Patent EA-001561-B1 (EA)
Title: Biphenylsulfonamide matrix metalloproteinase inhibitors
Inventor: O'BRIEN PATRICK MICHAEL
IPC: A61K31/00
Filed: 1997-04-24
Abstract: 1. A compound of the Formula I   wherein R<1> is alkyl with the number of carbon atoms from 1 to 6, halo, nitro group, (CH2)0-4-NR<4>R<5>, cyano group, OR<4>,   R<2> is hydrogen or alkyl with the number of carbon atoms from 1 to 6, optionally substituted by the following groups: phenyl, substituted phenyl, phenoxy-, substituted phenoxy-, NR<4>R<5>, OR<6>, carboxy-, carboxyamido-,  thio-, methylthio-, indole, imidazole, and phthalimido-; R<3> is OH, OC1-C6 alkyl, or NHOH; R<4> is hydrogen, alkyl with the number of carbon atoms from 1 to 6, or alkanoyl with the number of carbon atoms from 1 to 6; R<5> is hydrogen or alkyl with the number of carbon atoms from 1 to 6; and R<6> is hydrogen, alkyl with the number of carbon atoms from 1 to 6, alkanoyl with the number of carbon atoms from 1 to 6, phenyl, or substituted phenyl; R<7> is hydrogen or halo; and pharmaceutically acceptable salts and solvates thereof. 2. A compound of claim 1 having the formula   wherein: R<1> is alkyl with the number of carbon atoms from 1 to 6, halo, nitro-group, NR<4>R<5>, cyano-group, OR<4>, and COOR<4>; R<2> is alkyl with the number of carbon atoms from 1 to 6, optionally substituted by the group selected from: phenyl, substituted phenyl, NR<4>R<5>, OR<6>, carboxy-, carboxamido-,    thio-, methylthio-, indole, imidazole, and phthalimido-; R<3> is OH, OC1-C6-alkyl, or NHOH; R<4> is hydrogen, alkyl with the number of carbon atoms from 1 to 6, or alkanoyl with the number of carbon atoms from 1 to 6; R<5> is hydrogen or alkyl with the number of carbon atoms from 1 to 6;  R<6> is hydrogen, alkyl with the number of carbon atoms from 1 to 6, alkanoyl with the number of carbon atoms from 1 to 6, phenyl, or substituted phenyl. 3. A compound of claim 2 wherein R<3> is OH. 4. A compound of claim 3 wherein R<2> is alkyl with the number of carbon atoms from 1 to 6. 5. A compound of claim 4 wherein R<1> is at the 4' position. 6. A compound of claim 1 which is selected from (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(4'-chlorobiphenyl-4-sulfonylamino)-3-methylbutanoic acid;  (S)-3-methyl-2-(4'-nitrobiphenyl-4-sulfonylamino)butanoic acid; (S)-2-(4'-aminobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(4'-cyanobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(3',4'-dibromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid, sodium salt; (S)-2-(3'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid (S)-2-(4'-bromo-2'-fluorobiphenyl-4-sulfonylamino)-3-methylbutanoic acid, (R)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-4-methylpentanoic acid; (S)-2-(4'-methoxybiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(4'-fluorobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-2-(3'-fluorobiphenyl-4-sulfonylamino)-3-methylbutanoic acid; (S)-3-methyl-2-(4'-trifluoromethylbiphenyl-4-sulfonylamino)butanoic acid; 2-(4'-formylbiphenyl-4-sulfonylamino)-3-methylbutanoic acid; 4'-(1-carboxy-2-methylpropylsulfamoyl)biphenyl-4-carbonic acid; 2-(4'-hydroxymethylbiphenyl-4-sulfonylamino)-3-methylbutanoic acid; 2-(4'-aminomethylbiphenyl-4-sulfonylamino)-3-methylbutanoic acid. 7. A compound of claim 2 wherein R<2> is alkyl with the number of carbon atoms from 1 to 6 substituted with phenyl or substituted phenyl. 8. A compound of claim 7 which is (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-phenylpropionic acid, or (S)-(4`-isopropylbiphenyl-4-sulfonylamino)-3-phenylpropionic acid. 9. The compound of claim 7 which is (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid. 10. A compound of claim 1 wherein R<3> is OC1-C6alkyl. 11. A compound of claim 10 which is (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid tert-butyl ester. 12. A pharmaceutical formulation comprising a compound of claim 1 admixed with a diluent, carrier, or excipient therefor. 13. A pharmaceutical formulation of claim 12 comprising (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid as an active ingredient. 14. A method for inhibiting a matrix metalloproteinase enzyme by administering a matrix metalloproteinase inhibiting amount of a compound of claim 1. 15. A method for inhibiting a matrix metalloproteinase enzyme of claim 14 comprising administering a matrix metalloproteinase inhibiting amount of (S)-2-(4'-bromobiphenyl-4-sulfonylamino)-3-methylbutanoic acid. 16. A method of treating arthritis or restenosis or atherosclerosis comprising administering a matrix metalloproteinase inhibiting amount of a compound of claim 1.