Phenylketone carboxylate compounds and pharmaceutical compositions for the prevention and treatment of osteoporosis
The present invention concerns the use of compounds for preventing and/or treating osteoporosis, for stimulating bone formation, for stimulating the differentiation and mineralization of osteoblasts, or for inhibiting bone resorption in a subject. These novel uses have been found for compounds represented by Formula I and pharmaceutically acceptable salts thereof. wherein: R 1 and R 2 are independently equal to H, F or OH; A is (CH 2 ) m COOH, W(CH2)mCOOH, or Y—CH(COOH)—(CH2)p-CH3 when B is H; or B is (CH2)mCOOH, W(CH2)mCOOH, or Y—CH(COOH)—(CH 2 ) p —CH 3 when A is H; or A and B are covalently bonded to form a five (5), six (6), or seven (7)-membered cycloalkyl substituted with COOH; where: Y is O, S, HN or CH 2 ; W is 0, S or NH; m is 0-2; and p is 3-7; D is CO(CH 2 ) n CH 3 or CHOH(CH 2 )nCH 3 or O(CH 2 ) n CH 3 where n is 2-6; and E is H or F.
1. A method for the treatment of primary type 1 osteoporosis, primary type 2 osteoporosis, or secondary osteoporosis, comprising the step of administering to a subject in need thereof a compound represented by Formula I or a pharmaceutical acceptable salt thereof:
wherein:
R 1 and R 2 are independently H, F or OH;
A is H, (CH 2 ) m COOH, W(CH 2 ) m COOH or
and B is H, (CH 2 ) m COOH, W(CH 2 ) m COOH or
with the proviso that A is (CH 2 ) m COOH, W(CH 2 ) m COOH or
when B is H; and B is (CH 2 ) m COOH, W(CH 2 ) m COOH or
when A is H; or A and B are covalently bonded to form a five (5), six (6) or seven (7)-membered cycloalkyl substituted with COOH;
wherein:
Y is O, S, NH, or CH 2 ;
W is O, S, or NH;
m is 0-2; and
p is 3-7;
D is C(O)—(CH 2 ) n —CH 3 or CH(OH)—(CH 2 ) n —CH 3 or O—(CH 2 ) n —CH 3 wherein n is 2-6; and
E is H or F.
2. The method of claim 1 , wherein R 1 is H and R 2 is H.
3. The method of claim 1 , wherein E is H.
4. The method of claim 1 , wherein m is 1 or 2.
5. The method of claim 1 , wherein A is H and B is
wherein Y is O, and p is 5-7.
6. The method of claim 1 , wherein R 1 and R 2 are H; B is H; A is
wherein p is 5-7, Y is O, and E is H.
7. The method of claim 1 , wherein R 1 and R 2 are H; A is H; B is
wherein p is 5-7, Y is O, and E is H.
8. The method of claim 1 , wherein D is C(O)—(CH 2 ) n —CH 3 .
9. The method of claim 1 , wherein n is 4-6.
10. The method of claim 1 , wherein said compound is selected from the group consisting of the compounds represented by the following structures:
and pharmaceutically acceptable salts thereof.
11. The method of claim 10 , wherein said compound is represented by the following structure:
or pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the pharmaceutically acceptable salt is a base addition salt comprising a metal counterion selected from the group consisting of sodium, potassium, calcium, magnesium lithium, ammonium, manganese, zinc, iron, or copper.
13. The method of claim 12 , wherein the pharmaceutically acceptable salt is sodium.
14. The method of claim 1 , wherein the osteoporosis is primary type 2 osteoporosis.
15. The method of claim 1 , wherein the osteoporosis is post-menopausal osteoporosis (primary type 1).
16. The method of claim 1 , wherein administration of said compound results in one or more of the following biological activities in the subject:
inhibition of osteoclastogenesis;
stimulation interleukin-12 (IL-12) production in bone;
reduction of acid phosphatase activity in bone;
reduction of Receptor activator of NF-κB ligand/Osteoprotegerin ratio (RANKL/OPG ratio) in bone;
increase of collagen content in bone.
17. The method of claim 1 , further comprising the step of administering concomitantly a drug selected from the group consisting of:
bisphosphonates, Odanacatib, Alendronate, Risedronate, Etidronate, Zoledronate, Pamidronate, Teriparatide, Tamoxifen, Raloxifene, and Denosumab.