Patent EA-003529-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 n has a value from 0 to 5 CH3-(CH2)n- moiety is optionally mono-, di- or tri- substituted on carbon independently with hydroxy, (C1-C4)alkyl or halo; Q is -(C2-C6)alkylene-W-(C1-C3)alkylene-, -(C3-C8)alkylene-, said -(C3-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, -X-(C1-C5)alkylene-, -(C1-C5)alkylene-X-, -(C1-C3)alkylene-X-(C1-C3)alkylene-, -(C2-C4)alkylene-W-X-(C0-C3)alkylene-, -(C0-C4)alkylene-X-W-(C1-C3)alkylene-, -(C2-C5)alkylene-W-X-W-(C1-C3)alkylene-, wherein the two occurrences of W are independent of each other, -(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-, -(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X-(C0-C5)alkylene-, -(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-X-W-(C1-C3)alkylene-, -(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-, or -(C1-C4)alkylene-ethenylene-X-(C0-C3)alkylene-; W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N-(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, N-(C1-C4)alkylenesulfonylamino, carboxamido, N-(C1-C4)alkylenecarboxamido, carboxamidooxy, N-(C1-C4)alkylenecarboxamidooxy, carbamoyl, -mono-N-(C1-C4)alkylenecarbamoyl, carbamoyloxy, or -mono-N-(C1-C4)alkylenecarbamoyloxy, wherein said W alkyl groups are optionally substituted on carbon with one to three fluorines; X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, nitrogen, and sulfur; said ring optionally mono-, or di-substituted independently with halo, (C1-C3)alkyl, trifluoromethyl, trifluoromethyloxy, difluoromethyloxy, hydroxyl, (C1-C4)alkoxy, or carbamoyl; Z is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 1,2,4-oxadiazolyl, 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl; R<6> is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene or oxy(C1-C4)alkylene, said (C1-C8)alkylene optionally mono-unsaturated and wherein R<6> is optionally mono-, di- or tri-substituted independently with fluoro, methyl or chloro; Ar is partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic 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 selected independently from nitrogen, sulfur and oxygen; R<7> is -H, -V-Ar<2>, -S-Ar<2> or -O-Ar<2>, wherein Ar<2> is partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic 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 selected independently from nitrogen, sulfur and oxygen; said Ar and Ar<2> moieties optionally substituted on carbon, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, with up to three substituents independently selected from R<1>, R<2> and R<3> wherein R<1>, R<2> and R<3> are hydroxy, nitro, halo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, formyl, (C1-C8)alkanoyl, (C1-C6)alkanoyl(C1-C6)alkyl, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl; R<1>, R<2> and R<3> are optionally mono-, di- or tri-substituted on carbon independently with halo or hydroxy; and V is a bond or (C1-C3)alkylene optionally mono- or di-substituted independently with hydroxy or fluoro with the proviso that when R<6> is (C2-C4)alkylene and R<7> is H, and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cyclooct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy; 2. A compound according to claim 1, wherein CH3-(CH2)n- moiety is 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; R<6> is methylene or ethylene; Ar, and Ar<2> are each independently (C5-C7)cycloalkyl, phenyl, thienyl, thiazolyl, pyridyl, pyrimidyl, oxazolyl, furanyl, imidazolyl, isoxazolyl, pyrazinyl or pyrazolyl; R<1> is halo, (C1-C6)alkoxy, (C1-C6)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 n has a value from 0 to 5; Q is -(C2-C6)alkylene-W-(C1-C3)alkylene-, -(C3-C8)alkylene-, said -(C3-C8)alkylene- optionally substituted with up to four substituents independently selected from fluoro or (C1-C4)alkyl, -X-(C1-C5)alkylene-, -(C1-C5)alkylene-X-, -(C1-C3)alkylene-X-(C1-C3)alkylene-, -(C2-C4)alkylene-W-X-(C0-C3)alkylene-, -(C0-C4)alkylene-X-W-(C1-C3)alkylene-, R7 is -V-Ar<2> or -O-Ar<2>; Ar<1> and Ar<2> are each independently phenyl, pyridyl or thienyl; V is a bond or (C1-C2)alkylene; R<1> 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<2> and R<3> 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 n is 0; Q is n-hexylene; Z is carboxyl; R<6> methylene; and -Ar- R<7> moiety is -4-(2-hydroxymethylphenyl)phenyl. 6. A compound as recited in claim 3 wherein n is 0; Q is n-hexylene; Z is carboxyl; R<6> methylene; and -Ar- R<7> moiety is -4-(3-hydroxymethylthien-2-yl)phenyl. 7. A compound as recited in claim 3 wherein n is 0; Q is n-hexylene; Z is carboxyl; R<6> methylene; and -Ar- R<7> moiety is -4-(2-chlorophenyl)phenyl. 8. A compound as recited in claim 1 wherein n is from 0 to 5; 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; R<6> 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; R<7> is -H; 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; R<1> 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 R<2> and R<3> 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 R<6> is methylene; n is from 0 to 2; R<7> is -H; Ar is phenyl, thiazolyl, pyridyl, thienyl, oxazolyl, furanyl, cyclopentyl or cyclohexyl wherein -Ar is substituted with at least R<1>; R<1> 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 R<2> and R<3> 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 n is 0; Q is n-hexylene; Z is carboxyl; R<6> is methylene; and -Ar-R<7> is -4-(1-hydroxy-n-hexylene-1-yl)phenyl. 14. A compound as recited in claim 12 wherein n is 0; Q is n-hexylene; Z is carboxyl; R<6> is methylene; and -Ar-R<7> is -4-(n-butylene-1-yl)phenyl. 15. A compound as recited in claim 12 wherein n is 0; Q is n-hexylene; Z is carboxyl; R<6> is methylene; and -Ar-R<7> 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