Claims
- 1. A compound represented by a formula (III): whereinY is: provided that when R5 is —OH then Y can also be m is 0 or 1; Z is —CH2—, —C(O)—, or —C(═N—OR21)—; C is benzo, wherein the ring is optionally singly or multiply substituted with —R4; R1 is -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, wherein each -aryl or -heteroaryl is optionally singly or multiply substituted with R17; R2 is a bond, —C(O)—, —C(O)C(O)—, —S(O)2—, —OC(O)—, —N(H)C(O)—, —N(H)S(O)2—, —N(H)C(O)C(O)—, —CH═CHC(O)—, —OCH2C(O)—, —N(H)CH2C(O)—, —N(R19)C(O)—, —N(R19)S(O)2—, —N(R19)C(O)C(O)—, or —N(R19)CH2C(O)—; R4 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —CON(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S(O)2alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2; R5 is —OH, —OR8, or —N(H)OH; R6 is —H, —CH2OR9, —CH2SR10, —CH2N(H)R9, —CH2N(R9)R12, —CHN2, —CH2F, —CH2Cl, —C(O)N(R11)R12, —R13, or —R14; R8 is -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, or -alkylheterocycle; R9 is —H, —COaryl, —COheteroaryl, —COalkylaryl, —COalkylheteroaryl, -alkylaryl, -alkylheteroaryl, -aryl, -heteroaryl, or —P(O)R15R16; R10 is -alkylaryl or -alkylheteroaryl; R11 and R12 are independently —H, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, or -alkylheteroaryl; R13 is -alkylaryl or -alkylheteroaryl; R14 is wherein (i) is optionally substituted with one or more —R17 and (ii) is optionally substituted with one or more —R17, —R18 or —R20; X is O or S; R15 and R16 are independently —H, —OH, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, -alkylheteroaryl, —Oalkyl, —Oaryl, —Oheteroaryl, —Oalkylaryl, or —Oalkylheteroaryl; R17 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, —S(O)2NH2, —C(O)H, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —CO2alkyl, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S(O)2N(H)alkyl, —S(O)2N(alkyl)2, —S-alkyl, —S(O)2alkyl, or —C(O)alkyl; R18 is -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, —O-aryl, —O-heteroaryl, —O-alkylaryl, —O-alkylheteroaryl, —N(H)aryl, —N(aryl)2, —N(H)heteroaryl, —N(heteroaryl)2, —N(H)alkylaryl, —N(alkylaryl)2, —N(H)alkylheteroaryl, —N(alkylheteroaryl)2, —S-aryl, —S-heteroaryl, —S-alkylaryl, —S-alkylheteroaryl, —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, —CO2aryl, —CO2heteroaryl, —CO2alkylaryl, —CO2alkylheteroaryl, —C(O)N(H)aryl, —C(O)N(aryl)2, —C(O)N(H)heteroaryl, —C(O)N(heteroaryl)2, —C(O)N(H)alkylaryl, —C(O)N(alkylaryl)2, —C(O)N(H)alkylheteroaryl, —C(O)N(alkylheteroaryl)2, —S(O)2-aryl, —S(O)2-heteroaryl, —S(O)2-alkylaryl, —S(O)2-alkylheteroaryl, —S(O)2N(H)-aryl, —S(O)2N(H)-heteroaryl, —S(O)2N(H)-alkylaryl, —S(O)2N(H)-alkylheteroaryl, —SO2N(aryl)2, —SO2N(heteroaryl)2, —SO2N(alkylaryl)2, —SO2N(alkylheteroaryl)2, —N(H)C(O)N(H)aryl, —N(H)C(O)N(H)heteroaryl, —N(H)C(O)N(H)alkylaryl, —N(H)C(O)N(H)alkylheteroaryl, —N(H)C(O)N(aryl)2, —N(H)C(O)N(heteroaryl)2, N(H)C(O)N(alkylaryl)2, or —N(H)C(O)N(alkylheteroaryl)2; R19 is —H, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle; R20 is -alkyl-R18; and R21 is H, alkyl, alkylaryl, or -alkylheteroaryl.
- 2. A compound represented by formula (III): wherein Y is: m is 0 or 1; Z is —CH2, —, [—O—, —S—, —S(O)—, —S(O)2—,] —C(O)—, or —C (═N—OR21)—; C is benzo, wherein the ring is optionally singly or multiply substituted with —R4; R1 is -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, wherein each -aryl or -heteroaryl is optionally singly or multiply substituted with R17; R2 is a bond, —C(O)—, —C(O)C(O)—, —S(O)2—, —OC(O)—, —N(H)C(O)—, —N(H)S(O)2—, —N(H)C(O)C(O)—, —CH═CHC(O)—, —OCH2C(O)—, —N(H)CH2C(O)—, —N(R19)C(O)—, —N(R19)S(O)2—, —N(R19)C(O)C(O)—, or —N(R19)CH2C(O)—; R4 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —CON(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S(O)2alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2; R6 is —H, —CH2OR9, —CH2SR10, —CH2N(H)R9, —CH2N(R9)R12, —CHN2, —CH2F, —CH2Cl, —C(O)N(R11)R12, —R13, or —R14; R7 is —C(O)alkyl, —C(O)cycloalkyl, —C(O)alkyenyl, —C(O)alkylaryl, —C(O)alkylheteroaryl, —C(O)heterocycle, or —C(O)alkylheterocycle; R8 is -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, or -alkylheterocycle; R9 is —H, —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, -alkylaryl, -alkylheteroaryl, -aryl, -heteroaryl, or —P(O)R15R16; R10 is -alkylaryl or -alkylheteroaryl; R11 and R12 are independently —H, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, or -alkylheteroaryl; R13 is -alkylaryl or -alkylheteroaryl; R14 is wherein (i) is optionally substituted with one or more —R17 and (ii) is optionally substituted with one or more —R17, —R18 or —R20; X is O or S; R15 and R16 are independently —H, —OH, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, -alkylheteroaryl, —Oalkyl, —Oaryl, —Oheteroaryl, —Oalkylaryl, or —Oalkylheteroaryl; R17 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, —S(O)2NH2, —C(O)H, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —CO2alkyl, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S(O)2N(H)alkyl, —S(O)2N(alkyl)2, —S-alkyl, —S(O)2alkyl, or —C(O)alkyl; R18 is -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, —O-aryl, —O-heteroaryl, —O-alkylaryl, —O-alkylheteroaryl, —N(H)aryl, —N(aryl)2, —N(H)heteroaryl, —N(heteroaryl)2, —N(H)alkylaryl, —N(alkylaryl)2, —N(H)alkylheteroaryl, —N(alkylheteroaryl)2, —S-aryl, —S-heteroaryl, —S-alkylaryl, —S-alkylheteroaryl, —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, —CO2aryl, —CO2heteroaryl, —CO2alkylaryl, —CO2alkylheteroaryl, —C(O)N(H)aryl, —C(O)N(aryl)2, —C(O)N(H)heteroaryl, —C(O)N(heteroaryl)2, —C(O)N(H)alkylaryl, —C(O)N(alkylaryl)2, —C(O)N(H)alkylheteroaryl, —C(O)N(alkylheteroaryl)2, —S(O)2-aryl, —S(O)2-heteroaryl, —S(O)2-alkylaryl, —S(O)2-alkylheteroaryl, —S(O)2N(H)-aryl, —S(O)2N(H)-heteroaryl, —S(O)2N(H)-alkylaryl, —S(O)2N(H)-alkylheteroaryl, —SO2N(aryl)2, —SO2N(heteroaryl)2, —SO2N(alkylaryl)2, —SO2N(alkylheteroaryl)2, —N(H)C(O)N(H)aryl, —N(H)C(O)N(H)heteroaryl, —N(H)C(O)N(H)alkylaryl, —N(H)C(O)N(H)alkylheteroaryl, —N(H)C(O)N(aryl)2, —N(H)C(O)N(heteroaryl)2, N(H)C(O)N(alkylaryl)2, or —N(H)C(O)N(alkylheteroaryl)2; R19 is —H, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle; R20 is -alkyl-R18; and R21 is H, alkyl, alkylaryl, or -alkylheteroaryl.
- 3. The compound according to claims 1 or 2, wherein:m is 0; C is benzo, wherein the C ring is optionally singly or multiply substituted with —R4; R1 is phenyl, naphthyl, or isoquinolinyl, each optionally singly or multiply substituted with R17, wherein R17 is —OH, —NH2, —Cl, —F, —Oalkyl, or —N(alkyl)2; R2 is —C(O)—, —S(O)2—, —C(O)C(O)— or —CH2C(O)—; R4 is fluoro or chloro; R6 is —H or —R14 wherein X is O and for formula (i) R17 is —Oalkyl, —F or —Cl and for formula (ii) R18 is aryl wherein aryl is phenyl; R8 is methyl, ethyl, n-propyl, isopropyl, cyclopentyl, phenethyl, or benzyl; and R9 is —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, -alkylaryl, -alkylheteroaryl, -aryl, or -heteroaryl.
- 4. The compound according to claim 3 wherein C is benzo and R6 is H.
- 5. The compound according to claim 1 wherein R5 is —OH.
- 6. The compound according to claim 2 wherein R7 is —C(O)alkyl.
- 7. The compound according to claims 1 or 2, wherein Z is —C(O)—.
- 8. A pharmaceutical composition comprising: a) a compound according to any one of claims and b) a pharmaceutical accepatable carrier, adjuvant or vehicle.
- 9. A method for treating a disease selected from an inflammatory disease, osteoarthritis, glomerulonephritis, rheumatoid arthritis, psoriasis, graft vs host disease, sepsis, or septic shock in a patient comprising the step of administering to said patient a pharmaceutical composition according to claim 8.
- 10. The method according to claim 9, wherein the disease is osteoarthritis, rheumatoid arthritis, or psoriasis.
- 11. A process for preparing a compound represented by formula (V): wherein:R22 is: R23 is: m is 1 or 2; Z is —CH2—, [—O—, —S—, —S(O)—, —S(O)2—,] —C(O)—, or —C (═N—OR21)—; C is benzo, wherein the ring is optionally singly or multiply substituted with —R4; R1 is -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, wherein each -aryl or -heteroaryl is optionally singly or multiply substituted with R17; R2 is a bond, —C(O)—, —C(O)C(O)—, —S(O)2—, —OC(O)—, —N(H)C(O)—, —N(H)S(O)2—, —N(H)C(O)C(O)—, —CH═CHC(O)—, —OCH2C(O)—, —N(H)CH2C(O)—, —N(R19)C(O)—, —N(R19)S(O)2—, —N(R19)C(O)C(O)—, or —N(R19)CH2C(O)—; R4 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —CON(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S(O)2alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2; R19 is —H, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle; R21 is H, alkyl, alkylaryl, or alkylheteroaryl; and R24 -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle; comprising the steps of: a) reacting a compound represented by formula (VI): (VI) R22—OH, wherein R22 is as defined above, with a compound represented by formula (VII): wherein R24 is as defined above, in the presence of an inert solvent, triphenylphoshine, a nucleophilic scavenger, and tetrakis-triphenyl phosphine palladium(0) at ambient temperature under an inert atmosphere; and b) adding to the mixture formed in step a), HOBT and EDC.
- 12. The process according to claim 11, wherein:C is benzo, wherein any hydrogen bound to any ring atom is optionally replaced by R4; R1 is phenyl, naphthyl, or isoquinolinyl, each optionally singly or multiply substituted with R17, wherein R17 is —OH, —NH2, —Cl, —F, —Oalkyl, or —N(alkyl)2; R2 is —C(O)—, —S(O)2—, —C(O)C(O)—, or —CH2C(O)—; R4 is fluoro or chloro; and m is 1.
- 13. The process according to claim 12, wherein:C is benzo, wherein any hydrogen bound to any ring atom is optionally replaced by R4; and R6 is H.
- 14. The process according to claim 12 wherein the inert solvent is CH2Cl2, DMF, or a mixture of CH2Cl2 and DMF.
- 15. The process according to any one of claims 12 or 13, wherein the nucleophilic scavenger is dimedone, morpholine, or dimethyl barbituric acid.
- 16. The process according to claim 14, wherein the nucleophilic scavenger is dimethyl barbituric acid.
- 17. The process according to claim 14, wherein the inert solvent is CH2Cl2, DMF, or a mixture of CH2Cl12 and DMF.
- 18. The process according to claim 17, wherein the nucleophilic scavenger is dimethyl barbituric acid.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuing application of co-pending International patent application PCT/US97/22355, filed Dec. 5, 1997, which claims priority from United States provisional patent application No. 60/050,796, filed Jun. 26, 1997, which is a continuation-in-part of U.S. provisional patent application No. 60/041,938, filed Apr. 4, 1997, which is a continuation-in-part of U.S. provisional patent application No. 60/032,129, filed Dec. 6, 1996.
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Provisional Applications (3)
|
Number |
Date |
Country |
|
60/050796 |
Jun 1997 |
US |
|
60/041938 |
Apr 1997 |
US |
|
60/032129 |
Dec 1996 |
US |
Continuations (1)
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Number |
Date |
Country |
| Parent |
PCT/US97/22355 |
Dec 1997 |
US |
| Child |
09/326494 |
|
US |
Patent Grant
6350741
