Patent EA-004747-B1 (EA)
Title: Substituted 8-arylquinoline phosphodiesterase-4 inhibitors
Inventor: DESCHENES DENIS
IPC: C07D405/12
Filed: 2000-12-20
Abstract: 1. A compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: S1, S2, and S3 are H; R1 is C1-C6alkyl group optionally substituted with -CN group or -SO2-C1-C6alkyl; A is CH; R2 is di(C1-C6)amino C1-C6alkyl; phenyl, optionally substituted with halogen or -SO2-C1-C6alkyl; -C(O)OH; carbamoyl optionally substituted with -C1-C6alkyl or C3-C6cycloalkyl; pyrrolidinocarbamoyl; or heteroaryl selected from the group comprising imidazolyl, thiazolyl, oxadiazolyl or pyridyl, each of them is optionally substituted with C1-C6alkyl, hydroxy-C1-C6alkyl or C1-C6alkoxyphenoxy-C1-C6alkyl. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is heteroaryl selected from the group comprising imidazolyl, thiazolyl, oxadiazolyl or pyridyl, each of them is optionally substituted with C1-C6alkyl, hydroxy-C1-C6alkyl or C1-C6alkoxyphenoxy-C1-C6alkyl. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with halogen or -SO2-C1-C6alkyl. 4. The compound according to claim 1 comprising or a pharmaceutically acceptable salt thereof. 5. 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{E/Z)-2-(3-methyl-1,2,4-oxa-diazol-5-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline of the formula 6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula(I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 7. The pharmaceutical composition according to claim 6, further comprising a Leukotriene receptor antagonist, a Leukotriene biosynthesis inhibitor, anM2/M3 antagonist, a corticosteroid, an HI receptor antagonist or a beta 2 adrenoceptor agonist. 8. The pharmaceutical composition according to claim 20, further comprising a COX-2 selective inhibitor, a statin, or an NSAID. 9. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crolm's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 10. A method of treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of forming in vivo a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1. 11. A compound of formula (I), according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use as phosphodiesterase inhibitors. 12. Use of a compound of formula (I), according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn's disease, reperfusiori injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, monopolar depression, acute and chronic neurodegenerative disorders with inflammatory components, Parkinson disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumour growth and cancerous invasion of normal tissues comprising the step of administering a therapeutically effective amount, or a prophylactically effective amount, of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 13. A phosphodiesterase-4 inhibitor pharmaceutical composition comprising an acceptable phosphodiesterase-4-inhibiting amount of a compound of formula (I), as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.