IMIDAZO [2,1,-b]-1,3,4-THIADIAZOLE SULFONAMIDES

Abstract

This invention relates to compounds of Formula I and the use of compounds of Formula I as neuroprotective agents in the treatment of neuronal disorders of the central and peripheral nervous systems. Formula I:

1 . An imidazo[2,1-b]-1,3,4-thiadiazole sulfonamide compound of  claim 1  represented by the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein 
       R 1  and R 2  are individually selected from H and C(1-8)-alkyl; 
       R 5  is selected from H, halogen, substituted and unsubstituted C(1-8)-alkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; 
       R 7 , R 8 , R 9 , R 10  and R 11  are independently selected from: 
       a) H, halogen, nitro, cyano, substituted and unsubstituted C(1-8)-alkyl, fluoroalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted C(1-8)-alkylcarbonyl, substituted and unsubstituted arylcarbonyl, substituted and unsubstituted heteroarylcarbonyl, azide, B(OH) 2 ; 
       b) SO 2 NR 16 R 17  wherein R 16  and R 17  are independently selected from the group consisting of substituted and unsubstituted C(1-8)-alkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, or wherein R 16  and R 17  are joined to form a substituted or unsubstituted alkyl or heteroalkyl ring system; 
       c) SO n R 18  wherein n=0, 1 or 2, and wherein R 18  is selected from the group consisting of C(1-8)-alkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroaralkyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl; 
       d) OR 19  wherein R 19  is selected from the group consisting of substituted and unsubstituted alkyl, fluoroalkyl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted C(1-8)-alkylcarbonyl, substituted and unsubstituted arylcarbonyl, substituted and unsubstituted heteroarylcarbonyl, C(1-8)-alkylaminocarbonyl, and substituted and unsubstituted arylaminocarbonyl; 
       e) NR 14 R 15  wherein R 14  and R 15  are defined as C(1-8)-alkyl or are joined to form a substituted or unsubstituted alkyl or heteroalkyl ring system; and 
       f) CONR 21 R 22 , wherein R 21  and R 22  are independently selected from the group consisting of C(1-8)-alkyl, aralkyl, and aryl. 
     
   
   
       2 . A compound according to  claim 1  wherein the compound is a pharmaceutically acceptable salt. 
   
   
       3 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       4 . A method for the prevention or treatment of a neurological disorder in a subject, comprising administering to said subject a therapeutically effective amount of a compound of  claim 1 . 
   
   
       5 . The method of  claim 4 , wherein the neurological disorder results from axonal and/or neuronal cell body damage, and/or the loss of axonal growth and repair. 
   
   
       6 . The method of  claim 4 , wherein the neurological disorder is a neurodegenerative condition of the central nervous system or the peripheral nervous system. 
   
   
       7 . The method of  claim 6 , wherein the neurodegenerative condition results from a toxic agent. 
   
   
       8 . The method of  claim 7 , wherein the toxic agent is a neurotoxic agent selected from the group consisting of acetazolimide, acrylamide, adriamycin, ethanol, almitine, amiodarone, amphotericin, arsenic, aurothioglucose, barbiturates, buckthorn, carbamates, carbon disulfide, chloramphenicol, chloroquine, chlorestyramine, cisplatin, clioquinol, colestipol, colchicine, colistin, cycloserine, cytarabine, dapsone, dideoxycytidine, dideoxyinosine, dideoxythymidine, disulfiram, doxorubicin, ethambutol, ethionamide, glutethimide, gold, hexacarbons, hormonal contraceptives, hexamethylolmelamine, hydralazine, hydroxychloroquine, imipramine, indomethacin, inorganic lead, iso-niazid, lithium, methylmercury, metformin, methylhydrazine, metronidazole, misonidazole, nitrofurantoin, nitrogen mustard, nitrous oxide, organophosphates, ospolot, penicillin, perhexyline, perhexyline maleate, phenyloin, platinum, primidone, procarbazine, pyridoxine, sodium cyanate, streptomycin, sulphonamides, suramin, tamoxifen, Taxol™, thalidomide, thallium, triamterene, trimethyltin, L-trypophan, vincristine, vinblastine, vindesine, vitamin A or D. 
   
   
       9 . The method of  claim 8  wherein the toxic agent is a chemotherapeutic agent. 
   
   
       10 . The method of  claim 9  wherein the chemotherapeutic agent is administered to the subject for the treatment of HIV, proliferative diseases or inflammatory diseases. 
   
   
       11 . The method of  claim 4  wherein the neurological disorder results from Alzheimer's disease; Huntington's disease; Parkinson's disease; muscular dystrophy; ischemic insults, retinal degeneration; hypertension; viral infection, macular degeneration, glaucoma, and nerve crush or injury. 
   
   
       12 . The method of  claim 11  wherein the ischemic insult is cerebral stroke. 
   
   
       13 . A method of  claim 4 , wherein the neurological disorder results from diabetes. 
   
   
       14 . A method of  claim 4 , wherein the neurological disorder results from HIV. 
   
   
       15 . The method of  claim 4 , wherein the neurological disorder results from a degenerative disease of the eye. 
   
   
       16 . The method of  claim 15 , wherein the degenerative disease of the eye is retinal ischemia. 
   
   
       17 . A method of  claim 4  further comprising the step of administering a therapeutically effective amount of a chemotherapeutic agent prior to, simultaneously with, or after administration of the compound. 
   
   
       18 . A method for altering signal transduction in a subject, comprising administering to said subject a therapeutically effective amount of a compound of  claim 1 . 
   
   
       19 . A compound of  claim 1  for use as a neuroprotective agent. 
   
   
       20 . A pharmaceutical package comprising the pharmaceutical composition according to  claim 4  and instructions for use.