Isoprenoid pathway inhibitors for stimulating cartilage growth
Compounds of the formula wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C; Y is of the formula or a stereoisomer thereof, wherein R 1 is substituted or unsubstituted alkyl; each R 2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C); R 3 is H, hydroxy, or alkoxy (1-6C); or Y is of the formula wherein each n is 1, Z is N, K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR 6 — wherein R 6 is H or linear, branded or cyclic alkyl (1-6C), R 5 is H or linear, branched or cyclic alkyl, and R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C, promote bone formation and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation. Also disclosed is a method to identify additional compounds which are inhibitors of enzymes in the isoprenoid scheme especially of HMG-CoA reductase which results in prenylation of proteins and in the synthesis of steroids or of inhibitors of their production which are useful in treating bone disorders.
1 . A method to enhance cartilage formation in a vertebrate animal which method comprises administering to a vertebrate subject in need of such treatment an amount of a composition comprising a statin compound of the formula:
wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C;
Y is of the formula
or a stereoisomer thereof,
wherein R 1 is substituted or unsubstituted alkyl;
each R 2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C);
R 3 is H, hydroxy, or alkoxy (1-6C); or
Y is of the formula
wherein each n is 1,
Z is N,
K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR 6 — wherein R 6 is H or linear, branded or cyclic alkyl (1-6C),
R 5 is H or linear, branched or cyclic alkyl, and
R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C,
wherein bone formation is effected.
2 . The method of claim 1 wherein X is selected from the group consisting of —CH 2 CH 2 —; —CH═CH—; and —C≡C—.
3 . The method of claim 2 wherein Y is of the formula 4(g) or a stereoisomer or mixture of stereoisomers thereof.
4 . The method of claim 3 wherein R 1 alkyl 4-5C.
5 . The method of claim 3 wherein each R 2 is independently H, methyl or hydroxy.
6 . The method of claim 5 wherein each of R 2 is independently H or methyl.
7 . The method of claim 2 wherein Y is of formula (7) as shown.
8 . The method of claim 2 wherein Y is of formula (7) where Z is spaced from the carbon bonded to X by ═CR 6 —, wherein R 6 is H or linear, branched or cyclic alkyl (1-6C).
9 . The method of claim 7 wherein K is a substituted or unsubstituted carbocyclic aromatic system.
10 . The method of claim 8 wherein K is a substituted or unsubstituted carbocyclic aromatic system.
11 . The method of claim 9 wherein K is p-fluorophenyl.
12 . The method of claim 10 wherein K is p-fluorophenyl.
13 . The method of claim 2 wherein Y is of formula (8).
14 . The method of claim 13 wherein K is substituted pyrrole.
15 . The method of claim 14 wherein said substitutions comprise aromatic systems.
16 . The method of claim 15 wherein said substitutions comprise substituted and unsubstituted phenyl groups.
17 . The method of claim 16 wherein said substitutions comprise p-fluorophenyl and phenyl.
18 . The method of claim 13 wherein K is substituted pyridyl.
19 . The method of claim 18 wherein the pyridyl is 2- pyridyl.
20 . The method of claim 19 wherein the substitutions comprise alkyl (1-6c) and alkoxy (1-6c).
21 . The method of claim 2 wherein said compound is atorvastatin, cerivastatin, lovastatin, mevastatin, simvastatin, fluvastatin, pravastatin or NK-104 in hydrolyzed or unhydrolyzed form.