Crystalline dibenzothiazepine derivative and its use as an antipsychotic agent

Abstract

Crystalline 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine (I) may be prepared by crystallising 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo[b,f] [1,4]thiazepine from a non-aromatic solvent such as ethyl acetate, isobutyl acetate, methyl iso-butylketone or methyl tert-butyl ether, preferably in the absence of water. The crystalline material produced may be converted into a pharmaceutically acceptable salt such as a fumarate. The crystalline 11-(4-[2-(2-hydroxyethoxy) ethyl]-1-piperazinyl)-dibenzo [b,f] [1,4]thiazepine may be used to treat psychoses.

1 . A compound which is crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1 -piperazinyl)-dibenzo[b,f][1,4]thiazepine.  
     
     
         2 . A compound as claimed in  claim 1  in which the crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is greater than 90% pure.  
     
     
         3 . A compound as claimed in  claim 2  wherein the crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is greater than 99% pure.  
     
     
         4 . A process for preparing crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl)-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, or a pharmaceutically acceptable salt thereof which comprises crystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl )-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent; 
 and whereafter. when a pharmaceutically acceptable salt is required, reacting 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine with an acid which affords a pharmaceutically acceptable anion.    
     
     
         5 . A process for preparing 1-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, or a pharmaceutically-acceptable salt thereof, which comprises crystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]- 1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from a solution of 1-(4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl)-debenzo[b,f][1,4]thiazepine in a non-aromatic solvent and in which the solution is substantially free from water.  
     
     
         6 . A process as claimed in any one of claims  4  or  5  wherein the non-aromatic solvent is selected from an ester of formula R 1 CO 2 R 2  wherein R 1  and R 2  are alkyl groups; an ether of formula R 3 OR 4  wherein R 3  and R 4  are alkyl groups. and a ketone of formula R 5 COR 6  wherein R 5  and R 6  are alkyl groups.  
     
     
         7 . A process as claimed in  claim 6  wherein R 1 , R 2 , R 3  and R 4  are selected from (1-4C)alkyl.  
     
     
         8 . A process as claimed in  claim 6  wherein the non-aromatic solvent is selected from ethyl acetate, isobutyl acetate, methyl iso-butylketone and methyl tert-butyl ether.  
     
     
         9 . A process as claimed in any one of  claims 4  to  8  wherein the solvent is selected from methyl tert-butyl ether.  
     
     
         10 . A process of purifying 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine comprising crystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from methyl tert-butylether in the absence of water.  
     
     
         11 . A process as claimed in claim any one of  claims 4  to  10  wherein the 11-(4-[2-(2-hyddroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine and the non-aromatic solvent are heated to give a solution and the temperature of the solution containing the 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is decreased to ambient temperature and then further decreased to about O C over a period greater than 1 hour.  
     
     
         12 . A process as claimed in  claim 11  wherein the temperature is decreased from ambient temperature to 0° C. over a period of about 2 to 4 hours.  
     
     
         13 . A process as claimed in  claim 11  or  12  wherein the temperature is decreased from ambient temperature to 0° C. over a period of about 3 hours.  
     
     
         14 . A process as claimed in claim any one of  claims 4  to  13  wherein the quantity of the non-aromatic solvent is that which, when 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine is dissolved in it, gives a concentration (before crystallisation) of about 120 to 160 mg/ml.  
     
     
         15 . A process as claimed in  claim 14  wherein the quantity of non-aromatic solvent gives a 135 to 145 mg/ml.  
     
     
         16 . A process as claimed in any one of  claims 4  to  15  in which comprises reacting crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine with fumaric acid to give the fumarate salt of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine.  
     
     
         17 . A process for preparing crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine. or a pharmaceutically acceptable salt thereof, from a solution of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in an aromatic solvent which process comprises: 
 a) adding water and an acid to the solution of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in the aromatic solvent;    b) separating the aqueous and organic phases:    c) adding a non-aromatic solvent and a base to the aqueous phase;    d) separating the aqueous and the non-aromatic solvent phases;    e) drying the non-aromatic solvent phase:    f) crystallising 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from the non-aromatic solvent; and whereafter, if a pharmaceutically acceptable salt is desired. reacting the 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine with an acid which affords a pharmaceutically acceptable anion.    
     
     
         18 . A process as claimed in  claim 17  wherein the aromatic solvent is toluene.  
     
     
         19 . A process as claimed in  claim 17  or  18  wherein step (f) is carried out as claimed in any one of  claims 4  to  17 .  
     
     
         20 . A pharmaceutical composition comprising crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine and a pharmaceutically acceptable diluent or carrier.  
     
     
         21 . The use of crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in the manufacture of a medicament for treating neuropsychiatric disorders.  
     
     
         22 . The use of crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine in the manufacture of a medicament for treating psychoses.