Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-06-28
1997-12-02
Fan, Jane
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514338, C07D40112
Patent
active
056938187
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation. The invention also relates to novel intermediates in the preparation of the compounds of the invention.
BACKGROUND OF THE INVENTION
The compound imidazole, having the generic name omeprazole, and therapeutically acceptable alkaline salts thereof are described in EP 5129 and EP 124 495, respectively. Omeprazole and its alkaline salts are effective gastric acid secretion inhibitors, and are useful as antiulcer agents. The compounds, being sulfoxides, have an asymmetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation. The present invention provides such compounds, which are novel salts of single enantiomers of omeprazole.
The separation of the enantiomers of omeprazole in analytical scale is described in e.g. J. Chromatography, 532 (1990), 305-19 and in a preparative scale in DE 4035455. The latter has been done by using a diastereomeric ether which is separated and thereafter hydrolysed in an acidic solution. Under the acidic conditions needed for hydrolysis of the attached group, omeprazole is quite sensitive and the acid has to be quickly neutralized with a base to avoid degradation of the acid-sensitive compound. In the above mentioned application this is done by adding the reaction mixture containing concentrated sulfuric acid to a concentrated solution of NaOH. This is disadvantageous because there is a great risk of locally reaching pH values between 1-6, which would be devastating for the substance. Moreover, instantaneous neutralisation will create heat which will be difficult to handle in large scale production.
SUMMARY OF THE INVENTION
The present invention in a further aspect provides a novel method for preparing the novel compounds of the invention in large scale. This novel method can also be used in large scale to obtain single enantiomers of omeprazole in neutral form.
There is no example known in the prior art of any isolated or characterized salt of optically pure omeprazole, i.e. single enantiomers of omeprazole neither of any isolated or characterized salt of any optically pure omeprazole analogue.
DETAILED DESCRIPTION OF THE INVENTION
The present invention refers to the new Na.sup.+, Mg.sup.2+, Li.sup.+, K.sup.+, Ca.sup.2+ and N.sup.+ (R).sub.4 salts of the single enantiomers of omeprazole, where R is an alkyl with 1-4 carbon atoms, i.e. Na.sup.+, Mg.sup.2+, Li.sup.+, K.sup.+, Ca.sup.2+ and N.sup.+ (R).sub.4 salts of benzimidazole and benzimidazole, where R is an alkyl with 1-4 carbon atoms.
Particularly preferred salts according to the invention are the Na.sup.+, Ca.sup.2+ and Mg.sup.2+ salts, i.e benzimidazole sodium salt, benzimidazole sodium salt, benzimidazole magnesium salt, benzimidazole magnesium salt, benzimidazole calcium salt and benzimidazole calcium salt.
Most preferred salts according to the invention are the optically pure Na.sup.+ salts of omeprazole according to compounds Ia and Ib ##STR1## and the optically pure magnesium salts of omeprazole according to compounds IIa and IIb ##STR2##
With the expression "optically pure Na.sup.+ salts of omeprazole" is meant the (+)-enantiomer of omeprazole Na-salt essentially free of the (-)-enantiomer of omeprazole Na-salt and the (-)-enantiomer essentially free of the (+)-enantiomer, respectively. Single enantiomers of omeprazole have hitherto only been obtained as syrups and not as crystalline products. By means of the novel specific method according to one aspect of the invention of preparing the single enantiomers of omeprazole, the salts defined by the present invention are easy to obtain. In addition, the salts, however not the neutral forms, are obtained as crystalline products. Because it
REFERENCES:
Cairns, et al. "Enantioselective HPLC determination . . . " Journal of Chromatography 8,666 (1995) 323-328.
Yamada et al. "Synthesis and isomerization of optical active . . . " Chem. Pharm. Bull. 42(8) (1994) 1679-1681.
K. Miwa et al. Jpn. Pharmacol. Ther. "Proton pump inhibitor in rats, mice and dogs" 18 (1990) 165-187 (transl.).
H. Katsuki et al. "Determination of R(+)- and S(-)-Lansoprazole" Pharmaceutical Research 13(4) (1996) 611-615.
M. Tanaka et al. "Direct determination of pantoprazole enantiomers . . . " Anal. Chem. 68 (1996) 1513-1516.
Erlandsson et al., J. Chromatography vol. 532, pp.305-319 (1990).
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Fan Jane
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