Novel C-4 Substituted Retinoids

Abstract

C-4 substituted retinoic acid analogs, synthesis methods of C-4 substituted retinoic acid analogs and methods of using C-4 substituted retinoic acid analogs to treat various cancers and dermatological diseases and conditions. The C-4 substituted retinoic acid analogs include C-4 all-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-CRA) analogs. The C-4 substituted retinoic acid analogs inhibit all-trans retinoic acid (ATRA) 4-hydroxylase activity, thereby inhibiting the catabolism of ATRA. The C-4 substituted retinoic acid analogs also have ATRA-mimetic activity. The preferred substitutions at C-4 are an azole group, a sulfur, oxygen, or nitrogen containing group, a pyridyl group, an ethinyl group, a cyclopropyl-amine group, an ester group, or a cyano group, or forms, together with the C-4 carbon atom, an oxime, an oxirane or aziridine group.

1 . A chemical compound having the formula (I) 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is selected from the group consisting of a sulfur containing group, an oxygen containing group that forms, together with the 4-position carbon, an oxirane group, —OR 4 , where R 4  is hydrogen or an alkyl group, a nitrogen containing group, an ethinyl group, and an ester group; and 
         R 2  is selected from the group consisting of a hydroxyl group, an aminophenol group, an azole group, and —OR 3 , wherein R 3  is selected from the group consisting of an alkyl, an aryl and a heterocyclic group, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The chemical compound as in  claim 1 , wherein R 2  is hydroxyl. 
     
     
         3 . The chemical compound as in  claim 1 , wherein R 2  is —OCH 3 . 
     
     
         4 . The chemical compound as in  claim 1 , wherein R 1  is a sulfur containing group selected from the group consisting of thiol and alkylthiols, or R 1  is a sulfur containing group that forms, together with the 4-position carbon, a thiirane. 
     
     
         5 . The chemical compound as in  claim 1 , wherein R 1  is an —OR 4  group, where R 4  is a methyl or an ethyl group. 
     
     
         6 . The chemical compound as in  claim 1 , wherein R 1  is cyclopropylether or an oxygen containing group that forms, together with the 4-position carbon, an oxirane group. 
     
     
         7 . The chemical compound as in  claim 1 , wherein R 1  is a nitrogen containing group and said nitrogen containing group has the formula —NR 5 R 6  group, where R 5  and R 6  are independently selected from the group consisting of a hydrogen group and an alkyl group, or R 5  and R 6  may together form a ring. 
     
     
         8 . The chemical compound as in  claim 7 , wherein R 5  and R 6  form an imidazolyl ring or a triazole ring. 
     
     
         9 . The chemical compound as in  claim 8 , wherein R 5  and R 6  form an 1H-imidazolyl ring. 
     
     
         10 . The chemical compound as in  claim 9 , wherein R 2  is an 1H-imidazolyl ring. 
     
     
         11 . The chemical compound as in  claim 9 , wherein the compound is (±)-4-(1H-imidazol-1-yl)-13-cis-methylretinoate or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The chemical compound as in  claim 9 , wherein the compound is (±)-4-(1H-imidazol-1-yl),N-(4 1 -hydroxyphenol)retinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The chemical compound as in  claim 9 , wherein the compound is (±)-4-(1H-imidazol-1-yl)-13-cis-retinoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The chemical compound as in  claim 9 , wherein the compound is (±)-4-(1H-imidazol-1-yl)-13-cis-retinoyl-imidazole or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The chemical compound as in  claim 9 , wherein the compound is (±)-4-(1H-imidazol-1-yl)-N-(4 1 -hydroxyphenol)13-cis-retinamide or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The chemical compound as in  claim 1 , wherein R 1  is a nitrogen containing group and said nitrogen containing group is selected from the group consisting of a cyano group, an amino group, an azido group, and a cyclopropylamino group, or R 1  is a nitrogen containing group that forms, together with the 4-position carbon, an aziridine group or an oxime group. 
     
     
         17 . The chemical compound as in  claim 1 , wherein R 1  is a nitrogen containing group and said nitrogen containing group is a pyridyl group. 
     
     
         18 . The chemical compound as in  claim 1 , wherein R 1  is a nitrogen containing group and said nitrogen containing group is an allylic azole group. 
     
     
         19 . The chemical compound as in  claim 18 , wherein R 1  is a methyleneazolyl group. 
     
     
         20 . The chemical compound as in  claim 1 , wherein the compound is formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The method of synthesizing the chemical compound as in  claim 20 , comprising the steps of:
 contacting (±)-4-hydroxymethyl retinoate with carbonyldiimidazole in CH 3 CN at room temperature to obtain (±)-4-(1H-imidazol-1-yl)methyl retinoate; and   hydrolysizing (±)-4-(1H-imidazol-1-yl)methyl retinoate in refluxing methanolic KOH to obtain (±)-4-(1H-imidazol-1-yl)retinoic acid.   
     
     
         22 . The chemical compound as in  claim 1 , wherein the compound is formula (III) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         23 . The method of synthesizing the chemical compound as in  claim 22 , comprising the steps of:
 contacting (±)-4-hydroxymethyl retinoate with carbonylditriazole in CH 3 CN at room temperature to obtain (±)-4-(1H-1,2,4-triazol-1-yl)methyl retinoate; and   hydrolysizing of (±)-4-(1H-1,2,4-triazol-1-yl)methyl retinoate in refluxing methanolic KOH to obtain (±)-4-(1H-1,2,4-triazol-1-yl)retinoic acid.   
     
     
         24 . The chemical compound as in  claim 1 , wherein the compound is formula (IV) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The method of synthesizing the chemical compound as in  claim 24 , comprising the steps of:
 contacting (±)-4-hydroxymethyl retinoate with carbonylditriazole in CH 3 CN at room temperature to obtain (±)-4-(1H-1,2,4-triazol-1-yl)methyl retinoate; and   hydrolysizing (±)-4-(1H-1,2,4-triazol-1-yl)methyl retinoate in refluxing methanolic KOH to obtain (±)-4-(1H-1,2,4-triazol-1-yl)retinoic acid.   
     
     
         26 . A method of treating an animal having cancer comprising administering a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         27 . The method of  claim 26 , wherein said animal has a cancer selected from the group consisting of prostate, breast, ovarian, lung, melanoma, leukemia and lymphoma. 
     
     
         28 . A method of treating an animal having a dermatological condition comprising administering a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         29 . The method of  claim 28 , wherein said animal has a dermatological condition selected from the group consisting of old age, wrinkling, and skin photodamage. 
     
     
         30 . A method of treating an animal having a dermatological disease comprising administering a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         31 . The method of  claim 30 , wherein said animal has a dermatological disease selected from the group consisting of psoriasis and acne. 
     
     
         32 . A method for inhibiting all-trans retinoic acid 4-hydroxylase in an animal, comprising administering an effective amount of at least one compound according to  claim 1 . 
     
     
         33 . The method of  claim 26  wherein said animal is a mammal. 
     
     
         34 . The method of  claim 26  wherein said animal is a human. 
     
     
         35 . A pharmaceutical composition comprising a compound selected from the group consisting of:
 (±)-4-(1H-imidazole-1-yl)retinoic acid or a pharmaceutically acceptable salt thereof,   (±)-4-(1H-1,2,4-triazol-1-yl)retinoic acid or a pharmaceutically acceptable salt thereof,   (±)-4-(1H-imidazol-1-yl)-13-cis-methylretinoate or a pharmaceutically acceptable salt thereof;   (±)-4-(1H-imidazol-1-yl),N-(4 1 -hydroxyphenol)retinamide or a pharmaceutically acceptable salt thereof,   (±)-4-(1H-imidazol-1-yl)-13-cis-retinoic acid or a pharmaceutically acceptable salt thereof,   (±)-4-(1H-imidazol-1-yl)-13-cis-retinoyl-imidazole or a pharmaceutically acceptable salt thereof, and   (±)-4-(1H-imidazol-1-yl)-N-(4 1 -hydroxyphenol)13-cis-retinamide or a pharmaceutically acceptable salt thereof;   and a pharmaceutically acceptable inactive ingredient.   
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein said pharmaceutically acceptable inactive ingredient is at least one selected from the group consisting of diluent, carrier, solvent, disintegrant, lubricant, stabilizer, and coating. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the compositions is formulated for oral administration. 
     
     
         38 . The pharmaceutical composition of  claim 35 , wherein the compositions is formulated for parentral administration. 
     
     
         39 . The pharmaceutical composition of  claim 35 , wherein the compositions is formulated for injectable administration. 
     
     
         40 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable inactive ingredient. 
     
     
         41 . The pharmaceutical composition as claimed in  claim 35  further comprising all-trans retinoic acid (ATRA).