Hexahydro-cyclooctyl pyrazole cannabinoid modulators

Abstract

This invention is directed to a hexahydro-cyclooctyl pyrazole cannabinoid modulator compound of formula (I): and a method for use in treating, ameliorating or preventing a cannabinoid receptor mediated syndrome, disorder or disease.

1 .- 20 . (canceled) 
     
     
         21 . The method of treating, ameliorating or preventing a cannabinoid receptor mediated syndrome, disorder or disease in a subject in need thereof, wherein the cannabinoid receptor is a CB1 or CB2 receptor, said method comprising administering to said subject an effective amount of the compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt, isomer, prodrug, metabolite or polymorph thereof wherein
 the dashed lines between positions 2-3 and positions 3a-9a in formula (I) represent locations for each of two double bonds present when X 1 R 1  is present; 
 the dashed lines between positions 3-3a and positions 9a-1 in formula (I) represent locations for each of two double bonds present when X 2 R 2  is present; 
 the dashed line between position 9 and X 4 R 4  in formula (I) represents the location for a double bond; 
 X 1  is absent or lower alkylene; 
 X 2  is absent or lower alkylene; 
 wherein only one of the X 1 R 1  and X 2 R 2  are present; 
 X 3  is absent, lower alkylene, lower alkylidene or —NH—; 
 when the dashed line between position 9 and X 4 R 4  is absent, X 4  is absent or lower alkylene; 
 when the dashed line between position 9 and X 4 R 4  is present, X 4  is absent; 
 X 5  is absent or lower alkylene; 
 R 1  is selected from hydrogen, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), lower alkyl-sulfonyl, aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted at one or more positions by halogen, aminosulfonyl, lower alkyl-aminosulfonyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), hydroxy or alkoxy (optionally substituted at one or more positions by halogen or hydroxy); 
 R 2  is selected from hydrogen, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), lower alkyl-sulfonyl, aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted at one or more positions by halogen, aminosulfonyl, lower alkyl-aminosulfonyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), hydroxy or alkoxy (optionally substituted at one or more positions by halogen or hydroxy); 
 R 3  is —C(O)—Z 1 (R 6 ), —SO 2 —NR 7 —Z 2 (R 8 ) or —C(O)—NR 9 —Z 3 (R 10 ); 
 when the dashed line between position 9 and X 4 R 4  is absent, X 4  is absent or lower alkylene and R 4  is hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted at one or more positions by hydroxy, oxo, lower alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), lower alkoxy (optionally substituted at one or more positions by halogen or hydroxy) or halogen; 
 when the dashed line between position 9 and X 4 R 4  is present, is absent and R 4  CH-aryl or CH-heterocyclyl, wherein aryl or heterocyclyl are each optionally substituted at one or more positions by hydroxy, oxo, lower alkyl, lower alkoxy or halogen; 
 R 5  is absent, hydroxy, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl; 
 R 6  is aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted by one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl; 
 R 7  is hydrogen or lower alkyl; 
 R 8  is aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted by one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl; 
 R 9  is hydrogen or lower alkyl; 
 R 10  is aryl, C 3 -C 12  cycloalkyl or heterocyclyl, wherein aryl, C 3 -C 12  cycloalkyl or heterocyclyl are each optionally substituted by one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally substituted at one or more positions by halogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at one or more positions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aminosulfonyl, lower alkyl-aminosulfonyl, aryl, aryloxy, arylalkoxy or heterocyclyl; 
 Z 1  and Z 2  are each absent or alkyl; and, 
 Z 3  is absent, —NH—, —SO 2 — or alkyl (wherein alkyl is optionally substituted at one or more positions by halogen, hydroxy, lower alkyl, lower alkoxy, carboxy or carbonylalkoxy) is an agonist, antagonist or inverse-agonist of the receptor. 
 
     
     
         22 . The method of  claim 21 , wherein the compound is a CB1 receptor inverse-agonist. 
     
     
         23 . The method of  claim 21 , wherein the compound is a CB2 receptor agonist. 
     
     
         24 . The method of  claim 21 , wherein the syndrome, disorder or disease is related to appetite, metabolism, diabetes, glaucoma-associated intraocular pressure, social and mood disorders, seizures, substance abuse, learning, cognition or memory, organ contraction or muscle spasm, bowel disorders, respiratory disorders, locomotor activity or movement disorders, immune and inflammation disorders, unregulated cell growth, pain management or neuroprotection. 
     
     
         25 . The method of  claim 24  wherein bowel related syndromes, disorders, or diseases associated with inflammation, with or without pain, are selected from inflammatory bowel disease, disordered bowel motility associated with inflammation arising from surgery, traumatic injury or any sequelae resulting from traumatic injury, intraperitoneal inflammation, basal pneumonia, myocardial infarction, metabolic disturbances or any combination thereof. 
     
     
         26 . The method of  claim 25  wherein inflammatory bowel diseases are selected from ulcerative colitis, Crohn's disease or celiac disease. 
     
     
         27 . The method of  claim 25  wherein surgery is selected from abdominal surgery, transplantation surgery, bowel resection, orthopedic surgery, cardiovascular surgery or gynecological surgery. 
     
     
         28 . The method of  claim 25  wherein traumatic injury is selected from falls, car accident or personal assault. 
     
     
         29 . The method of  claim 25  wherein sequelae resulting from traumatic injury are selected from limb fractures, rib fractures, fractures of the spine, thoracic lesions, ischemia or retroperitoneal hecatomb. 
     
     
         30 . The method of  claim 25  wherein intraperitoneal inflammation is selected from intraabdominal sepsis, acute appendicitis, cholecystitis, pancreatitis or ureteric colic. 
     
     
         31 . The method of  claim 21 , wherein the effective amount of the compound of Formula I is from about 0.001 mg/kg/day to about 300 mg/kg/day. 
     
     
         32 . The method of  claim 21 , wherein the syndrome, disorder or disease is a CB1 receptor inverse-agonist mediated appetite related, obesity related or metabolism related syndrome, disorder or disease. 
     
     
         33 . The method of  claim 21 , wherein the syndrome, disorder or disease is a CB2 receptor agonist mediated bowel related syndrome, disorder, or disease associated with inflammation, with or without pain, selected from inflammatory bowel disease, disordered bowel motility associated with inflammation arising from surgery, traumatic injury or any sequelae resulting from traumatic injury, intraperitoneal inflammation, basal pneumonia, myocardial infarction, metabolic disturbances or any combination thereof. 
     
     
         34 . The method of  claim 21 , further comprising the step of administering to the subject a combination product and/or therapy comprising an effective amount of a compound of Formula I and a therapeutic agent. 
     
     
         35 . The method of  claim 34  wherein the therapeutic agent is an anticonvulsant or a contraceptive agent. 
     
     
         36 . The method of  claim 35  wherein the anticonvulsant is topiramate, analogs of topiramate, carbamazepine, valproic acid, lamotrigine, gabapentin, phenyloin and the like and mixtures or pharmaceutically acceptable salts thereof. 
     
     
         37 . The method of  claim 35  wherein the contraceptive agent is a progestin-only contraceptive, a contraceptive having a progestin component and an estrogen component, or an oral contraceptive optionally having a folic acid component. 
     
     
         38 . A method of contraception in a subject comprising the step of administering to the subject a composition, wherein the composition comprises a contraceptive and a CB1 receptor inverse-agonist or antagonist compound of Formula I, wherein the composition reduces the urge to smoke in the subject and/or assists the subject in losing weight. 
     
     
         39 .- 41 . (canceled)