Claims
- 1. A compound having the Formula I
- 2. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein B is N; Z is carboxyl, (C1-C6)alkoxycarbonyl or tetrazolyl; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, cyclopentenyl, cyclohexenyl, benzo(b)thienyl, benzoxazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl and 1,4-benzodioxan; Ar1, Ar2, Ar3, Ar4 and Ar5 are each independently cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinylpiperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctadienyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl, benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, 1,4-benzodioxan, pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and 4H-1,4-benzoxazinyl; and X is tetrahydrofuranyl, phenyl, thiazolyl, thienyl, pyridyl, pyrrazolyl, furanyl or pyrimidyl, wherein X is optionally mono-, di- or tri-substituted independently with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein each of said Ar, Ar1 and Ar2 groups are optionally substituted on carbon or nitrogen independently with up to three substituents independently selected from R3, R4 and R5; each of said Ar, Ar1 and Ar2 groups are optionally substituted independently on carbon or sulfur with one or two oxo groups; each of said Ar3, Ar4 and Ar5 groups are optionally substituted on carbon or nitrogen independently with up to three R31, R41 and R51 groups and each of said Ar3, Ar4 and Ar5 groups are optionally substituted independently on carbon or sulfur with one or two oxo groups.
- 3. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is oxy(C1-C6)alkylene; Q is
-(C2-C6)alkylene-O—(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-, -(C—C5)alkylene-X—, -(C1-C3)alkylene-X—(C1-C3)alkylene-, -(C2-C4)alkylene-O—X—(C0-C3)alkylene-, or -(C0-C4)alkylene-X—O—(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 4. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar; Q is
-(C2-C6)alkylene-O—(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-O—X—(C0-C3)alkylene-, or -(C0-C4)alkylene-X—O—(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 5. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is R1R2-amino or amino substituted with Ar, or amino substituted with Ar(C1-C4)alkylene and R11, wherein R11 is H; Q is
-(C2-C6)alkylene-O—(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-O—X—(C0-C3)alkylene-, or -(C0-C4)alkylene-X—O—(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1and R2 are taken together to form a five- or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom.
- 6. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is SO2; G is R1R2-amino, or amino substituted with Ar and R11; Q is
-(C2-C6)alkylene-O—(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-O—X—(C0-C3)alkylene-, or -(C0-C4)alkylene-X—O—(C1-C3)alkylene-; and X is phenyl, thienyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; and wherein R1and R2 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R1and R2 are taken together to form a five- or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom.
- 7. A compound of claim 2, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is SO2; G is Ar, Ar(C1-C2)alkylene or Ar1—V—Ar2; Q is
-(C2-C6)alkylene-O—(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-O—X—(C0-C3)alkylene-, or -(C0-C4)alkylene-X—O—(C1-C3)alkylene-; and X is phenyl, pyrimidyl, pyridyl, thienyl, tetrahydrofuranyl, furanyl or thiazolyl, wherein X is optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 8. A compound of claim 7, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar or Ar-(C1-C2)— alkylene; Ar is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,4-thiadiazolyl wherein each of said Ar groups is optionally substituted on carbon or nitrogen with R1, R2 or R3; Ar4 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl wherein each of said Ar4 groups is optionally mono- di- or tri-substituted on carbon or nitrogen with R31, R41 or R51; Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, 1,4-dioxanyl, thiomorpholinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl or thiepinyl wherein each of said Ar5 groups is optionally mono- di- or tri-substituted on carbon or nitrogen with R31, R41 or R51; Q is -(C5-C7)-alkylene-, -(C1-C2)-alkylene-X—(C1-C2)-alkylene-, -(C1-C2)—X—O—(C1-C2)-alkylene-, -(C2-C4)-alkylene-thienyl-, -(C2-C4)-alkylene-furanyl- or -(C2-C4)-alkylene-thiazolyl-; X is phenyl, pyridyl, pyrimidyl or thienyl; and said X groups are optionally mono-, di- or tri- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl; said -(C2-C4)-alkylene-furanyl- and -(C2-C4)-alkylene-thienyl- having a 2,5-substitution pattern, e.g.,
- 9. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein K is methylene, M is Ar4—Ar5, Ar4—O—Ar5 or Ar4—S—Ar5 and Ar is phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or tri-substituted on carbon or nitrogen with R3, R4 or R5.
- 10. A compound of claim 9, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein M is Ar4—Ar5; Ar is phenyl, pyridyl or imidazolyl; Ar4 is phenyl, furanyl or pyridyl; and Ar5 is cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl, wherein Ar, Ar4 and Ar5 are optionally mono, -di- or tri-substituted on carbon or nitrogen independently with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.
- 11. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C5-C7)alkylene-.
- 12. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is CH2—X—CH2— and X is metaphenylene optionally mono- or di- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 13. A compound of claim 12 selected from (3-(((pyridine-3-sulfonyl)-(4-pyrimidin-5-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((5-phenyl-furan-2-ylmethyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenyl)-acetic acid; and (3-(((4-pyrazin-2-yl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
- 14. The compound of claim 12 wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4—Ar5 wherein Ar4 is a furanyl ring and Ar5 is phenyl wherein said phenyl moiety is substituted at the 5-position of said furanyl ring; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 15. The compound of claim 12 wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4—Ar5 wherein Ar4 is phenyl and Ar5 is pyrimid-2-yl and said pyrimid-2-yl moiety is substituted at the 4-position of said phenyl ring; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 16. The compound of claim 12 wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4—Ar5 wherein Ar4 is phenyl and Ar5 is thiazol-2-yl and said thiazol-2-yl moiety is substituted at the 4-position of said phenyl ring; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 17. The compound of claim 12 wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4—Ar5 wherein Ar4 is phenyl and Ar5 is pyrimid-5-yl and said pyrimid-5-yl moiety is substituted at the 4-position of said phenyl ring; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 18. The compound of claim 12 wherein Ar is pyrid-3-yl; Z is carboxy; M is Ar4—Ar5 wherein Ar4 is phenyl and Ar5 is pyrazin-2-yl and said pyrazin-2-yl is substituted at the 4-position of said phenyl ring; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 19. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C2-C4)-alkylene-thienyl-, -(C2-C4)-alkylene-furanyl- or -(C2-C4)-alkylene-thiazolyl-.
- 20. The compound of claim 19 which is 5-(3-((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-propyl)-thiophene-2-carboxylic acid.
- 21. The compound of claim 19 wherein Q is n-propylenyl; X is thienyl; Z is carboxy; Ar is 3-pyridyl; Ar4 is phenyl; and Ar5 is 2-thiazolyl; said 2-thiazolyl being substituted at the 4-position of said phenyl.
- 22. A compound of claim 10, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is —CH2—X—O—CH2—; Ar4 is phenyl or pyridyl; said phenyl and pyridyl are optionally substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl and methyl; and X is metaphenylene.
- 23. A compound of claim 22 selected from (3-(((4-cyclohexyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyridin-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4- pyridin-3-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; (3-(((pyridine-3-sulfonyl)-(4-pyridin-4-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid; and (3-(((pyridine-3-sulfonyl)-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid.
- 24. The compound of claim 22 wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is cyclohexyl; and said cyclohexyl moiety is substituted at the 4-position of said phenyl ring.
- 25. The compound of claim 22 wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is thiazol-2-yl; and said thiazol-2-yl moiety is substituted at the 4-position of said phenyl ring.
- 26. The compound of claim 22 wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 2-pyridyl; and said 2-pyridyl moiety is substituted at the 4-position of said phenyl ring.
- 27. The compound of claim 22 wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 3-pyridyl; and said 3-pyridyl moiety is substituted at the 4-position of said phenyl ring.
- 28. The compound of claim 22 wherein Ar is pyrid-3-yl; Z is carboxy; Ar4 is phenyl; Ar5 is 4-pyridyl; and said 4-pyridyl moiety is substituted at the 4-position of said phenyl ring.
- 29. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein K is methylene, G is Ar; Ar is phenyl, pyridazinyl, pyrazolyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, Ar is optionally mono-, di- or tri-substituted with R3, R4 or R5, and M is Ar3, wherein said Ar3 is cyclopentyl, cyclohexyl, phenyl, thienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuryl, benzo(b)thienyl, benzoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, naphthyl, tetralinyl, 2H-1-benzopyranyl or 1,4-benzodioxan and is optionally mono-, di- or tri-substituted with R31, chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy.
- 30. A compound of claim 29 selected from (3-(((2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; and (3-((benzofuran-2-ylmethyl-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
- 31. The compound of claim 29 wherein Ar is pyrid-3-yl; Z is carboxy; M is 6-(1,4-benzodioxan); and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 32. The compound of claim 29 wherein Ar is pyrid-3-yl; Z is carboxy; M is 2-benzofuryl; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 33. A compound of claim 29, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar is phenyl, pyridyl or imidazolyl, said phenyl, pyridyl and imidazolyl optionally substituted independently with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethyl or trifluoromethoxy; Ar3 is phenyl substituted with R31, wherein R31 is (C1-C7)alkyl, mono-N- or di-N,N-(C1-C4)alkylamine, or (C1-C5)alkoxy, said (C1-C7)alkyl or (C1-C5)alkoxy optionally mono-, di- or tri-substituted with independently hydroxy or fluoro; and Ar3 is further optionally mono- or di-substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 34. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C5-C7)alkylene-.
- 35. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is —CH2—X—CH2— and X is phenyl optionally mono-, di- or tri- substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 36. A compound of claim 35 selected from (3-(((4-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; (3-((benzenesulfonyl-(4-butyl-benzyl)-amino)-methyl)-phenyl)-acetic acid; (3-(((4-butyl-benzyl)-(1-methyl-1H-imidazole-4-sulfonyl)-amino)-methyl)-phenyl)-acetic acid; and (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
- 37. The compound of claim 35 wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 38. The compound of claim 35 wherein Ar is phenyl; Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is —CH2—X—CH2— wherein X is metaphenylene.
- 39. The compound of claim 35 wherein Ar is 4-(1-methyl-imidazolyl); Z is carboxy; M is phenyl substituted at the 4-position with n-butyl; and Q is —CH2—X—CH2-wherein X is metaphenylene.
- 40. The compound of claim 35 wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with dimethylamino; and Q is —CH2—X—CH2-wherein X is metaphenylene.
- 41. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C2-C4)alkylene-thienyl, -(C2-C4)alkylene-furanyl or -(C2-C4)alkylene-thiazolyl.
- 42. A compound of claim 33, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C1-C2)—X—O—(C1-C2)alkylene- and X is metaphenylene, said X being optionally mono-, di- or tri-substituted with chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl.
- 43. A compound of claim 42 selected from (3-(((4-dimethylamino-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid and (3-(((4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.
- 44. The compound of claim 42 wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with dimethylamino; and Q is —CH2—X—O—CH2-wherein X is metaphenylene.
- 45. The compound of claim 42 wherein Ar is pyrid-3-yl; Z is carboxy; M is phenyl substituted at the 4-position with tert-butyl; and Q is —CH2—X—O—CH2— wherein X is metaphenylene.
- 46. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar; K is (C2-C4) alkylene or n-propenylene; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally mono-, di- or tri-substituted with R3, R4 or R5; and M is Ar3, optionally mono-, di- or tri-substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy and trifluoromethyl.
- 47. A compound of claim 46 which is trans-(3-(((3-(3,5-dichloro-phenyl)-allyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenyl)-acetic acid.
- 48. The compound of claim 46 wherein K is trans-n-propenylene, said M group being attached to the 1-position of the n-propenylene and said N atom being attached to the 3-position of the n-propenylene; Ar is pyrid-3-yl; M is phenyl 3,5-disubstituted with chloro; Z is carboxy; and Q is CH2—X—CH2— wherein X is metaphenylene.
- 49. A compound of claim 46, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar3 is phenyl optionally substituted with chloro, fluoro, methyl, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 50. A compound of claim 49, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C5-C7)alkylene-.
- 51. A compound of claim 49, wherein Q is —CH2—X—CH2— and X is metaphenylene.
- 52. A compound of claim 49, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C2-C4)alkylene-X— and X is furanyl, thienyl or thiazolyl.
- 53. A compound of claim 49, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C1-C2)—X—O—(C1-C2)alkylene- and X is metaphenylene.
- 54. A compound of claim 8, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein G is Ar; K is thioethylene or oxyethylene, Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar is optionally substituted with up to three R3, R4 or R5; and M is Ar3, optionally mono-, di- or tri-substituted with chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 55. A compound of claim 54, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Ar3 is phenyl.
- 56. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C5-C7)alkylene-.
- 57. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is —CH2—X—CH2— and X is metaphenylene.
- 58. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C2-C4)alkylene-X— and X is furanyl, thienyl or thiazolyl.
- 59. A compound of claim 55, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Q is -(C1-C2)—X—O—(C1-C2)alkylene- and X is metaphenylene.
- 60. A compound of claim 59 which is (3-(((2-(3,5-dichloro-phenoxy)-ethyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.
- 61. A compound of claim 59 wherein K is ethylenyloxy; said M group being attached to the oxygen atom of the ethylenyloxy group and said N atom being attached to the 2-position of the ethylenyloxy group; Ar is pyrid-3-yl; M is phenyl 3,5-disubstituted with chloro; Z is carboxy and Q is —CH2—X—O—CH2— wherein X is a second phenyl ring and said CH2 and OCH2 substituents are situated in a meta substitution pattern on said second phenyl ring.
- 62. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein B is CH.
- 63. A compound of claim 62, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar, K is methylenyl, propylenyl, propenylenyl or oxyethylenyl; M is Ar3 or Ar4—Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl ; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar, Ar3, Ar4 and Ar5 are optionally substituted independently with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 64. A compound of claim 62, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein A is CO; G is Ar, K is methylenyl, propylenyl, propenylenyl or oxyethylenyl; M is Ar3 or Ar4—Ar5; Ar3 is phenyl or pyridyl; Ar4 is phenyl, thienyl, pyridyl or furanyl; Ar5 is (C5-C7) cycloalkyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl or thiazolyl ; Ar is phenyl, pyrazolyl, pyridazinyl, pyrazinyl, pyridyl, imidazolyl, pyrimidyl, thienyl or thiazolyl, wherein Ar, Ar3, Ar4 and Ar5 are optionally substituted independently with up to three chloro, fluoro, methyl, difluoromethoxy, trifluoromethoxy or trifluoromethyl.
- 65. A method for treating a vertebrate having a condition which presents with low bone mass comprising administering to said vertebrate a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
- 66. The method of claim 65 wherein osteoporosis, osteotomy, childhood idiopathic bone loss or bone loss associated with periodontitis is treated.
- 67. The method of claim 66 wherein osteoporosis is treated in a human.
- 68. The method of claim 67 wherein glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis or immunosuppressive-induced osteoporosis is treated.
- 69. A method for augmenting and maintaining bone mass in a vertebrate comprising administering to said vertebrate a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
- 70. The method of claim 69 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.
- 71. The method of claim 69 wherein a bone fracture is treated in a human.
- 72. A pharmaceutical composition which comprises an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
- 73. A pharmaceutical composition of claim 72, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, for the treatment of osteoporosis wherein the amount is an osteoporosis treating amount.
- 74. A pharmaceutical composition of claim 72 for the augmentation of bone mass which comprises a bone mass augmenting amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
- 75. The pharmaceutical composition of claim 74 for the treatment of a bone fracture which comprises a bone fracture treating amount of said compound, prodrug thereof, or pharmaceutically acceptable salt of said compound or said prodrug.
- 76. A pharmaceutical composition of claim 72 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 said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
- 77. A pharmaceutical composition comprising:
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug; and c. a pharmaceutical carrier or diluent.
- 78. A pharmaceutical composition of claim 77 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;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid; 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol; 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-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′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 79. A pharmaceutical composition of claim 77 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 80. A method for treating a vertebrate having a condition which presents with low bone mass comprising administering to said vertebrate
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 81. The method of claim 80 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;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid; 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol; 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-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′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 82. A method of claim 80 wherein the anti-resorptive agent is, tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 83. A kit comprising:
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said salt in a first unit dosage form; b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. container means for containing said first and second dosage forms.
- 84. A kit of claim 83 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;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid; 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol; 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-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′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 85. A kit of 83 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 86. A pharmaceutical composition comprising:
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; b. an amount of another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug; and c. a pharmaceutical carrier or diluent.
- 87. The pharmaceutical composition of claim 86 wherein said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, prostaglandin, a prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), an active fragment or fragments of parathyroid hormone, a growth hormone or a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 88. A method for treating a mammal which presents with low bone mass comprising administering to said mammal
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 89. A method of claim 88 wherein said bone anabolic agent in component b is IGF-1, a bone morphogenetic protein, a prostaglandin, a prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), an active fragment or fragments of parathyroid hormone, a growth hormone or a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 90. A method for treating a mammal which presents with kidney degeneration comprising administering to said mammal a kidney regenerating effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
- 91. A kit comprising:
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug in a first unit dosage form; b. an amount of another anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug in a second unit dosage form; and c. container means for containing said first and second dosage forms.
- 92. A kit of claim 91 wherein said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), an active fragment or fragments of parathyroid hormone, a growth hormone or a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 93. A method for augmenting and maintaining bone mass in a vertebrate comprising administering to said vertebrate
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 94. The method of claim 93 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;
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid; 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-ol; 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-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′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 95. A method of claim 93 wherein the anti-resorptive agent is, tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 96. A method for augmenting and maintaining bone mass in a vertebrate comprising administering to said vertebrate
a. an amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and b. an amount of another bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
- 97. A method of claim 96 wherein said bone anabolic agent in component b is IGF-1, bone morphogenetic protein, a prostaglandin, a prostaglandin agonist/antagonist, sodium fluoride, parathyroid hormone (PTH), an active fragment or fragments of parathyroid hormone, a growth hormone or a growth hormone secretagogue, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority of U.S. Non-Provisional application Ser. No. 09/367,970 filed on Aug. 20, 1999, which is a 371 of PCT/IB98/01540 filed Oct. 5, 1998, which claims priority of U.S. Provisional Application No. 60/061,727 filed on Oct. 10, 1997.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60061727 |
Oct 1997 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09367970 |
Aug 1999 |
US |
Child |
10256198 |
Sep 2002 |
US |