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US 6,720,315 B2Granted
Dihydrostilbene alkanoic acid derivatives
AssigneePharmacia Corporation
InventorsThomas Rogers, Michael Clare, Hwang-Fun Lu, Mark Russell, James W. Malecha, Ish Kumar Khanna, Thomas Penning, Srinivasan Raj Nagarajan, Heather Stenmark
Life of this patent
Estimating the term…
Abstract
The present invention relates to a class of compounds represented by the Formula 1. or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula 1, and methods of selectively inhibiting or antagonizing the αVβ3 and/or the αVβ5 integrin.
Claims16
A compound of the Formula:
- or a pharmaceutically acceptable salt thereof, wherein
- is a phenyl ring, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- acylamino, sulfone, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from the group consisting of hydroxy, alkoxy, alkyl and amino;
- A1 is a pyridine, optionally substituted by one or more Rk selected from the group consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and —COR wherein R is selected from hydroxy, alkoxy, alkyl and amino;
- Z1 is selected from the group consisting of CH2, CH2CO, S, SO, CH(OH) and SO2;
- Z2 is a 1-5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N;
- wherein the carbon and nitrogen atoms of Z1-Z2 are optionally substituted by a moiety selected from the group consisting of alkyl, alkoxy, thioalkyl, alkylsulfone, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalky and acylamino;
- n is an integer 0, 1 or 2;
- Rc is selected from the group consisting of hydrogen;
- alkyl;
- halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl, acylamino, sulfonyl, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
- X is selected from the group consisting of —CHRe—, —NRf—, —O—, —S—, —SO2—, and CO wherein Re is selected from H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl, phenyl, pyridyl, naphthyl, thiophene, furan, and biphenyl;
- wherein when Re is hydroxy the hydroxy optionally forms a lactone with the carboxylic acid function of the chain;
- wherein Rf is selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, benzyl and haloalkyl;
- Y is selected from the group consisting of —CRg— and —Ng—wherein Rg is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, piperidine, aralkyl, hydroxy, alkoxy, and carboxyalkyl;
- Rb is X2—Rh wherein X2 is selected from the group consisting of O, S and NRj wherein Rh and Rj are independently selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, aralkyl, alkoxyalkyl, and
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl alkoxyalkyl;
- and
- Ra is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, hydroxyalkyl, alkynyl, alkynylalkyl, alkenylalkyl, haloalkyl, phenyl, benzofuran, benzothiophene, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, 1,3-benzodioxole, 1,4-benzodioxane, benzopyran, quinolone, imidazopyridine, tetrahydroquinoline, benzotriazole, dihydroindole, dihydrobenzofuran, furan, thiophene, phenyl, oxazole, thiazole, isoxazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridone, triazole, thiadiazole all optionally substituted at one or more position with a substituent selected from the group consisting of alkyl, alkoxy, hydroxy, cyano, halogen, and haloalkyl;
- aralkyl, heteroaralkyl, cycloalkyl, carboxyl, amino, alkylamine, alkoxycarbonyl, carboxamido, hydroxy, cyano, alkoxy, thioalkyl, acylamino, sulfonyl amino, alkylsulfonyl, and —(CH2)nCORb wherein n is 0-2 and Rb is as defined above.
19 more elements
A compound of the Formula:
- or a pharmaceutically acceptable salt thereof, wherein
- is a phenyl ring, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, naphthyl, thiophene, furan, biphenyl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- acylamino, sulfone, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from the group consisting of hydroxy, alkoxy, alkyl and amino;
- A1 is a pyridine selected from the group consisting of:
- wherein:
- X4 and X5 are selected from the group consisting of H, alkyl, alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano and acylamino groups;
- X6 is selected from the group consisting of H, alkyl, hydroxy, halogen, alkoxy and haloalkyl,
- Z1 is selected from the group consisting of CH2, CH2O, O, NH, CO, S, SO, CH(OH) and SO2;
- Z2 is a 1-5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N;
- wherein the carbon and nitrogen atoms of Z1—Z2 are optionally substituted by a moiety selected from the group consisting of alkyl, alkoxy, thioalkyl, alkylsulfone, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalky and acylamino;
- n is an integer 0, 1 or 2;
- Rc is selected from the group consisting of hydrogen;
- alkyl;
- halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- acylamino, sulfonyl, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
- X is selected from the group consisting of —CHRe—, —NRf—, —O—, —S—, —SO2—, and CO wherein Re is selected from H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl phenyl, pyridyl, naphthyl, thiophene, furan, and biphenyl;
- wherein when Re is hydroxy the hydroxy optionally forms a lactone with the carboxylic acid function of the chain;
- wherein Rf is selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, benzyl and haloalkyl;
- Y is selected from the group consisting of —CRg— and —Ng— wherein Rg is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, piperidine, aralkyl, hydroxy, alkoxy, and carboxyalkyl;
- Rb is X2—Rh wherein X2 is selected from the group consisting of O, S and NRj wherein Rh and Rj are independently selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, aralkyl, alkoxyalkyl, and
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- and
- Ra is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, hydroxyalkyl, alkynyl, alkynylalkyl, alkenylalkyl, haloalkyl;
- phenyl, benzofuran, benzothiophene, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, 1,3-benzodioxole, 1,4-benzodioxane, benzopyran, quinolone, imidazopyridine, tetrahydroquinoline, benzotriazole, dihydroindole, dihydrobenzofuran, furan, thiophene, phenyl, oxazole, thiazole, isoxazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridone, triazole, thiadiazole all optionally substituted at one or more position with a substituent selected from the group consisting of alkyl, alkoxy, hydroxy, cyano, halogen, and haloalkyl;
- aralkyl, heteroaralkyl, cycloalkyl, carboxyl, amino, alkylamine, alkoxycarbonyl, carboxamido, hydroxy, cyano, alkoxy, thioalkyl, acylamino, sulfonyl amino, alkylsulfonyl, and —(CH2)nCORb wherein n is 0-2 and Rb is as defined above.
24 more elements
A compound of the Formula:
- or a pharmaceutically acceptable salt thereof, wherein
- is a phenyl ring, optionally substituted with one or more substituent selected from the group consisting of alkyl, haloalkyl, naphthyl, thiophene, furan, biphenyl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- acylamino, sulfone, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from the group consisting of hydroxy, alkoxy, alkyl and amino;
- A1 is a pyridine selected from the group consisting of:
- wherein:
- Za is selected from the group consisting of H, alkyl, alkoxy, hydroxy, amine, alkylamine, dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen and haloalkyl;
- and
- R1 is selected from the group consisting of H, alkyl, alkoxyalkyl,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- haloalkyl and alkoxycarbonyl,
- Z1 is selected from the group consisting of CH2,CH2O, O, NH, GO, S, SO, CH(OH) and SO2;
- Z2 is a 1-5 carbon linker optionally containing one or more heteroatom selected from the group consisting of O, S and N;
- wherein the carbon and nitrogen atoms of Z1-Z2 are optionally substituted by a moiety selected from the group consisting of alkyl, alkoxy, thioalkyl, alkylsulfone, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalky and acylamino;
- n is an integer 0, 1 or 2;
- Rc is selected from the group consisting of hydrogen;
- alkyl;
- halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino, alkylsulfonylamino,
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- acylamino, sulfonyl, sulfonamide, alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and —(CH2)nCOR wherein n is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;
- X is selected from the group consisting of —CHRe—, —NRf—, —O—, —S—, —SO2—, and CO wherein Re is selected from H, lower alkyl, alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl, haloalkyl, thioalkyl phenyl, pyridyl, naphthyl, thiophene, furan, and biphenyl;
- wherein when Re is hydroxy the hydroxy optionally forms a lactone with the carboxylic acid function of the chain;
- wherein Rf is selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, benzyl and haloalkyl;
- Y is selected from the group consisting of —CRg— and —Ng— wherein Rg is selected from the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, piperidine, aralkyl, hydroxy, alkoxy, and carboxyalkyl;
- Rb is X2—Rh wherein X2 is selected from the group consisting of O, S and NRj wherein Rh and Rj are independently selected from the group consisting of H, alkyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, aralkyl, alkoxyalkyl, and
- wherein R26 is selected from alkyl, alkenyl, alkynyl, phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl, and aralkyl;
- and
- Ra is selected from the group consisting of hydrogen, alkyl, alkenyl, alkoxyalkyl, hydroxyalkyl, alkynyl, alkynylalkyl, alkenylalkyl, haloalkyl;
- phenyl, benzofuran, benzothiophene, indole, quinoline, isoquinoline, benzimidazole, benzoxazole, 1,3-benzodioxole, 1,4-benzodioxane, benzopyran, quinolone, imidazopyridine, tetrahydroquinoline, benzotriazole, dihydroindole, dihydrobenzofuran, furan, thiophene, phenyl, oxazole, thiazole, isoxazole, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, pyridone, triazole, thiadiazole all optionally substituted at one or more position with a substituent selected from the group consisting of alkyl, alkoxy, hydroxy, cyano, halogen, and haloalkyl;
- aralkyl, heteroaralkyl, cycloalkyl, carboxyl, amino, alkylamine, alkoxycarbonyl, carboxamido, hydroxy, cyano, alkoxy, thioalkyl, acylamino, sulfonyl amino, alkylsulfonyl, and —(CH2)nCORb wherein n is 0-2 and Rb is as defined above.
27 more elements
Dependencies are inferred from the claim text.