US2006004057A1PendingUtilityA1

New compounds

50
Individually held — no corporate assignee on recordPriority: May 28, 1993Filed: Dec 1, 2004Published: Jan 5, 2006
Est. expiryMay 28, 2013(expired)· nominal 20-yr term from priority
Inventors:Per L. LindbergSverker Von Unge
C07D 401/12
50
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Claims

Abstract

The novel optically pure compounds Na + , Mg 2 +, Li + , K + , Ca 2+ and N + (R) 4 salts of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole, in particular sodium and magnesium salt form thereof, where R is an alkyl with 1-4 carbon atoms, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.

Claims

exact text as granted — not AI-modified
1 . An optically pure enantiomeric compound comprising a Na + , Mg 2+ , Li + , K + , Ca 2+  or N + (R) 4  salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]- H -benzimidazole or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole, wherein R is an alkyl with 1-4 carbon atoms.  
   
   
       2 . The optically pure enantiomeric compound according to  claim 1  selected from the group consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt, (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole calcium salt and (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole calcium salt.  
   
   
       3 . The optically pure enantiomeric compound according to  claim 1  selected from the group consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt and (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt.  
   
   
       4 . The optically pure enantiomeric compound according to  claim 1  selected from the group consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl-1 H -benzimidazole sodium salt and (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1 H -benzimidazole sodium salt in their crystalline forms.  
   
   
       5 . The optically pure enantiomeric compound according to  claim 1  which is (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl-1 H -benzimidazole sodium salt in its crystalline form.  
   
   
       6 . The optically pure enantiomeric compound according to  claim 1  which is the compound (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl-1 H -benzimidazole sodium salt in its crystalline form.  
   
   
       7 . A process for the preparation of an optically pure enantiomeric compound according to  claim 1  which comprises separating from a racemic mixture a diastereomeric ester of formula IV  
     
       
         
         
             
             
         
       
     
     wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or S configuration, and dissolving each of the separated R or S diastereomers is solved in an alkaline solution whereby the acyloxymethyl is hydrolyzed to give the optically pure enantiomeric compound.  
   
   
       8 . The process according to  claim 7  wherein the diastereomers are separated by chromatography or fractional crystallization.  
   
   
       9 . The process according to  claim 7  wherein the solvolysis is performed in alkaline solution consisting of a base in a protic solvent comprising alcohol or water; or a base in an aprotic solvent, such as dimethylsulfoxide or dimethylformamide.  
   
   
       10 . The process for the preparation of a pure enantiomeric compound according to  claim 7  wherein a product from the process in crystalline form is neutralized with a neutralizing agent which can be an acid or an ester, followed by treatment with a base in non-aqueous solution.  
   
   
       11 . A process for the preparation of crystalline sodium salt of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl-1 H -benzimidazole sodium salt or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1 H -benzimidazole sodium salt in crystalline form which comprises neutralizing (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1 H -benzimidazole sodium salt crude product or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-1 H -benzimidazole sodium salt crude product, respectively, is neutralized and treating said crude product with NaOH in a non-aqueous medium.  
   
   
       12 . A process for the preparation of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole which comprises separating a diastereomeric ester of formula IV  
     
       
         
         
             
             
         
       
     
     wherein Acyl designates a chiral acyl group such as mandeloyl, having either R or S configuration is and dissolving each of the separated diastereomers in an alkaline solution where the acyloxymethyl group is hydrolyzed off to give the optically pure enantiomeric compound after neutralization with a neutralizing agent which can be an acid or an ester.  
   
   
       13 . The process according to  claim 12  wherein the diastereomers are separated by chromatography or fractional crystallization.  
   
   
       14 . The process according to  claim 12  wherein the solvolysis is performed in alkaline solution consisting of a base in a protic solvent or of a base in an aprotic solvent.  
   
   
       15 . The process according to claims  12  or  14  wherein the aprotic solvent comprises alcohol or water.  
   
   
       16 . The process according to claims  12  or  14  wherein the aprotic solvent comprises dimethylsulforide or dimethylformamide.  
   
   
       17 . The compound (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1 H -benzimidazole obtained by the process defined in  claim 12 .  
   
   
       18 . The compound (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1 H -benzimidazole obtained by the process defined in  claim 12 .  
   
   
       19 . A pharmaceutical composition comprising an optically pure enantiomeric compound according to the claims  1  as active ingredient and a pharmaceutically acceptable carrier.  
   
   
       20 . An optically pure enantiomeric compound or salt thereof according to claims  1  or  2  for use in therapy.  
   
   
       21 . A method for inhibiting gastric acid secretion comprising administration to a mammal including man in need of such treatment an effective amount of an optically pure compound according to  claim 1 .  
   
   
       22 . A method for the treatment of gastrointestinal inflammatory diseases comprising administration to a mammal including man in need of such treatment an effective amount of an optically pure compound or salt thereof according to claims  1  or  2 .  
   
   
       23 . The compound 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-1-[mandeloyloxymethyl]-1 H -benzimidazole.  
   
   
       24 . The optically pure enantiomeric compound according to  claim 1  consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1 H -benzimidazole magnesium salt in its crystalline form.  
   
   
       25 . The optically pure enantiomeric compound of  claim 1  consisting of (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt in its crystalline form.  
   
   
       26 . The method of  claim 21  wherein the optically pure enantiomeric compound is selected from the group consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (−)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt and (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt.  
   
   
       27 . The method of  claim 21  wherein the selected optically pure enantiomeric compound is in crystalline form.  
   
   
       28 . The method according to  claim 22 , wherein the optically pure enantiomeric compound is selected from the group consisting of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (−)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole sodium salt, (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt and (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole magnesium salt.  
   
   
       29 . The method according to  claim 22  or  claim 28  wherein the selected optically pure enantiomeric compound is in crystalline form.  
   
   
       30 . An optically pure enantiomeric salt compound comprising the R or S diastereomeric structure of formula Ia, Ib, IIa or IIb, produced from a diastereomeric ester of formula IV, one diastereomer having been separated from the other, dissolved in an alkaline solution and hydrolyzed therein resulting in the optically pure compound.  
   
   
       31 . The compound according to  claim 30  wherein one diastereomeric form is separated from the other by chromatography or fractional crystallization.  
   
   
       32 . A nonaqueous process for preparing a crystalline form of an optically pure enantiomer of omeprazole magnesium salt which comprises stirring a crude preparation of the omeprazole enantiomer under nitrogen into a methanolic magnesium methoxide solution; precipitating any inorganic magnesium salts with a small addition of water; removing any precipitated inorganic magnesium salts; concentrating the residual methanolic solution; precipitating the omeprazole enantiomer by adding acetone; and filtering off the optically pure enantiomer crystals of magnesium omeprazole.  
   
   
       33 . The process of  claim 32 , wherein the optically pure enantiomer is (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole magnesium salt or (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1 H -benzimidazole magnesium crystal salt.  
   
   
       34 . The process according to  claim 7  or  12 , wherein the chiral acyl group is mandeloyl.

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