Hydrazone modulators of cannabinoid receptors

Abstract

Hydrazone compounds which modulate cannabinoid receptors are presented. Pharmaceutical compositions containing these compounds, methods of using these compounds as modulators of cannabinoid receptors and processes for synthesizing these compounds are also described herein.

1 - 24 . (canceled) 
     
     
         25 . A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of bladder dysfunction, prevention of miscarriage and ectopic pregnancy, social and mood disorders, seizure-related disorders, learning disorders, cognition disorders, memory disorders, bowel disorders, gastrointestinal disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, organ contraction, muscle spasm, neuroprotection disorders, dermatological complaints associated with a keratinization disorder relating to cell differentiation and proliferation, dermatological complaints without cell proliferation disorders, dermal and epidermal proliferations, cicatrization disorders, immunological related dermatological complaints, skin disorders related to exposure of UV radiation, sebaceous function disorders, aging of the skin, and pigmentation disorders, the hydrazone compound comprising a compound of structural Formula I: 
       
         
           
           
               
               
           
         
         or a salt or prodrug thereof, wherein: 
         R 1  is selected from the group consisting of n-hexyl and 2-cyclohexyl ethyl. 
       
     
     
         26 . The method of  claim 25 , the hydrazone compound comprising the structural formula IV: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The method of  claim 25 , the hydrazone compound comprising the structural formula V: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method of  claim 25 , wherein the cannabinoid receptor-mediated disease or disorder is selected from cognition and memory disorders. 
     
     
         29 . A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of bladder dysfunction, prevention of miscarriage and ectopic pregnancy, social and mood disorders, seizure-related disorders, learning disorders, cognition disorders, memory disorders, bowel disorders, gastrointestinal disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, organ contraction, muscle spasm, neuroprotection disorders, dermatological complaints associated with a keratinization disorder relating to cell differentiation and proliferation, dermatological complaints without cell proliferation disorders, dermal and epidermal proliferations, cicatrization disorders, immunological related dermatological complaints, skin disorders related to exposure of UV radiation, sebaceous function disorders, aging of the skin, and pigmentation disorders, the hydrazone compound comprising a compound of structural Formula II: 
       
         
           
           
               
               
           
         
         or a salt or prodrug thereof; wherein: 
         X is selected from the group consisting of C═O, C═S, or SO 2 ; 
         R 1  is selected from the group consisting of alkyl containing from 6 to 12 carbon atoms, a polyether, a substituted benzyl and a radical defined by the following structure: 
       
       
         
           
           
               
               
           
         
         where n is an integer ranging from 1 to 4; but if R 2  is an alkoxy at position 6, then R 1  can also be selected from the group consisting of alkyl containing from 1 to 12 carbon atoms; 
         R 2  and R′ 2  vary independently and are selected from the group consisting of hydrogen, aryl, alkyl, cycloalkyl, aralkyl, alkenyl, alkynyl, halogen, an alkoxyl or a hydroxyl; 
         R 3  is selected from the group consisting of NR 15 R 16 , aryl, a heteroaryl, alkenyl, an alkynyl, an alkoxyl, a cycloalkyl containing from 5 to 10 carbon atoms and containing eventually —CO—, —O—, —S—, —SO—, —SO 2 —, —CHOH— or —NR 12 — or one of the radicals defined by the following structure: 
       
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  taken together form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms that are eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 14 —; 
         R 6  is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms; 
         R 7  is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms; 
         R 6  and R 7  taken together can form a cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 13 —; 
         R 8  is selected from the group consisting of hydrogen and alkyl from 1 to 3 carbon atoms; 
         R 9  and R 10  vary independently and are selected from the group consisting of methyl or a hydrogen; 
         R 11  is selected from the group consisting of aryl, heteroaryl, or alkyl containing from 1 to 6 carbon atoms, but if R 2  is alkoxyl, R 11  is heterocycloalkyl; 
         R 12  is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms; 
         R 13  is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms; 
         R 14  represents an alkyl containing from 1 to 3 carbon atoms; and 
         R 15  and R 16  vary independently and are selected from the group consisting of an alkyl containing 1 to 6 carbon atoms or taken together might form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms that are eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO2-, —CHOH— or —NR 14 —. 
       
     
     
         30 . The method of  claim 29 , wherein the cannabinoid receptor-mediated disease or disorder is selected from cognition and memory disorders. 
     
     
         31 . A method of treating a cannabinoid receptor-mediated disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a hydrazone compound or a pharmaceutically-acceptable salt thereof, the cannabinoid receptor-mediated disease or disorder selected from the group consisting of bladder dysfunction, prevention of miscarriage and ectopic pregnancy, social and mood disorders, seizure-related disorders, learning disorders, cognition disorders, memory disorders, bowel disorders, gastrointestinal disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, organ contraction, muscle spasm, neuroprotection disorders, dermatological complaints associated with a keratinization disorder relating to cell differentiation and proliferation, dermatological complaints without cell proliferation disorders, dermal and epidermal proliferations, cicatrization disorders, immunological related dermatological complaints, skin disorders related to exposure of UV radiation, sebaceous function disorders, aging of the skin, and pigmentation disorders, the hydrazone compound comprising a compound of structural Formula III: 
       
         
           
           
               
               
           
         
         or a salt or prodrug thereof, wherein: 
         R 1  is selected from the group consisting of n-hexyl and 2-cyclohexyl ethyl; 
         R 2  is selected from the group consisting of a hydrogen atom or a methoxy; 
         R 3  is selected from the group consisting of NR 4 R 5 , aryl, heteroaryl, alkenyl, an alkynyl, an alkoxyl, a cycloalkyl containing from 5 to 10 carbon atoms and containing eventually —CO—, —O—, —S—, —SO—, —SO 2 —, —CHOH— or —NR 12 —, or one of the radicals defined by the following structure: 
       
       
         
           
           
               
               
           
         
         wherein R 4  and R 5  taken together form a group consisting of a radical cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 14 —; 
         R 6  is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms; 
       
       R 7  is selected from the group consisting of alkyl containing from 1 to 3 carbon atoms;
 R 6  and R 7  taken together might form a cycloalkyl containing from 3 to 10 carbon atoms and eventually interrupted with one or more hetero atoms or by —CO—, —SO—, —SO 2 —, —CHOH— or —NR 13 —; 
 R 8  is selected from the group consisting of hydrogen and alkyl from 1 to 3 carbon atoms; 
 R 9  and R 10  vary independently and are selected from the group consisting of methyl or a hydrogen; 
 R 11  is selected from the group consisting of aryl, heteroaryl or an alkyl from 1 to 6 carbon atoms; 
 R 12  is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms; 
 R 13  is selected from the group consisting of hydrogen or alkyl containing from 1 to 3 carbon atoms; and 
 R 14  represents an alkyl containing from 1 to 3 carbon atoms. 
 
     
     
         32 . The method of  claim 31 , the hydrazone compound comprising the structural formula VI: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 31 , wherein the cannabinoid receptor-mediated disease or disorder is selected from cognition and memory disorders.