Antiiflammatory and antitumor 2-oxothiazoles abd 2-oxothiophenes compounds

Abstract

A compound of formula (I) wherein X is O, C═O or S; Y is N or CH; R 2 and R 4 are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2 or —(CH 2 ) p COOC 1-6 alkyl; or R 2 and R 4 together form a 6-membered phenyl ring fused to the five membered ring; each R 1 is independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12 arylalkyl, C 2-12 alkenyl; OC 1-12 alkyl, OC 2-12 alkenyl or a C 1-12 alkyl group; each R 5 is H or C 1-6 alkyl; each p is 0 to 3; n is 1 to 4; or a salt, ester, solvate, N-oxide, or prodrug thereof, e.g. a salt thereof

1 - 34 . (canceled) 
     
     
         35 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein X is O, C═O or S; 
         Y is N or CH; 
         R 2  and R 4  are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2  or —(CH 2 ) p COOC 1-6 alkyl; or R 2  and R 4  together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring; 
         each R 1  is independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12 arylalkyl, C 2-12  alkenyl; OC 1-12  alkyl, OC 2-12  alkenyl or a C 1-12  alkyl group; 
         each R 5  is H or C 1-6  alkyl; 
         each p is 0 to 3; 
         n is 1 to 4; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         36 . A compound of  claim 35  wherein the compound corresponds to formula (Ia) 
       
         
           
           
               
               
           
         
         wherein X is O, C═O or S; 
         Y is N or CH; 
         R 2  and R 4  are each independently H, —(CH 2 ) p COOH, —(CH 2 ) p CON(R 5 ) 2  or —(CH 2 ) p COOC 1-6 alkyl; or R 2  and R 4  together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring; 
         R 1  and R 3  are each independently selected from H, halo (e.g. fluoro or chloro), C 6-10 aryl, C 7-12  arylalkyl, C 2-12  alkenyl; OC 1-12  alkyl, OC 2-12  alkenyl or a C 1-12  alkyl group; 
         each R 5  is H or C 1-6  alkyl; 
         each p is 0 to 3; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         37 . A compound of  claim 35  wherein X is O. 
     
     
         38 . A compound of  claim 35  wherein Y is N. 
     
     
         39 . A compound of  claim 35  wherein R 1  or R 3  is a C 6-10  alkyl, C 7-12 arylalkyl or C 6-10  aryl group. 
     
     
         40 . A compound of  claim 35  wherein R 4  is H. 
     
     
         41 . A compound of  claim 35  wherein R 2  is COOC 1-2 alkyl. 
     
     
         42 . A compound of formula (IX): 
       
         
           
           
               
               
           
         
         wherein X is O, C═O or S; 
         Y is N or CH; 
         R 2  and R 4  are each independently H, —(CH 2 ) p COOH or —(CH 2 ) p COOC 1-6 alkyl; or R 2  and R 4  together with the atoms linking them form a 6-membered phenyl ring fused to the five membered ring; 
         n is 2; 
         one R 1  is H, Hal, or OC1-6 alkyl; 
         one R 1  is H, C 6-10 aryl, C 7-12 arylalkyl, C 2-10  alkenyl; OC 4-10  alkyl or a C 4-10  alkyl group; 
         each p is 0 to 2; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         43 . A compound of  claim 35   35  wherein the compound corresponds to formula (X) 
       
         
           
           
               
               
           
         
         wherein R 2  is COOH or COOC 1-6 alkyl; 
         R 1  is a C 4-10 alkyl group, OC 4-10 alkyl, C 4-10  alkenyl, C 7-12 arylalkyl or C 6-10 -aryl group; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         44 . A compound of  claim 35  wherein the compound corresponds to formula (XI) 
       
         
           
           
               
               
           
         
         R 1′  is H, Hal, e.g. F, C 7-12 arylalkyl or C 6-10 -aryl group; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         45 . A compound of  claim 35  wherein the compound corresponds to formula (III) 
       
         
           
           
               
               
           
         
         wherein R 2  is COOH or COOC 1-6 alkyl; 
         R 1  is a C 4-10 alkyl group, or C 6-10 -aryl group; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof; or 
         a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R 1′  is a C 6-10 -aryl group; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         46 . The compound of  claim 35  wherein said compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 . A pharmaceutical composition comprising a compound of formula (I) of  claim 35 . 
     
     
         48 . A method for treating a subject suffering from a disease or disorder comprising administering to the subject an effective amount of a compound of  claim 35 . 
     
     
         49 . A method for treating a subject suffering or susceptible to a chronic inflammatory condition comprising administering to the subject an effective amount of a compound of  claim 35 . 
     
     
         50 . A method of  claim 49  wherein the chronic inflammatory condition is selected from the group consisting of glomerulonephritis, rheumatoid arthritis, psoriasis, atopic dermatitis, allergic contact dermatitis, seborrheic dermatitis, pityriasis rosea, lichen planus, drug eruption, inflammatory CNS diseases, multiple sclerosis, chronic obstructive pulmonary disease, chronic lung inflammatory conditions, inflammatory bowel disease such as ulcerative colitis and crohns disease, juvenile arthritis, Crohn's colitis, psoriatic arthritis, ankylosing spondylitis, and cardiovascular disease. 
     
     
         51 . A method of  claim 49  wherein the compound is administered to a subject as a sole active agent. 
     
     
         52 . A method of  claim 49  wherein the compound is administered along with one or more of a steroid, non-steroidal anti-inflammatory drug (NSAID), analgesic such as aspirin, ibuprofen, or disease modifying antirheumatic drug (DMARD) such as methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine. 
     
     
         53 . A method for treating a subject suffering or susceptible to a hyperproliferative disorder comprising administering to the subject an effective amount of a compound of  claim 35 . 
     
     
         54 . A method of  claim 53  wherein the hyperproliferative disorder is a neoplastic disorder. 
     
     
         55 . A method of  claim 53  wherein the hyperproliferative disorder is cancer. 
     
     
         56 . A method of  claim 55  wherein the cancer is selected from the group consisting of solid tumors and haematological cancers. 
     
     
         57 . A method of  claim 55  wherein the cancer is cervical cancer, uterine cancer, ovarian cancer, pancreatic cancer, kidney cancer, gallbladder cancer, liver cancer, head and neck cancer, squamous cell carcinoma, gastrointestinal cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, brain cancer, astrocytoma, glioblastoma, medulloblastoma, neuroblastoma, sarcomas, colon cancer, rectum cancer, stomach cancer, anal cancer, bladder cancer, pancreatic cancer, endometrial cancer, plasmacytoma, lymphomas, retinoblastoma, Wilm's tumor, Ewing sarcoma, skin cancer, or melanoma. 
     
     
         58 . A method of  claim 55  wherein the compound is administered along with at least one of a cytotoxic or cytostatic agent. 
     
     
         59 . A method of  claim 58  wherein the cytotoxic or cytostatic agent is a chemotherapeutic agent such as a biologic or small molecule. 
     
     
         60 . A method for treating a subject suffering or susceptible to a hyperproliferative disorder comprising administering to the subject an effective amount of a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein Z is O or S; 
         W is N or CH; 
         R 6  is H, C 1-6 alkyl, —(CH 2 ) p COOH, —(CH 2 ) p COOC 1-6 alkyl, —(CH 2 ) p CONH 2 , —(CH 2 ) p CONHC 1-6 alkyl, —(CH 2 ) p CON(C 1-6 alkyl) 2 , 
         R 7  is as defined for R 6 ; or 
         R 6  and R 7  taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring optionally substituted by up to 4 groups R 8 ; 
         each R 8  is defined as for R 6  or is oxo; 
         R 10  is the same or different and is H, C 1-6 alkylCOOR a , halo (preferably fluoro), or CHal 3  (preferably CF 3 ); 
         R a  is H or C 1-6  alkyl, 
         V 1  is O, S, C(═O), —NHCO—, —CONH—, C 1-10 alkylene group, or a C 2-10 -mono or multiply unsaturated alkenylene group, said alkylene or alkenylene group optionally interrupted by C═O and/or one or more heteroatoms selected from O, NH, N(C 1-6  alkyl), S, SO, or SO 2 ; 
         Ar is a C 6-14  aryl group, wherein the aryl group may be optionally substituted with one or more R 9  groups; 
         each R 9  is halo, OH, CN, nitro, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , haloC 1-6 alkyl, C 6-10  aryl group, C 7-12 arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group; 
         each p is 0 to 3; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof; 
       
     
     
         61 . A method of  claim 60  wherein a compound of the following formula (VI) is administered: 
       
         
           
           
               
               
           
         
         wherein W is N or CH; 
         R 6  is H, —(CH 2 ) p COOH, or —(CH 2 ) p COOC 1-6 alkyl, 
         R 7  is as defined for R 6 ; or 
         R 6  and R 7  taken together with the atoms joining them can form a 6-membered aromatic or non aromatic, saturated or unsaturated, carbocyclic or heteroatom containing (e.g. O, N or S containing) ring; 
         V 1  is O, S, C(═O), or C 1-10 alkylene group, said alkylene group being optionally interrupted by C═O and/or one or more heteroatoms selected from O or NH; 
         Ar is a C 6-14  aryl group, wherein aryl group may be optionally substituted (preferably in the meta or para position relative to V 1 ) with one or two R 9  groups; 
         each R 9  is halo, C 6-10  aryl group, C 7-12 arylalkyl, a C 1-10 alkyl group, C 2-10 -mono or multiply unsaturated alkenyl group, OC 1-10 alkyl group, or OC 2-10 -mono or multiply unsaturated alkenyl group; and 
         each p is 0 to 3; 
         or a salt, ester, solvate, N-oxide, or prodrug thereof. 
       
     
     
         62 . A method of  claim 60  wherein the administered compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         63 . The method of  claim 62  wherein the hyperproliferative disorder is a neoplastic disorder. 
     
     
         64 . The method of  claim 62  wherein the hyperproliferative disorder is a cancer. 
     
     
         65 . The method of  claim 64  wherein the cancer is selected from the group consisting of solid tumours and haematological cancers. 
     
     
         66 . The method of  claim 64  wherein the cancer is selected from the group consisting of cervical cancer, uterine cancer, ovarian cancer, pancreatic cancer, kidney cancer, gallbladder cancer, liver cancer, head and neck cancer, squamous cell carcinoma, gastrointestinal cancer, breast cancer, prostate cancer, testicular cancer, lung cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, multiple myeloma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia, brain cancer, astrocytoma, glioblastoma, medulloblastoma, neuroblastoma, sarcomas, colon cancer, rectum cancer, stomach cancer, anal cancer, bladder cancer, pancreatic cancer, endometrial cancer, plasmacytoma, lymphomas, retinoblastoma, Wilm's tumor, Ewing sarcoma, skin cancer, melanoma. 
     
     
         67 . The method of  claim 64  wherein the cancer is breast cancer. 
     
     
         68 . The method of  claim 64  wherein the compound is administered along with at least one of a cytotoxic or cytostatic agent. 
     
     
         69 . The method of  claim 68  wherein the cytotoxic or cytostatic agent is a chemotherapeutic agent. 
     
     
         70 . A method for preventing or treating breast cancer in a patient, the method comprising the steps of administering to the patient an effective amount of at least one chemotherapeutic agent; and administering an effective amount of at least one compound of formula (I) of  claim 35 . 
     
     
         71 . The method of  claim 70  wherein the chemotherapeutic agent is administered to the patient before the administration of the compound of formula (I). 
     
     
         72 . The method of  claim 70  wherein the chemotherapeutic agent is one or more of paclitaxel, doxorubicin, cyclophosphamide and cisplatin. 
     
     
         73 . The method of  claim 70  wherein the method further comprises administering one or more of trastuzumab (Herceptin), trastuzumab-doxorubicin conjugate (TDM1) and pertuzumab (Perjeta) to the patient.