THIOPHENE DERIVATIVES AS S1P1/EDG1 RECEPTOR AGONISTS

摘要

Disclosed are tricyclic aryl thiophene derivatives and their salts as represented by the general formula (I) wherein: A represents an oxazole, oxadiazole, thiazole or thiadiazole moiety as defined herein; or A represents -CO-CH2CH2- or -CO-CH=CH-; R1 represents alkyl; R2 represents hydrogen, methyl or ethyl; R3 represents hydrogen; R4 represents methyl, ethyl, or methoxy; R6 represents methyl, ethyl or halogen; and R5 represents a substituent as defined herein. Of particular importance are the compounds 2-hydroxy-N-((2S)-2-hydroxy-3-{ 4-[5-(5-isobutyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy} -propyl)-acetamide; N-((2S)-3-{ 2-ethyl-6-methyl-4-[5-(5-propyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-phenoxy} -2-hydroxy-propyl)-2-hydroxy-acetamide; (2R)-3-{ 2-ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl-6-methyl-phenoxy} -propane-1,2-diol; (2S)-3-{ 2-ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenoxy} -propane-1,2-diol; N-((2R)-3-{ 2-ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenoxy} -2-hydroxy-propyl)-2-hydroxy-acetamide and N-((2S)-3-{ 2-ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenoxy} -2-hydroxy-propyl)-2-hydroxy-acetamide. Further disclosed is a pharmaceutical composition which comprises a compound as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the prevention or treatment of diseases or disorders selected from the group consisting of rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; graft-versus-host diseases brought about by stem cell transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis such as Hashimoto's thyroiditis, uveoretinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; type I diabetes; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancers and tumour metastasis.