Patent EA-003396-B1 (EA)
Title: Prostaglandin agonists and their use to treat bone disorders
Inventor: CAMERON KIMBERLY O'KEEFE
IPC: A61K31/44
Filed: 1998-10-05
Abstract: 1. A compound having the Formula I Formula I prodrugs thereof and the pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2 or CO; G is Ar, Ar<1>-V-Ar<2>, Ar- (C1-C6) alkylene, Ar-CONH- (C1-C6) alkylene, R<1>R<2>-amino, oxy (C1-C6) alkylene, amino substituted with Ar, or amino substituted with Ar (C1-C4) alkylene and R<11>, wherein R<11> is H or (C1-C8) alkyl, R<1> and R<2> may be taken separately and are independently selected from H and (C1-C8) alkyl, or R<1>and R<2> are taken together with the nitrogen atom of the amino group to form a five-or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally mono-, di-or tri-substituted independently with up to two oxo, hydroxy, (C1-C4) alkyl, fluoro or chloro; B is N; Q is - (C4-C8) alkylene-, -X- (C1-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X- (C1-C3) alkylene-, said alkylene optionally substituted with (C1-C4) alkyl, -(C2-C4) alkylene-W-X- (C0-C3) alkylene-, -(C0-C4) alkylene-X-W- (C1-C3) alkylene-, Z is carboxyl, (C1-C6) alkoxycarbonyl, tetrazolyl; K is a bond, (C1-C9) alkylene, or oxy (C1-C4) alkylene or oxy (C1-C4) alkylene, said (C1-C9) alkylene optionally mono-unsaturated M is --Ar<3>,-Ar<4>-V<1>-Ar<5>, -Ar<4>-SO2-Ar<5>, or -Ar<4>-O-Ar<5>; Ar is a partially 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 independently 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 partially or fully saturated ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon; or Ar is a fully saturated five to seven membered ring having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen; Ar<1> and Ar<2> 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: said Ar, Ar<1> and Ar<2> moieties are optionally substituted on carbon or nitrogen with up to three substituents per moiety independently selected from R<3>, R<4> and R<5> wherein R<3>, R<4> and R<5> are independently nitro, halo, carboxy, (C1-C7) alkoxy, (C1-C4) alkoxycarbonyl (C1-C7) alkyl, (C1-C4) alkanoylamino, or cyano; Ar<3>, Ar<4> and Ar<5> 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 independently 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<3>, Ar<4> and Ar<5> moieties are optionally substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, with up to three substituents per moiety independently selected from R<31>, R<41> and R<51>wherein R<31>, R<41> and R<51>are independently hydroxy, nitro, halo, (C1-C7) alkoxy, (C1-C7) alkyl, (C1-C7) cycloalkyl, (C1-C4) alkylsulfonamido, amino, or di-N, N- (C1-C4) alkylamino; W is oxy; X is a five or six membered aromatic ring optionally having one or two heteroatoms selected independently from oxygen, and sulfur; R<1>, R<2>, R<3>, R<4>, R<5>, R<11>, R<31>, R<41> and R<51>, when containing an alkyl moiety, are optionally substituted on carbon independently with halo or hydroxy; and V and V<1> are each independently a bond; with the provisos that: a) when K is (C2-C4) alkylene and M is Ar<3> and Ar<3> 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; and b) when K is a bond; G is phenyl, phenylmethyl, substituted phenyl or substituted phenylmethyl; Q is (C3-C8) alkylene; and M is Ar<3> or Ar<4>-Ar<5>, then A is sulfonyl. 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; Ar is phenyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, morpholinyl, benzoxazolyl, benzthiazolyl, quinazolinyl, naphthyl; Ar<1>, Ar<2>, Ar<3>, Ar<4> and Ar<5>are each independently cyclohexyl, phenyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 2H-imidazolyl, 1,2,3-triazolyl, indolyl, benzofuryl, naphthyl, 1,4benzodioxan; and X is phenyl, thienyl, furanyl, wherein each of said Ar, Ar<1> and Ar<2> groups are optionally substituted on carbon or nitrogen independently with up to three substituents independently selected from R<3>, R<4> and R<5>; each of said Ar, Ar<1> and Ar<2> groups are optionally substituted independently on carbon with one or two oxo groups; each of said Ar<3>, Ar<4> and Ar<5> groups are optionally substituted on carbon or nitrogen independently with up to three R<31>, R<41> and R<51> groups and each of said Ar<3>, Ar<4> and Ar<5> groups are optionally substituted independently on carbon 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 (C4-C8) alkylene-, X-(C2-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X-(C1-C3) alkylene-, -(C2-C4) alkylene-O-X-(C0-C3) alkylene-, -(C0-C4) alkylene-X-O-(C1-C3) alkylene-, and X is phenyl, thienyl, furanyl. 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 (C4-C8) alkylene-, X-(C2-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X- (C1-C3) alkylene-, -(C2-C4) alkylene-O-X- (C0-C3) alkylene-, -(C0-C4) alkylene-X-O- (C1-C3) alkylene-, and X is phenyl, thienyl, furanyl. 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 R<1>R<2>-amino or amino, substituted with Ar, or amino substituted with Ar (C1-C4) alkylene and R<11>, wherein R<11> is H; Q is (C4-C8) alkylene-, X-(C2-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X-(C1-C3) alkylene-, -(C2-C4) alkylene-O-X-(C0-C3) alkylene-, -(C0-C4) alkylene-X-O-(C1-C3) alkylene-, and X is phenyl, thienyl, furanyl, wherein R<1> and R<2> may be taken separately and are independently selected from H and (C1-C8) alkyl, or R<1> and R<2> are taken together to form a five-or six-membered 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 R<1>R<2>-amino, or amino substituted with Ar and R<11>; Q is -(C4-C8) alkylene-, X-(C2-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X-(C1-C3) alkylene-, -(C2-C4) alkylene-O-X-(C0-C3) alkylene-, -(C0-C4) alkylene-X-O-(C1-C3) alkylene-, and X is phenyl, thienyl, furanyl; and wherein R<1> and R<2> may be taken separately and are independently selected from H and (C1-C8) alkyl, or R<1> and R<2> are taken together to form a five-or six-membered 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 Ar<1>-V-Ar<2>; Q is -(C4-C8) alkylene-, X-(C2-C5) alkylene-, -(C1-C5) alkylene-X-, -(C1-C3) alkylene-X-(C1-C3) alkylene-, -(C2-C4) alkylene-O-X-(C0-C3) alkylene-,-(C0-C4) alkylene-X-O-(C1-C3) alkylene-, and X is phenyl, thienyl, furanyl. 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, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, wherein each of said Ar groups is optionally substituted on carbon or nitrogen with R<1>, R<2> or R<3>; Ar<4> is cycloheptyl, phenyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, 1,2,4triazinyl, wherein each of said Ar<4> groups is optionally mono-di-or tri-substituted on carbon or nitrogen with R<31>, R<41>or R<51>; Ar<5> is cyclohexyl, phenyl, furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinyl 1,2,4-triazinyl wherein each of said Ar<5> groups is optionally mono-di-or tri-substituted on carbon or nitrogen with R<31>, R<41>or R<51>; 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-; X is phenyl or thienyl; 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 Ar<4>- Ar<5>, Ar<4>-O-Ar<5> or Ar<4>-S-Ar<5> 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 R<3>, R<4> or R<5>. 10. A compound of claim 9, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein M is Ar<4>- Ar<5>; Ar is phenyl, pyridyl or imidazolyl; Ar<4> is phenyl, furanyl or pyridyl; and Ar<5> is cyclohexyl, phenyl, pyridyl, imidazolyl, pyrimidyl, thienyl, pyridazinyl, pyrazinyl, pyrazolyl or thiazolyl, wherein Ar, Ar<4> an