Novel oxime azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators

Abstract

The present invention relates to novel oxime azetidine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

What is claimed is: 
     
         1 . A compound having Formula I, its enantiomers, diastereoisomers, hydrates, solvates, crystal forms and individual isomers, tautomers or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 2  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 3  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 4  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 5  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 6  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 7  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 8  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 L is O, S, NH or CH 2 ; 
 D is a group of formula 
 
       
         
           
           
               
               
           
         
       
       “*” indicating the point of attachment to the rest of the molecule;
 R 9  is H or C 1-6  alkyl; 
 R 19  is H or C 1-6  alkyl; 
 R 11  is H or C 1-6  alkyl; and 
 a is 0 or 1. 
 
     
     
         2 . A compound according to  claim 1  selected from:
 1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 
 1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 
 3-(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid; 
 3-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid. 
 
     
     
         3 . A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable adjuvant, diluents or carrier. 
     
     
         4 . A pharmaceutical composition according to  claim 3  wherein the compound is selected from:
 1-{4-[({[(1E)-2-(3,5-difluorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 
 1-{4-[({[(1E)-2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)-1-methylpropylidene]amino}oxy)methyl]benzyl}azetidine-3-carboxylic acid; 
 3-(4-{(1E)-N-[3-(3,4-dimethylphenyl)-2-(3-methylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid; 
 3-(4-{(1E)-N-[2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propoxy]ethanimidoyl}benzyl)cyclobutanecarboxylic acid. 
 
     
     
         5 . A method of treating a disorder associated with sphingosine-1-phosphate receptor modulation, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 2  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 3  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 4  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 5  is H, halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 6  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 7  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 8  is halogen, —OC 1-3  alkyl, C 1-3  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 L is O, S, NH or CH 2 ; 
 D is a group of formula 
 
       
         
           
           
               
               
           
         
       
       “*” indicating the point of attachment to the rest of the molecule;
 R 9  is H or C 1-6  alkyl; 
 R 19  is H or C 1-6  alkyl; 
 R 11  is H or C 1-6  alkyl; and 
 a is 0 or 1. 
 
     
     
         6 . A method of  claim 5 , wherein the pharmaceutical composition is administered to the mammal to treat ocular disease, wet and dry age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, retinal edema, geographic atrophy, glaucomatous optic neuropathy, chorioretinopathy, hypertensive retinopathy, ocular ischemic syndrome, prevention of inflammation-induced fibrosis in the back of the eye, various ocular inflammatory diseases including uveitis, scleritis, keratitis, and retinal vasculitis; or systemic vascular barrier related diseases, various inflammatory diseases, including acute lung injury, its prevention, sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and ventilation-induced lung injury; or autoimmune diseases and immunosuppression, rheumatoid arthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermatitis, and organ transplantation; or allergies and other inflammatory diseases, urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases; or cardiac protection, ischemia reperfusion injury and atherosclerosis; or wound healing, scar-free healing of wounds from cosmetic skin surgery, ocular surgery, GI surgery, general surgery, oral injuries, various mechanical, heat and burn injuries, prevention and treatment of photoaging and skin ageing, and prevention of radiation-induced injuries; or bone formation, treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity, visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains. 
     
     
         7 . The method of  claim 6  wherein the mammal is a human