Carboxylic acid derivatives useful for inhibiting the degradation of cartilage

Claim 2

A compound of the formula and the pharmaceutically-acceptable acid addition salts thereof and the pharmaceutically-acceptable base salts thereof, wherein X is 0, S, SO, SO 2 or NR 2 ; R is H or CH 3 ; Y is OH, OR 3 or NHR 4 ; and n is zero or one; wherein R 2 is H, CH 3 or CO-CH 3 ; R 3 is alkyl having 1 to 5 carbons or phenyl; and R 4 is H , alkyl having 1 to 5 carbons, phenyl, hydroxyphenyl or 5-tetrazolyl;

Claim 3

A compound according to claim 1, wherein R is hydrogen.

Claim 4

A compound according to claim 1, wherein R is methyl.

Claim 5

A compound according to claim 2 or claim 3, wherein n is zero.

Claim 6

A compound according to claim 4, wherein X is 0.

Claim 7

A compound according to claim 4, wherein X is S, SO, or SO 2 .

Claim 8

A compound according to claim 5 or claim 6, wherein Y is OH.

Claim 9

A compound according to claim 5 or claim 6, wherein Y is OR 3 and R 3 is said alkyl.

Claim 10

A pharmaceutical composition which comprises a compound according to any of claims 1 to 8 and a pharmaceutically-acceptable carrier.

Claim 11

1Q. A method for preparing a compound of the formula or a pharmaceutically-acceptable acid addition salt thereof or a pharmaceutically-acceptable base salt thereof, wherein X is O, S, SO, SO 2 or NR 2 ; R 1 is H or CH 3 ; Y is OH, OR 3 or NHR 4 ; and n is zero or one; wherein R 2 is H, CH 3 or CO-CH 3 : R 3 is alkyl having 1 to 5 carbons or phenyl; and R 4 is H , alkyl having 1 to 5 carbons, phenyl, hydroxyphenyl or 5-tetrazolyl; characterized in that a phosphonium halide of the formula reacts with an aldehyde of the formula wherein Z is chloro or bromo; X 1 is 0, S, SO, SO 2 or NCOCH 3 ; R 1 is H or CH 3 ; n is zero or one; and Y 1 is OR , wherein R is alkyl having 1 to 5 carbons or phenyl; followed thereafter, when desired, by carrying out one or more of the following transformations: (i) hydrolyzing Y as OR 3 , wherein R 3 is alkyl having 1 to 5 carbons or phenyl, to Y is OH; (ii) hydrolyzing X as NCOCH 3 to X is NH; (iii) converting Y as OH into Y is NHR 4 , wherein R 4 is H , alkyl having 1 to 5 carbons, phenyl, hydroxyphenyl or 5-tetrazolyl; and (iv) methylating X as NH to X is NCH 3 .

Claim 12

1Q. A method for preparing a compound of the formula or a pharmaceutically-acceptable acid addition salt thereof or a pharmaceutically-acceptable base salt thereof, wherein X is O, S, SO, SO 2 or NR 2 ; R 1 is H or CH 3 ; Y is OH, OR 3 or NHR 4 ; and n is zero or one; wherein R 2 is H, CH 3 or CO-CH 3 : R 3 is alkyl having 1 to 5 carbons or phenyl; and R 4 is H , alkyl having 1 to 5 carbons, phenyl, hydroxyphenyl or 5-tetrazolyl; characterized in that a phosphonium halide of the formula reacts with an aldehyde of the formula wherein Z is chloro or bromo; X 1 is 0, S, SO, SO 2 or NCOCH 3 ; R 1 is H or CH 3 ; n is zero or one; and Y 1 is OR , wherein R is alkyl having 1 to 5 carbons or phenyl; followed thereafter, when desired, by carrying out one or more of the following transformations: (i) hydrolyzing Y as OR 3 , wherein R 3 is alkyl having 1 to 5 carbons or phenyl, to Y is OH; (ii) hydrolyzing X as NCOCH 3 to X is NH; (iii) converting Y as OH into Y is NHR 4 , wherein R 4 is H , alkyl having 1 to 5 carbons, phenyl, hydroxyphenyl or 5-tetrazolyl; and (iv) methylating X as NH to X is NCH 3 .

Claim 13

A compound or salt thereof as claimed in claim 1 for use in medicine, in particular for use in inhibiting the degradation of cartilage in a human subject.

Claim 14

CLAIMS for the Contracting State AT

Claim 17

A process according to claim 1, wherein X is 0, S, SO, SO 2 or NCOCH 3 ; and Y is OH or OR 3 , wherein R 3 is alkyl having 1 to 5 carbons or phenyl.

Claim 18

A process according to claim 2, wherein the reaction between the phosphonium halide and the aldehyde is carried out in an epoxyalkane having 3 to 6 carbons at a temperature in the range from 30 to 100° C.

Claim 19

A process according to claim 3, wherein said epoxyalkane is 1,2-epoxybutane.

Claim 20

A process according to any of claims 1 to 4, wherein Y is OR 3 , wherein R 3 is alkyl having 1 to 5 carbons.

Claim 21

A process according to any of claims 1 to 4, wherein Y as OR 3 is hydrolyzed to Y is OH.

Claim 22

A process according to claim 6, wherein the hydrolysis is carried out using an alkali metal hydroxide.