5-[(3,3,3-trifluoro-2-hydroxy-1-arylpropyl)amino]-1H-quinolin-2-ones, a process for their production and their use as anti-inflammatory agents

Abstract

The present invention relates to compounds of formula I, processes for their production and their use as anti-inflammatory agents.

The invention claimed is: 
     
       1. A method for the treatment of
 Atopic dermatitis, 
 Psoriasis, 
 Pityriasis rubra pilaris, 
 Erythematous diseases, triggered by different noxae, 
 Bullous dermatoses, 
 Diseases of the lichenoid group, 
 Pruritis, 
 Seborrheal eczema, 
 Rosacea, 
 Pemphigus vulgaris, 
 Erythema exudativum multiforme, 
 Balanitis, 
 Vulvitis, 
 Hair loss from alopecia areata, 
 Cutaneous lymphoma, 
 Quincke's edema, 
 insect bites, 
 allergic reactions to pharmaceutical agents, blood derivatives, or contrast media, 
 anaphylactic shock, 
 urticarial, 
 contact dermatitis, 
 Anal eczema, 
 Fissures, 
 Hemorrhoids, 
 Idiopathic proctitis, 
 Allergic rhinitis, hay fever, 
 Otitis externa, or 
 Otitis media 
 
       comprising administering to a host in need thereof an effective amount of
 5-{[1-(2-Fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[2-([Ethylsulfanyl]methyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino}-1H-quinolin-1-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 
       or salts, solvates or salts of solvates thereof. 
     
     
       2. The method according to  claim 1 , wherein compounds, their salts, solvates or salts of solvates are in enantiomerically pure form. 
     
     
       3. The method according to  claim 1 , comprising administering the enantiomerically pure compounds
 5-{(1S,2R)[1-(2-Fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-[([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{(1S,2R)[2-([Ethylsulfanyl]methyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-1H-quinolin-2-one 
 5-{(1S,2R)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{(1S,2R)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2R)[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino}-1H-quinolin-1-one 
 5-{(1S,2R)[[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{(1S,2S)[1-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 
       or their salts, solvates or salts of solvates. 
     
     
       4. The method according to  claim 1 , comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt, solvate or salt of a solvate thereof. 
     
     
       5. The method according to  claim 1 , comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       6. The method according to  claim 3 , comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt, solvate or salt of a solvate thereof. 
     
     
       7. The method according to  claim 3 , comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       8. A method for the treatment of
 Lung disease due to inflammatory, allergic and/or proliferative processes,   rheumatic disease due to inflammatory, allergic and/or proliferative processes,   joint diseases due to inflammatory, allergic and/or proliferative processes,   autoimmune diseases due to inflammatory, allergic and/or proliferative processes,   vascular inflammation,   kidney disease due to inflammatory, allergic and/or proliferative processes,   liver disease due to inflammatory, allergic and/or proliferative processes,   gastrointestinal disease due to inflammatory, allergic and/or proliferative processes,   eye diseases due to inflammatory, allergic and/or proliferative processes,   neurological disease due to inflammatory, allergic and/or proliferative processes,   blood disease due to inflammatory, allergic and/or proliferative processes,   tumors due to inflammatory, allergic and/or proliferative processes,   endocrine disease due to inflammatory, allergic and/or proliferative processes,   graft-versus-host disease in organ and tissue transplants,   shock,   emesis due to inflammatory, allergic and/or proliferative processes, or   Collagenoses,   
       comprising administering to a host in need thereof an effective amount of
 5-{[1-(2-Fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[2-([Ethylsulfanyl]methyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino}-1H-quinolin-1-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one, 
 
       or salts, solvates or salts of solvates thereof. 
     
     
       9. A method according to claim 8, comprising treating
 chronic, obstructive lung diseases,   bronchial asthma,   Bronchitis of different origins,   Adult respiratory distress syndrome,   acute respiratory distress syndrome,   Bronchiectases,   allergic alveolitis,   toxic pulmonary edema,   radiogenic pneumonitis,   Sarcoidoses,   granulomatoses,   Boeck's disease,   rheumatoid arthritis,   acute rheumatic fever,   polymyalgia rheumatica,   Behçet's disease,   Reactive arthritis,   arthroses,   Traumatic arthritides,   Vitiligo,   systemic lupus erythematodes,   sclerodermia,   polymyositis,   dermatomyositis,   Sjögren's syndrome,   Still's syndrome,   Felty's syndrome,   Sarcoidoses,   Soft-tissue rheumatism,   Panarteritis nodosa,   temporal arteritis,   erythema nodosum,   Polyarteris nodosa,   Wegner's granulomatosis,   Giant-cell arteritis,   Nephrotic syndrome,   nephritides,   glomerulonephritis,   Acute liver cell decomposition,   Acute viral hepatitis,   Acute toxic hepatitis,   Acute pharmaceutical agent-induced hepatitis,   Regional enteritis (Crohn's disease),   Colitis ulcerosa,   Gastritis,   Reflux esophagitis,   Ulcerative colitis,   Allergic keratitis, uveitis, iritis,   Conjunctivitis,   Blepharitis,   Optic neuritis,   Chorioiditis,   Sympathetic ophthalmia,   Cerebral edema,   Multiple sclerosis,   Acute encephalomyelitis,   Meningitis,   convulsions,   Acute spinal cord injury,   Stroke,   M. Hodgkins or Non-Hodgkins lymphoma,   thrombocythemias,   erythrocytoses,   Acquired hemolytic anemia,   Idiopathic thrombocytopenia,   carcinomas or sarcomas,   Acute lymphatic leukemia,   Malignant lymphoma,   Lymphogranulomatoses,   Lymphosarcoma,   Extensive metastases,   Endocrine orbitopathy,   Thyreotoxic crisis,   De Quervain's thyroiditis,   Hashimoto's thyroiditis,   Basedow's disease,   Granulomatous thyroiditis or   Lymphadenoid goiter.   
     
     
       10. A method for substitution therapy in:
 Innate primary suprarenal insufficiency,   Acquired primary suprarenal insufficiency,   Innate secondary suprarenal insufficiency, or   Acquired secondary suprarenal insufficiency,   
       comprising administering to a host in need thereof an effective amount of
 5-{[1-(2-Fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[2([Ethylsulfanyl]methyl)-1-(2-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-([methylsulfanyl]methyl)propyl]amino}-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-([ethylsulfanyl]methyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)-propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(5-Chloro-3-fluoro-2-methoxyphenyl)-2-(chloromethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[3,3,3-trifluoro-2-hydroxy-2-([methoxymethyl)-1-phenylpropyl]amino}-1H-quinolin-1-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(diaminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(4-Chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-2-(ethoxymethyl)-3,3,3-trifluoro-2-hydroxypropyl]amino}-7-fluoro-1H-quinolin-2-one 
 5-{[1-(2-Chloro-3-fluoro-4-hydroxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(hydroxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one, 
 
       or salts, solvates or salts of solvates thereof. 
     
     
       11. The method according to claim 8, comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       12. The method according to claim 8, comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       13. The method according to claim 8, comprising administering enantiomerically pure 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       14. The method according to claim 8, comprising administering enantiomerically pure
 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof.   
     
     
       15. The method according to claim 9, comprising admisistering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       16. The method according to claim 9, comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       17. The method according to claim 9, comprising administering enantiomerically pure5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       18. The method according to claim 9, comprising administering enantiomerically pure 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       19. The method according to claim 10, comprising admisistering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       20. The method according to claim 10, comprising administering 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof. 
     
     
       21. The method according to claim 10, comprising administering enantiomerically pure 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one
 or a salt, solvate or salt of a solvate thereof.   
     
     
       22. The method according to claim 10, comprising administering enantiomerically pure 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one or a salt thereof.