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US 2002/0165255 A1Published application
Osteoporosis compounds
OwnerKimberly O. Cameron, Bruce A. Lefker +1inventors
InventorsKimberly O. Cameron, Bruce A. Lefker, Robert L. Rosati
Life of this patent
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Abstract
This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.
Claims78
A compound of Formula I
- 10
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- B is N or C(Q1), where Q1 is H or (C1-C3)alkyl;
- L is n-propylenyl-X- or CH2-metaphenylene-CH2, wherein X is furanyl, thienyl, thiazolyl or tetrahydrofuranyl, said CH2-metaphenylene-CH2 or X being optionally mono-, di- or tri-substituted on aromatic carbon independently with one to three chloro, fluoro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
- R is carboxyl, (C1-C6)alkoxycarbonyl, tetrazolyl, 5-oxo-1,2,4-thiadiazolyl;
- 5-oxo-1,2,4-oxadiazolyl, (C1-C4)alkylsulfonylcarbamoyl or phenylsulfonylcarbamoyl;
- R1 is H, methyl, ethyl or propyl;
- R2 is H or (C2-C5) alkanoyl;
- R3 is independently H fluoro or methyl;
- R4 is H. (C1-C7) alkyl, or R4 and R1 are taken together to form a 5-9 membered carbocyclic ring, said alkyl being optionally monounsaturated and optionally mono-, di- or tri-substituted independently with one to three fluoro, chloro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
- R5 is (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, (C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkylcarbonyl, (C3-C7)cycloalkyl(C1-C6)alkylcarbonyl, G-sulfonyl or G-carbonyl, said (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, (C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkylcarbonyl, (C3-C7)cycloalkyl(C1-C6)alkylcarbonyl optionally mono-, di- or tri-substituted on carbon independently with hydroxy, fluoro, chloro, methoxy, difluoromethoxy, trifluoromethoxy, trifluoromethyl or methyl;
- Z is methylene, ethylene, propylene or ethenylene;
- G is Ar, Ar1-V-Ar2, Ar-(C1-C6)alkylene, Ar-CONH-(C1-C6)alkylene, R12R13-amino, oxy(C1-C6)alkylene, amino substituted with Ar, or amino substituted with Ar(C1-C4)alkylene and R11, wherein R11 is H or (C1-C8)alkyl, R12 and R13 may be taken separately and are independently selected from H and (C1-C8)alkyl, or R12 and R13 are taken together with the nitrogen atom to which they are attached to form a five- or six-membered azacycloalkyl, said azacycloalkyl optionally containing an oxygen atom and optionally substituted with up to two oxo, hydroxy, (C1-C4)alkyl, fluoro or chloro;
- 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, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five or six membered rings, 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 one or two oxo groups substituted on sulfur, or Ar is a fully saturated five to seven membered ring having one or two heteroatoms selected independently from oxygen, sulfur and nitrogen;
- 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 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, or a tricyclic ring consisting of three 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 one or two oxo groups substituted on sulfur;
- said Ar, Ar1 and Ar2 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, or on one, two or three rings if the moiety is tricyclic, with up to three substituents per moiety, independently selected from R14, R15 and R16 wherein R14, R15 and R16 are independently hydroxy, nitro, halo, carboxy, (C1-C7)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (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, hydroxysulfonyl, aminocarbonylamino or mono-N—, di-N,N—, di-N,N′- or tri-N,N,N′-(C1-C4)alkyl substituted aminocarbonylamino, 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;
- and
- V is a bond, thio(C1-C4)alkylene, (C1-C4)alkylenethio, (C1-C4)alkyleneoxy, oxy(C1-C4)alkylene or (C1-C3)alkylene optionally mono- or di-substituted, when V is not a bond, independently with hydroxy or fluoro.
15 more elements
A method of treating a vertebrate which presents with low bone mass comprising administering to said vertebrate a therapeutically effective amount of a compound of Formula II
- 11
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- A is ethylene, n-propylene, α-methylethylene, β-methylethylene, α, α-dimethylethylene, β, β-dimethylethylene or oxymethylene;
- B is N or C(Q);
- R is carboxy, (C1-C10) alkoxycarbonyl, carbamoyl, mono-N— or di-N,N—(C1-C4)alkyl-substituted carbamoyl or —COOY wherein Y is 1-succinimidoethyl, 1-pivaloyloxyethyl, 2-acetamidoethyl, diloweralkylaminoloweralkyl, or carbazoyl;
- R1 is H, methyl, ethyl or propyl;
- R2 is H or (C2-C5) alkanoyl;
- R3 is independently H or methyl;
- R4 is H, (C1-C4) alkyl, vinyl or 2,2,2-trifluoroethyl;
- or R4 and R1 are taken together to form a 5-9 membered carbocyclic ring;
- R5, when B is C(Q), is formyl, acetyl, pivaloyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl or 1-hydroxyl-1-methylethyl;
- R5, when B is N, is formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 2,2,2-trifluoroethyl or R6SOy;
- Z is methylene, ethylene, n-propylene, tetramethylene, vinylene or ethynylene;
- Q is H, chloro, bromo, methyl, phenyl or substituted phenyl;
- R6 is methyl, ethyl, propyl or isopropyl;
- and
- y is 1 or2.
14 more elements
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 formula II
- 12
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- A is ethylene, n-propylene, α-methylethylene, β-methylethylene, α, α-dimethylethylene, β, β-dimethylethylene or oxymethylene;
- B is N or C(Q);
- R is carboxy, (C1-C10) alkoxycarbonyl, carbamoyl, mono-N— or di-N,N—(C1-C4)alkyl-substituted carbamoyl or —COOY wherein Y is 1-succinimidoethyl, 1-pivaloyloxyethyl, 2-acetamidoethyl, diloweralkylaminoloweralkyl, or carbazoyl;
- R1 is H, methyl, ethyl or propyl;
- R2 is H or (C2-C5) alkanoyl;
- R3 is independently H or methyl;
- R4 is H, (C1-C4) alkyl, vinyl or 2,2,2-trifluoroethyl;
- or R4 and R1 are taken together to form a 5-9 membered carbocyclic ring;
- R5, when B is C(Q), is formyl, acetyl, pivaloyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl or 1-hydroxyl-1-methylethyl;
- R5, when B is N, is formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 2,2,2-trifluoroethyl or R6SOy;
- Z is methylene, ethylene, n-propylene, tetramethylene, vinylene or ethynylene;
- Q is H, chloro, bromo, methyl, phenyl or substituted phenyl;
- R6 S methyl, ethyl, propyl or isopropyl;
- and
- y is 1 or 2;
- and
- b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
17 more elements
A method for treating a vertebrate which presents with low bone mass comprising administering to said vertebrate
- a. an amount of a compound of formula II
- 13
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- A is ethylene, n-propylene, α-methylethylene, β-methylethylene, α, α-dimethylethylene, β, β-dimethylethylene or oxymethylene;
- B is N or C(Q);
- R is carboxy, (C1-C10) alkoxycarbonyl, carbamoyl, mono-N— or di-N,N—(C1-C4)alkyl-substituted carbamoyl or —COOY wherein Y is 1-succinimidoethyl, 1-pivaloyloxyethyl, 2-acetamidoethyl, diloweralkylaminoloweralkyl, or carbazoyl;
- R1 is H, methyl, ethyl or propyl;
- R2 is H or (C2-C5) alkanoyl;
- R3 is independently H or methyl;
- R4 is H, (C1-C4) alkyl, vinyl or 2,2,2-trifluoroethyl;
- or R4 and R1 are taken together to form a 5-9 membered carbocyclic ring;
- R5, when B is C(Q), is formyl, acetyl, pivaloyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl or 1-hydroxyl-1-methylethyl;
- R5, when B is N, is formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 2,2,2-trifluoroethyl or R6SOy;
- Z is methylene, ethylene, n-propylene, tetramethylene, vinylene or ethynylene;
- Q is H, chloro, bromo, methyl, phenyl or substituted phenyl;
- R6 is methyl, ethyl, propyl or isopropyl;
- and
- y is 1 or 2;
- and
- b. an amount of a bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
17 more elements
A method for treating a vertebrate which presents with kidney degeneration comprising administering to said vertebrate a kidney regenerating effective amount of a compound of formula II
- 14
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- A is ethylene, n-propylene, α-methylethylene, β-methylethylene, α, α-dimethylethylene, β, β-dimethylethylene or oxymethylene;
- B is N or C(Q);
- R is carboxy, (C1-C10) alkoxycarbonyl, carbamoyl, mono-N— or di-N,N—(C1-C4)alkyl-substituted carbamoyl or —COOY wherein Y is 1-succinimidoethyl, 1-pivaloyloxyethyl, 2-acetamidoethyl, diloweralkylaminoloweralkyl, or carbazoyl;
- R1 is H, methyl, ethyl or propyl;
- R2 is H or (C2-C5) alkanoyl;
- R3 is independently H or methyl;
- R4 is H, (C1-C4) alkyl, vinyl or 2,2,2-trifluoroethyl;
- or R4 and R1 are taken together to form a 5-9 membered carbocyclic ring;
- R5, when B is C(Q), is formyl, acetyl, pivaloyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl or 1-hydroxyl-1-methylethyl;
- R5, when B is N, is formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 2,2,2-trifluoroethyl or R6SOy;
- Z is methylene, ethylene, n-propylene, tetramethylene, vinylene or ethynylene;
- Q is H, chloro, bromo, methyl, phenyl or substituted phenyl;
- R6 is methyl, ethyl, propyl or isopropyl;
- and
- y is 1 or 2.
14 more elements
A method of treating a vertebrate which presents with low bone mass comprising administering to said vertebrate a therapeutically effective amount of a compound of formula II
- 15
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- R7 (C1-C4) alkyl;
- R8 is carboxy or (C1-C10) alkoxycarbonyl;
- R9 is H or methyl;
- R10 is independently H or methyl;
- R11 is (C3-C6) alkyl;
- or R11 and R9 are taken together to form a 5-9 membered carbocyclic ring;
- G is (CH2)n, oxymethylene or vinylene;
- X is (CH2)m;
- L is ethylene, vinylene or ethynylene;
- n is 0 or 2;
- and
- m is 1, 3 or 4;
- provided that the sum of chain-forming elements in G and X is limited to either 3 or 4.
12 more elements
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 formula II
- 16
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- R7 is (C1-C4) alkyl;
- R8 is carboxy or (C1-C10) alkoxycarbonyl;
- R9 is H or methyl;
- R10 is independently H or methyl;
- R11 is (C3-C6) alkyl;
- or R11 and R9 are taken together to form a 5-9 membered carbocyclic ring;
- G is (CH2)n, oxymethylene or vinylene;
- X is (CH2)m;
- L is ethylene, vinylene or ethynylene;
- n is 0 or 2;
- and
- m is 1, 3 or 4;
- provided that the sum of chain-forming elements in G and X is limited to either 3 or 4;
- and
- b. an amount of an anti-resorptive agent, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
15 more elements
A method for treating a vertebrate which presents with low bone mass comprising administering to said vertebrate
- a. an amount of a compound of formula III
- 17
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- R7 is (C1-C4) alkyl;
- R8 is carboxy or (C1-C10) alkoxycarbonyl;
- R9 is H or methyl;
- R10 is independently H or methyl;
- R11 is (C3-C6) alkyl;
- or R11 and R9 are taken together to form a 5-9 membered carbocyclic ring;
- G is (CH2)n, oxymethylene or vinylene;
- X is (CH2)m;
- L is ethylene, vinylene or ethynylene;
- n is 0 or2;
- and
- m is 1, 3 or 4;
- provided that the sum of chain-forming elements in G and X is limited to either 3 or 4;
- and
- b. an amount of a bone anabolic agent, a prodrug thereof or a pharmaceutically acceptable salt of said agent or said prodrug.
15 more elements
A method for treating a vertebrate which presents with kidney degeneration comprising administering to said vertebrate a kidney regenerating effective amount of a compound of formula III
- 18
- a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
- R7 is (C1-C4) alkyl;
- R8 is carboxy or (C1-C10) alkoxycarbonyl;
- R9 is H or methyl;
- R10 is independently H or methyl;
- R11 is (C3-C6) alkyl;
- or R11 and R9 are taken together to form a 5-9 membered carbocyclic ring;
- G is (CH2)n,, oxymethylene or vinylene;
- X is (CH2)m;
- L is ethylene, vinylene or ethynylene;
- n is 0 or 2;
- and
- m is 1, 3 or 4;
- provided that the sum of chain-forming elements in G and X is limited to either 3 or 4.
12 more elements
A kit of 72 wherein the anti-resorptive agent is tiludronic acid, alendronic acid, zoledronic acid, ibandronic acid, risedronic acid, etidronic acid, clodronic acid, and pamidronic acid or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.