Patent EA-005161-B1 (EA)
Title: Prevention of loss and restoration of bone mass by certain prostaglandin agonists
Inventor: CAMERON KIMBERLY O'KEEFE
IPC: C07C311/06
Filed: 1997-11-10
Abstract: 1. A compound having the Formula or a pharmaceutically acceptable salt or prodrug thereof; wherein Y is H or (C3-C7)cycloalkyl; n is 0 to 5; the Y-(CH2)n- moiety is optionally mono-, di- or tri-substituted on carbon with hydroxy or halo; Q is (C4-C8)alkylene- or (C1-C5)alkylene-X; X is a five or six membered aromatic ring optionally having one heteroatom selected independently from oxygen and sulfur; Z is carboxyl or (C1-C6)alkoxycarbonyl; R<4> is (C1-C8)alkylene; Ar is fully saturated five to eight membered ring or a bicyclic ring consisting of two fused membered ring consisting of two fused partially saturated, fully saturated or fully unsaturated five or six membered rings, taken independently, optionally having one to-four heteroatoms being oxygen; R<5> is H; said Ar moiety optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R<1>, R<2> and R<3> wherein R<1>, R<2> and R<3> are halo or (C1-C7)alkyl; R<1>, R<2> and R<3> are optionally mono- substituted independently on carbon with hydroxy; and with the proviso that when R<4> is (C2-C4)alkylene and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy and with the proviso that 6-(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included. 2. A compound as recited in claim 1 wherein X is thienyl, and Ar is benzo[b]furanyl or 2,3-dihydrobenzo[1,4]dioxinyl. 3. A compound as recited in claim 1 wherein X is thienyl, and Ar is phenyl. 4. A compound as recited in claim 3 wherein the Y-(CH2)n- moiety is optionally mono-, di- or tri-substituted on carbon with halo; R<4> is methylene; R<1> is chloro, fluoro or (C1-C4)alkyl. 5. A compound as recited in claim 2 wherein R<4> is methylene; Ar is phenyl, wherein - Ar is substituted with at least R<1>; and R<1> is (C1-C7)alkyl, optionally mono-substituted with hydroxy. 6. A compound as recited in claim 5 wherein n is 2; Q is n-hexylene; Z is carboxyl; the -Ar-R<5> moiety is 4-(n-1-hydroxyhexyl)phenyl. 7. A compound as recited in claim 2 wherein the Y-(CH2)n- moiety is optionally mono-, di- or tri-substituted on carbon with halo; 8. A compound as recited in claim 2 wherein the Y-(CH2)n- moiety is optionally mono-, di- or tri-substituted on carbon with halo; Ar is phenyl. 9. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof. 10. The method as recited in claim 9 wherein osteoporosis, osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis is treated. 11. The method as recited in claim 10 wherein osteoporosis is treated in a human. 12. The method as recited in claim 9 where in glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis is treated. 13. A method for augmenting and maintaining bone mass in a mammal comprising administering to a mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof. 14. The method as recited in claim 13 wherein bone healing following facial reconstruction, maxillary reconstruction or mandibular reconstruction is treated, vertebral synostosis is induced or long bone extension is enhanced, the healing rate of a bone graft is enhanced or prosthetic ingrowth is enhanced. 15. The method as recited in claim 5 wherein a bone fracture is treated in a human. 16. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier. 17. The pharmaceutical composition as recited in claim 16 for the treatment of osteoporosis wherein the therapeutically effective amount is an osteoporosis treating amount. 18. A pharmaceutical composition for the augmentation of bone mass which comprises a bone mass augmenting amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier. 19. The pharmaceutical composition as recited in claim 18 for the treatment of a bone fracture wherein a bone fracture treating amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof is used. 20. A pharmaceutical composition for the treatment of a condition which presents with low bone mass in a mammal which comprises a low bone mass condition treating amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier. 21. A pharmaceutical composition comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; b. a therapeutically effective amount of an anti-resorptive agent; and c. a pharmaceutical carrier. 22. A pharmaceutical composition as recited in claim 21 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-prienyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; (-)-Cis-6'-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-[4-2-pyrrolidin-1-yl-ethoxy}-phenyl]-5,6,7,8-tetrahydro-naohthalene-2-ol; Cis-1-[6'-pyrrolidinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene; 1-(4'-Pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6-{4-hydroxyphenyl}-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4'-Pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition as recited in claim 21 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt thereof. 24. A method for treating a mammal having a condition which presents with low bone mass comprising administering to said mammal a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; and b. a therapeutically effective amount of an anti-resorptive agent. 25. The method as recited in claim 24 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-{4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-(2-(2-Aza-bicydo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-1-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-pheny1]-5,6,7,8-tetrahydronaphthalene-2-ol; Cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-prienyl-6-hydroxy-1,2,3,4-tetrariydronaphthalene; 1-(4'-Pyrrolidinoethoxyphenyl)-2-(4''-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydro isoquinoline; Cis-6-(4-hydroxyphenyl)-5-[4-2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof. 26. The method as recited in claim 24 wherein the anti-resorptive agent is, tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt. 27. A kit comprising: a. a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a first unit dosage form; b. a therapeutically effective amount of an anti-resorptive agent and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing said first and second dosage forms. 28. The kit as recited in claim 27 wherein the anti-resorptive agent is droloxifene, raloxifene, tamoxifen, 4-hydroxy-tamoxifen, toremifene, centchroman, levormeloxifene, idoxifene, 6-(4-hydroxy-phenyl)-5-[4-2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-ol, {4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl]-methanone, Cis-6-(4-fluoro-phenyl)-5-{4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthatene-2-ol; (-)-Cis-6-phenyl-5-{4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; Cis-1-[6'-pyrrodinoethoxy-3'-pyridyf]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 1-(4'-Pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyf)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline; Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or 1-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof. 29. The kit as recited in claim 27 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt thereof. 30. A Pharmaceutical composition comprising: a. a therapeuti