CA2090767A1 - 1,4-dioxino[2,3-b]pyridine derivatives - Google Patents
1,4-dioxino[2,3-b]pyridine derivativesInfo
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- CA2090767A1 CA2090767A1 CA002090767A CA2090767A CA2090767A1 CA 2090767 A1 CA2090767 A1 CA 2090767A1 CA 002090767 A CA002090767 A CA 002090767A CA 2090767 A CA2090767 A CA 2090767A CA 2090767 A1 CA2090767 A1 CA 2090767A1
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- Prior art keywords
- dioxino
- hydrogen
- pyridine
- pyridine derivative
- formula
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, ***e
Abstract
Abstract:
This invention is concerned with 1,4-dioxino[2,3-b]-pyridine derivatives having formula I
I
wherein each of the groups R is indepenclently selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
R1 is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=O, or SO2; and Y is substituted or unsubstituted 1,2-phenylene, -(CH2)4-, -CH2CR2R3- or -CH2CR2R3CH2-, in which R2 and R3 are independently hydrogen or lower alkyl, or together 1,4-butanediyl or 1,5-pentanediyl; or pharmaceutically acceptable salts thereof.
The compounds according to the invention are strong serotonin ligands with preference for the 5HTlA receptor and may, therefore, find application as anti-depressants or as a drug in combating anxiety disorders.
This invention is concerned with 1,4-dioxino[2,3-b]-pyridine derivatives having formula I
I
wherein each of the groups R is indepenclently selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
R1 is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=O, or SO2; and Y is substituted or unsubstituted 1,2-phenylene, -(CH2)4-, -CH2CR2R3- or -CH2CR2R3CH2-, in which R2 and R3 are independently hydrogen or lower alkyl, or together 1,4-butanediyl or 1,5-pentanediyl; or pharmaceutically acceptable salts thereof.
The compounds according to the invention are strong serotonin ligands with preference for the 5HTlA receptor and may, therefore, find application as anti-depressants or as a drug in combating anxiety disorders.
Description
7 6 ~
1,4-DIOXINOt2,3 b]PYRIDINE DERIVATIVES
The invention relates to 1/4-dioxino[2,3-b]pyridine derivatives having serotonergic activity. The invention is further concerned with a process for t:he preparation of said pyri~ine deriva~ives, with a pharmaceutical compoæition containing the same, and with a use thereof for the preparation of a medicament.
Some 1,4-dioxino[2,3-b]pyridine derivatives are known, for example from ~. Neunhoeffer and 0. Sponheimer ~Chem.
Ber., 123 (1990), 2453-2454), bu~ these compounds have no fun~tionality at the dioxin moiety and no pharmacolo-gical activity is described.
Corresponding derivatives having a benzo[1,4]dioxan moiety are also known. For example, European paterlt application EP 170,213 discloses glutarimide agents having antianxiety and antihypertensive activity, and European patent application EP 236,930 (Example I) and German patent application DE 3,726,~25 (Example 3) disclose 2-[4-[(2,3-dihydro-1,4-benzodioxin 2-yl)methyl-amino]butyl]-1,2-benzisothiazol-3(~H)one-l,1-dioxide.
These compounds, however, although displaying affinity to the 5HT1A receptor, have an unfavourable pharmaco-log;ca~r-profile in comparison with the compounds of the present invention, which render these known compounds less suitable for administration in humans.
!. 30 The compounds of this invention are 1,4-dioxino[2,3-b~-pyridine derivatives having formula I
R~O~ (Cl{/)n N--X
,, .
;~
' ' `~ .
1,4-DIOXINOt2,3 b]PYRIDINE DERIVATIVES
The invention relates to 1/4-dioxino[2,3-b]pyridine derivatives having serotonergic activity. The invention is further concerned with a process for t:he preparation of said pyri~ine deriva~ives, with a pharmaceutical compoæition containing the same, and with a use thereof for the preparation of a medicament.
Some 1,4-dioxino[2,3-b]pyridine derivatives are known, for example from ~. Neunhoeffer and 0. Sponheimer ~Chem.
Ber., 123 (1990), 2453-2454), bu~ these compounds have no fun~tionality at the dioxin moiety and no pharmacolo-gical activity is described.
Corresponding derivatives having a benzo[1,4]dioxan moiety are also known. For example, European paterlt application EP 170,213 discloses glutarimide agents having antianxiety and antihypertensive activity, and European patent application EP 236,930 (Example I) and German patent application DE 3,726,~25 (Example 3) disclose 2-[4-[(2,3-dihydro-1,4-benzodioxin 2-yl)methyl-amino]butyl]-1,2-benzisothiazol-3(~H)one-l,1-dioxide.
These compounds, however, although displaying affinity to the 5HT1A receptor, have an unfavourable pharmaco-log;ca~r-profile in comparison with the compounds of the present invention, which render these known compounds less suitable for administration in humans.
!. 30 The compounds of this invention are 1,4-dioxino[2,3-b~-pyridine derivatives having formula I
R~O~ (Cl{/)n N--X
,, .
;~
' ' `~ .
2 @ ~ ~ r~
wherein each of the groups R is independsntly selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
Rl is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=0, or S02; and Y is substituted or unsubstituted 1,2-phenylene, ( 2)4 CH2CR2R3-, or -CH2CR2R3CH2-, in which R~ and R3 are independently hydrogen or lower alkyl, or together 1,4-but~nediyl or 1,5-pentanediyl; ~r pharmaceutically acceptabls salts thereof.
The compounds according to the invention are strong serotonin liyands with pre~erence for the 5HT~A
receptor. They have a favourable pharmacological profile (as shown, for example, by th~ir favourable ratio for affinity to the 5H~lA receptor with respect to the ~1-adrenoceptor), displaying minimal side-~f~ects like sedation and orthostatic hypotension. The compounds may, therefore, find application as anti-depressants or as a drug in combating anxiety disorders.
The term lower alkyl used in the definition of general formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the ; like.~P~eferred alkyl groups have 1-4 car~on atoms, and ; the most preferred is the methyl group.
The alkyl moiety which is present in the lower alkoxy group has the same meaning as previously defined for lower alkyl.
The term halogen used in the definition of formula I
;~ 35 means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.
., , :
7 ~ 7 The substituents which may be present at the 1,2-phenylene moiety, are selected from hydroxy, lower alkyl, lower alkoxy, CF3, and halogen.
The novel compounds of formula ~ may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HCl, HBr, HI, H2S04, H3P04, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acicl, methane-sulphonic acid, fumaric aci~, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
The compounds o this invention possess one or more chiral carhon atoms, and may therefore be obtained as a pure enantiomsr, or as a mixture of enantiomers, among which the racemic mixture. Methods for obtaining the pure enantiomers are well known in the art, e.g.
synthesis with chiral induction, synthesis starting from chiral intermediates, crystallization o~ salts which are obtained from optically active acids and the racemic mixture, or chromatography using a chiral column.
Preferred compounds according to the invention are the 1,4-dioxino[2,3-b~pyridine derivatives in which R ls hydroge~, or pharmaceutically acceptable salts thereoX.
Other preferred compounds have X is C=O, or pharmaceutically acceptable salts thereof. Most preferred are the 1,4-dioxino~2,3~b]pyridine derivatives in which Rl is hydrogen, n is 4, X is C=O, Y :is -CH2CR2R3CH2 , and R2 and R3 are together 1,4-butanediyl, or pharmaceutically acceptable salts thereof.
The compounds of the invention can be prepared by methods which are in use for the preparation of :
.
2 0 ~ ~ t ~ ~
analogous compounds. A suitable method of preparing the ~ dioxino[2,3-b]pyridine derivatives according to the invention is characterized in that a) a pyridine derivative having the ~ormula II
OH
R~ ~--N"Rl o~ II
R }lal (CH2)n - N--X
wh~rein R, Rl, n, X and Y have the previously given meanings, and Hal is Cl, Br, or I, is cyclized, vr ~ b) an amine having formula III
; 15 ~ ~ ~1 III
wherein R and Rl have the previously given meanings, is condensed with a compound having ~; formula IV
o~,_ 2 5 ~N--X
Hal~ (CH2)n IV
.; ~
wherein Hal, n, X and Y have the previously given meanings, or c) a halide having formula V
:~ R
wherein each of the groups R is independsntly selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
Rl is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=0, or S02; and Y is substituted or unsubstituted 1,2-phenylene, ( 2)4 CH2CR2R3-, or -CH2CR2R3CH2-, in which R~ and R3 are independently hydrogen or lower alkyl, or together 1,4-but~nediyl or 1,5-pentanediyl; ~r pharmaceutically acceptabls salts thereof.
The compounds according to the invention are strong serotonin liyands with pre~erence for the 5HT~A
receptor. They have a favourable pharmacological profile (as shown, for example, by th~ir favourable ratio for affinity to the 5H~lA receptor with respect to the ~1-adrenoceptor), displaying minimal side-~f~ects like sedation and orthostatic hypotension. The compounds may, therefore, find application as anti-depressants or as a drug in combating anxiety disorders.
The term lower alkyl used in the definition of general formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the ; like.~P~eferred alkyl groups have 1-4 car~on atoms, and ; the most preferred is the methyl group.
The alkyl moiety which is present in the lower alkoxy group has the same meaning as previously defined for lower alkyl.
The term halogen used in the definition of formula I
;~ 35 means fluorine, chlorine, bromine or iodine. Fluorine is the preferred halogen.
., , :
7 ~ 7 The substituents which may be present at the 1,2-phenylene moiety, are selected from hydroxy, lower alkyl, lower alkoxy, CF3, and halogen.
The novel compounds of formula ~ may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HCl, HBr, HI, H2S04, H3P04, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acicl, methane-sulphonic acid, fumaric aci~, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
The compounds o this invention possess one or more chiral carhon atoms, and may therefore be obtained as a pure enantiomsr, or as a mixture of enantiomers, among which the racemic mixture. Methods for obtaining the pure enantiomers are well known in the art, e.g.
synthesis with chiral induction, synthesis starting from chiral intermediates, crystallization o~ salts which are obtained from optically active acids and the racemic mixture, or chromatography using a chiral column.
Preferred compounds according to the invention are the 1,4-dioxino[2,3-b~pyridine derivatives in which R ls hydroge~, or pharmaceutically acceptable salts thereoX.
Other preferred compounds have X is C=O, or pharmaceutically acceptable salts thereof. Most preferred are the 1,4-dioxino~2,3~b]pyridine derivatives in which Rl is hydrogen, n is 4, X is C=O, Y :is -CH2CR2R3CH2 , and R2 and R3 are together 1,4-butanediyl, or pharmaceutically acceptable salts thereof.
The compounds of the invention can be prepared by methods which are in use for the preparation of :
.
2 0 ~ ~ t ~ ~
analogous compounds. A suitable method of preparing the ~ dioxino[2,3-b]pyridine derivatives according to the invention is characterized in that a) a pyridine derivative having the ~ormula II
OH
R~ ~--N"Rl o~ II
R }lal (CH2)n - N--X
wh~rein R, Rl, n, X and Y have the previously given meanings, and Hal is Cl, Br, or I, is cyclized, vr ~ b) an amine having formula III
; 15 ~ ~ ~1 III
wherein R and Rl have the previously given meanings, is condensed with a compound having ~; formula IV
o~,_ 2 5 ~N--X
Hal~ (CH2)n IV
.; ~
wherein Hal, n, X and Y have the previously given meanings, or c) a halide having formula V
:~ R
3 5 R~Ol~Hal V
.~ ~
.
`' 5 2 ~ 7 ~` ~
wherein R and Hal have the previously given meanings, is condensed with an amine having formula VI
o~,_ ~N - (~}12)n VI
H
wherein Rl~ n, X and Y have the previously given meanings, after which the compound obt:ained may be separated into its enantiomers and/or converted into a pharmaceutically acceptable salt.
The compounds of the invention may be administered enterally or parenterally, and ~or humans preferably in a daily d~sage of 0,001-10 mg per kg bod~ weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., .: Remington~s Pharmaceuti~al Sciences, (18th ed., Mack ~ 20 Publishing Company, lg90, see especially Part 8:
-~ Pharmaceutical Preparations and Their Manufaature) the : compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable . 25 liquids the compounds can also be applied as an injection preparation in the form of a solution, suspe~on, emulsion, or as a spray, e.g. a nasal spray.
For making dosage units, e.g. tablets, thP use of conventional additives such as fillers, colorants, poly-meric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can ~: be used.
.:~ Suitable carriers with which the compositions can be -. 35 administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
,,~
': ' ~,' .
~$~ 7 The invention is further illustrated by the following examples.
Example 1 1.3-dihydro-2- r N-(2~3-~ihy~E~ dioxinoL2~3-blpy~id~=
3-ylmeth~ 4-aminobutyll-1,3-~ioxo-2H-isnindole a. Under an inert atmosphere 3,B8 g of 2-chloro-3-pyridinol in 60 ml of dry N,N-dimethylforma~ide ~DMF) were added portionwise at room tem~erature to 1,58 g of sodium hydride 50%, which were washed with a minimum amount of tetrahydro~uran (TH~). Then 27,75 g of epichlorohydrin, dissolved in 50 ml of dry DMF, were added, and the reaction mixture was stirred for 48 h at 60 C. When the reaction wa~ terminated, the mixture was cooled and hydrolysed with 150 ml of water. The reaction product was extracted into dichloromethane, the organic layer was wa~hed with 5%
aqueous sodium carbonate and dried over magnesium sul~ate. The solvent was evaporated and the residue was purified by silica chromatography (petroleum ether-diethyl ether 8:2~3:7) to give 5 g (89%) of 2-chloro-3-(oxiranylmethoxy)pyridine. m.p. 34-36 C.
b. Benzylamine (1,79 g) was added to 1,25 g of 2-chloro-3-(oxiranylmethoxy)pyridine in 30 ml of THF, and the ~e~ion mixture was s~irred for 30 h at 60 C. The mixture was cooled, extracted with dichloromethane, and the organic layer was washed with 5% aqueous sodium carbonate and dried over magnesium sulfatle.
The solvent was evaporated to give after purification by silica chromatography (dichloromethane-methanol 95:5~90:10) 1,77 g (90%) of 1-(2-chloro-3-pyridinyl-oxy)-3-(phenylmethylamino)-2-propanol. m.p. 65-66 C.
c.1-(2 chloro-3-pyridinyloxy)-3-(phenylmethylamino)-2-propanol was cyclized to 3-(2,3-dihydro-N-phenyl-7 2 ~
methyl~ dioxino[2,3-b]pyridine)methanamine by one of the following methods:
(i) 300 mg of 1-(2-chloro-3-pyridinyloxy)-3-(phenyl-methylamino~-2-propanol dissolved in ~ ml o~ tert-butanol was added to a solution of 48 mg of potassium in 10 ml of tert-butanol, and the mixture was heated at 70 C ~or 20 h. A~ter addi.tion of water the product was extracted with dichloro-methane, the organic layer was washed with 5%
aqueous sodium hydrogen carbonate and dried over maynesium sulfate. After evaporation to dryness 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained.
(ii) 300 mg of 1-(2-chloro-3~pyridinyloxy)-3-(phenyl-methylamino~-2-propanol dissolved in 3 ml of D~F
wa~ added to a suspension of 6~ mg of 50% sodium hydride in 10 ml of DMF. The mixture was stirred at 95 C ~or 24 h to afford 3-(~,3-dihydro-N-phanyl-methyl-1,4-dioxino[2,3-b]pyridine)methanamine~
(iii) In a manner similar as described in ii 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium hydride in THF at 55 C.
~iv) In a manner similar as described in (ii) 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was ohtained, using sodium ride in a mixture of THF and 10% hexamethyl phosphorous triamide at 55 C.
: (v) In a manner similar as described in (ii) 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium hydride in dimethyl sulfoxide at 60 C.
: (vi) In a manner similar as described in (ii) 63% of 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium . hydride in 1,2-dimethoxyethane at 80 C.
.
~.
~o~at~J6~
d. To 3-(2,3-dihydro-N-phenylme~hyl-1,4-dioxino[2,3-b]-pyridine)methanamine, dissolved in dry methanol wh.ich was acidified using concentrated hydrochloric acid, : 10~ palladium on charcoal was added. The mixture was stirred undPr an atmosphere of hydrogen, and after complete hydrogenation the product was filtered, neutralized using potassium carbonate, and purified by column chromatography over silica (dichloro-methane-methanol 9:1) to o~tain pure 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)methanamine (yield 77%)~
e. 200 ~g of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)-: methanamine were dissolved in 7 ml of D~F~ and 406 mg of (4-bromobutyl)-phthalimide, 363 mg of triethyl-amine, and lO mg of potassium iodids were added. The reaction mixture was heated at 60 C, and monitored by thin layer chromatography. After completion, water was added and the product was extracted with dichloroMethane. The organic layer was wash~d with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, evaporated to drynes~, and the residue was purified by column chromatography over silica (dichloromethane-methanol 98:2~9U:10) to obtain 229 mg (52~) o~ 1,3-dihydro-2-[N-(~,3-dihydro-.~ 1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-~ 25 1,3-dioxo-2H-isoindole. m.p. 80 C.
.
. ~_ Example 2 In an analogous manner as described in Example 1 were prepared:
l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-4,4-dimethyl-piperidine-2,6-dione ethanedioate (1 1). m.p. 208 C.
rf 7 1-[N-~2,3-dihydro-1,~-dioxino[~,3 b]pyridin-3-ylmethyl)-4-aminoethyl]-4,4-dime~hyl-piperidine-2,6-dione (E)-2-butenedioate (1:1).
S 1,3-dihydro-2-[N-(2,3-dihydro-1,4-~ioxino[2,3 b]pyridin-3-ylmethyl)-N-methyl-4-aminobutyl]-1,3-dioxo-2H-i~o-indole ethanedioate (1:1). m~p. 159 C.
1,3-dihydro-2~[N-(2,3-dihydro-1,4-dioxino~2,3-b]pyridin-3-ylmethyl)-3-aminopropyl]-1,3-dioxo-2H-isoindole. m.p.
114 C.
B-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl~-: 4-aminob~tyl]-8-azaspiro[4.5]decane-7,9-dione hydro-chloride (1:2). IR (cm~1) 1710, 1650.
8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-8-azaspiro[4.5]decane-7,9 dione (E)-2-butenedioate (1~ m.p. 1~1 C.
: 1,3-dihydro-2-[~-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-~ 3-ylmethyl)~2-aminoethyl]-1,3-dioxo-2~-isoindole. m.p.
: 146-148 C.
2-[N-~2,3-dihydro-1,4-dioxinoE2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-3-oxo-2H-1,2-benzisothiazol-1,1-dioxide tE)~ 6~tenedioate (1:1). syrup; IR (cm~l): 1715, 1660.
8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-N-methyl-4-aminobutyl]-8-aza~piro[4.5]decane-7,9-dione ethanedioate (1:1). m.p. 153 C.
l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-pyrrolidin-2-one (E)-2-butenedioate (1:1).
m.p. 147 ~C.
lo ~ 7 l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminoblltyl]-piperidln-2-one (E)-2-butenedioate (1:1).
m.p. 1~2 C.
`:5 1-[N-(2,3-dihydro-1,4-dioxino[~,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-hexahydro-2El-azepin-~-one (~)-2-butene-dioate (1:1). m.p. 124 C.
Example 3 The amine of Example ld can also be prepared from 2-chloro-3-(oxiranylmethoxy)pyridine (Example la) by refluxing 1.07 g of the oxirane derivative and 525 mg of sodium azide in 23 ml of dioxane during 7 h. After evaporation of the solvent, extraction with dichloro-methane and drying over magnesiu~ sulfate, 1,17 g (88%) : of 3-azido~ 2-chloro-3-pyridinyloxy)-2-propanol was obtained after silica column chromatography (diethyl ether-petroleum ether 2:1). l.Q6 g 0~ this compound dissolved in 15 ml of 1,2-dime~hoxymethane was added portionwise under an atmosphere of nitrogen, to 240 mg of sodium hydride 50%, which were washed with a minimum amount of tetrahydrofuran. The reaction mixture ~as stirred for 24 h at 80 C, cooled, hydrolized with water, extracted with dichloromethane, and purified by sil~e~-~hromatography (diethyl ether-petroleum ether 2:1), to give 550 mg (62%) of 3-(2,3-dihydro-1,4-dioxino~2,3-b]pyridine)methanazide. 500 ~g Of this azide was hydrogenated in a Parr apparatus in 16 ml of ethanol with 80 mg of Lindlar catalyst under a pressure of hydrogen (30 PSI). After 4 h the solution was filtered and purified by silica chromatography (dichloro~ethane-methanol 9:1~ to give 420 mg (98%) of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine~methanamine.
20~7b ~J
Example 4 The amine of Example ld can also be prepared from 2-chloro-3-~oxiranylmethoxy~pyridine (Example la) by adding 1 g of the oxirane derivative to a suspension of ; 34 g of aluminum oxide in 50 ml of tetrahydrofuran and 5.82 g of benzylalcohol, and stirring the mixture during 24 ~. Methanol (20 ml) was ad~ed and the mixture was stirred during 2.5 h. After filtration, evaporation of the solvent and purification by silica chromatography (diethyl ether-petroleum ether 2:1), 1,33 g (83%1 of 1-(2-chloro-3-pyridinyloxy)-3-(phenylmethyloxy)-2-propanol were obtained. In a manner, similar as described in Example lc, this derivative was cyclized, and then hydrogenated, in a way as described in Example 3, to give 3-(2,3-dihydro-1,4-dioxino E 2,3-b]pyridine)methanol.
To a suspension of 81 mg of this alcohol and 3~2 mg of triphenylphosphine~ was added under an atmosphere of arqon a complex of zinc azide in pyridine (141 mg).
After stirring 0.2~6 g of diisopropyl azodicarboxylats were addad portionwise and the mixture was stirr2d during 30 min~ After purificatio-n by silica chromato-graphy (petroleum ether-ethyl acetate 7:3~1:1), 75 % of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)methana2ide was obtained, which was hydrog~nated in a Parr apparatus as described in Example 3.
Example 5 To a suspension containing 0.5 g (R)- or (S)- glycidol in 10 ml of tetrahydrofuran, were added 1.14 g of 2-chloro-3-pyridinol and 2.12 g of triphenylphosphine. The mixture is stirred under argon for 15 min at room temperature, after which 1.6 ml of diisopropyl azodicarboxylate were added at 0 C. The solution was stood for 1 h at ambient temperature. The mixture was 12 ~ 7 6 i washed with 0.5% aqueous sodium carbonate, extracted with dichloromethane, dried over magnesium sulfate and chromatographed over silica to obtain 82% yield of 2-chloro-3-(oxiranylmethoxy)pyridine, m.p. 36 C.
1.07 g Of 2~chloro-3-(oxiranylmethoxy)pyridine were dis-solved in 23 ml of dioxane, and 525 mg of sodium azide in 6 ml of water were added. The reaction mixture is refluxed for 7 h, after which the sc,lvents were removed, 15 ml of water were added to the rasidue, and the organic material was ex~racted with dichloromethane, dried o~er magnesium sul~ate, and chromatographed over silica to give 88~ yield of 1-(2-chloro-3-pyridinyloxy)-3-azido-2-propanol.
To a suspension of 0.75 g of sodium hydride, which Wc15 w~shed with a small amount of tetrahydrofuran, were added ~.23 g of 1-(2-chloro-3-pyridinyloxy)~3-azido-2-propanol in 25 ml of ethylene glycol dimethyl eth~r. The r~action mixture is heated for one night at 80 ~C, hydrolysed, extracted, and purified by chromatography - 20 vver silica to give 62% yiald of 2,3-dihydro-3-azido-methyl-1,4-dioxino[2,3-b]pyridine, m.p. ~4 ~C.
0.54 g 0~ this azide in 17 ml of ethanol is stirred with 86 mg of Lindlar catalyst in a Parr apparatus at a hydrogen pressure of 207 kPa. After 24 h the catalyst is removed by filtration and washed with ethanol. The solvent is removed and the residue purified by : chrom~R~graphy over silica to give 98~ yield o~ (R) or (S) 3~(2,3-dihydro-1,4-dioxino[2,3-b]pyridinyl)methan-amine. Thess products were further processed according to the method of example 1 to obtain:
(R)(+) 8-[N-(2,3-dihydro-1,4-dioxino[2,3 b]pyridin-3-yl-methyl)-4-aminc,butyl]-8-azaspiro[4.5]decane-7,9-dione;
[a]D20 = ~18 (c=1.1, chloroform).
13 ~ ~ ~ 7~ 7 (S)(-) 8-EN-~2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-methyl)-~-aminobutyl]-B-azaspiro[4.5]decane-7,9-dione;
[~]D20 = -18 (c=1.1, chloroform).
(R)(+) 8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-methyl)-4-aminobutyl]-8-azaspiro[4.5]decane-7,9-dione (E)-2-butenedioate; m.p. 189 C; [~]D20 = +34 ~c=1~0, methanol).
(S)(-) 8-[N ~2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-~ethyl)-4-aminobutyl]-8-azaspiro[~.5]decane-7,9-dione (E)-2-~utenedioate, m.p. 174 C; [~]D2~ = -37 (c=l.O, methanol).
~v _
.~ ~
.
`' 5 2 ~ 7 ~` ~
wherein R and Hal have the previously given meanings, is condensed with an amine having formula VI
o~,_ ~N - (~}12)n VI
H
wherein Rl~ n, X and Y have the previously given meanings, after which the compound obt:ained may be separated into its enantiomers and/or converted into a pharmaceutically acceptable salt.
The compounds of the invention may be administered enterally or parenterally, and ~or humans preferably in a daily d~sage of 0,001-10 mg per kg bod~ weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., .: Remington~s Pharmaceuti~al Sciences, (18th ed., Mack ~ 20 Publishing Company, lg90, see especially Part 8:
-~ Pharmaceutical Preparations and Their Manufaature) the : compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable . 25 liquids the compounds can also be applied as an injection preparation in the form of a solution, suspe~on, emulsion, or as a spray, e.g. a nasal spray.
For making dosage units, e.g. tablets, thP use of conventional additives such as fillers, colorants, poly-meric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can ~: be used.
.:~ Suitable carriers with which the compositions can be -. 35 administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
,,~
': ' ~,' .
~$~ 7 The invention is further illustrated by the following examples.
Example 1 1.3-dihydro-2- r N-(2~3-~ihy~E~ dioxinoL2~3-blpy~id~=
3-ylmeth~ 4-aminobutyll-1,3-~ioxo-2H-isnindole a. Under an inert atmosphere 3,B8 g of 2-chloro-3-pyridinol in 60 ml of dry N,N-dimethylforma~ide ~DMF) were added portionwise at room tem~erature to 1,58 g of sodium hydride 50%, which were washed with a minimum amount of tetrahydro~uran (TH~). Then 27,75 g of epichlorohydrin, dissolved in 50 ml of dry DMF, were added, and the reaction mixture was stirred for 48 h at 60 C. When the reaction wa~ terminated, the mixture was cooled and hydrolysed with 150 ml of water. The reaction product was extracted into dichloromethane, the organic layer was wa~hed with 5%
aqueous sodium carbonate and dried over magnesium sul~ate. The solvent was evaporated and the residue was purified by silica chromatography (petroleum ether-diethyl ether 8:2~3:7) to give 5 g (89%) of 2-chloro-3-(oxiranylmethoxy)pyridine. m.p. 34-36 C.
b. Benzylamine (1,79 g) was added to 1,25 g of 2-chloro-3-(oxiranylmethoxy)pyridine in 30 ml of THF, and the ~e~ion mixture was s~irred for 30 h at 60 C. The mixture was cooled, extracted with dichloromethane, and the organic layer was washed with 5% aqueous sodium carbonate and dried over magnesium sulfatle.
The solvent was evaporated to give after purification by silica chromatography (dichloromethane-methanol 95:5~90:10) 1,77 g (90%) of 1-(2-chloro-3-pyridinyl-oxy)-3-(phenylmethylamino)-2-propanol. m.p. 65-66 C.
c.1-(2 chloro-3-pyridinyloxy)-3-(phenylmethylamino)-2-propanol was cyclized to 3-(2,3-dihydro-N-phenyl-7 2 ~
methyl~ dioxino[2,3-b]pyridine)methanamine by one of the following methods:
(i) 300 mg of 1-(2-chloro-3-pyridinyloxy)-3-(phenyl-methylamino~-2-propanol dissolved in ~ ml o~ tert-butanol was added to a solution of 48 mg of potassium in 10 ml of tert-butanol, and the mixture was heated at 70 C ~or 20 h. A~ter addi.tion of water the product was extracted with dichloro-methane, the organic layer was washed with 5%
aqueous sodium hydrogen carbonate and dried over maynesium sulfate. After evaporation to dryness 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained.
(ii) 300 mg of 1-(2-chloro-3~pyridinyloxy)-3-(phenyl-methylamino~-2-propanol dissolved in 3 ml of D~F
wa~ added to a suspension of 6~ mg of 50% sodium hydride in 10 ml of DMF. The mixture was stirred at 95 C ~or 24 h to afford 3-(~,3-dihydro-N-phanyl-methyl-1,4-dioxino[2,3-b]pyridine)methanamine~
(iii) In a manner similar as described in ii 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium hydride in THF at 55 C.
~iv) In a manner similar as described in (ii) 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was ohtained, using sodium ride in a mixture of THF and 10% hexamethyl phosphorous triamide at 55 C.
: (v) In a manner similar as described in (ii) 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium hydride in dimethyl sulfoxide at 60 C.
: (vi) In a manner similar as described in (ii) 63% of 3-(2,3-dihydro-N-phenylmethyl-1,4-dioxino[2,3-b]-pyridine)methanamine was obtained, using sodium . hydride in 1,2-dimethoxyethane at 80 C.
.
~.
~o~at~J6~
d. To 3-(2,3-dihydro-N-phenylme~hyl-1,4-dioxino[2,3-b]-pyridine)methanamine, dissolved in dry methanol wh.ich was acidified using concentrated hydrochloric acid, : 10~ palladium on charcoal was added. The mixture was stirred undPr an atmosphere of hydrogen, and after complete hydrogenation the product was filtered, neutralized using potassium carbonate, and purified by column chromatography over silica (dichloro-methane-methanol 9:1) to o~tain pure 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)methanamine (yield 77%)~
e. 200 ~g of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)-: methanamine were dissolved in 7 ml of D~F~ and 406 mg of (4-bromobutyl)-phthalimide, 363 mg of triethyl-amine, and lO mg of potassium iodids were added. The reaction mixture was heated at 60 C, and monitored by thin layer chromatography. After completion, water was added and the product was extracted with dichloroMethane. The organic layer was wash~d with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulphate, evaporated to drynes~, and the residue was purified by column chromatography over silica (dichloromethane-methanol 98:2~9U:10) to obtain 229 mg (52~) o~ 1,3-dihydro-2-[N-(~,3-dihydro-.~ 1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-~ 25 1,3-dioxo-2H-isoindole. m.p. 80 C.
.
. ~_ Example 2 In an analogous manner as described in Example 1 were prepared:
l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-4,4-dimethyl-piperidine-2,6-dione ethanedioate (1 1). m.p. 208 C.
rf 7 1-[N-~2,3-dihydro-1,~-dioxino[~,3 b]pyridin-3-ylmethyl)-4-aminoethyl]-4,4-dime~hyl-piperidine-2,6-dione (E)-2-butenedioate (1:1).
S 1,3-dihydro-2-[N-(2,3-dihydro-1,4-~ioxino[2,3 b]pyridin-3-ylmethyl)-N-methyl-4-aminobutyl]-1,3-dioxo-2H-i~o-indole ethanedioate (1:1). m~p. 159 C.
1,3-dihydro-2~[N-(2,3-dihydro-1,4-dioxino~2,3-b]pyridin-3-ylmethyl)-3-aminopropyl]-1,3-dioxo-2H-isoindole. m.p.
114 C.
B-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl~-: 4-aminob~tyl]-8-azaspiro[4.5]decane-7,9-dione hydro-chloride (1:2). IR (cm~1) 1710, 1650.
8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-8-azaspiro[4.5]decane-7,9 dione (E)-2-butenedioate (1~ m.p. 1~1 C.
: 1,3-dihydro-2-[~-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-~ 3-ylmethyl)~2-aminoethyl]-1,3-dioxo-2~-isoindole. m.p.
: 146-148 C.
2-[N-~2,3-dihydro-1,4-dioxinoE2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-3-oxo-2H-1,2-benzisothiazol-1,1-dioxide tE)~ 6~tenedioate (1:1). syrup; IR (cm~l): 1715, 1660.
8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-N-methyl-4-aminobutyl]-8-aza~piro[4.5]decane-7,9-dione ethanedioate (1:1). m.p. 153 C.
l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-pyrrolidin-2-one (E)-2-butenedioate (1:1).
m.p. 147 ~C.
lo ~ 7 l-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-ylmethyl)-4-aminoblltyl]-piperidln-2-one (E)-2-butenedioate (1:1).
m.p. 1~2 C.
`:5 1-[N-(2,3-dihydro-1,4-dioxino[~,3-b]pyridin-3-ylmethyl)-4-aminobutyl]-hexahydro-2El-azepin-~-one (~)-2-butene-dioate (1:1). m.p. 124 C.
Example 3 The amine of Example ld can also be prepared from 2-chloro-3-(oxiranylmethoxy)pyridine (Example la) by refluxing 1.07 g of the oxirane derivative and 525 mg of sodium azide in 23 ml of dioxane during 7 h. After evaporation of the solvent, extraction with dichloro-methane and drying over magnesiu~ sulfate, 1,17 g (88%) : of 3-azido~ 2-chloro-3-pyridinyloxy)-2-propanol was obtained after silica column chromatography (diethyl ether-petroleum ether 2:1). l.Q6 g 0~ this compound dissolved in 15 ml of 1,2-dime~hoxymethane was added portionwise under an atmosphere of nitrogen, to 240 mg of sodium hydride 50%, which were washed with a minimum amount of tetrahydrofuran. The reaction mixture ~as stirred for 24 h at 80 C, cooled, hydrolized with water, extracted with dichloromethane, and purified by sil~e~-~hromatography (diethyl ether-petroleum ether 2:1), to give 550 mg (62%) of 3-(2,3-dihydro-1,4-dioxino~2,3-b]pyridine)methanazide. 500 ~g Of this azide was hydrogenated in a Parr apparatus in 16 ml of ethanol with 80 mg of Lindlar catalyst under a pressure of hydrogen (30 PSI). After 4 h the solution was filtered and purified by silica chromatography (dichloro~ethane-methanol 9:1~ to give 420 mg (98%) of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine~methanamine.
20~7b ~J
Example 4 The amine of Example ld can also be prepared from 2-chloro-3-~oxiranylmethoxy~pyridine (Example la) by adding 1 g of the oxirane derivative to a suspension of ; 34 g of aluminum oxide in 50 ml of tetrahydrofuran and 5.82 g of benzylalcohol, and stirring the mixture during 24 ~. Methanol (20 ml) was ad~ed and the mixture was stirred during 2.5 h. After filtration, evaporation of the solvent and purification by silica chromatography (diethyl ether-petroleum ether 2:1), 1,33 g (83%1 of 1-(2-chloro-3-pyridinyloxy)-3-(phenylmethyloxy)-2-propanol were obtained. In a manner, similar as described in Example lc, this derivative was cyclized, and then hydrogenated, in a way as described in Example 3, to give 3-(2,3-dihydro-1,4-dioxino E 2,3-b]pyridine)methanol.
To a suspension of 81 mg of this alcohol and 3~2 mg of triphenylphosphine~ was added under an atmosphere of arqon a complex of zinc azide in pyridine (141 mg).
After stirring 0.2~6 g of diisopropyl azodicarboxylats were addad portionwise and the mixture was stirr2d during 30 min~ After purificatio-n by silica chromato-graphy (petroleum ether-ethyl acetate 7:3~1:1), 75 % of 3-(2,3-dihydro-1,4-dioxino[2,3-b]pyridine)methana2ide was obtained, which was hydrog~nated in a Parr apparatus as described in Example 3.
Example 5 To a suspension containing 0.5 g (R)- or (S)- glycidol in 10 ml of tetrahydrofuran, were added 1.14 g of 2-chloro-3-pyridinol and 2.12 g of triphenylphosphine. The mixture is stirred under argon for 15 min at room temperature, after which 1.6 ml of diisopropyl azodicarboxylate were added at 0 C. The solution was stood for 1 h at ambient temperature. The mixture was 12 ~ 7 6 i washed with 0.5% aqueous sodium carbonate, extracted with dichloromethane, dried over magnesium sulfate and chromatographed over silica to obtain 82% yield of 2-chloro-3-(oxiranylmethoxy)pyridine, m.p. 36 C.
1.07 g Of 2~chloro-3-(oxiranylmethoxy)pyridine were dis-solved in 23 ml of dioxane, and 525 mg of sodium azide in 6 ml of water were added. The reaction mixture is refluxed for 7 h, after which the sc,lvents were removed, 15 ml of water were added to the rasidue, and the organic material was ex~racted with dichloromethane, dried o~er magnesium sul~ate, and chromatographed over silica to give 88~ yield of 1-(2-chloro-3-pyridinyloxy)-3-azido-2-propanol.
To a suspension of 0.75 g of sodium hydride, which Wc15 w~shed with a small amount of tetrahydrofuran, were added ~.23 g of 1-(2-chloro-3-pyridinyloxy)~3-azido-2-propanol in 25 ml of ethylene glycol dimethyl eth~r. The r~action mixture is heated for one night at 80 ~C, hydrolysed, extracted, and purified by chromatography - 20 vver silica to give 62% yiald of 2,3-dihydro-3-azido-methyl-1,4-dioxino[2,3-b]pyridine, m.p. ~4 ~C.
0.54 g 0~ this azide in 17 ml of ethanol is stirred with 86 mg of Lindlar catalyst in a Parr apparatus at a hydrogen pressure of 207 kPa. After 24 h the catalyst is removed by filtration and washed with ethanol. The solvent is removed and the residue purified by : chrom~R~graphy over silica to give 98~ yield o~ (R) or (S) 3~(2,3-dihydro-1,4-dioxino[2,3-b]pyridinyl)methan-amine. Thess products were further processed according to the method of example 1 to obtain:
(R)(+) 8-[N-(2,3-dihydro-1,4-dioxino[2,3 b]pyridin-3-yl-methyl)-4-aminc,butyl]-8-azaspiro[4.5]decane-7,9-dione;
[a]D20 = ~18 (c=1.1, chloroform).
13 ~ ~ ~ 7~ 7 (S)(-) 8-EN-~2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-methyl)-~-aminobutyl]-B-azaspiro[4.5]decane-7,9-dione;
[~]D20 = -18 (c=1.1, chloroform).
(R)(+) 8-[N-(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-methyl)-4-aminobutyl]-8-azaspiro[4.5]decane-7,9-dione (E)-2-butenedioate; m.p. 189 C; [~]D20 = +34 ~c=1~0, methanol).
(S)(-) 8-[N ~2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl-~ethyl)-4-aminobutyl]-8-azaspiro[~.5]decane-7,9-dione (E)-2-~utenedioate, m.p. 174 C; [~]D2~ = -37 (c=l.O, methanol).
~v _
Claims (9)
1. A 1,4-dioxino[2,3-b]pyridine derivative having formula I
I
wherein each of the groups R is independently selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
R1 is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=O, or SO2; and Y is substituted or unsubstituted 1,2-phenylene, -(CH2)4-, CH2CR2R3-, or -CHCR2R3CH2-, in which R2 and R3 are independently hydrogen or lower alkyl, or together 1,4-butanediyl or 1,5-pentanediyl; or a pharmaceutically acceptable salt thereof.
I
wherein each of the groups R is independently selected from hydrogen, hydroxy, lower alkyl, lower alkoxy, CF3, and halogen;
R1 is hydrogen or lower alkyl;
n is 2, 3, or 4;
X is CH2, C=O, or SO2; and Y is substituted or unsubstituted 1,2-phenylene, -(CH2)4-, CH2CR2R3-, or -CHCR2R3CH2-, in which R2 and R3 are independently hydrogen or lower alkyl, or together 1,4-butanediyl or 1,5-pentanediyl; or a pharmaceutically acceptable salt thereof.
2. The 1,4-dioxino[2,3-b]pyridine derivative of claim 1, wherein R is hydrogen; or a pharmaceutically acceptable salt thereof.
3. The 1,4-dioxino[2,3-b]pyridine derivative of claim 1 or 2, wherein X is C=O; or a pharmaceutically acceptable salt thereof.
4. The 1,4-dioxino[2,3-b]pyridine derivative of claim 2, wherein R1 is hydrogen, n is 4, X is C=O, Y is -CH2CR2R3CH2-, and R2 and R3 are together 1,4-butanediyl; or pharmaceutically acceptable salts thereof.
5. The levorotatory enantiomer of the 1,4-dioxino[2,3 b]pyridine derivative of claim 2, wherein R1 is hydrogen, n is 4, X is C=O, Y is -CH2CR2R3CH2-, and R2 and R3 are together 1,4-butanediyl; or pharmaceu-tically acceptable salts thereof.
6. The 1,4-dioxino[2,3-b]pyridine derivative of any one of claims 1-5 for use in therapy.
7. A process for the preparation of the 1,4-dioxino-[2,3-b]pyridine derivative of claim 1, characterized in that a) a pyridine derivative having the formula II
II
wherein R, R1, n, X and Y have the previously given meanings, and Hal is Cl, Br, or I, is cyclized, or b) an amine having formula III
III
wherein R and R1 have the previously given meanings, is condensed with a compound having formula IV
IV
wherein Hal, n, X and Y have the previously given meanings, or c) a halide having formula V
V
wherein R and Hal have the previously given meanings, is condensed with an amine having formula VI
VI
wherein R1, n, X and Y have the previously given meanings, after which the compound obtained may be separated into its enantiomers and/or converted into a pharmaceutically acceptable salt.
II
wherein R, R1, n, X and Y have the previously given meanings, and Hal is Cl, Br, or I, is cyclized, or b) an amine having formula III
III
wherein R and R1 have the previously given meanings, is condensed with a compound having formula IV
IV
wherein Hal, n, X and Y have the previously given meanings, or c) a halide having formula V
V
wherein R and Hal have the previously given meanings, is condensed with an amine having formula VI
VI
wherein R1, n, X and Y have the previously given meanings, after which the compound obtained may be separated into its enantiomers and/or converted into a pharmaceutically acceptable salt.
8. A pharmaceutical composition containing at least one of the 1,4-dioxino[2,3-b]pyridine derivatives of any one of claims 1-6, admixed with pharmaceutically acceptable auxiliaries.
9. A use of the 1,4-dioxino[2,3-b]pyridine derivative of any one of claims 1-6 for the manufacture of a medicament having serotonergic activity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP92400603.4 | 1992-03-06 | ||
| EP92400603 | 1992-03-06 |
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|---|---|
| EP (1) | EP0559285A1 (en) |
| JP (1) | JPH069641A (en) |
| KR (1) | KR930019679A (en) |
| AU (1) | AU3395293A (en) |
| CA (1) | CA2090767A1 (en) |
| FI (1) | FI930964A (en) |
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| JPH06100139B2 (en) * | 1988-02-08 | 1994-12-12 | トヨタ自動車株式会社 | Fuel supply correction device for internal combustion engine |
| JP3430540B2 (en) * | 1993-02-26 | 2003-07-28 | いすゞ自動車株式会社 | Ozone deodorization system |
| FR2707294B1 (en) * | 1993-07-06 | 1995-09-29 | Pf Medicament | New derivatives of 3,5-dioxo- (2H, 4H) -1,2,4-triazine, their preparation and their application in human therapy. |
| FR2727682A1 (en) * | 1994-12-02 | 1996-06-07 | Pf Medicament | NOVEL DERIVATIVES OF 3,5-DIOXO- (2H, 4H) -1,2,4-TRIAZINES, THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT |
| TW446706B (en) * | 1995-02-07 | 2001-07-21 | Janssen Pharmaceutica Nv | Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines, a pharmaceutical composition containing them, their intermediates and a process for their preparation |
| JO2352B1 (en) | 2000-06-22 | 2006-12-12 | جانسين فارماسيوتيكا ان. في | Compounds for treating fundic disaccomodation |
| US6656950B2 (en) | 2001-04-25 | 2003-12-02 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of 1,4-dioxino[2,3-b]pyridine |
| CN100352820C (en) * | 2002-09-12 | 2007-12-05 | 惠氏公司 | Antidepressant azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans |
| US7135479B2 (en) | 2002-09-12 | 2006-11-14 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of heterocycle-fused benzodioxans |
| WO2007118130A2 (en) | 2006-04-06 | 2007-10-18 | Glaxo Group Limited | Antibacterial agents |
| EP1992628A1 (en) | 2007-05-18 | 2008-11-19 | Glaxo Group Limited | Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones |
| EA031589B1 (en) | 2014-08-22 | 2019-01-31 | Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед | Tricyclic nitrogen containing compounds for treating neisseria gonorrhoea infection |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR241161A1 (en) * | 1984-07-30 | 1991-12-30 | Merrelll Dow Pharmaceuticals I | "PROCEDURE FOR THE PREPARATION OF SUBSTITUTED N-AMINOALKYLEN DERIVATIVES OF GLUTARIMIDE" |
| US4748182A (en) * | 1986-03-05 | 1988-05-31 | Merrell Dow Pharmaceuticals Inc. | Aromatic 2-aminoalkyl-1,2-benzoisothiazol-3(2H)one-1,1-dioxide derivatives and their use as anti-hypertensive and anxiolytic agents |
| DE3726425A1 (en) * | 1987-03-18 | 1988-09-29 | Bayer Ag | Basically substituted saccharins |
| US4910302A (en) * | 1988-12-19 | 1990-03-20 | American Home Products Corporation | Psychotropic polycyclic imides |
-
1993
- 1993-02-25 CA CA002090767A patent/CA2090767A1/en not_active Abandoned
- 1993-02-25 ZA ZA931343A patent/ZA931343B/en unknown
- 1993-03-02 EP EP93200570A patent/EP0559285A1/en not_active Withdrawn
- 1993-03-03 AU AU33952/93A patent/AU3395293A/en not_active Abandoned
- 1993-03-04 FI FI930964A patent/FI930964A/en not_active Application Discontinuation
- 1993-03-05 JP JP5044808A patent/JPH069641A/en not_active Withdrawn
- 1993-03-05 KR KR1019930003273A patent/KR930019679A/en not_active Application Discontinuation
- 1993-03-05 NO NO93930822A patent/NO930822L/en unknown
- 1993-03-05 MX MX9301235A patent/MX9301235A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI930964A0 (en) | 1993-03-04 |
| EP0559285A1 (en) | 1993-09-08 |
| FI930964A (en) | 1993-09-07 |
| MX9301235A (en) | 1993-09-01 |
| NO930822L (en) | 1993-09-07 |
| KR930019679A (en) | 1993-10-18 |
| AU3395293A (en) | 1993-09-09 |
| NO930822D0 (en) | 1993-03-05 |
| ZA931343B (en) | 1993-09-24 |
| JPH069641A (en) | 1994-01-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |