Back to results
US 2004/0176400 A1Published application
Fused pyrimidines as antagonists of the corticotropin releasing factor (crf)
AssigneeGlaxo Group Limited
InventorsAnna Maria Capelli, Chiara Marchionni, Fabrizio Micheli, Alessandra Pasquarello, Benedetta Perini, Yves St-Denis, Romano Di Fabio
Life of this patent
Estimating the term…
Abstract
The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof wherein the variables are as defined in the description, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF). 1
Claims27
Compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof
- 179
- wherein
- R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from:
- halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —COR4, nitro, —NR9R10 cyano, and a group R5;
- R1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR9R10 or cyano;
- R2 is hydrogen, C3-C7 cycloalkyl, or a group R6;
- R3 has the same meanings as R2, but R2 and R3 may not be simultaneously hydrogen;
- or
- R2 and R3 together with N form a saturated or unsaturated heterocycle, which may be substituted by 1 to 3 R7 groups;
- or
- R2 and R3 together with N form a 5-10 membered heteroaryl group, in which the 5-membered heteroaryl group contains at least one heteroatom selected from oxygen, sulphur or nitrogen and the 6-10 membered heteroaryl group contains from 1 to 3 nitrogen atoms and wherein said 5-10 membered heteroaryl may be substituted by 1 to 3 R7 groups;
- R4 is a C1-C4 alkyl, —OR9 or —NR9R10;
- R5 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R8 groups;
- R6 is a C1-C6 alkyl that may be substituted by one or more groups selected from:
- C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl;
- R7 is a group R5, a group R6, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR9R10, phenyl which may be substituted by 1 to 4 R8 groups;
- R8 is C1-C6 alkyl, halo C1-C2 alkyl, halogen, nitro, C1-C6 alkoxy or cyano;
- R9 is hydrogen or C1-C6 alkyl;
- R10 independently from R9, has the same meanings;
- X is carbon or nitrogen;
- n is 1 or 2.
18 more elements
Compounds, according to any of claims from 1 to 11, wherein
- R1 is C1-C3 alkyl group or halo C1-C3 alkyl group.
Compounds, according to any of claims from 1 to 12, wherein
- R is an aryl group selected from:
- 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and 3-chloro-5-tricloromethyl-pyridin-2-yl.
A compound, according to any of claims from 1 to 13, selected in a group consisting from:
- [7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-ethyl-propyl)amine;
- [7-(2-bromo 4-isopropylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-ethylpropyl)amine;
- [7-(2,4-bis-trifluoromethylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-propylbutyl)amine;
- butyl-[7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]-pyrimidin-4-yl]ethyl-amine;
- [7-(2-bromo-4-isopropylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-butylethylamine;
- butyl-[7-(2-chloro-4-trifluoromethylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]ethylamine;
- [7-(2,4-bis-trifluoromethylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-butylethylamine;
- [7-(2-chloro-4-trifluoromethylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]cyclopropylmethylpropylamine;
- [7-(2,4-bis-trifluoromethylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-cyclopropylmethylpropylamine;
- [7-(2-bromo-4-isopropylphenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-cyclopropylmethylpropylamine;
- cyclopropylmethyl[7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]propylamine;
- 7-(2,4-dichlorophenyl)-4-(2-ethyl-piperidin-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-2-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-bis-trifluoromethylphenyl)-2-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2-bromo-4-isopropylphenyl)-2-methyl-4-(3-trifluoromethyl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-(5-isopropyl-3-trifluoromethyl-pyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 7-(2,4-dichlorophenyl)-4-(3-isopropyl-S-trifluoromethylpyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-(3-ethyl-5-trifluoromethylpyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-(3,5-dimethylpyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-(3-dimethoxymethyl-pyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-(3-ethyl-5-trifluoromethylpyrazol-1-yl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 4-(4-bromo-3-methyl-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 4-(4-bromopyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-[3-(4-chlorophenyl)-pyrazol-1-yl]-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,4-dichlorophenyl)-4-[3-(2-nitrophenyl)-pyrazol-1-yl]-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine;
- 7-(2,6-dimethoxy-pyridin-3-yl)-2-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[(2,3-d)]pyrimidine;
- 7-(2,4-bis-trifluoromethyl-phenyl)-2-methyl-4-(3-morpholyn-4-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[(2,3-d)]pyrimidine;
- 7-(2,4-bis-trifluoromethyl-phenyl)-2-methyl-4-(3-pyridin-3-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[(2,3-d)]pyrimidine;
- 7-(2,4-bis-trifluoromethyl-phenyl)-2-methyl-4-(3-pyrazin-2-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[(2,3-d)]pyrimidine;
- 7-(2,4-bis-trifluoromethyl-phenyl)-2-methyl-4-(3-oxalol-5-yl-pyrazol-1-yl)-6,7-dihydro-5H-pyrrolo[(2,3-d)]pyrimidine;
- 7-(2,4-dichlorophenyl-2-methyl-4-(3-trifluoromethyl-(1,2,4)triazol-1-yl)-6,7-dihydro-5H-pyrrolo(2,3-d)pyrimidine;
- butyl-[7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-ethyl-amine;
- cyclopropylmethyl[7-(2,4-dimethoxyphenyl)-2-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-propyl-amine;
- cyclopropylmethyl[7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-propylamine;
- 7-(2,4-dichlorophenyl)4-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine;
- 7-(2,4-dichlorophenyl)-4-[(2R,5R)-2,5-dimethylpyrrolidin-1-yl]-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine;
- [8-(2,4-bis-trifluoromethylphenyl)-2-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl](1-propylbutyl)amine;
- butyl-[8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl]-ethylamine;
- cyclopropylmethyl[8-(2,4-dichlorophenyl)-2-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl]propylamine.
36 more elements
The use of a compound according to any of claims from 1 to 12, in the preparation of a medicament for use in the treatment of conditions mediated by CRF (corticotropin-releasing factor).
A pharmaceutical composition comprising a compound according to any of claims from 1 to 12, in admixture with one or more physiologically acceptable carriers or excipients.
A method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by CRF (corticotropin-releasing factor), comprising administration of an effective amount of a compound according to any of claims from 1 to 12.
Dependencies are inferred from the claim text.