Highly pure bases of 3,3-dipheyl propylamine monoesters

Abstract

The invention relates to a compound of general formula (I) wherein A represents deuterium or hydrogen, R represents a group selected from C 1-6 alkyl, C 3-10 cycloalkyl or phenyl, which can be substituted by C1-3 alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium. The C atom marked with a * (star) can be present in an (R) configuration, in an (S)-configuration or a mixture thereof. The invention is characterised in that the above-mentioned compounds are free bases with a degree of purity of more than 97 wt %. The invention also relates to a method for the production of highly pure compounds of general formula (I) and to the use thereof in the production of medicaments.

1 - 34 . (canceled)  
     
     
         35 . A compound of the following Formula I:  
       
         
           
           
               
               
           
         
         wherein each A is independently hydrogen or deuterium, R is C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “★” may be present in the (R)-configuration, the (S)-configuration or as a mixture of such configurations,  
         and the compound is present as a free base in a degree of purity of above 97 percent by weight.  
       
     
     
         36 . A compound of  claim 35  wherein R is methyl, ethyl, isopropyl 1,1-propyl, 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl.  
     
     
         37 . A compound of  claim 35  wherein the compound is 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate.  
     
     
         38 . A compound of  claim 35  wherein the C-atom marked with “★” is present in the (R)-configuration.  
     
     
         39 . A compound of  claim 35  wherein the compound is (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate (Fesoterodine).  
     
     
         40 . A method of producing a compound of the following Formula I  
       
         
           
           
               
               
           
         
         wherein in Formula I each A is independently hydrogen or deuterium, R is C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “★” may be present in the (R)-configuration, the (S)-configuration or as a mixture of such configurations, the compound being a free base having a purity of at least 97 percent by weight,  
         the method comprising:  
         releasing the compound of Formula I as a base from a crystalline salt of the following Formula II:  
         
           
             
             
                 
                 
             
           
         
         with a degree of purity of at least 97 percent by weight where in Formula II each A and R are the same as defined for Formula I and X −  is the acid residue of a physiological compatible acid and where the C-atom marked with “★” (a star) can be present in the (R)-configuration, in the (S)-configuration or as a mixture of such configurations,  
         wherein the releasing of the compound of Formula II comprises use of a releasing reagent in aqueous solution, whereby the releasing reagent has a pK B  of 8-11 and does not lead to the precipitation of the compound of Formula I.  
       
     
     
         41 . The method of  claim 40  wherein the free base of Formula I is released from the crystalline salt of Formula II by use of an added reagent chosen from among: 
 (a) alkaline, alkaline earth- or ammonium hydrogen carbonates,    (b) amines, polyamines and alkaline polyamino acids, and    (c) alkaline ionic exchangers.    
     
     
         42 . The method of  claim 40  wherein the compound of Formula I is released from a crystalline salt of the Formula II through the addition of an alkaline, earth-alkaline or ammonium hydrogen carbonate.  
     
     
         43 . The method of  claim 40  wherein after release of the base of Formula I from the salt of Formula II, the aqueous solution is extracted with an organic solvent, and the base of Formula I is then isolated in the organic phase of the extraction.  
     
     
         44 . The method of  claim 43  wherein the organic solvent is one or more of dichloromethane, ethyl methyl ketone, ethyl acetate, tertiary butyl methyl ether, diethylether, and toluene.  
     
     
         45 . The method of  claim 40  wherein R of both Formula I and Formula II is methyl, ethyl, isopropyl, 1-Propyl, 1-butyl, 2-butyl, tertiary butyl, iso-butyl, pentyl and hexyl and the C-atom marked with an “★” (star) is present in the (R)-configuration.  
     
     
         46 . The method of  claim 40  wherein the compound of Formula I is (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate.  
     
     
         47 . The method of  claim 40  wherein the compound of Formula II (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate hydrogen fumarate.  
     
     
         48 . The method of  claim 40  further comprising admixing the compound of Formula I with a pharmaceutically acceptable carrier.  
     
     
         49 . A pharmaceutical formulation comprising a compound of Formula I of  claim 35  and a pharmaceutically acceptable carrier.  
     
     
         50 . A pharmaceutical formulation of  claim 49  wherein the pharmaceutically acceptable carrier is a polymer.  
     
     
         51 . A pharmaceutical formulation of  claim 49  wherein the formulation exhibits a stabilization factor of at least 2, as determined by the division of the average monthly drop in concentration of the compound of Formula I during storage as oil and in the absence of the pharmaceutically acceptable carrier at 5° C. by the average monthly drop in concentration of the corresponding compound of Formula I during storage in the pharmaceutical formulation at 5° C.  
     
     
         52 . A pharmaceutical formulation of  claim 49  wherein the formulation has a pH value of from 3.0 to 6.0.  
     
     
         53 . A pharmaceutical formulation of  claim 49  wherein the pharmaceutical formulation is suitable for transdermal delivery.  
     
     
         54 . A pharmaceutical formulation of  claim 49  wherein the pharmaceutical formulation is suitable for transmucosal delivery.  
     
     
         55 . A pharmaceutical formulation of  claim 49  wherein the pharmaceutical formulation comprises a polymer layer that comprises a compound of Formula I.  
     
     
         56 . A pharmaceutical formulation of  claim 55  wherein the polymer layer comprises a contact adhesive which can facilitate attachment of the pharmaceutical composition to the skin or the mucous membrane of a patient.  
     
     
         57 . A pharmaceutical formulation of  claim 56  wherein the contact adhesive comprises one or more of a silicone, acrylate, SXS-, PIB- or EVA based contact adhesives.  
     
     
         58 . A pharmaceutical formulation of  claim 49  wherein the pharmaceutical formulation is a transdermal therapeutic system of the active ingredient-in-adhesive type.  
     
     
         59 . A kit containing a pharmaceutical formulation of  claim 49  and a drying agent.  
     
     
         60 . A dosing unit which comprises at least 3 mg of a compound of the following Formula I:  
       
         
           
           
               
               
           
         
       
       and at least one pharmaceutically acceptable carrier, wherein each A is independently hydrogen or deuterium, R is C 1-6 -alkyl, C 3-6 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “★” may be present in the (R)-configuration, the (S)-configuration or as a mixture of such configurations, and the free base of the compound of Formula I being present in a purity of above 97 percent by weight.  
     
     
         61 . A dosing unit of  claim 60  wherein whereby the compound is (R) 2-[3-(1,1-Diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate (Fesoterodine).  
     
     
         62 . Fesoterodin Hydrogen carbonate.  
     
     
         63 . A method for the treatment of a mammal suffering from or susceptible to incontinence, hyperactivity of the detrusor, hyperactivity of the bladder, pollakisuria, nocturia or imperative urinary urgency, the method comprising: 
 administering a compound of  claim 35 ,  50  or  60  to the mammal.    
     
     
         64 . The method of  claim 63  wherein the mammal is identified as suffering from incontinence, hyperactivity of the detrusor, hyperactivity of the bladder, pollakisuria, nocturia and/or imperative urinary urgency, and the compound is administered to the identified mammal.  
     
     
         65 . The method of  claim 63  wherein the mammal is a human.  
     
     
         66 . The method of  claim 63  wherein compound is administered to the mammal transdermally.  
     
     
         67 . The method of  claim 63  wherein the compound is administered to the mammal transmucosally.  
     
     
         68 . The method of  claim 63  wherein the compound is administered to the mammal with use of a patch.  
     
     
         69 . The method of  claim 63  wherein Fesoterodin is administered to the mammal in the form of a pharmaceutical composition that comprises a self-adhesive polymer layer which comprises Fesoterodin and delivers Fesoterodin at a flux rate of 3-15 mg/day through human skin.