Non-hormonal steroid modulators of NF-κB for treatment of disease
The present invention relates to compounds and methods which may be useful as treatments of neuromuscular diseases such as muscular dystrophy, and as inhibitors of NF-κB for the treatment or prevention of muscular wasting disease, including muscular dystrophy.
1. A compound selected from the group consisting of:
2. A pharmaceutical composition comprising a compound selected from the group consisting of
together with a pharmaceutically acceptable carrier.
3. The pharmaceutical composition as recited in claim 2 wherein said pharmaceutical composition comprises a tablet or a capsule.
4. The pharmaceutical composition as recited in claim 2 wherein said pharmaceutical composition comprises another therapeutic agent.
5. A method of reducing the symptoms of a disease selected from the group consisting of muscular dystrophy, arthritis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren's syndrome, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, gut diseases, peritoneal endometriosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia-ID, Behcet's disease, incontinentia pigmenti, tuberculosis, asthma, crohn's disease, colitis, ocular allergy, appendicitis, paget's disease, pancreatitis, periodonitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica-induced diseases, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary periodic fever syndrome, psychosocial stress diseases, neuropathological diseases, familial amyloidotic polyneuropathy, inflammatory neuropathy, parkinson's disease, multiple sclerosis, alzheimer's disease, amyotropic lateral sclerosis, huntington's disease, cataracts, and hearing loss, comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a compound selected from the group consisting of
6. The method as recited in claim 5 , wherein said disease is muscular dystrophy.
7. The method as recited in claim 6 , wherein said muscular dystrophy is selected from the group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.
8. The method as recited in claim 7 , wherein said muscular dystrophy is Duchenne muscular dystrophy.
9. The method as recited in claim 5 , wherein said disease is selected from the group consisting of asthma and chronic obstructive pulmonary disease.
10. The method as recited in claim 9 , wherein said disease is asthma.
11. The method as recited in claim 9 , wherein said disease is chronic obstructive pulmonary disease.
12. The method as recited in claim 5 , wherein said disease is arthritis.
13. The method as recited in claim 5 , wherein said disease is selected from the group consisting of traumatic brain injury and spinal cord injury.
14. The method as recited in claim 13 , wherein said disease is traumatic brain injury.
15. The method as recited in claim 13 , wherein said disease is spinal cord injury.
16. The method as recited in claim 5 , wherein said disease is amyotropic lateral sclerosis.
17. The method as recited in claim 5 , wherein said disease is Sjogren's syndrome.
18. The method as recited in claim 5 , wherein said compound has the structural formula:
19. The method as recited in claim 5 , wherein said compound has the structural formula:
20. The method as recited in claim 5 , wherein said compound has the structural formula:
21. The method as recited in claim 5 , wherein said compound has the structural formula:
22. The method as recited in claim 5 , wherein said compound has the structural formula:
23. The method as recited in claim 5 , wherein said compound has the structural formula:
24. The method as recited in claim 5 , wherein said compound has the structural formula:
25. The method as recited in claim 5 , wherein said compound has the structural formula:
26. The method as recited in claim 5 , comprising the administration of another therapeutic agent.
27. A method of reducing the symptoms of a disease selected from the group consisting of muscular dystrophy, arthritis, traumatic brain injury, spinal cord injury, sepsis, rheumatic disease, cancer atherosclerosis, type 1 diabetes, type 2 diabetes, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, ischemia/reperfusion, stroke, cerebral aneurysm, angina pectoris, pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, asthma, chronic obstructive pulmonary disease, Sjogren's syndrome, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, gut diseases, peritoneal endometriosis, skin diseases, nasal sinusitis, mesothelioma, anhidrotic ecodermal dysplasia-ID, Behcet's disease, incontinentia pigmenti, tuberculosis, asthma, crohn's disease, colitis, ocular allergy, appendicitis, paget's disease, pancreatitis, periodonitis, endometriosis, inflammatory bowel disease, inflammatory lung disease, silica-induced diseases, sleep apnea, AIDS, HIV-1, autoimmune diseases, antiphospholipid syndrome, lupus, lupus nephritis, familial mediterranean fever, hereditary periodic fever syndrome, psychosocial stress diseases, neuropathological diseases, familial amyloidotic polyneuropathy, inflammatory neuropathy, parkinson's disease, multiple sclerosis, alzheimer's disease, amyotropic lateral sclerosis, huntington's disease, cataracts, and hearing loss, comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a compound selected from the group consisting of
28. The method as recited in claim 27 , wherein said disease is muscular dystrophy.
29. The method as recited in claim 28 , wherein said muscular dystrophy is selected from the group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and Emery-Dreifuss muscular dystrophy.
30. The method as recited in claim 29 , wherein said muscular dystrophy is Duchenne muscular dystrophy.
31. The method as recited in claim 27 , wherein said disease is selected from the group consisting of asthma and chronic obstructive pulmonary disease.
32. The method as recited in claim 31 , wherein said disease is asthma.
33. The method as recited in claim 31 , wherein said disease is chronic obstructive pulmonary disease.
34. The method as recited in claim 27 , wherein said disease is arthritis.
35. The method as recited in claim 27 , wherein said disease is selected from the group consisting of traumatic brain injury and spinal cord injury.
36. The method as recited in claim 35 , wherein said disease is traumatic brain injury.
37. The method as recited in claim 35 , wherein said disease is spinal cord injury.
38. The method as recited in claim 27 , wherein said disease is amyotropic lateral sclerosis.
39. The method as recited in claim 27 , wherein said disease is Sjogren's syndrome.
40. The method as recited in claim 27 , wherein said compound has the structural formula:
41. The method as recited in claim 27 , wherein said compound has the structural formula:
42. The method as recited in claim 27 , wherein said compound has the structural formula:
43. The method as recited in claim 27 , wherein said compound has the structural formula:
44. The method as recited in claim 27 , wherein said compound has the structural formula:
45. The method as recited in claim 27 , wherein said compound has the structural formula:
46. The method as recited in claim 27 , wherein said compound has the structural formula:
47. The method as recited in claim 27 , wherein said compound has the structural formula:
48. The method as recited in claim 27 , comprising the administration of another therapeutic agent.