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US 2002/0058641 A1Published application
2-aminocarbonyl-9H-purine derivatives
AssigneePfizer Inc.
InventorsSimon John Mantell, Peter Thomas Stephenson
Life of this patent
Estimating the term…
Abstract
The present invention relates to compounds of the formula. 1 and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.
Claims78
A compound of the formula:
- 128
- or a pharmaceutically acceptable salt or solvate thereof, wherein
- R1 is H, C1-C6 alkyl or fluorenyl, said C1-C6 alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
- (A) R2 is H or C1-C6 alkyl, R15 is H or C1-C6 alkyl, and X is either (I) unbranched C2-C3 alkylene optionally substituted by C1-C6 alkyl or C3-C8 cycloalkyl, or (ii) a group of the formula
- —(CH2)n—W—(CH2)p—
- where W is C5-C7 cycloalkylene optionally substituted by C1-C6 alkyl, n is 0 or 1 and p is 0 or 1, or
- (B) R15 is H or C1-C6 alkyl, and R2 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, or
- (C) R2 is H or C1-C6 alkyl, and R15 and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl,
- either, R3 and R4, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C1-C6 alkyl or C3-C8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by —NR6R7,
- or, R3 is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl and R4 is
- (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het, or
- (b) —(C2-C6 alkylene)-R8,
- (c) —(C1-C6 alkylene)-R13 or
- (d) C1-C6 alkyl or C3-C8 cycloalkyl;
- R5 is CH2OH or CONR14 R14,
- R6 and R7 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl;
- R8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy—(C1-C6)-alkyl, R9R9N-(C1-C6)-alkyl, fluoro—(C1-C6)-alkyl, —CONR9R9, —COOR9 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, —OR9, cyano, —S(O)mR10, —NR9R9, —SO2NR9R9, —NR9COR10 or —NR9SO2R10, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C2-C6 alkylene group by C1-C6 alkyl, phenyl, C1-C6 alkoxy—(C2-C6)-alkyl, R9R9N-(C2-C6)-alkyl, fluoro—(C1-6)-alkyl, C2-C5 alkanoyl, -COOR10, C3-C8 cycloalkyl, —SO2Rlo, —SO2NR9R9 or —CONR9R9, or
- (ii) NR11R12;
- R9 is H, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl,
- R10 is C1-C6 alkyl, C3-C8 cycloalkyl or phenyl,
- R11 is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl;
- R12 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, —CONR9R9, COOR10, C2-C5 alkanoyl or —SO2NR9R9;
- R13 is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, —(C1-C3 alkylene)—(C1-6 alkoxy), halo, cyano, —(C1-C3 alkylene)-CN, -CO2H, —(C1-C3 alkylene)-CO2H, —CO2(C1-6 alkyl), —(C1-C3 alkylene)-CO2(C1-C6 alkyl), —(C1-C3 alkylene)-NR14R14, —CONR R or —(C1-3 alkylene)-CONR14R14, or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het;
- R14 is H or C1-C6 alkyl optionally substituted by cyclopropyl;
- m is 0, 1 or 2;
- Y is CO, CS, SO2 or C═N(CN);
- and
- “het”, used in the definition of R4 and R13, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo
25 more elements
A compound as claimed in any one of the preceding claims wherein R2 is H.
A compound as claimed in any one of the preceding claims wherein R15 is H
A compound as claimed in any one of the preceding claims wherein X is 1,2-ethylene or 1,3-propylene.
A compound as claimed in any one of the preceding claims wherein R3 is H
A compound as claimed in any one of the preceding claims wherein R4 is piperidin-3-yl or piperidin-4-yl, each optionally substituted by benzyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, said pyridin-2-yl, pyridin-3-yl and pyridin-4-yl each optionally substituted by C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo
A compound as claimed in any one of the preceding claims wherein R5 is —CH2OH or —CONH(C1-C6 alkyl).
A compound as claimed in any one of the preceding claims wherein Y is CO.
Ethyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate;
- ethyl 9-{(2R,3R,4R,5R)-3,4-bis(acetyloxy)-5-[(acetyloxy)methyl]tetrahydro-2-furanyl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate;
- ethyl 9-[(2R73R,4S, 5R)-3,4-dihydroxy-5-(hydroxymethyl )tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylateI ethyl 9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl )-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate;
- (3aS,4S,6R,6aR)-6-[6-[(2,2-diphenylethyl)amino]-2-ethoxycarbonyl)-9H-purn-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid;
- ethyl 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate;
- 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylic acid,
- 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-N-{2-[({[1-(2-pyridinyl)-4-piperidinyl]amino}carbonyl)amino]ethyl}-9H-purine-2-carboxamide;
- tert-butyl 2-[({[1—(2-pyridinyl)-4-piperidinyl]amino}carbonyl)amino]ethylcarbamate,
- N-(2-aminoethyl)-N′-[1—(2-pyridinyl)-4-piperidlnyl]urea dihydrochloride, or
- N-(2-aminoethyl)-N′-[1-(2-pyridinyl)-4-piperidinyl]urea.
6 more elements
A compound of the formula:
- 150
- or a pharmaceutically acceptable salt or solvate thereof, wherein
- R1 is H, C1-C6 alkyl or fluorenyl, said C1-C6 alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
- R2 is H or C1-C6 alkyl;
- either, R3 and R4, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C1-C6 alkyl or C3-C8 cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by —NR6R7,
- or, R is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl and R4 is
- (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or het, or
- (b) —(C2-C6 alkylene)-R8, or
- (c) —(C1-C6 alkylene)-R13;
- R5 is CH2H or CONR14R14,
- R6 and R7 are either each independently H or C1-C6 alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C1-C6 alkyl,
- R8 is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy—(C1-C6)-alkyl, R9R9N-(C1-C6)-alkyl, fluoro—(C1-C6)-alkyl, -CONR9R9, —COOR9 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro—(C1-C6)-alkoxy, halo, —OR9, cyano, —S(O)mR10, —NR9R9, —SO2NR9R9, —NR9COR13 or —NR9SO2R10, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C2-C6 alkylene group by C1-C6 alkyl, phenyl, C1-C6 alkoxy—(C2-C6)-alkyl, R9R9N-(C2-C6)-alkyl, fluoro—(C1-C6)-alkyl, C2-C5 alkanoyl —COOR10, C3-C8 cycloalkyl, —SO2R10, —SO2NR9R9 or —CONR9R9, or (ii) NR11R12;
- R9 is H, C1-C6 alkyl, C3-C8 cycloalkyl or phenyl;
- R10 is C1-C6 alkyl, C3-C8 cycloalkyl or phenyl;
- R11 is H, C1-C6 alkyl, C3-C8 cycloalkyl or benzyl;
- R12 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro—(C1-C6)-alkyl, —CONR9R9, —COOR10, C2-C5 alkanoyl or —SO2NR9R9,
- R13 is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
- R14 is H or C1-C6 alkyl optionally substituted by cyclopropyl;
- R15 is H or C1-C6 alkyl;
- m is 0, 1 or2;
- X is unbranched C2-C3 alkylene optionally substituted by C1-C6 alkyl or C3-C8 cycloalkyl;
- Y is CO, CS, SO2 or C═N(CN);
- and
- “het”, used in the definition of R4, is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, hydroxy, oxo or halo
21 more elements
Dependencies are inferred from the claim text.