Salts of quinoline derivatives as NK3 antagonists

Abstract

A compound of formula (I) or a solvate thereof, characterized in that salt comprises a compound of formula (I) in anionic form and a salting cation; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
         or a solvate thereof, wherein Ar is an optionally substituted phenyl, naphthyl or C 5-7  cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containino from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, 0, N;  
         R is linear or branched C 1-8 alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkylalkyl, optionally substituted phenyl or phenyl C 1-6  alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom selected from 0 and N, hydroxy C 1-6  alkyl, amino C 1-6  alkyl, C 1-6  alkylaminoalkyl, di C 1-6  alkylaminoalkyl, C 1-6  acylaminoalkyl, C 1-6  alkoxyalkyl, C 1-6  alkylcarbonyl, carboxy, C 1-6  alkoxyxcarbonyl, C 1-6  alkoxycarbonyl C 1-6  alkyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, di C 1-6  alkylaminocarbonyl, halogeno C 1-6  alkyl; or is a group —(CH 2 )p- when cyclized onto Ar, where p is 2 or 3;  
         R 1  and R 2 , which may be the same or different, are independently hydrogen or C 1-6  linear or branched alkyl, or togelher form a —(CH2)n— group in which n represents 3, 4, or 5; or R 1  together with r forms a group —(CH 2 )q—, in which q is 2, 3, 4 or 5.  
         R 3  and R 4 , which may be the same or different, are independently hydrogen, C 1-6  linear or branched alkyl, C 1-6  alkenyl, aryl, C 1-6  alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C 1-6  alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C  1-6  alkylamino,  
         —O(CH 2 ) r —NT 2 , in which r is 2, 3, or 4 and T is hydrogen or C 1-6  alkyl or it forms with the adjacent nitrogen a group  
         
           
             
             
                 
                 
             
           
         
         in which V and V 1  are independently hydrogen or oxygen and u is 0,1 or 2; —O(CH 2 ) s —OW in which s is 2, 3, or 4 and W is hydrogen or C 1-6  alkyl; hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to four R 3  substituents being present in the quinoline nucleus; or R 4  is a group —(CH 2 ) t — when cyclized onto R 5  as aryl, in which t is 1, 2, or 3;  
         R 5  is branched or linear C 1-6  alkyl, C 3-7  cycloalkyl, C 4-7  cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character′, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each rino selected from S, O, N;  
         X is O, S, or N—C≡N; characterised in that salt comporises a compound of formula (I) in anionic form and a salting cation.  
       
     
     
         2 . A compound according to  claim 1  of formula (A):  
       S t− M t+   (A)  or a solvate thereof, wherein; 
 t is an integer 1, 2 or 3;  
 M t+  is a salting cation; and  
 S t−  is an anion provided by an appropriate compound of formula (I) in  claim 1 .  
   
     
     
         3 . A compound according to  claim 2 , wherein salting cation M′+is a metal ions or an organic cation.  
     
     
         4 . A compound according to  claim 2 , wherein metal salting cation M t+  is selected from aluminium, alkali metal or alkaline earth metal ions.  
     
     
         5 . A compound accordin, to  claim 2 , wherein organic salting cation M t+  is selected from ammonium or substituted amnionium ions.  
     
     
         6 . A compound according to  claim 2 , wherein salting cation M t+  is a sodium ion.  
     
     
         7 . A compound according to any one of  claims 2  to  6 , wherein t is 1 or 2.  
     
     
         8 . A compound according to  claim 1 , being (S)-(+)-N-(α-ethylbenzyl)-3-hydroxy-2-phenyl-4-quinoline carboxamide sodium salt sesquihydrate.  
     
     
         9 . A process for the preparation of a compound according to  claim 1 , which process comprises admixing a compound of formula (I) and a source of salting cation; and thereafter, as required, preparing a solvate of the salt so formed.  
     
     
         10 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.  
     
     
         11 . A compound according to  claim 1 , or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.  
     
     
         12 . The use of a compound according to  claim 1 , or a pharmaceutically acceptable solvate thereof, in the manufacture of a medicament for the treatment of the Primary, Secondary or Further Disorders disclosed herein before.  
     
     
         13 . A method for the treatment and/or prophylaxis of the Primary, Secondary or Further Disorders in mammals which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic pharmaceutically acceptable amount of a compound according to  claim 1  or a pharmaceutically acceptable solvate thereof.