Patent EA-003641-B1 (EA)
Title: Biaryl derivatives, process for the preparation thereof, use thereof, pharmaceutical composition and method for treatment
Inventor: DONALDSON KELLY HORNE
IPC: C07D257/04
Filed: 1999-06-09
Abstract: 1. A compound of Formula (I) or a pharmaceutically acceptable derivative thereof: wherein R<1> is a phenoxymethyl or a phenyl, naphthyl, optionally substituted by chlorine, fluorine or bromine methyl or trifluoromethyl; R<2> is hydrogen or C1-6 alkyl; X is oxygen, or -NH; R<3> is cyano, tetrazol-5-yl, or -CO2R<7> where R<7> is hydrogen or C1-6 alkyl; R<4> and R<5> are independently hydrogen, methyl, trifluoromethyl, -CO2H, or when R<4> and R<5> are bonded to adjacent carbon atoms, R<4> and R<5> may, together with the carbon atoms to which they are bonded, form a fused dihydrofuran; and 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms; and Y is N or CH. 2. A compound according to claim 1 wherein R<2> is hydrogen or methyl. 3. A compound according to any one of claims 1 or 2 wherein R<2> is hydrogen. 4. A compound according to claim 1 wherein X is NH. 5. A compound according to any one of claims 1-4 wherein R<3> is CO2 H. 6. A compound according to any one of claims 1-5 wherein at least one of R<4> and R<5> is hydrogen. 7. A compound according to any one of claims 1-6 wherein at least one of R<4> and R<5> are both hydrogen. 8. A compound according to any one of claims 1-7 wherein Y is CH. 9. A compound selected from the group consisting of: (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid methyl ester; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-2,4-dicarboxylic acid dimethyl ester; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-2-methyl-5-carboxylic acid methyl ester; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3,4-dicarboxylic acid dimethyl ester; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-chloro-4-carboxylic acid methyl ester; (R)-3'-[[2-[[2-(3,5-dichlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid methyl ester; (R)-3'-[[2-[[2-(3,5-dichiorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-2,4-dicarboxylic acid 2-methyl ester; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-2,4-dicarboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-2-methyl-5-carboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-chloro-4-carboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3,4-dicarboxylic acid; (R)-3'-[[2-[(2-hydroxy-3-phenoxypropyl)amino]ethyl]amino-[1,1'-biphenyl]-3-carboxylic acid; (R)-3'-[[2-[[2-(3-chloropheny)-2-hydroxyethyl]amino]ethoxy]-1,1'-biphenyl]-3-carboxylic acid; 3'-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]-[1,1'-biphenyl]-4-carboxylic acid; 3'-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]-[1,1'-biphenyl]-2-carboxylic acid; 3'-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]-[1,1'-biphenyl]-2,4-dicarboxylic acid; 5-[3-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]phenyl]-3-pyridinecarboxylic acid; 2-[3-[[2R-[[2-(3-chlorophenyl)-2R-hydroxyethyl]amino]propyl]amino]phenyl]-3-pyridinecarboxylic acid; (R)-5-[3-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]phenyl]-2,3-dihydro-7-benzofurancarboxylic acid; (R)-5-[3-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]phenyl]-3-pyridinecarboxylic acid; (R)-2-[3-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]phenyl]-4-pyridinecarboxylic acid; (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-(1H-5-tetrazole); (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3- 11. A compound according to any one of claims 1-10 for use in therapy. 12. Use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of a mammal, including man, of conditions susceptible of amelioration by an atypical beta-adrenoceptor agonist. 13. A method for the treatment of a mammal, including man, of conditions susceptible of amelioration by an atypical beta-adrenoceptor agonist comprising administration of an effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition comprising a compound according to any one of claims 1- 10 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. 15. A process for the preparation of a compound of formula (I) comprising deprotection of a compound of Formula (II): 16. A process for the preparation of a compound of formula (I) comprising interconversion of another compound of Formula (I). 17. A process for the preparation of a compound of formula (I) comprising reaction of compound of Formula (III) with a compound of Formula (IV) to obtain a compound of formula (II) followed by deprotection of a compound of formula (II) without purification of intermediate products 18. A process for the preparation of a compound of formula (I) comprising reaction of a compound of Formula (VIII) with a compound of Formula (IX)