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

Abstract

The present invention relates to novel benzyl 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, tautomers or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         A is a heterocycle; 
         B is C 6-10  aryl, heterocycle, C 3-8  cycloalkyl or C 3-8  cycloalkenyl 
         R 1  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 2  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 3  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 4  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 5  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 6  is H, halogen, —OC 1-8  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 7  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 8  is halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         L is CH 2 ; 
         R 9  is H, hydroxyl or C 1-6  alkyl; 
         R 10  is H or C 1-8  alkyl; 
         R 11  is H or C 1-8  alkyl; and 
         a is 0 or 1. 
       
     
     
         2 . A compound according to  claim 1  wherein:
 A is a heterocycle; 
 B is C 6  aryl or C  3-8  cycloalkyl; 
 R 1  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 2  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 3  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 4  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 5  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 6  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 7  is H, halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 R 8  is halogen, —OC 1-6  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
 L is CH 2 ; 
 R 9  is H, hydroxyl or C 1-6  alkyl; 
 R 10  is H or C 1-6  alkyl; 
 R 11  is H or C 1-6  alkyl; and 
 a is 0 or 1. 
 
     
     
         3 . A compound according to  claim 2  wherein: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 2  wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, halogen or —C 1-6  alkyl; 
         R 2  is H or halogen; 
         R 3  is H, halogen or —C 1-6  alkyl; 
         R 4  is H or C 1-6  alkyl; 
         R 5  is H or C 1-6  alkyl; 
         R 6  is H or C 1-6  alkyl; 
         R 7  is H; and 
         a is 0. 
       
     
     
         5 . A compound according to  claim 4  wherein: 
       
         
           
           
               
               
           
         
         R 1  is H, chloro, fluoro, trifluoromethyl or methyl; 
         R 2  is H, chloro or fluoro, 
         R 3  is H, fluoro or methyl; 
         R 4  is H or methyl; 
         R 5  is H or methyl; 
         R 6  is H or methyl; 
         R 7  is H; and 
         a is 0. 
       
     
     
         6 . A compound according to  claim 1  selected from:
 1-(4-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(3,4-Dimethylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(4-methylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(4-Methylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; and 
 1-(4-{5-[2-(3,4-dimethylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid. 
 
     
     
         7 . 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. 
     
     
         8 . A pharmaceutical composition according to  claim 7  wherein the compound is selected from:
 1-(4-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(3,4-Dimethylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(4-methylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; 
 1-(4-{5-[2-(4-Methylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid; and 
 1-(4-{5-[2-(3,4-dimethylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid. 
 
     
     
         9 . 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: 
         A is a heterocycle; 
         B is C 6-10  aryl, heterocycle, C 3-8  cycloalkyl or C 3-8  cycloalkenyl 
         R 1  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 2  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 3  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 4  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 5  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 6  is H, halogen, —OC 1-8  alkyl, C 1-6  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 7  is H, halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         R 8  is halogen, —OC 1-8  alkyl, C 1-8  alkyl, CN, C(O)R 9 , NR 10 R 11  or hydroxyl; 
         L is CH 2 ; 
         R 9  is H, hydroxyl or C 1-6  alkyl; 
         R 10  is H or C 1-8  alkyl; 
         R 11  is H or C 1-8  alkyl; and 
         a is 0 or 1. 
       
     
     
         10 . A method of  claim 9 , 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 such as but not limited to:
 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 such as but not limited to: rheumatoid arthritis, osteoarthritis, Crohn's disease, Graves' disease, inflammatory bowel disease, multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion injury, contact hypersensitivity, atopic dermititis, and organ transplantation including cornea, graft vs. host diseases, pterygium, dry eye, and posterior blepharitis; or allergies and other inflammatory diseases such as but not limited to: urticaria, bronchial asthma, and other airway inflammations including pulmonary emphysema and chronic obstructive pulmonary diseases pulmonary injuries from virulent influenza virus infection; or cardiac protection such as but not limited to: ischemia reperfusion injury and atherosclerosis; or wound healing such as but not limited to: 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- or chemotherapy-induced injuries; or bone formation such as but not limited to: treatment of osteoporosis and various bone fractures including hip and ankles; or anti-nociceptive activity such as but not limited to: visceral pain, pain associated with diabetic neuropathy, rheumatoid arthritis, chronic knee and joint pain, tendonitis, osteoarthritis, neuropathic pains; or central nervous system neuronal activity in Alzheimer's disease, age-related neuronal injuries; or in organ transplant such as renal, corneal, cardiac or adipose tissue transplant.   
     
     
         11 . The method of  claim 10  wherein the mammal is a human.