Claims
- 1. A compound having the formula (I)
- 2. The compound of claim 1 wherein L is an amino acid residue having the formula
- 3. A compound of the formula (IA):
- 4. The compound of claim 3 wherein R1a is methyl or chloro; m is 2; R1 is hydrogen; R2 is hydrogen; R3 is hydrogen; R1b is methyl, trifluoromethyl, amino, iodo, bromo, chloro or nitro; and n is 1 or 2;
a prodrug thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound or the prodrug.
- 5. A compound selected from the group consisting of
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide; 2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide; 2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide; 2-amino-5-bromo-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl)-benzamide; 3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide; 3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and 3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl)-benzamide; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.
- 6. A pharmaceutical composition comprising a compound of claim 1, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug and a pharmaceutically acceptable excipient, diluent or carrier.
- 7. The pharmaceutical composition of claim 6 wherein said compound, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug is present in a therapeutically effective amount for the treatment or prevention of a disease associated with monocyte accumulation, lymphocyte accumulation or both.
- 8. The pharmaceutical composition of claim 6 wherein said compound, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug is present in a therapeutically effective amount for the treatment or prevention of a disease associated with leucocyte accumulation.
- 9. A method for treating or preventing a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation comprising the step of administering a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug to an animal in need thereof.
- 10. The method of claim 9 wherein said disease is selected from the group consisting of atherosclerosis, restenosis, gingivitis, psoriasis, rheumatoid arthritis, glomerulonephritis, wound healing, Crohn's disease, encephalomyelitis and transplant rejection.
- 11. The method of claim 10 wherein said disease is atherosclerosis.
- 12. The method of claim 10 or 11 wherein said compound is a compound of Formula 1B
- 13. The method of claim 12 wherein said compound is selected from the group consisting of
N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-3-trifluoromethyl-benzamide; 2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-nitro-benzamide 2-amino-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-5-iodo-benzamide; 2-amino-5-bromo-N-[2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3,4-dichloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and 3-bromo-4-chloro-N-{2-[5-(2,4-dimethyl-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.
- 14. The method of claim 9 wherein said disease is a chronic inflammatory disease.
- 15. The method of claim 14 wherein said chronic inflammatory disease is selected from the group consisting of allergic rhinitis, eczema and atopic dermatitis.
- 16. The method of claim 14 or 15 wherein said compound is a compound of Formula 1C
- 17. The method of claim 16 wherein said compound is selected from the group consisting of
3,4-dichloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-bromo-4-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-bromo-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; 3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-benzamide; and 3-chloro-N-{2-[5-(2,4-dichloro-benzyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-2-oxo-ethyl}-4-fluoro-benzamide; a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug.
- 18. A pharmaceutical kit comprising a) a suitable dosage form comprising a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug; and b) instructions describing a method of using the dosage form to treat or prevent a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation.
- 19. A pharmaceutical combination comprising a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug and at least one other pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-COA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor. a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor.
- 20. A pharmaceutical kit comprising:
a) a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of said compound or said prodrug, and a pharmaceutically acceptable carrier, excipient or diluent in a first unit dosage form; b) a pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-COA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-COA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor. a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor, and a pharmaceutically acceptable carrier, excipient or diluent in a second unit dosage form; and c) a container.
- 21. A method for treating or preventing a disease associated with monocyte accumulation, lymphocyte accumulation or leucocyte accumulation comprising administering to a mammal in need of such treatment
a) a therapeutically effective amount of a compound of claim 1, a prodrug thereof, or a pharmaceutically acceptable salt, solvate, or hydrate of said compound or said prodrug; and b) a therapeutically effective amount of at least one pharmaceutical agent selected from the group consisting of a nutraceutical, a cholesterol absorption inhibitor, a HMG-CoA reductase inhibitor, a MTP/Apo B secretion inhibitor, a HMG-CoA synthase inhibitor, a HMG-CoA reductase transcription inhibitor, a HMG-CoA reductase translation inhibitor, a CETP inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, an ACAT inhibitor, a lipase inhibitor. a peroxisome proliferator-activated receptor agonist, a nonsteroidal anti-inflammatory drug and a COX-2 inhibitor.
- 22. The method of claim 21 wherein said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered simultaneously.
- 23. The method of claim 21 wherein said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered sequentially.
- 24. The method of claim 21 wherein said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered as a single pharmaceutical composition comprising said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug, said pharmaceutical agent, and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof.
- 25. The method of claim 21 wherein said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug, and said pharmaceutical agent is administered as two separate pharmaceutical compositions comprising (i) a first composition comprising said compound of claim 1, prodrug thereof, or pharmaceutially acceptable salt, hydrate or solvate of said compound or said prodrug and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof; and (ii) a second composition comprising said pharmaceutical agent and a pharmaceutically acceptable excipient, diluent, carrier or mixtures thereof.
- 26. The method of claim 25 wherein said first composition and said second composition is administered simultaneously.
- 27. The method of claim 25 wherein said first composition and said second composition is administered sequentially.
- 28. The use of a compound of claim 1, prodrug thereof, or pharmaceutically acceptable salt, hydrate or solvate of said compound or said prodrug in the manufacture of a medicament for the treatment or prevention of a disease associated with monocyte, lymphocyte accumulation, or leucocyte accumulation.
Parent Case Info
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/273,984 filed Mar. 7, 2001, which is incorporated in its entirety herein by reference.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60273984 |
Mar 2001 |
US |