Claims
- 1. A compound having the Formula I
- 2. A compound as recited in claim 1 wherein
B is N; A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl or (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, said A moieties optionally mono-, di-, or tri-substituted on carbon with fluoro; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl; K is methylene or ethylene; Ar, Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl; R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R2 and R3 are chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 3. A compound as recited in claim 2 wherein
A is (C1-C3)alkylsulfonyl; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar1—V—Ar2 or —Ar1—O—Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl; V is a bond or (C1-C2)alkylene; R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R and R are each independently chloro or fluoro.
- 4. A compound as recited in claim 3 wherein the compound is
7-[(2′-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid, 7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-heptanoic acid, or 7-[(2′-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid.
- 5. A compound as recited in claim 3 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(2-hydroxymethylphenyl)phenyl.
- 6. A compound as recited in claim 3 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(3-hydroxymethylthien-2-yl)phenyl.
- 7. A compound as recited in claim 3 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(2-chlorophenyl)phenyl.
- 8. A compound as recited in claim 1 wherein
B is N; A is (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethyloxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl; K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro; M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl or chromanyl; R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently hydroxy, halo, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl, difluoromethoxy, trifluoromethoxy or carbamoyl.
- 9. A compound as recited in claim 8 wherein
K is methylene; A is (C1-C3)alkylsulfonyl; M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R1; R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 10. A compound as recited in claim 9 wherein the compound is
7-{[4-(1-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid, 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid, 7-{[5-(1-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoic acid or (3-{[(4-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid.
- 11. A compound as recited in claim 9 wherein
Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-; and W is oxy.
- 12. A compound as recited in claim 9 wherein
Q is —(C3-C8)alkylene-, said —(C3-C8)alkylene- optionally substituted with from one to four fluorines.
- 13. A compound as recited in claim 12 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(1-hydroxy-n-hexylene-1-yl)phenyl.
- 14. A compound as recited in claim 12 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(n-butylene-1-yl)phenyl.
- 15. A compound as recited in claim 12 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 5-(1-hydroxy-n-hexylene-1-yl)thien-2-yl.
- 16. A compound as recited in claim 9 wherein
Q is —X—(C1-C5)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 17. A compound as recited in claim 9 wherein
Q is —(C1-C5)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 18. A compound as recited in claim 9 wherein
Q is —(C1-C3)alkylene-X—(C1-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 19. A compound as recited in claim 18 wherein
A is methylsulfonyl; Q is 3-methylenephenylmethyl; Z is carboxyl; K is methylene; and M is 4-(n-butylene-1-yl)phenyl.
- 20. A compound as recited in claim 9 wherein
Q is —(C2-C4)alkylene-W—X—(C0-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 21. A compound as recited in claim 9 wherein
Q is —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 22. A compound as recited in claim 9 wherein
Q is —(C2-C4)alkylene-W—X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 23. A compound as recited in claim 9 wherein
Q is —(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
- 24. A compound as recited in claim 9 wherein
Q is —(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 25. A compound as recited in claim 9 wherein
Q is —(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 26. A compound as recited in claim 9 wherein
Q is —(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
- 27. A compound as recited in claim 9 wherein
Q is —(C1-C4)alkylene-ethynylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 28. A compound as recited in claim 8 wherein
A is (C1-C3)alkylsulfonyl; K is (C1-C8)alkylene; —Ar is phenyl, thiazolyl, pyridyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 29. A compound as recited in claim 28 wherein the compound is
7-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid, 7-{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid or 5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid.
- 30. A compound as recited in claim 28 wherein
Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-; and W is oxy.
- 31. A compound as recited in claim 28 wherein
Q is —(C3-C8)alkylene-, said —(C3-C8)alkylene- optionally substituted with from one to four fluorines.
- 32. A compound as recited in claim 31 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is 3-chlorophenyl.
- 33. A compound as recited in claim 31 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is propylene; and M is 3,5-dichlorophenyl.
- 34. A compound as recited in claim 28 wherein
Q is —X—(C1-C5)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 35. A compound as recited in claim 28 wherein
Q is —(C1-C5)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 36. A compound as recited in claim 35 wherein
A is methylsulfonyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene K is propylene; and M is 3-chlorophenyl.
- 37. A compound as recited in claim 28 wherein
Q is —(C1-C3)alkylene-X—(C1-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 38. A compound as recited in claim 28 wherein
Q is —(C2-C4)alkylene-W—X—(C0-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 39. A compound as recited in claim 28 wherein
Q is —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 40. A compound as recited in claim 28 wherein
Q is —(C2-C4)alkylene-W—X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 41. A compound as recited in claim 28 wherein
Q is —(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl;
- 42. A compound as recited in claim 28 wherein
Q is —(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 43. A compound as recited in claim 28 wherein
Q is —(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 44. A compound as recited in claim 28 wherein
Q is —(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
- 45. A compound as recited in claim 28 wherein
Q is —(C1-C4)alkylene-ethynylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 46. A compound as recited in claim 8 wherein
A is (C1-C3)alkylsulfonyl; K is oxy(C1-C4)alkylene; —Ar is phenyl, thienyl, thiazolyl, pyridyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 47. A compound as recited in claim 46 wherein the compound is
7-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid, 5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(1H-tetrazol-5-yl)-hexyl]-methanesulfonamide.
- 48. A compound as recited in claim 46 wherein
Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-; and W is oxy.
- 49. A compound as recited in claim 46 wherein
Q is —(C3-C8)alkylene-, said —(C3-C8)alkylene- optionally substituted with from one to four fluorines.
- 50. A compound as recited in claim 49 wherein
A is methylsulfonyl; Q is n-hexylene; Z is carboxyl; K is oxyethylene; and M is 3,5-dichlorophenyl.
- 51. A compound as recited in claim 46 wherein
Q is —X—(C1-C5)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 52. A compound as recited in claim 46 wherein
Q is —(C1-C5)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 53. A compound as recited in claim 52 wherein
A is methylsulfonyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene; K is oxyethylene; and M is 3,5-dichlorophenyl.
- 54. A compound as recited in claim 46 wherein
Q is —(C1-C3)alkylene-X—(C1-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 55. A compound as recited in claim 46 wherein
Q is —(C2-C4)alkylene-W—X—(C0-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 56. A compound as recited in claim 46 wherein
Q is —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 57. A compound as recited in claim 46 wherein
Q is —(C2-C4)alkylene-W—X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 58. A compound as recited in claim 46 wherein
Q is —(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
- 59. A compound as recited in claim 46 wherein
Q is —(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 60. A compound as recited in claim 46 wherein
Q is —(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 61. A compound as recited in claim 46 wherein
Q is —(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
- 62. A compound as recited in claim 46 wherein
Q is —(C1-C4)alkylene-ethynylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 63. A compound as recited in claim 8 wherein
A is (C1-C3)alkylsulfonyl; K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated; —Ar is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 64. A compound as recited in claim 63 wherein the compound is
Trans-(4-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-butoxy)-acetic acid, Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(1H-tetrazolyl-5-yl)-hexyl]-methanesulfonamide, Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid or Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid.
- 65. A compound as recited in claim 63 wherein
Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-; and W is oxy.
- 66. A compound as recited in claim 65 wherein
A is methylsulfonyl; Q is methyloxy-n-butylene; Z is carboxyl; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
- 67. A compound as recited in claim 63 wherein
Q is —(C3-C8)alkylene-, said —(C3-C8)alkylene- optionally substituted with from one to four fluorines.
- 68. A compound as recited in claim 67 wherein
A is methylsulfonyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl); K is trans-2-n-propeneylene; and M is 3,5-dichlorophenyl.
- 69. A compound as recited in claim 63 wherein
Q is —X—(C1-C5)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 70. A compound as recited in claim 63 wherein
Q is —(C1-C5)alkylene-X-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 71. A compound as recited in claim 70 wherein
A is methylsulfonyl; Q-Z is 3-(2-carboxylthien-5-yl)-n-propylene; K is trans-2-n-propeneylene; and M is 3,5-dichlorophenyl.
- 72. A compound as recited in claim 63 wherein
Q is —(C1-C3)alkylene-X—(C1-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 73. A compound as recited in claim 63 wherein
Q is —(C2-C4)alkylene-W—X—(C0-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 74. A compound as recited in claim 63 wherein
Q is —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy; and W is oxy.
- 75. A compound as recited in claim 63 wherein
Q is —(C2-C4)alkylene-W—X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 76. A compound as recited in claim 63 wherein
Q is —(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-; and M is —Ar and —Ar is phenyl, thiazolyl, pyridyl or thienyl.
- 77. A compound as recited in claim 63 wherein
Q is —(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 78. A compound as recited in claim 63 wherein
Q is —(C1-C3)alkylene-ethenylene-(C0-C2)alkylene-X—W—(C1-C3)alkylene-; W is oxy; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 79. A compound as recited in claim 63 wherein
Q is —(C1-C4)alkylene-ethynylene-(C1-C4)alkylene-.
- 80. A compound as recited in claim 63 wherein
Q is —(C1-C4)alkylene-ethynylene-X—(C0-C3)alkylene-; and X is thienyl or phenyl; said phenyl and thienyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl or methoxy.
- 81. A compound as recited in claim 1 wherein
B is N; A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl; K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with methyl, fluoro or chloro; Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl; Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl; R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
- 82. A compound as recited in claim 81 wherein
A is (C1-C6)alkanoyl, said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; K is methylene or ethylene; M is —Ar1—V—Ar2 or —Ar1—O—Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl; V is a bond or (C1-C2)alkylene; R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C6)alkoxy, said (C1-C4)alkyl and (C1-C6)alkoxy optionally mono-, di-or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently chloro or fluoro.
- 83. A compound as recited in claim 81 wherein
A is (C1-C6)alkanoyl said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo; K is methylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-, M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R1; R1 is (C1-C7)alkyl or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 84. A compound as recited in claim 81 wherein
A is (C1-C6)alkanoyl said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted independently on carbon with halo; K is (C1-C8)alkylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 85. A compound as recited in claim 81 wherein
A is (C1-C6)alkanoyl said (C1-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo; K is oxy(C1-C4)alkylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 86. A compound as recited in claim 81 wherein
A is (C3-C6)alkanoyl said (C3-C6)alkanoyl optionally mono-, di- or tri-substituted on carbon independently with halo; K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 87. A compound as recited in claim 1 wherein
B is C(H); A is (C1-C6)alkanoyl, or (C3-C7)cycloalkyl(C1-C6)alkanoyl, said A moieties optionally mono-, di- or tri-substituted independently on carbon with hydroxy or halo; X is phenyl, thienyl, or thiazolyl said phenyl, thienyl or thiazolyl optionally mono- or di-substituted independently with fluoro, chloro, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; W is oxy, thio or sulfonyl; Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl; K is (C1-C8)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein K is optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; Ar is (C5-C7)cycloalkyl, phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, naphthalenyl, benzo[b]furanyl, benzo[b]thiophenyl, indanyl, furanyl, benzo[1,3]dioxolyl, benzimidazolyl, benzisoxazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, pyrazolyl, pyrimidyl, pyrazinyl, imidazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl, indolyl, 1,2,3,4-tetrahydronaphthalenyl, cyclohexyl, cyclopentyl, or chromanyl; Ar1 and Ar2 are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl; R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently hydroxy, halo, difluoromethoxy, trifluoromethoxy, trifluoromethyl, (C1-C7)alkyl, (C1-C4)alkoxy, (C1-C5)alkanoyl, cyano, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, formyl or carbamoyl.
- 88. A compound as recited in claim 87 wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; K is methylene or ethylene; M is —Ar1—V—Ar2 or —Ar1—O—Ar2 wherein Ar1 and Ar2 are each independently phenyl, pyridyl or thienyl; V is a bond or (C1-C2)alkylene; R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently chloro or fluoro.
- 89. A compound as recited in claim 87 wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with hydroxy or halo; K is methylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein —Ar is substituted with at least R1; R1 is (C1-C7)alkyl or (C1-C6)alkoxy, said (C1-C7)alkyl or (C1-C6)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 90. A compound as recited in claim 87 wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo; K is (C1-C8)alkylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, benzofuranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzo[b]thiophenyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 91. A compound as recited in claim 87 wherein
A is (C1-C6)alkanoyl said A optionally mono-, di- or tri-substituted on carbon independently with halo; K is oxy(C1-C4)alkylene; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, benzo[1,3]dioxolyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 92. A compound as recited in claim 87 wherein
A is (C1-C6)alkanoyl, said A optionally mono-, di- or tri-substituted on carbon independently with halo; K is (C3-C8)alkylene, said (C3-C8)alkylene being mono-unsaturated; Q is —(C2-C6)alkylene-W—(C1-C3)alkylene-, —(C4-C8)alkylene-, said —(C4-C8)alkylene- optionally substituted with up to four substituents independently selected from fluorines or (C1-C4)alkyl, —X—(C2-C5)alkylene-, —(C1-C5)alkylene-X-, —(C1-C3)alkylene-X—(C1-C3)alkylene-, —(C2-C4)alkylene-W—X—(C0-C3)alkylene-, or —(C0-C4)alkylene-X—W—(C1-C3)alkylene-; M is —Ar and —Ar is phenyl, thienyl, cyclopentyl or cyclohexyl; and R1, R2 and R3 are each independently hydroxy, halo, trifluoromethyl, trifluoromethoxy, (C1-C4)alkoxy or (C1-C7)alkyl.
- 93. A compound as recited in claim 83 wherein
A is propanoyl; Q is n-hexylene; Z is carboxyl; K is methylene; and M is 4-(n-1-hydroxylhexyl)phenyl.
- 94. A compound as recited in claim 49 wherein
A is methylsulfonyl; Q is n-hexylene; Z is 5-(1H-tetrazolyl); K is oxyethyl; and M is 3,5-dichlorophenyl.
- 95. A compound as recited in claim 72 wherein
A is methylsulfonyl; Q is 3-methylenephenylmethyl; Z is carboxyl; K is trans-2-n-propenylene; and M is 3,5-dichlorophenyl.
- 96. 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.
- 97. The method as recited in claim 96 wherein osteoporosis, osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis is treated.
- 98. The method as recited in claim 97 wherein osteoporosis is treated in a human.
- 99. The method as recited in claim 96 wherein glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis is treated.
- 100. 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.
- 101. The method as recited in claim 100 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.
- 102. The method as recited in claim 100 wherein a bone fracture is treated in a human.
- 103. 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.
- 104. The pharmaceutical composition as recited in claim 103 for the treatment of osteoporosis wherein the therapeutically effective amount is an osteoporosis treating amount.
- 105. 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.
- 106. The pharmaceutical composition as recited in claim 105 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.
- 107. 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.
- 108. 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.
- 109. A pharmaceutical composition as recited in claim 108 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-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-naphthalene-2-ol; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 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′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
- 110. A pharmaceutical composition as recited in claim 108 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.
- 111. 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.
- 112. The method as recited in claim 111 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-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-naphthalene-2-ol; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 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′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
- 113. The method as recited in claim 111 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.
- 114. 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.
- 115. The kit as recited in claim 114 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-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-naphthalene-2-ol; Cis-1-[6′-pyrrolodinoethoxy-3′-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydrohaphthalene; 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′-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline or a pharmaceutically acceptable salt thereof.
- 116. The kit as recited in 114 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.
- 117. 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 anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof; and c. a pharmaceutical carrier.
- 118. The pharmaceutical composition as recited in claim 117 wherein the anabolic agent other than the claim 1 compound is IGF-1 optionally with IGF-1 binding protein 3 prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
- 119. A method for treating a mammal which presents with low bone mass comprising administering to said
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 a bone anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof.
- 120. The method as recited in claim 119 wherein the anabolic agent other than the claim 1 compound is IGF-1, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
- 121. 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 anabolic agent other than a compound of claim 1 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing said first and second dosage forms.
- 122. The kit as recited in claim 121 wherein the anabolic agent other than the claim 1 compound is IGF-1, prostaglandin, prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), active fragments of parathyroid hormone, growth hormone or growth hormone secretagogues or a pharmaceutically acceptable salt thereof.
- 123 A compound as recited in claim 1 wherein
B is N; A is (C1-C3) alkylsulfonyl; Q is —(C3-C5)alkylene-O—(C1-C3)alkylene-, —(C5-C7)alkylene-, said —(C5-C7)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, —(C2-C4)alkylene-X-, —(CH2)-meta-phenylene-O—(CH2)— optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro or —(CH2)-meta-phenylene-(CH2)— optionally mono- or di-substituted independently with methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro; M is —Ar1—V—Ar2 or —Ar1—O—Ar2; V is a bond or —CH2—; Z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl; X is thienyl, thiazolyl, or furanyl; K is methylene; Ar1 is phenyl, (C5-C7)cycloalkyl , furanyl, thienyl, thiazolyl, or pyridyl; Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl, triazolyl or pyrazolyl; R1 is chloro, fluoro, (C1-C4)alkyl or (C1-C4)alkoxy, said (C1-C4)alkyl and (C1-C4)alkoxy optionally mono-, di- or tri-substituted independently with hydroxy or fluoro; and R2 and R3 are each independently, methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
- 124. A compound as recited in claim 123 wherein
Q is —(CH2)-meta-phenylene-(CH2)—, M is —Ar1—Ar2, Ar1 is phenyl; Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar2 optionally mono- or di-substituted independently with R1 or R2; R1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and R2 is methoxy, chloro or fluoro.
- 125. A compound as recited in claim 123 wherein
Q is —(CH2)-meta-phenylene-O—(CH2)—, M is —Ar1—Ar2, Ar1 is phenyl; Ar2 is (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl, said Ar2 optionally mono- or di-substituted independently with R1 or R2; R1 is chloro, fluoro, methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy; and R2 is methoxy, chloro or fluoro.
- 126. A compound of claim 124 wherein
A is methylsulfonyl; Z is carboxyl; and M is 4-(cyclohexyl)phenyl.
- 127. A compound of claim 124 wherein
A is methylsulfonyl; Z is carboxyl; and M is 4-(thiazol-2-yl)phenyl.
- 128. A compound of claim 124 wherein
A is methylsulfonyl; Z is carboxyl; and M is 4-(pyrazin-2-yl)phenyl.
- 129. A compound as recited in claim 124 wherein the compound is
a. (3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid; b. (3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid; or c. (3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid.
- 130. A compound as recited in claim 1 wherein
B is N; A is (C1-C3)alkylsulfonyl Q is —(C2-C4)alkylene-X-; X is thiazolyl or furanyl; said thiazolyl or furanyl optionally mono- or di-substituted independently with methyl, methoxy, fluoro, chloro, trifluoromethyl, difluoromethoxy or trifluoromethoxy; K is oxy-ethylene or propylene, said propylene optionally being mono-unsaturated; M is —Ar, said —Ar is phenyl, thienyl, pyridyl, thiazolyl, oxazolyl, isoxazolyl, pyrimidyl, imidazolyl, cyclohexyl, cyclopentyl, cyclobutyl, or cycloheptyl; R1 is halo, (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, said (C1-C6)alkoxy, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C1-C7)alkanoyl or (C3-C7)cycloalkyl(C1-C4)alkyl, optionally mono-, di- or tri-substituted independently with hydroxy, fluoro or chloro; and R2 and R3 are each independently methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, chloro or fluoro.
- 131. A compound as recited in claim 130 wherein
A is methylsulfonyl; Z is carboxyl, or (C1-C4)alkoxycarbonyl; Q is -propylene-X-; X is thiazolyl; K is oxy-ethylene or propylene; M is phenyl optionally mono- or di-substituted independently with fluoro, chloro, methoxy, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 132. A compound as recited in claim 131 wherein
Z is carboxyl; K is propylene; and M is 3-(chloro)phenyl.
- 133. A compound as recited in claim 131 wherein
Z is carboxyl; K is oxy-ethylene; and M is 3,5-dichlorophenyl.
- 134. A compound as recited in claim 130 wherein the compound is
a. 2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylic acid or b. 2-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiazole-4-carboxylic acid.
- 135. A compound having the Formula IA
- 136. A pharmaceutical composition comprising:
a. a therapeutically effective amount of a compound of claim 135 or a pharmaceutically acceptable salt or prodrug thereof; b. a therapeutically effective amount of 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or a pharmaceutically acceptable salt thereof and c. a pharmaceutical carrier.
- 137. 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 135 or a pharmaceutically acceptable salt or prodrug thereof; and b. a therapeutically effective amount of 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]- benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or pharmaceutically acceptable salt thereof.
- 138. A kit comprising:
a. a therapeutically effective amount of a compound of claim 135 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 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol or a pharmaceutically acceptable salt thereof or 3-[4-(1,2-diphenyl-but-1-enyl)-phenyl]-acrylic acid or a pharamceutically acceptable salt thereof and a pharmaceutically acceptable carrier in a second unit dosage form; and c. container means for containing said first and second dosage forms.
- 139. A method for treating a mammal in need of kidney regeneration comprising administering to said mammal a therapeutically effective amount of a compound of claim 135 or a pharmaceutically acceptable salt or prodrug thereof.
- 140. 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 135 or a pharmaceutically acceptable salt or prodrug thereof.
- 141. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 135 or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. application Ser. No. 10/256,985, filed Sep. 26, 2002, now allowed, which is a divisional application of U.S. application Ser. No. 09/897,824, filed Jun. 29, 2001, now U.S. Pat. No. 6,492,412, which is a divisional application of U.S. application Ser. No. 09/331,081, filed Jun. 11, 1999, now U.S. Pat. No. 6,288,120, which is a 371 of PCT/IB97/01417 Filed Nov. 10, 1997, which claims priority of U.S. provisional application No. 60/033,451, filed Dec. 20, 1996.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60033451 |
Dec 1996 |
US |
Divisions (3)
|
Number |
Date |
Country |
Parent |
10256985 |
Sep 2002 |
US |
Child |
10652188 |
Aug 2003 |
US |
Parent |
09897824 |
Jun 2001 |
US |
Child |
10256985 |
Sep 2002 |
US |
Parent |
09331081 |
Jun 1999 |
US |
Child |
09897824 |
Jun 2001 |
US |