  • trialkyl or triaryl phosphine and a trialkylamine e.g. triphenyl phosphine and tributylamine.
  • the acid and amide are preferably reacted in the presence of an activating agent such as l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT),
  • an activating agent such as l-(dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBT)
  • a final reduction step provides the required amine.
  • the reaction is a standard amine formation reaction such as direct alkylation described in (Malpass, J. R., in Comprehensive Organic Chemistry, Vol. 2 (Ed. Sutherland, I. O.), p 4 ff.) or aromatic nucleophilic displacement reactions (see references cited in Comprehensive Organic Chemistry, Vol. 6, p 946-947 (reaction index); Smith, D. M. in Comprehensive Organic Chemistry, Vol. 4 (Ed. Sammes, P. G.) p 20 ff.). This is analogous to the methods described in GB 1177849.
  • reaction is a standard reductive alkylation using, e.g., sodium triacetoxyborohydride (Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649).
  • sodium triacetoxyborohydride Gribble, G. W. in Encyclopedia of Reagents for Organic Synthesis (Ed. Paquette, L. A.) (John Wiley and Sons, 1995), p 4649.
  • reaction variant (a)(xiv) the reaction of the compounds of formulae (IV) and (V) is a standard urea or carbamate formation reaction conducted by methods well known to those skilled in the art (for example see March, J; Advanced Organic Chemistry, Edition 3 (John Wiley and Sons, 1985)).
  • the process is preferably carried out in a polar, non-nucleophilic solvent such as N,N-dimethylformamide.
  • the rearrangement may be effected by treatment with an acid, preferably an organic acid such as acetic acid and the reaction temperature is 80- 120°C.
  • an acid preferably an organic acid such as acetic acid and the reaction temperature is 80- 120°C.
  • the compound of formula (II) is quaternised by treatment with an alkylating agent and treated with base such as KOH to give, depending upon the stereochemistry of the OH and the nature of the quaternery salt and base, either the ketone of formula (HI) or an epoxide which can be opened to the alcohol of formula (VII by reduction (see EP0035821 ).
  • the reaction is preferably carries out in an alcohol, preferably methanol under irradiation conditions which are known to generate singlet oxygen as described in M. Ihara et.al. (1988), J.Chem Soc Perkin Trans. 1, 1277.
  • Reduction of A or B CO to CHOH can be readily accomplished using reducing agents well known to those skilled in the art, e.g. sodium borohydride in aqueous ethanol or lithium aluminum hydride in ethereal solution.. This is analogous to methods described in EP 53964, US 384556 and J. Gutzwiller et. al. (1978) J.Amer.Chem.Soc, 100, 576.
  • the carbonyl group A or B may be reduced to CH2 by treatment with a reducing agent such as hydrazine in ethylene glycol at 130-160°C in the presence of potassium hydroxide.
  • a reducing agent such as hydrazine in ethylene glycol at 130-160°C in the presence of potassium hydroxide.
  • Reaction of a carbonyl group A or B with an organometallic reagent yields a group where R 6 or R 8 is OH and R 7 or R 9 is alkyl.
  • a hydroxy group in A or B may be oxidised to a carbonyl group by oxidants well known to those skilled in the art , for example, manganese dioxide, pyridinium chlorochromate or pyridinium dichromate.
  • An A-B group COCH2 may be converted to COCH-halogen, by treating the ketone or a derivative with a halogenating agent, reduced to CHOHCHC1 and then converted to the epoxide which may in turn be reduced to CH2CHOH.
  • An amide group CONHR 1 1 ' or NHR 1 ⁇ CO may be reduced to the amine using a reducing agent such as lithium aluminium hydride
  • a ketone group may be converted to an amide CONH via the oxime by a Beckmann rearrangement (Ogliaruso, M.A.; Wolfe, J. F., ibid, pp 450-451; Beckwith, A. L. I., ibid, pp 131 ff.)
  • a hydroxy group in A or B may be converted to azido by activation and displacement e.g. under Mitsunobu conditions using hydrazoic acid or by treatment with diphenylphosphorylazide and base, and the azido group in turn may be reduced to amino by hydrogenation.
  • a sulphur group A or B may be converted to the sulphoxide S(O) x by oxidation with peracids or a wide range of oxidants known to those skilled in the art (see Advanced Organic Chemistry (Ed. March, J.) (John Wiley and Sons, 1985), p 1089 and refs. cited therein).
  • R 1 ', R 2 ', R 3 ' and R 4 ' are preferably R 1 , R 2 , R 3 and R 4 .
  • R 1 ' is preferably methoxy.
  • R 2 ' is preferably hydrogen.
  • R 3 ' is preferably vinyl or contains a carboylate ester group.
  • R 4 ' is preferably H, R 4 or a protecting group.
  • R 1 ', R 2 ', R 3 ' and R 4 ' and interconversions of R 1 , R 2 , R 3 and R 4 are conventional.
  • suitable conventional hydroxy protecting groups which may be removed without disrupting the remainder of the molecule include acyl and alkylsilyl groups.
  • R 1 ' methoxy is convertible to R 1 ' hydroxy by treatment with lithium and diphenylphosphine (general method described in Ireland et. al. (1973) J.Amer.Chem.Soc.,7829) or HBr.
  • Z 1 -Z ⁇ ' examples are CR l a ' where R l a ' is a group convertible to R l a .
  • R 3 ' alkenyl is convertible to hydroxyalkyl by hydroboration using a suitable reagent such as 9-borabicyclo[3.3.1]nonane, epoxidation and reduction or oxymercuration.
  • R 3 ' 1 ,2-dihydroxy can be prepared from R 3' alkenyl using osmium tetroxide or other reagents well known to those skilled in the art (see Advanced Organic Chemistry (Ed. March, J.) (John Wiley and Sons, 1985), p 732-737 and refs.
  • Opening an epoxide-containing R 3 ' group with azide anion yields an azide derivative which can be reduced to the amine. Conversion of the amine to a carbamate is followed by ring closure with base to give the 2-oxo-oxazolidinyl containing R 3 group.
  • Substituted 2-oxo-oxazolidinyl containing R 3 groups may be prepared from the corresponding aldehyde by conventional reaction with a glycine anion equivalent, followed by cyclisation of the resulting amino alcohol (M Grauert et al, Ann Chem (1985) 1817, Rozenberg et al, Angew Chem Int Ed Engl (1994) 33(1) 91). The resulting 2-oxo- oxazolidinyl group contains a carboxy group which can be converted to other R 1 ⁇ groups by standard procedures.
  • Carboxy groups within R3 may be prepared by Jones' oxidation of the corresponding alcohols CH2OH using chromium acid and sulphuric acid in water/methanol (E.R.H. Jones et al, J.C.S. 1946,39).
  • Other oxidising agents may be used for this transformation such as sodium periodate catalysed by ruthenium trichloride (G.F.Tutwiler et al, J.Med.Chem., 1987, 30(6), 1094), chromium trioxide-pyridine (G. Just et al, Synth. Commun. 1979, 9(7), 613), potassium permanganate (D.E.Reedich et al, J. Org. Chem.,1985,50(19),3535, and pyridinium chlorochromate (D. Askin et al, Tetrahedron Letters, 1988, 29(3), 277.
  • the carboxy group may alternatively be formed in a two stage process, with an initial oxidation of the alcohol to the corresponding aldehyde using for instance dimethyl sulphoxide activated with oxalyl chloride (N.Cohen etal, J. Am. Chem. Soc, 1983, 105, 3661) or dicyclohexylcarbodiimide (R.M.Wengler, Angew. Chim. Int. Ed. Eng., 1985, 24(2), 77), or oxidation with tetrapropylammonium perruthenate (Ley et al, J. Chem.Soc. Chem Commun., 1987, 1625).
  • dimethyl sulphoxide activated with oxalyl chloride N.Cohen etal, J. Am. Chem. Soc, 1983, 105, 3661
  • dicyclohexylcarbodiimide R.M.Wengler, Angew. Chim. Int. Ed. Eng
  • the aldehyde may then be separately oxidised to the corresponding acid using oxidising agents such as silver (H) oxide (R.Grigg et al, J. Chem. Soc. Perkinl,1983, 1929), potassium permanganate (A.Zurcher, Helv. Chim. Acta., 1987, 70 (7), 1937), sodium periodate catalysed by ruthenium trichloride (T.Sakata et al, Bull. Chem. Soc. Jpn., 1988, 61(6), 2025), pyridinium chlorochromate (R.S.Reddy et al, Synth. Commun., 1988, 18(51), 545) or chromium trioxide (R.M.Coates et al, J. Am. Chem. Soc, 1982, 104, 2198).
  • oxidising agents such as silver (H) oxide (R.Grigg et al, J. Chem. Soc. Perkinl,1983, 1929), potassium per
  • R 3 CO2H group may also be prepared from oxidative cleavage of the corresponding diol, CH(OH)CH2OH, using sodium periodate catalysed by ruthenium trichloride with an acetontrile-carbontetrachloride- water solvent system (V.S.Martin et al, Tetrahedron Letters, 1988, 29(22), 2701).
  • R 3 groups containing a cyano or carboxy group may also be prepared by conversion of an alcohol to a suitable leaving group such as the corresponding tosylate by reaction with para-toluenesulphonyl chloride (M.R.Bell, J. Med. Chem., 1970, 13, 389), or the iodide using triphenylphosphine, iodine, and imidazole (G. Lange, Synth. Commun., 1990, 20, 1473).
  • the second stage is the displacement of the leaving group with cyanide anion (LA.Paquette et al, J. Org. Chem.,1979, 44 (25), 4603; P.A.Grieco et al, J. Org.
  • the tetrazol-5-ylaminocarbonyl group may be prepared from the corresponding carboxylic acid and 2-aminotetrazole by dehydration with standard peptide coupling agents such as l,l'-carbonyldiimidazole (P. L. Ornstein et al, J. Med Chem, 1996, 39 (11), 2232).
  • the alkyl- and alkenyl-sulphonylcarboxamides are similarly prepared from the corresponding carboxylic acid and the alkyl- or alkenyl-sulphonamide by dehydration with standard peptide coupling agents such as 1 , 1 -carbonyldiimidazole (P. L. Ornstein et al, J.Med.Chem., 1996, 39 (11), 2232).
  • hydroxamic acid groups are prepared from the corresponding acids by standard amide coupling reactions eg N. R. Patel et al, Tetrahedron, 1987, 43 (22), 5375 2,4-Thiazolidinedione groups may prepared from the aldehydes by condensation with 2,4-thiazolidinedione and subsequent removal of the olefinic double bond by hydrogenation.
  • l,2,4-Triazol-5-yl groups may be prepared from the corresponding nitrile by reaction with an alcohol under acid conditions followed by reaction with hydrazine and then an R ⁇ -substituted activated carboxylic acid (see JB Polya in 'Comprehensive Heterocyclic Chemistry' Edition 1 p762, Ed AR Katritzky and CW Rees, Pergamon Press, Oxford 1984 and J.J. Ares et al, J. Heterocyclic Chem., 1991, 28(5), 1197).
  • R 3 alkyl or alkenyl may be interconverted by conventional methods, for example hydroxy may be derivatised by esterification, acylation or etherification. Hydroxy groups may be converted to halogen, thiol, alkylthio, azido, alkylcarbonyl, amino, aminocarbonyl, oxo, alkylsulphonyl, alkenylsulphonyl or aminosulphonyl by conversion to a leaving group and substitution by the required group or oxidation as appropriate or reaction with an activated acid, isocyanate or alkoxyisocyanate.
  • Primary and secondary hydroxy groups can be oxidised to an aldehyde or ketone respectively and alkyated with a suitable agent such as an organometallic reagent to give a secondary or tertiary alcohol as appropriate.
  • NH is converted to NR 4 by conventional means such as alkylation with an alkyl halide in the presence of base, acylation/reduction or reductive alkylation with an aldehyde.
  • Compounds of formula (II) include quinine and derivatives thereof.
  • Compounds of formula (VI) are known compounds or may be prepared analogously, see for example Ihara et al JCS Perkin 1 1988, 1277-1281.
  • Compounds of formulae (IV), (V) and (Vb) are known compounds, (see for example Smith et al, J. Amer. Chem. Soc, 1946, 68, 1301) or prepared analogously, see for example the references cited above for reaction variant (a).
  • An isocyanate of formula (IV) may be prepared conventionally.
  • a 4-amino derivative such as 4-amino-quinoline, and phosgene, or phosgene equivalent (eg triphosgene) provide the isocyanate or it may be prepared more conveniently from a 4-carboxylic acid by a 'one-pot' Curtius Reaction with diphenyl phosphoryl azide (DPP A) [see T. Shiori et al. Chem. Pharm. Bull. 35, 2698-2704 (1987)].
  • DPP A diphenyl phosphoryl azide
  • the 4-carboxy derivatives are commercially available or may be prepared by conventional procedures for preparation of carboxy heteroaromatics well known to those skilled in the art.
  • quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield.
  • Pyridazines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volume 3, Ed A.J. Boulton and A.
  • McKillop and napthyridines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A.J. Boulton and A. McKillop.
  • the 4-amino derivatives are commercially available or may be prepared by conventional procedures from a corresponding 4-chloro derivative by treatment with ammonia (O.G. Backeberg et. al., J. Chem Soc, 381, 1942.) or propylamine hydrochloride (R. Radinov et. al., Synthesis, 886, 1986).
  • a 4-chloroquinoline is prepared from the corresponding quinolin-4-one by reaction with phosphorus oxychloride (POCl 3 ) or phosphorus pentachloride, PC1 5
  • a 4-chloroquinazoline is prepared from the corresponding quinazolin-4-one by reaction with phosphorus oxychloride (POCl 3 ) or phosphorus pentachloride, PC1 5 .
  • a quinazolinone and quinazolines may be prepared by standard routes as described by T.A. Williamson in Heterocyclic Compounds, 6, 324 (1957) Ed. R.C. Elderfield.
  • Pyridazines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volume 3, Ed A.J. Boulton and A. McKillop and napthyridines may be prepared by routes analogous to those described in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A.J. Boulton and A. McKillop.
  • 4-Hydroxy-l,5-naphthyridines can be prepared from 3-aminopyridine derivatives by reaction with diethyl ethoxymethylene malonate to produce the 4-hydroxy-3- carboxylic acid ester derivative with subsequent hydrolysis to the acid, followed by thermal decarboxylation in quinoline (as for example described for 4-Hydroxy- [l,5]naphthyridine-3-carboxylic acid, Joe T. Adams et al, J ⁇ mer.Chem.Soc, 1946, 68, 1317).
  • a 4-hydroxy-[l,5]naphthyridine can be converted to the 4-chloro derivative by heating in phosphorus oxychloride.
  • a 4-amino 1 ,5-naphthyridine can be obtained from the 4-chloro derivative by reaction with n-propylamine in pyridine.
  • 6-methoxy-l,5-naphthyridine derivatives can be prepared from 3-amino-6- methoxypyridine.
  • 4-Methyl-l,5-naphthyridines can be prepared by methods well known to those skilled in the art (for example see H. Rapoport and A. D. Batcho, Journal of Organic Chemistry, 1963, 1753-1759). For example, nitrobenzene can be heated with oleum over a period of hours then water and a 3-aminopyridine added with heating. Slow addition of methyl vinyl ketone with heating produces the desired 4-methyl-l,5-naphthyridine.
  • 1,5-Naphthyridines may be prepared by other methods well known to those skilled in the art (for examples see P.A. Lowe in “Comprehensive Heterocyclic Chemistry” Volume 2, p581-627, Ed A.R. Katritzky and CW. Rees, Pergamon Press, Oxford, 1984).
  • the 4-hydroxy and 4-amino-cinnolines may be prepared following methods well known to those skilled in the art [see A.R. Osborn and K. Schofield, J. Chem. Soc. 2100 (1955)].
  • a 2-aminoacetopheneone is diazotised with sodium nitrite and acid to produce the 4- hydroxycinnoline with conversion to chloro and amino derivatives as described for 1 ,5- naphthyridines.
  • a 3-methyl substituent may be introduced by reaction of a 4-chlorocmnohne with lithium diisopropylamide at -75°C followed by alkylation with methyl iodide [see A. Turck et al. Tetrahedron, 47, 13045 ( 1995)].
  • suitable amines may be prepared from the corresponding acid or alcohol (Y is CO2H or CH2OH).
  • Y is CO2H or CH2OH.
  • an N-protected piperidine containing an acid bearing substituent can undergo a Curtius rearrangement and the intermediate isocyanate can be converted to a carbamate by reaction with an alcohol. Conversion to the amine may be achieved by standard methods well known to those skilled in the art used for amine protecting group removal.
  • an acid substituted N-protectedpiperidine can undergo a Curtius rearrangement e.g.
  • an acid group (CH2) n -lCO2H may be converted to (CH2) n NHRj j by reaction with an activating agent such as isobutyl chloro formate followed by an amine R 1 1 NH2 and the resulting amide reduced with a reducing agent such as
  • an N-protected piperidine containing an alcohol bearing substituent undergoes a Mitsunobu reaction (for example as reviewed in Mitsunobu, Synthesis, (1981), 1), for example with succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
  • a Mitsunobu reaction for example as reviewed in Mitsunobu, Synthesis, (1981), 1
  • succinimide in the presence of diethyl azodicarboxylate and triphenylphosphine to give the phthalimidoethylpiperidine.
  • a trans-substituted piperidine moiety of formula (V) may be prepared from the corresponding cis isomer of formula (V) having an R vinyl group in the 3-position with a substituent that can subsequently be converted to the required group (CH2) n Y, for example CH2CO2R
  • R is an alkyl group eg methyl or ethyl
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
  • the antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
  • the composition may be formulated for administration by any route, such as oral, topical or parenteral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.
  • the compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a ⁇ -lactamase inhibitor may be employed.
  • Example la A solution of Example la(231.5g, 0.71 mol) in ethylene glycol (1.01) was treated with hydrazine hydrate (50g, 1.0 mol) over 0.3 h. The mixture was warmed to 120°C for 1.5h. The mixture was then cooled to 10°C and potassium hydroxide (92.7g) was added and the mixture extracted with dichloromethane (2x). The dichloromethane extracts were washed with brine, dried (Na2SO4), and evaporated affording the title compound as a brown oil (217g, 100%). El MH+ 311 C20H26N2O requires 310.
  • Example 2b The above crude product (Example 2b) was dissolved in ethyl acetate and vigorously stirred with an equal volume of saturated aqueous sodium bicarbonate solution. Benzyl chloroformate (1.3 equivalents) was added and the mixture stirred under argon for 5 h. The phases were separated and the ethyl acetate extract dried and evaporated. The crude material was purified by chromatography eluting with an ethyl acetate/hexane gradient. E.I. MH+ 612, C36H41N3O6 requires 611
  • Example 3b was dissolved in dichloromethane-N,N-dimethylformamide and treated with triethylamine (1.2 eq),di-t-butylcarbonic anhydride (1.1 equivalents ) and N,N-dimethylaminopyridine (catalytic quantity). After stirring overnight the mixture was evaporated and purified by chromatography on silica eluting with a gradient of ethyl acetate/hexane, giving the product as an oil ( 3.8g, 34%)
  • Example 3c (2.2g, 5.1 mmol) was dissolved in dichloromethane (50ml), then triethylamine ( 0.85ml, 0.62g, 6.1 mmol), N,N- dimethylaminopyridine (catalytic) and 4-methylphenylsulfonyl chloride (l.lg, 5.6 mmol) were added. After 20h the mixture was diluted with more dichloromethane and washed with water. The organic extract was dried (Na2SO4) and evaporated. Chromatography on silica eluting with ethyl acetate: hexane (1: 1) afforded the product as a yellow oil ( 1.8g, 61%).
  • Example 3d (1.8g, 31mmol) was dissolved in N,N-dimethylformamide (15ml) and treated with sodium cyanide ( 0.3g, 6.2 mmol). The mixture was stirred at room temperature for 16 h then at 40° for lh. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The organic extract was dried (MgSO4) and evaporated to give the product as an oil, (67%). E.I. MH+ 438, C26H35N3O3 requires 437.
  • Example 3f The title compound was prepared from Example 3f by heptylation using the procedure of Example lh, giving the purified product as an oil (0.55g, 62%)
  • Example 1 A solution of Example 1(60 mg, 0.13 mmol) in concentrated hydrochloric acid:dioxane (6 ml:3 ml) was heated to reflux for 4h. The mixture was neutralised with saturated aqueous sodium bicarbonate solution and extracted (3X) with ethyl acetate. The combined organic extracts were dried and evaporated and the crude product chromatographed on silica eluting with aqueous ammonia:methanol:chloroform (1.5:15:50) giving the title compounds as a colourless oil, (0.019g, 30%). E.I. MH+ 471, C28H42N2O3 requires 470.
  • Example 1 A solution of Example 1(48 mg, 0.11 mmol) in concentrated hydrochloric acid:dioxane (5 ml:3 ml) was heated to reflux for 24h. The mixture was neutralised with saturated aqueous sodium bicarbonate solution and extracted (3X) with ethyl acetate. The combined organic extracts were dried and evaporated and the crude product chromatographed on silica eluting with aqueous ammonia:methano:chloroform (1.5:15:50) giving the title compound as a colourless oil, (0.015g, 31%).
  • E.I. MH+ 453, C28H40N2O2 requires 452.
  • the urea (lOe) (0.92g) was treated with dichloromethane (20ml) and trifluoroacetic acid (30ml) at room temperature for 3 hours and evaporated to dryness. It was basified with sodium carbonate solution and evaporated to dryness. The solid was extracted three times with warm ethanol-chloroform (1:9) and evaporated to dryness to afford a foam (0.80g).
  • Example 13b A solution of Example 13b (57g, 140 mmol) in toluene (1 1) was treated with triphenyl phosphine (114g, 440 mmol) and diethylazodicarboxylate (80 ml, 510 mmol). The mixture was heated to reflux for 8h, the cooled and chromatographed eluting with methanol in dichloromethane to give the product as an oil (12g, 22%).
  • El MH + 383 C22H26 2O4 requires 382.
  • Example 12a A solution of Example 12a (12g, 31.4 mmol) in N,N-dimethylformamide (100 ml) was treated with sodium azide (11.7g) and ammonium chloride (lg) and heated at 140° C for 7h. The mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated. The residue was chromatographed on silica eluting with methanol in dichloromethan affording the title compound as an orange foam (2.03g, 15%).
  • Example 12e(105 mg) in N,N-dimethylformamide (3 ml) was treated with potassium carbonate (0.14g) and heptyl iodide (0.2 ml). After 2h the reaction mixture was diluted with ethyl acetate and washed with sodium carbonate solution, brine, dried and evaporated.
  • Example 12f (42 mg, 0.09 mmol) in 2-propanol (5 ml) wastreated with sodium borohydride (20 mg). After 2h the mixture was diluted with water and extracted with dichloromethane. The organic extract was dried and evaporated. Chromatography on silica eluting with methanol in dichloromethan afforded the title compounds as a clear oil (30 mg, 71%),
  • Example 13d A solution of Example 13d (3.58 g) in glacial acetic acid (4 ml) and water (40 ml) was heated at reflux under a flow of argon for 36 hours. The reaction mixture was taken to pH12 with sodium hydroxide solution. The mixture was extracted into ethyl acetate, dried over anyhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. Chromatography on silica gel eluting with 5 to 10 % methanol in dichloromethane gave the compound as an oil (0.830 g, 23%).
  • Amine 13e (0.830g) was heptylated according to the method for example lh to give the compound as an oil (0.856g, 80%).
  • Example 14 [3R, 4R]-l-Heptyl-3-cyanomethyl-4-(2-(R)-hydroxy-3-(6- methoxyquinolin-4-yl)propyl]piperidine a) [3R,4R]- 1 -Heptyl-3-cyanomethyl-4-[2(R),3(R)-oxiranyl-3-(6-methoxyquinolin-4- yl)propyl]piperidine A solution of 13d (3.2 g) in toluene (30 ml) and N,N-dimethylformamide (3ml) was heated at 80°C with heptyl bromide( 1.65ml) overnight under a stream of argon.
  • the MIC ( ⁇ g/ml) of test compounds against various organisms was determined: S. aureus Oxford, S. aureus WCUH29, S. aureus Carter 37, E. faecalis I, M. catarrhalis Ravasio, S. pneumoniae R6.
  • Examples 1 to 8, 12 to 14, 18 to 25, 33 and 36 have an MIC of less than or equal to 1 ⁇ g/ml against one or more of the above range of gram positive and gram negative bacteria.
  • Examples 11, 17, 26 to 32, 34 and 35 showed an MIC of less than or equal to 16 ⁇ g/ml against one or more of the above range of gram positive and gram negative bacteria.
  • Examples 9, 10, 15 and 16 showed an MIC of less than or equal to 64 ⁇ g/ml against one or more of the above range of gram positive and gram negative bacteria.

Abstract

Cette invention a trait à des dérivés de pipéridine, à des procédés de fabrication de ceux-ci ainsi qu'à l'usage qui en est fait pour traiter des infections bactériennes chez des mammifères.
PCT/EP2000/000350 1999-01-20 2000-01-17 Piperidinylquinolines utilisees comme inhibiteurs de la proteine tyrosine kinase WO2000043383A1 (fr)

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US6403610B1 (en) 1999-09-17 2002-06-11 Aventis Pharma S.A. Quinolylpropylpiperidine derivatives, their preparation and the compositions which comprise them
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WO2002056882A1 (fr) * 2001-01-22 2002-07-25 Smithkline Beecham P.L.C. Quinolines et leurs derives azotes substitues en position 4 par un groupe contenant une piperidine et leur utilisation en tant qu'agents antibacteriens
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FR2844270A1 (fr) * 2002-09-11 2004-03-12 Aventis Pharma Sa Derives de la quinolyl propyl piperidine, leur procede et intermediaires de preparation et les compositions qui les contiennent
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JP2004527448A (ja) * 1999-09-17 2004-09-09 アベンテイス・フアルマ・ソシエテ・アノニム キノリルプロピルピペリジン誘導体および抗細菌剤としてのそれらの使用
US6803369B1 (en) 2000-07-25 2004-10-12 Smithkline Beecham Corporation Compounds and methods for the treatment of neoplastic disease
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US6835841B2 (en) 2002-09-13 2004-12-28 Bristol-Myers Squibb Company Asymmetric catalytic hydrogenation process for preparation of chiral cyclic β-aminoesters
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