Skin treatment compositons containing a cationic polymer and a microparticle or nanoparticle vector

Abstract

The present invention relates to the use of α 1L -agonists for treating urinary incontinence.

1 . Use of α 1L -agonists for the preparation of pharmaceutical compositions for treating urinary incontinence, particularly stress incontinence.  
     
     
         2 . Use according to  claim 1 , in which the α 1L -agonists have the general formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 Y denotes an optionally substituted phenyl or napthyl group or  
 Y denotes a 5- or 6-membered, optionally fully unsaturated, optionally substituted heterocyclic ring which contains oxygen, sulphur or nitrogen as heteroatoms, and  
 X denotes —NH—, —CH 2 —, —OCH 2 —, —O—CHCH 3 —, —CH═N—NH—, —N═N—or —NZ—, wherein Z═—CH 2 —CH═CH 2  or cyclopropylmethyl,  
 and the pharmacologically acceptable acid addition salts thereof.  
 
     
     
         3 . Use according to  claim 2 , wherein X in the compound of formula I denotes —NH—.  
     
     
         4 . Use according to  claim 2  or  3 , wherein in the compound of formula I Y is an optionally substituted thienyl, furyl, pyrrole, tetrahydropyrrolyl, pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl, imidazolyl, imidazolinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, isothiazolyl, pyrimidinyl, thiazolyl, thiadiazinyl or piperidinyl, which is bound to the group X via a carbon atom.  
     
     
         5 . Use according to one of  claims 2  to  4 , wherein the compound of formula I is tiamenidine.  
     
     
         6 . Use of phenylaminoimidazolines of general formula Ib  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 and R 5  denote, independently of one another: 
 hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogen, —CF 3 , —OCF 3  or —NR 6 R 7  wherein  
 R 6  denotes hydrogen, C 3-6 -cycloalkyl, C 1-6 -alkyl or C 2-4 -acyl,  
 R 7  denotes hydrogen, C 3-6 -cycloalkyl, C 1-6 -alkyl or C 2-4 -acyl; or  
 R 6  and R 7  together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two additional heteroatoms from the group comprising oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C 1-4 -alkyl; or  
 R 6  and R 7  together with the nitrogen atom form phthalimido; or  
 R 1  and R 2  together form a fused pyrazole of the formula  
                     
 wherein R 8  is C 1-3 -alkyl, or a fused thiadiazole of the formula  
                     
 wherein R 3 , R 4  and R 5  are as hereinbefore defined, and the pharmacologically acceptable acid addition salts thereof, for preparing pharmaceutical composition for treating urinary incontinence, particularly stress incontinence.  
 
     
     
         7 . Use of phenyliminoimidazolines of general formula Ib according to  claim 6 ,  
       wherein R 1 , R 2 , R 3 , R 4  and R 5  independently of one another denote: 
 hydrogen, C 1-4 -alkyl, preferably methyl, cyclopropyl, C 1-4 -alkoxy, preferably methoxy, halogen, CF 3 , —OCF 3  or NR 6 R 7  wherein  
 R 6  is hydrogen, C 3-6 -cycloalkyl, C 1-4 -alkyl, preferably methyl, or acetyl,  
 R 7  denotes hydrogen, cyclopropyl, C 1-4 -alkyl, preferably methyl, or acetyl; or  
 R 6  and R 7  together with the nitrogen atom form phthalimido; or  
 R 1  and R 2  together form a fused pyrazole of the formula  
                     
 wherein R 8  is methyl, or a fused thiadiazole of the formula  
                     
 wherein R 3 , R 4  and R 5  are as hereinbefore defined, and preferably represent hydrogen.  
 
     
     
         8 . Use of phenylaminoimidazolines of general formula Ib according to  claim 6 ,  
       wherein R 1 , R 2 , R 3 , R 4 , R 5  independently of one another denote: 
 hydrogen, ethyl, methyl, cyclopropyl, fluorine, chlorine, bromine, —CF 3  or —NR 6 R 7  wherein  
 R 6  denotes hydrogen, methyl or acetyl,  
 R 7  denotes hydrogen, methyl or acetyl; or  
 R 6  and R 7  together with the nitrogen atom form phthalimido; or  
 R 1  and R 2  together form a fused pyrazole of the formula  
                     
 wherein R 8  is methyl, or a fused thiadiazole of the formula  
                     
 wherein R 3 , R 4  and R 5  are as hereinbefore defined, and preferably represent hydrogen.  
 
     
     
         9 . Use of phenylaminoimidazolines of general formula Ib according to  claim 6 ,  
       wherein 
 R 1  denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromine or —CF 3,    
 R  2  denotes methyl, fluorine, chlorine, bromine or —NR 6 R 7 , wherein  
 R 6  denotes hydrogen, C 1-4 -alkyl, preferably methyl, C 2-4 -acyl, preferably acetyl and  
 R 7  denotes hydrogen, C 1-4 -alkyl, preferably methyl, C 2-4 -acyl, preferably acetyl or  
 R 6  and R 7  together with the nitrogen atom form phthalimido;  
 R 3  denotes hydrogen, fluorine, chlorine, bromine, C 1-4 -alkyl, preferably methyl, —NH 2  or cyclopropyl;  
 R 4  denotes hydrogen, C 1-4 -alkyl, preferably methyl, fluorine, chlorine, bromine or —CF 3;    
 R 5  denotes hydrogen, C 1-4 -alkyl, preferably ethyl or methyl, fluorine, chlorine, bromine or —CF 3 ; or  
 R 1  and R 2  together form a fused pyrazole of formula  
                     
 wherein R 8  is methyl, or a fused thiadiazole of the formula  
                     
 wherein R 3 , R 4  and R 5  are as hereinbefore defined, and preferably represent hydrogen.  
 
     
     
         10 . Use of phenylaminoimidazolines of formula Ib according to  claim 6 , wherein 
 R 1  is hydrogen or methyl;    R 2  is methyl, chlorine, —CF 3 , —NH 2  or —N(CH 3 ) 2;      R 3  is hydrogen, methyl, chlorine or bromine;    R 4  is hydrogen;    R 5  is hydrogen, methyl, methoxy, chlorine or bromine.    
     
     
         11 . Use of phenylaminoimidazolines of formula Ib according to  claim 6 , wherein the compound is 2-(3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, 2-(3- amino-2-methylphenylimino)-imidazolidine or 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.  
     
     
         12 . New phenyliminoimidazolidines of general formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  denotes hydrogen, C 1-6 -alkyl, C 3-6 -cycloalkyl, C 1-6 -alkoxy, halogen, —CF 3  or —OCF 3;    
 R 2  denotes —NR 6 R 7  wherein  
 R 6  is hydrogen, C 3-6 -cycloalkyl, C 1-6 -alkyl, C 2-4 -acyl,  
 R 7  is hydrogen, C 3-6 -cycloalkyl, C 1-6 -alkyl, C 2-4 -acyl, or  
 R 6  and R 7  together with the nitrogen atom form a 5- or 6-membered saturated or unsaturated ring which may contain up to two further heteroatoms from the group comprising oxygen, sulphur or nitrogen, whilst each additional nitrogen atom may be substituted by C 1-4 -alkyl, preferably methyl; or R 6  and R 7  together with the nitrogen atom form phthalimido;  
 R 3  denotes hydrogen, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, —CF 3  or —OCF 3;    
 R 4  denotes hydrogen, C 1-6 -alkyl or halogen;  
 R 5  denotes hydrogen, C 1-6 -alkyl, C 1-6 -alkoxy, halogen, —CF 3  or —OCF 3,    
 and the pharmacologically acceptable acid addition salts thereof, with the exception of 2-(3-diethylamino-2-methyl)-imidazolidine.  
 
     
     
         13 . Phenyliminoimidazolidines according to  claim 12 , wherein 
 R 1  denotes hydrogen, C 1-4 -alkyl, cyclopropyl, C 1-4 -alkoxy, halogen, —CF 3  or —OCF 3;      R 2  denotes —NR 6 R 7  wherein    R 6  is hydrogen, C 3-6 -cycloalkyl, C 1-4 -alkyl or acetyl,    R 7  is hydrogen, cyclopropyl C 1-4 -alkyl or acetyl, or    R 6  and R 7  together with the nitrogen atom form phthalimido;    R 3  is hydrogen, halogen, C 1-4 -alkyl, C 1-4 -alkoxy, —CF 3  or —OCF 3;      R 4  is hydrogen, C 1-4 -alkyl, methyl, halogen;    R 5  is hydrogen, C 1-4 -alkyl, C 1-4 -alkoxy, halogen, —CF 3  or —OCF 3.      
     
     
         14 . Phenyliminoimidazolidines according to  claim 12 , wherein 
 R 1  is hydrogen, C 1-3 -alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C 1-3 -alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF 3;      R 2  denotes —NR 6 R 7  wherein    R 6  is hydrogen, cyclopropyl, C 1-4 -alkyl, preferably methyl,    R 7  denotes hydrogen, C 1-4 -alkyl, preferably methyl, or R 6  and R 7  together with the nitrogen atom form phthalimido;    R 3  denotes hydrogen, C 1-3 -alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C 1-3 -alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF 3;      R 4  denotes hydrogen, C 1-3 -alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C 1-3 -alkoxy, preferably methoxy, halogen, preferably chlorine or bromine;    R 5  denotes hydrogen, C 1-3 -alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl, C 1-3 -alkoxy, preferably methoxy, halogen, preferably chlorine or bromine, —CF 3.      
     
     
         15 . Phenyliminoimidazolines according to  claim 12 , wherein 
 R 1  is hydrogen or methyl,    R 2  is —NR 6 R 7  wherein    R 6  and R 7  independently of each other denote hydrogen, methyl or methoxy or    R 6  and R 7  together with the nitrogen atom form phthalimido;    R 3  denotes hydrogen, methyl, fluorine, chlorine or bromine;    R 4  denotes hydrogen,    R 5  denotes hydrogen, methyl, chlorine or bromine.    
     
     
         16 . A phenyliminoimidazolidine according to  claim 12 , which is 2-(3-dimethylamino-2-methylphenylimino)-imidazolidine, 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine, 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine or 2-(3-amino-2-methylphenylimino)-imidazolidine.  
     
     
         17 . Pharmaceutical preparation comprising a compound of general formula II according to one of  claims 12  to  16  as well as conventional diluents, excipients and/or carriers.  
     
     
         18 . Process for preparing pharmaceutical preparations according to  claim 17 , characterised in that compounds of general formula II are mixed with conventional galenic diluents, excipients and/or carriers.  
     
     
         19 . Use of compounds of general formula II as defined in any one of  claims 12  to  16  for preparing pharmaceutical compositions for the treatment of urinary incontinence, particularly stress incontinence.  
     
     
         20 . Analogy processes for preparing compounds of general formula  
       
         
           
           
               
               
           
         
       
       according to any one of  claims 12  to  16  characterised in that an aniline of general formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  to R 5  are as hereinbefore defined is reacted with one of the following compounds  
       
         
           
           
               
               
           
         
       
       or  
       and  
       the compounds obtained according to one of processes a-c are optionally converted into the pharmacologically acceptable acid addition salts thereof.