Prevention of loss and restoration of bone mass by certain prostaglandin agonists

A compound having the Formula I

• or a pharmaceutically acceptable salt or prodrug thereof
• wherein either
• B is N;
• 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;
• 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-,
• —(C0-C4)alkylene-X—W—(C1-C3)alkylene-,
• —(C2-C4)alkylene-W—X—W—(C1-C3)alkylene-, wherein the two occurences 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-ethynylene-(C1-C4)alkylene-, or
• —(C1-C4)alkylene-ethynylene-X—(C0-C3)alkylene-;
• W is oxy, thio, sulfino, sulfonyl, aminosulfonyl-, -mono-N—(C1-C4)alkyleneaminosulfonyl-, sulfonylamino, N—(C1-C4)alkylenesufonylamino, 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;
• K is (C1-C8)alkylene, thio(C1-C4)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 fluoro, methyl or chloro;
• M is —Ar, —Ar1—V—Ar2, —Ar1—S—Ar2 or —Ar1-O—Ar2 wherein Ar, Ar1 and Ar2 are each independently a 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, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, 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;
• R1, R2 and R3 are optionally mono-, di- or tri-substituted independently on carbon 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 K is (C2-C4)alkylene and M is Ar and Ar is cyclopent-1-yl, cyclohex-1-yl, cyclohept-1-yl or cycloct-1-yl then said (C5-C8)cycloalkyl substituents are not substituted at the one position with hydroxy
• and with the proviso that 6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included
• or:
• 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 on carbon independently with hydroxy or 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—(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-ethynylene-(C1-C4)alkylene-, or
• —(C1-C4)alkylene-ethynylene-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;
• K is a bond, (C1-C8)alkylene, thio(C1-C4)alkylene, (C4-C7)cycloalkyl(C1-C6)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 fluoro, methyl or chloro;
• M is —Ar, —Ar1—V—Ar2, —Ar1—S—Ar2 or —Ar1—O—Ar2 wherein Ar, Ar1 and Ar2 are each independently a 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, Ar1 and Ar2 moieties optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon with up to three substituents independently selected from R1, R2 and R3 wherein R1, R2 and R3 are H, 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;
• R1, R2 and R3 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 K is (C2-C4)alkylene and M is Ar 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.