Compositions and Methods for Stimulating Collagen Synthesis in the Skin

Abstract

Cosmetic compositions comprising substituted carbamoyl heterocyclic analogs and methods of using such compositions to impart anti-aging benefits to the skin are disclosed. The substituted carbamoyl heterocyclic analogs are believed to have modulatory activity against one or more biochemical pathways implicated in skin aging.

1 . A cosmetic composition for improving the aesthetic appearance of human skin comprising a cosmetically acceptable vehicle in the form of a water-in-oil or oil-in-water emulsion, and an effective amount of a collagen-stimulating compound of formula I: 
       
         
           
           
               
               
           
         
         where: 
         ε 1 -ε 3  are independently selected from CR a , N, or NR b , and wherein the ring A is optionally aromatic or may comprise zero, one, or two double bonds;
 with the proviso that at least one of ε 1 , ε 2 , or ε 3  is NR b ; and in the case where ε 3  is NR b , then ε 2  is a nitrogen atom, and the bond between ε 1  and ε 2  is a double bond; in the case where ε 2  is NR b , then ε 1  is a nitrogen atom, and the bond between ε 1  and the carbon atom to which R 1  is attached is a double bond; and in the case where ε 1  is NR b , then ε 2  is a nitrogen atom, and the bond between ε 2  and ε 3  is a double bond; 
 
         R b  is an aryl group of the form, 
       
       
         
           
           
               
               
           
         
         R 1  is selected from a group consisting of H, or a C 1-6  alkyl, alkenyl, alkynyl, aryl, or heteroaryl group optionally substituted with one or more C 1-6  alkyl, alkenyl, alkynyl, aryl, or R a  groups; 
         R 2  and R 3  are independently selected from the group consisting of C 1-6  alkyl, alkenyl, alkynyl, and aryl, which could be optionally connected to form together with the nitrogen atom to which they are attached a 5, 6, or 7 membered ring, saturated or unsaturated, which optionally further comprises one or more heteroatoms in the ring, selected from oxygen, nitrogen, or sulfur, and wherein R 2  and R 3  are optionally substituted with one or more groups R a ; 
         R 4 -R 8  are independently selected from the group consisting of R a , C 1-6  alkyl, alkenyl, alkynyl, and aryl, each of which could be optionally further substituted with one or more groups R a ; 
         wherein R a  is independently, at each occurrence, selected from hydrogen, halogen (F, Cl, Br, or I); —OH; —NH 2 ; —NR N R N ; —SH; —CN; oxo; —CHO; —CO 2 H; —O—(C═O)—H; —O—(C═O)—C 1-10  alkyl; —O—(C═O)-Ar; —(C═O)—O—C 1-10  alkyl; —(C═O)—O—Ar; —(C═O)—NR N R N ; —O—C 1-10  alkyl; —O—Ar; —S—C 1-10  alkyl; —S—Ar; —Ar; —C 1-10  alkyl; —NR N —CHO; —NR N —(C═O)—C 1-10  alkyl; —C 1-10  alkyl-O—C 1-10  alkyl; perfluoroalkyl; epoxy; azido; thiocyanate; —SO 2 —R N ; or nitro; 
         wherein R N  is independently selected, at each occurrence, from hydrogen or a C 1-16  hydrocarbon radical, optionally substituted with a group R a ; and where any two adjacent groups R N  may together form a 5, 6, or 7 membered ring; 
         or a cosmetically acceptable salt thereof. 
       
     
     
         2 . The cosmetic composition to  claim 1 , wherein said compound of structure (I) is selected from the group of compounds consisting of:
 (a)   
       
         
           
           
               
               
           
         
         (b) 
       
       
         
           
           
               
               
           
         
         (c) 
       
       
         
           
           
               
               
           
         
         (d) 
       
       
         
           
           
               
               
           
         
         and mixtures thereof, 
         where R 1 , R 4 -R 8 , R a , and R N  are as defined in claim  22 ; and 
         Q is a 3-7 membered heterocyclic ring, optionally aromatic, and which may comprise zero, one, or two double bonds; 
         X is selected from CR a , C(R a ) 2 , N, O, S, NR N , or a bond (i.e., absent); and 
         L 1  and L 2  are independently selected from a bond or a group X 1 -(L 3 ) l -X 2 , where “l” is an integer from 0 to 4; where L 3  is selected from CR a , C(R a ) 2 , or a bond; and X 1  and X 2  are independently selected from N, NR N , O, S, or a bond; 
         or a cosmetically acceptable salt thereof. 
       
     
     
         3 . The cosmetic composition according to  claim 2 , wherein
 L 1  is —(CH 2 ) m —, and L 2  is —(CH 2 ) n —, wherein “m” and “n” are independently selected from integers from 1-3; and   X is selected from N, NR N , S, O, or a bond;   or a cosmetically acceptable salt thereof.   
     
     
         4 . The cosmetic composition according to  claim 3 , wherein ring Q is a heterocycle selected from the group consisting of aziridine, diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine, pyrrole, imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole, piperidine, morpholine, piperazine, and thiomorpholine, each being optionally substituted with one or more groups R a . 
     
     
         5 . The cosmetic composition according to  claim 4 , wherein ring Q is a heterocycle selected from the group consisting of pyrrolidine, morpholine, and piperazine, each being optionally substituted with one or more groups R a . 
     
     
         6 . The composition according to  claim 5 , wherein said compound has the structure I a . 
     
     
         7 . The composition according to  claim 6 , wherein R a  is hydrogen, methyl, ethyl, propyl, and R 1  is hydrogen, methyl, ethyl, or propyl. 
     
     
         8 . The composition according to  claim 7 , wherein R 4  to R 8  are independently hydrogen, methyl, ethyl, propyl, chloro, or bromo, with at least two of R 4  to R 8  being hydrogen. 
     
     
         9 . The composition according to  claim 6 , wherein the heterocycle is pyrrolidine. 
     
     
         10 . The composition according to  claim 6 , wherein the heterocycle is morpholine. 
     
     
         11 . The composition according to  claim 6 , wherein the heterocycle is piperazine. 
     
     
         12 . The method according to  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         and wherein R b , R a , R 1 , and Q are as set forth below: 
       
       
         
           
                 
                 
                 
                 
               
                     
                 
                             R b   
                             R a   
                             R 1   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         13 . The method according to  claim 1 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
         and wherein R b , R a , R 1 , and Q are as set forth below: 
       
       
         
           
                 
                 
                 
                 
               
                     
                 
                             R b   
                             R a   
                             R 1   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   H 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
               
            
           
         
       
     
     
         14 . The cosmetic composition according to  claim 1  wherein said effective amount comprises from about 0.0001% to about 1% by weight of the total composition. 
     
     
         15 . The cosmetic composition according  claim 14 , wherein said effective amount is between about 0.001% to about 0.5% by weight of the total composition. 
     
     
         16 . The cosmetic composition according to  claim 14 , wherein said effective amount is between about 0.01% to about 0.2% by weight of the total composition.