EP0264773A1
Expired / Lapsed
EP
⏱️ 0.0 years remaining
4,5-dihydro and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidines
Assignee: Wyeth Holdings LLC
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Filing: 1987-10-13
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Granted: —
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Expires: 2007-10-13
Abstract
Abstract A compound of the formula: Ia or Ib wherein -may represent the presence of a double bond between the C 6 and C 7 position, la, or the absence of a double bond between the C 6 and C 7 position, Ib; R 1 is hydrogen, bromo, chloro, carbamoyl, carboxamido, ethylcarboxylate, carboxyl, carboxyalkoxyl where alkoxy is (C 1 -C 3 ), cyano, -CO-CF 3 , COONa, -CO-C(CH 3 ) 3 . or where X is hydrogen, cyano, halogen or nitro; R 2 , R 4 and R 5 are hydrogen or lower alkyl(C 1 -C 3 ); R 3 ia hydrogen, alkyl(C 1 -C 3 ), where R 7 and R 8 may be the same or different and are hydrogen, halogen, alkyl(C 1 -C 3 ), nitro, alkoxy(Ci-C 3 ), trifluoromethyl, N-alkyl(C 1 -C 3 )-N-alkanoxyl(C 1 -C 3 )-amino, acetylamino or N-alkylacetylamino where alkyl is (C 1 -C 3 ), and R 3 may be a monovalent radical of 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, either of said pyridinyl radicals being optionally substituted with an alkyl radical R 9 , where alkyl is (C 1 -C 4 ), and the structures of the monovalent 2-pyridinyl, 3-pyridinyl and 4-pyridinyl moieties are depicted respectively as: R 6 is hydrogen, alkyl (C 1 -C 3 ) or , where n is an integer from 1 to 4 inclusive; and Z is CH-, N-and -O-such that when Z is -CH, R 10 is hydrogen, ethoxycarbonyl, phenyl, phenylmethyl, phenylmethyl(C 1 -C 6 )alkylenyl, when z is -0-, R 10 is nil and when Z is N-, R 10 is hydrogen, alkyl-(C 1 -C 3 ), alkenyl(C 2 -C 3 ), alkynyl(CrC 3 ), cycloalkyl(C 3 -C 6 ), dimethylaminoalkyl(C I -C 3 ), hydroxyalkyl(C 1 -C 3 ), ethylcarboxylate, alkyl(C I -C 3 )carbonyl, phenyl, benzyl, mono-or disubstituted benzyl [wherein the substituents are halogen, alkoxy(C I -C 3 ), alkyl (C 1 -C 3 ), and trifluoromethyl], benzoyl, 4-chlorophenylmethyl, 1,3-benzodioxol-5-yl-methyl, 1,3-benzodioxol-5-yl, 2-furanyl- carboxyl, 2-pyrimidinyl, 2-pyridinyl, 4-morpholinyl-2-oxoethyl, N-(1-methylethyl)-2-oxoethyl, 1-pyrrolidinyl-2-oxoethyl, bis(4-fluorophenyl)-methyl, 2-cyclohexylethyl, phenylcarboxamido, mono-and di-substituted phenylcarboxamido [wherein the substituents are trifluoromethyl, halogen and alkyl (C I -C 3 )], adamantanoyl, 3-phenoxypropyl, mono-and disubstituted phenyl [wherein the substituents are halogen, trifluoromethyl, alkoxy(C I -C 3 ) and alkyl(C 1 -C 3 )], 5-chloro-2-methoxy phenylacetamide and (2-oxo-1-pyrrolidinyl)-2-butynyl and the pharmacologically acceptable acid addition salts thereof.
Inventors
- 👤 Shin Shyong Tseng
- 👤 John Paul Dusza
- 👤 Herbert Joseph Brabander
- 👤 Joseph William Epstein
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-31 15:43
CPC Classifications
C; C07; C07D; C07D487/00; C07D487/02; C07D487/04; A; A61; A61P; A61P25/00; A61P25/20
Claims Analysis
Total Claims: 11
Claim 1
Independent Claim
380 words
A compound of the formula: Ia or Ib wherein --may represent the presence of a double bond between the C 6 and C 7 position, la, or the absence of a double bond between the C 6 and C 7 position, Ib; R, is hydrogen, bromo, chloro, carbamoyl, carboxamido, ethylcarboxylate, carboxyl, carboxyalkoxyl where alkoxyl is (C 1 -C 3 ), cyano, -CO-CF 3 , COONa, -CO-C(CH 3 ) 3 , or where X is hydrogen, cyano, halogen or nitro; R 2 , R 4 and R 5 are hydrogen or lower alkyl(C I -C 3 ); R 3 is hydrogen, alkyl(C I -C 3 ), where R 7 and R 8 may be the same or different and are hydrogen, halogen, alkyl(C 1 -C 3 ), nitro, alkoxy(C 1 -C 3 ), trifluoromethyl, N-alkyl(C 1 -C 3 )-N-alkanoxyl(C 1 -C 3 )-amino, acetylamino or N-alkylacetylamino where alkyl is (C 1 -C 3 ), and R 3 may be a monovalent radical of 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, either of said pyridinyl radicals being optionally substituted with an alkyl radical Rg, where alkyl is (C 1 -C 4 ), and the structures of the monovalent 2-pyridinyl, 3-pyridinyl and 4-pyridinyl moieties are depicted respectively as: R 6 is hydrogen, alkyl(CI-C 3 ) or , where n is an integer from 1 to 4 inclusive; and Z is CR-, R-and -0-such that when Z is -CH, R 10 is hydrogen, ethoxycarbonyl, phenyl, phenylmethyl, phenylmethyl(C I -C 6 )alkylenyl, when Z is -0-, R 10 is nil and when Z is N-, R 10 is hydrogen, alkyl-(C 1 -C 3 ), alkenyl(C 2 -C 3 ), alkynyl(C 2 -C 3 ), cycloalkyl(C 3 -C 6 ), dimethylaminoalkyl(C 1 -C 3 ), hydroxyalkyl(C 1 -C 3 ), ethylcarboxylate, alkyl(C 1 -C 3 )carbonyl, phenyl, benzyl, mono-or disubstituted benzyl [wherein the substituents are halogen, alkoxy(C I -C 3 ), alkyl(C 1 -C 3 ), and trifluoromethyl], benzoyl, 4-chlorophenylmethyl, 1,3-benzodioxol-5-yl-methyl, 1,3-benzodioxl-4-yl, 2-furanyl- carboxyl, 2-pyrimidinyl, 2-pyridinyl, 4-morpholinyl-2-oxoethyl, N-(1-methylethyl)-2-oxoethyl, 1-pyrrolidinyl-2-oxoethyl, bis(4-fluorophenyl)methyl, 2-cyclohexylethyl, phenylcarboxamido, mono-and disubstituted phenylcarboxamido [wherein the substituents are trifluoromethyl, halogen and alkyl (C 1 -C 3 )], adamantanoyl, 3-phenoxypropyl, mono-and disubstituted phenyl [wherein the substituents are halogen, trifluoromethyl, alkoxy(Ci-C3) and alkyl(C I -C 3 )], 5-chloro-2-methoxy phenylacetamide and (2-oxo-1-pyrrolidinyl)-2-butynyl and the pharmacologically acceptable acid addition salts thereof.
Claim 2
Dependent Claim
380 words
A compound of the formula: Ia or Ib wherein --may represent the presence of a double bond between the C 6 and C 7 position, la, or the absence of a double bond between the C 6 and C 7 position, Ib; R, is hydrogen, bromo, chloro, carbamoyl, carboxamido, ethylcarboxylate, carboxyl, carboxyalkoxyl where alkoxyl is (C 1 -C 3 ), cyano, -CO-CF 3 , COONa, -CO-C(CH 3 ) 3 , or where X is hydrogen, cyano, halogen or nitro; R 2 , R 4 and R 5 are hydrogen or lower alkyl(C I -C 3 ); R 3 is hydrogen, alkyl(C I -C 3 ), where R 7 and R 8 may be the same or different and are hydrogen, halogen, alkyl(C 1 -C 3 ), nitro, alkoxy(C 1 -C 3 ), trifluoromethyl, N-alkyl(C 1 -C 3 )-N-alkanoxyl(C 1 -C 3 )-amino, acetylamino or N-alkylacetylamino where alkyl is (C 1 -C 3 ), and R 3 may be a monovalent radical of 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, either of said pyridinyl radicals being optionally substituted with an alkyl radical Rg, where alkyl is (C 1 -C 4 ), and the structures of the monovalent 2-pyridinyl, 3-pyridinyl and 4-pyridinyl moieties are depicted respectively as: R 6 is hydrogen, alkyl(CI-C 3 ) or , where n is an integer from 1 to 4 inclusive; and Z is CR-, R-and -0-such that when Z is -CH, R 10 is hydrogen, ethoxycarbonyl, phenyl, phenylmethyl, phenylmethyl(C I -C 6 )alkylenyl, when Z is -0-, R 10 is nil and when Z is N-, R 10 is hydrogen, alkyl-(C 1 -C 3 ), alkenyl(C 2 -C 3 ), alkynyl(C 2 -C 3 ), cycloalkyl(C 3 -C 6 ), dimethylaminoalkyl(C 1 -C 3 ), hydroxyalkyl(C 1 -C 3 ), ethylcarboxylate, alkyl(C 1 -C 3 )carbonyl, phenyl, benzyl, mono-or disubstituted benzyl [wherein the substituents are halogen, alkoxy(C I -C 3 ), alkyl(C 1 -C 3 ), and trifluoromethyl], benzoyl, 4-chlorophenylmethyl, 1,3-benzodioxol-5-yl-methyl, 1,3-benzodioxl-4-yl, 2-furanyl- carboxyl, 2-pyrimidinyl, 2-pyridinyl, 4-morpholinyl-2-oxoethyl, N-(1-methylethyl)-2-oxoethyl, 1-pyrrolidinyl-2-oxoethyl, bis(4-fluorophenyl)methyl, 2-cyclohexylethyl, phenylcarboxamido, mono-and disubstituted phenylcarboxamido [wherein the substituents are trifluoromethyl, halogen and alkyl (C 1 -C 3 )], adamantanoyl, 3-phenoxypropyl, mono-and disubstituted phenyl [wherein the substituents are halogen, trifluoromethyl, alkoxy(Ci-C3) and alkyl(C I -C 3 )], 5-chloro-2-methoxy phenylacetamide and (2-oxo-1-pyrrolidinyl)-2-butynyl and the pharmacologically acceptable acid addition salts thereof.
Claim 3
Dependent Claim
217 words
A compound according to claim 1 of the formula: Ia or Ib wherein ---may represent the presence of a double bond between the C 6 and C 7 position, la, or the absence of a double bond between the C 6 and C 7 position, Ib; R 1 is hydrogen, bromo, chloro, carbamoyl, carboxyl, carboxyalkoxyl where alkoxyl is (C I -C 3 ), cyano, -CO-CF 3 , COONa, -CO-C(CH 3 ) 3 , or where X is hydrogen, cyano, halogen or nitro; R 2 , R 4 and R 5 may be hydrogen or lower alkyl(C I -C3); R 3 is hydrogen, alkyl(C 1 -C 3 ), where R 7 and Re may be the same or different and are hydrogen, halogen, alkyl(C 1 -C 3 ), nitro, alkoxy(C 1 -C 3 ), trifluoromethyl, acetylamino or N-alkylacetylamino where alkyl is (C 1 -C 3 ), and R 3 may also be a monovalent radical of 3-thienyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, either of said pyridinyl radicals being optionally substituted with an alkyl radical R 9 , where alkyl is (C 1 -C 4 ), and the structures of the monovalent 2-pyridinyl, 3-pyridinyl and 4-pryidinyl moieties are depicted respectively as: ; R 6 is hydrogen or alkyl(C 1 -C 3 ) and the pharmacologically acceptable acid addition salts thereof.
Claim 4
Dependent Claim
234 words
A compound according to claim 1 of the formula: wherein n is an integer from 1 to 4 inclusive; R 7 is a mono-or disubstituent of hydrogen, lower alkyl(C 1 -C 3 ), lower alkoxy(C 1 -C 3 ), halogen, nitro, N -alkyl(C 1 -C 3 )-N-alkanoyl(C 1 -C 3 )amino, trifluoromethyl; R 2 is cyano, carboxamido, ethyl carboxylate or halogen; Z is CH-, N-or -0-such that when Z is CH-, R 10 is hydrogen, ethoxy carbonyl, phenyl, phenylmethyl or phenylmethyl(C I -C 6 )alkylenyl, and when Z is -0-, R 3 is nil, and when Z is N-, R 3 is alkyl(C I -C 3 ), alkenyl(C 2 -C 3 ), alkynyl(C 2 -C 3 ), cycloalkyl(C 3 -C 6 , dimethylaminoalkyl(C I -C 3 ), hydroxyalkyl(C 1 -C 3 ), ethylcarboxylate, alkyl(C 1 -C 3 )carbonyl, phenyl, benzyl, mono-or disubstituted benzyl [wherein the substituents halogen, alkoxy(Ci-C 3 ), alkyl(C I -C 3 ), or trifluoromethyl], benzoyl, 4-chlorophenyl- phenylmethyl, 1,3-benzodioxol-5-ylmethyl, 1,3-benzodioxol-5-yl, 2-furanylcarbonyl, 2-pyrimidinyl, 2-pyridinyl, 4-morpholiny-2-oxoethyl, N-(1-methylethyl)-2-oxoathyl, 1-pyrrolidinyl-2-oxoethyl, bis(4-fluorophenyl)methyl, 2-cyclohexylethyl, phenylcarboxamido, mono-or disubstituted phenylcarboxamido [wherein the substituents are trifluoromethyl, halogen or alkyl(C 1 -C 3 )], adamantanoyl, 3-phenoxypropyl, mono-and disubstituted phenyl [wherein the substituents are halogen, trifluoromethyl, alkoxy(C 1 -C 3 ) or alkyl(C 1 -C 3 )], 5-chloro-2-methox- yphenylacetamide or (2-oxo-1-pyrrolidinyl)-2-butynyl; R 4 and R 5 are each hydrogen or alkyl(C 1 -C 3 ); and the pharmacologically acceptable acid addition salts thereof.
Claim 5
Dependent Claim
179 words
A compound according to claim 3 selected from those of the following formula: wherein n is an integer from 1 to 4 inclusive; R 7 represents a mono-or disubstitutent of hydrogen, lower alkyl(C 1 -C 3 ), lower alkoxy (C 1 -C 3 ), halogen, nitro or trifluoromethyl; R 2 is cyano, carboxamido, ethyl carboxylate or halogen; R 10 is hydrogen, alkyl(C 1 -C 3 ), alkenyl(C 2 -C 3 ), alkynyl(C 2 -C 3 ), cycloalkyl(C 3 -C 6 ), dimethylaminoalkyl(C 1 -C 3 ), hydroxyalkyl(C 1 -C 3 ), ethylcarboxylate, alkyl(C I -C 3 )carbonyl, phenyl, benzyl, mono-or disubstituted benzyl [wherein the substitutents are halogen, alkoxy(C 1 -C 3 ) or trifluoromethyl], benzoyl, 4-chlorophenylphenylmethyl, 1,3-benzodioxol-5-yl-methyl, 1,3-benzodioxol-5-yl, 2-furanylcarbonyl, 2-pyrimidinyl, 2-pyridinyl, 4-morpholin-yl-2-oxoethyl, -N-(1-methylethyl)-2-oxoethyl, 1-pyrrolidinyl-2-oxoethyl, bis(4-fluorophenyl)methyl, 2-cyclohexylethyl, phenylcarboxamido [wherein the substituents are trifluoromethyl, halogen or alkyl(C 1 -C 3 )], adamantanoyl, 3-phenoxypropyl, mono-or disubstituted phenyl [wherein the substituents are halogen, trifluoromethyl, alkoxy(C 1 -C 3 )], 5-chloro-2-methoxyphenylacetamide or (2-oxo-1-pyrrolidinyl)-2-butynyl; R 4 and R 5 are hydrogen or alkyl(C 1 -C 3 ); and the pharmacologically acceptable acid addition salts thereof.
Claim 6
Dependent Claim
54 words
A compound according to Claim 1 selected from those of the following formula: wherein R, represents a mono-or disubstituent of hydrogen, alkyl(C 1 -C 3 ), Alkoxy(C I -C 3 ), halogen, nitro or trifluoromethyl; and R 6 is hydrogen, alkyl(C I -C 3 ), alkoxy(C 1 -C 3 ), chloro, fluoro or trifluoromethyl.
Claim 7
Dependent Claim
32 words
A therapeutic composition of matter in dosage unit form comprising from about 5 to about 200 mg of a compound of Claim 2 in association with a pharmaceutically acceptable carrier or diluent.
Claim 8
Dependent Claim
110 words
A process for preparing a compound of Claim 2, which comprises reacting a compound of the formula: wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in Claim 2, with a suitable reducing agent such as an alkali metal borohydride, such as lithium borohydride, sodium borohydride, or sodium cyanoborohydride, or hydrogen in the presence of a catalyst such as palladium, platinum, activated nickel, activated cobalt, or the like; or by the use of a trialkylsilane such as triethylsilane in the presence of a proton donor such as trifluoroacetic acid when the compound of the hereinabove formula is in the 4,5-dihydroform.
Claim 9
Dependent Claim
215 words
A process for preparing a compound of Claim 2, wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in Claim 2, which comprises reacting a compound of the formula: with a compound of the formula: NaBH 3 CN in the presence of glacial acetic acid, under nitrogen, in an ice bath for about one hour, then at room temperature for from 1-12 hours, the resulting precipitate being washed with water, dissolved in an inert solvent such as dichloromethane or acetonitrile and the like, neutralized with aqueous saturated sodium bicarbonate and then recovering the dihydro product la of Claim 2 from the organic phase; then further reducing the dihydro product la by reacting it with a compound of the formula: (C 2 H 5 ) 3 SiH in trifluoroacetic acid at 60°C for 1-24 hours; and precipitating the tetrahydro product Ib with aqueous potassium hydroxide at pH 9.0 and recovering the product Ib therefrom; then dissolving the dihydro product la or the tetrahydro product Ib in a solvent such as N, H - dimethylformamide and reacting with an alkylating agent such as methyl iodide or dimethyl sulfate or the like in the presence of sodium hydride provides the product where R 6 is alkyl.
Claim 10
Dependent Claim
36 words
A therapeutic composition of matter in dosage unit form comprising form about 10 mg to about 500 mg per dosage unit of a compound of Claim 3, in association with a pharmaceutically acceptable carrier or diluent.
Claim 11
Dependent Claim
81 words
A process for producing a compound of the formula: wherein n, R 2 , R 4 , R 5 , R 10 and Z are as defined in Claim 3 which comprises reacting an amine of the formula: wherein R 10 and z are as described in Claim 3 with a compound of the formula: wherein R 7 , R 2 , R 4 , R 5 and n are as described in Claim 3 and X is chloro or iodo.
References Cited (Backward Citations)
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