Compositions and methods for the treatment of urinary incontinence

Abstract

A pharmaceutical composition comprising an effective amount of a compound of formula I It has been surprisingly discovered that the composition of the present invention is effective for treating for the treatment of increased urinary urgency or urinary incontinence. Also disclosed are methods of treatment using said pharmaceutical compositions.

We claim:  
     
         1 . A pharmaceutical composition for the treatment of increased urinary urgency or urinary incontinence, comprising an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 X is OH, F, Cl, H or OC(O)R 7 , where R 7  is C 1-3 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted,  
 R 1  is C 1-4 -alkyl, benzyl, CF 3 , OH, OCH 2 , C 6 H 5 , O—C 1-4 -alkyl, Cl or F, and  
 R 9  to R 13  are in each case selected independently of one another from the group consisting of H, F, Cl, Br, I, CH 2 F, CHF 2 , CF 3 , OH, SH, OR 14 , OCF 3 , SR 14 , NR 17 R 18 , SOCH 3 , SOCF 3 , SO 2 CH 3 , SO 2 CF 3 , CN, COOR 14 , NO 2 , CONR 17 R 18 ; C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; and phenyl that is unsubstituted or singly or multiply substituted; 
 where R 14  is C 1-6 -alkyl; pyridyl, thienyl, thiazolyl, phenyl, benzyl or phenethyl, in each case unsubstituted or singly or multiply substituted; PO(O—C 1-4 -alkyl) 2 , CO(OC 1-5 -alkyl), CONH—C 6 H 4 —(C 1-3 -alkyl), CO(C 1-5 -alkyl), CO—CHR 17 —NHR 8 , CO—C 6 H 4 —R 5 , where R 15  is ortho-OCOC 1-3 -alkyl, or meta- or para-CH 2 N(R 16 ) 2  where R 16  is C 1-4 -alkyl or 4-morpholino, wherein the alkyl groups in R 14 , R 15  and R 16  may be branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; 
 where R 17  and R 18  are in each case selected independently of one another from the group consisting of H; C 1-6 -alkyl that is branched or unbranched, saturated or unsaturated, unsubstituted or singly or multiply substituted; phenyl, benzyl or phenethyl that is in each case unsubstituted or singly or multiply substituted, or  
 
 
 R 9  and R 10  or R 10  and R 11  together form an OCH 2 O, OCH 2 CH 2 O, OCH═CH, CH═CHO, CH═C(CH 3 )O, OC(CH 3 )═CH, (CH 2 ) 4  or OCH═CHO ring,  
 wherein the compound is in the form of a racemate, enantiomer, diastereomer, a mixtures of enantiomers, a mixture of diastereomers, a free base, or a salt of a physiologically compatible acid,  
 and a pharmaceutically acceptable excipient.  
 
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein in formula I X is OH, F, Cl, OC(O)CH 3  or H.  
     
     
         3 . A pharmaceutical composition according to  claim 2 , wherein X is OH, F or H.  
     
     
         4 . A pharmaceutical composition according to  claim 2 , wherein X is OH.  
     
     
         5 . A pharmaceutical composition according to  claim 1 , wherein R 1  is C 1-4 -alkyl, CF 3 , OH, O—C 1-4 -alkyl, Cl or F.  
     
     
         6 . A pharmaceutical composition according to  claim 5 , wherein R 1  is OH, CF 3  or CH 3 .  
     
     
         7 . A pharmaceutical composition according to  claim 1 , wherein at least three of R 9  to R 13  are H, and the others of R 9  to R 13  are independently of one another 
 H, Cl, F, OH, CF 2 H, CF 3 , C 1-4 -alkyl that is saturated and unsubstituted, branched or unbranched; or OR 14  or SR 14  where R 14  is saturated or unsubstituted, branched or unbranched C 1-3 -alkyl; or    R 12  and R 11  form a 3,4-OCH═CH ring.    
     
     
         8 . A pharmaceutical composition according to  claim 7 , wherein at least three of R 9  to R 13  are H, and the others of R 9  to R 13  are independently of one another H, Cl, F, OH, CF 2 H, CF 3 , OCH 3  or SCH 3 .  
     
     
         9 . A pharmaceutical composition according to  claim 7 , wherein if R 9  and R 13  are H and R 11  is OH, OCH 3 , Cl or F, then one of R 10  or R 12  is also H, while the other is OH, OCH 3 , Cl or F.  
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein if R 9  and R 13  are H and R 11  is Cl, then one of R 10  or R 12  is also H, while the other is Cl.  
     
     
         11 . A pharmaceutical composition according to  claim 8 , wherein at least four of R 9  to R 13  are H, and the others of R 9  to R 13  are independently of one another H, Cl, F, OH, CF 2 H, CF 3 , OCH 3  or SCH 3 .  
     
     
         12 . A pharmaceutical composition according to  claim 11 , wherein if R 9 , R 11  and R 13  are H, then one of R 10  or R 12  is H, while the other is Cl, F, OH, CF 2 H, CF 3 , OR 14  or SR 14 .  
     
     
         13 . A pharmaceutical composition according to  claim 12 , wherein if R 9 , R 11  and R 13  are H, then one of R 10  or R 12  is H, while the other is preferably OH, CF 2 H, OR 14  or SCH 3 .  
     
     
         14 . A pharmaceutical composition according to  claim 13 , wherein if R 9 , R 11  and R 13  are H, then one of R 10  or R 12  is H, while the other is OH or OC 1-3 -alkyl.  
     
     
         15 . A pharmaceutical composition according to  claim 14 , wherein if R 9 , R 11  and R 13  are H, then one of R 10  or R 12  is H, while the other is OH or OCH 3 .  
     
     
         16 . A pharmaceutical composition according to  claim 11 , wherein if R 9 , R 10 , R 12  and R 13  are H, then R 11  is CF 3 , CF 2 H, Cl or F.  
     
     
         17 . A pharmaceutical composition according to  claim 16 , wherein if R 9 , R 10 , R 12  and R 13  are H, then R 11  is F.  
     
     
         18 . A pharmaceutical composition according to  claim 11 , wherein if R 10 , R 11  and R 12  are H, then one of R 9  or R 13  is also H, and the other is OH, OC 2 H 5  or OC 3 H 7 .  
     
     
         19 . A pharmaceutical composition according to  claim 11 , wherein if R 9 , R 11  and R 13  are H, one of R 10  or R 12  is also H, and the other is selected from the group consisting of Cl, F, OH, SH, CF 2 H, CF 3 , OR 14  and SR 14 .  
     
     
         20 . A pharmaceutical composition according to  claim 19 , wherein if R 9 , R 11  and R 13  are H, one of R 10  or R 12  is also H, and the other is OH or OR 14 .  
     
     
         21 . A pharmaceutical composition according to  claim 20 , wherein if R 9 , R 11  and R 13  are H, one of R 10  or R 12  is also H, and the other is OH or OC 1-3 -alkyl.  
     
     
         22 . A pharmaceutical composition according to  claim 21 , wherein if R 9 , R 11  and R 13  are H, one of R 10  or R 12  is also H, and the other is OH or OCH 3 .  
     
     
         23 . A pharmaceutical composition according to  claim 1 , wherein the compound of formula I is in the form of a diastereomer with the relative configuration Ia  
       
         
           
           
               
               
           
         
       
     
     
         24 . A pharmaceutical composition according to  claim 23 , wherein in the pharmaceutical composition other diastereomers of formula I are not present or are present in a lower proportion than the diastereomer of configuration Ia.  
     
     
         25 . A pharmaceutical composition according to  claim 1 , wherein the (−) enantiomer of the compound is not present or is present in a lower proportion than the (+) enantiomer.  
     
     
         26 . A pharmaceutical composition according to  claim 1 , wherein the compound of formula I is: 
 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxyphenyl)-cyclohexane-1,3-diol,    (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl)-phenol, or    (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl)-phenol,    or a respective hydrochloride thereof.    
     
     
         27 . A pharmaceutical composition according to  claim 26 , wherein the wherein the compound of formula I is a hydrochloride of: 
 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxyphenyl)-cyclohexane-1,3-diol,    (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,5 S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl)-phenol, or    (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl)-phenol.    
     
     
         28 . A method for treating increased urinary urgency or urinary incontinence, comprising administering an effective amount of a pharmaceutical composition according to  claim 1  to a subject in need thereof.  
     
     
         29 . A method according to  claim 28 , wherein the pharmaceutical composition comprises a hydrochloride of a compound selected from the group consisting of: 
 (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxyphenyl)-cyclohexane-1,3-diol,    (1RS,3 SR,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,    (+)-(1R,3R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methylcyclohexyl)-phenol, or    (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethylcyclohexyl)-phenol,    or a respective hydrochloride thereof.