Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-04-14
2004-04-20
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S023000
Reexamination Certificate
active
06723751
ABSTRACT:
The present invention relates to novel crystalline forms of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide, processes for their preparation, their use, and pharmaceutical preparations comprising them.
5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide of formula I,
also abbreviated below as “benzamide I”, is described, for example, in U.S. Pat. Nos. 5,574,069 and 5,776,980 and corresponding publications, for example EP-A-612 724, which are incorporated herein by reference and whose contents are explicitly part of the present disclosure. The benzamide I has valuable pharmacological properties. It inhibits ATP-sensitive potassium channels and prolongs or normalizes a shortened action potential of heart muscle cells, as can occur in ischemic conditions of the heart, without causing a marked depolarization of the cell membrane of &bgr;-cells of the pancreas and a hypoglycemic action. The benzamide I and its physiologically tolerable salts are suitable as pharmaceutical active compounds for the prevention and treatment of various disease states, for example of cardiac arrhythmias such as ventricular fibrillation, of ischemic conditions of the heart or of a weakened myocardial contractile force, or for the prevention of sudden cardiac death. The benzamide I and/or its physiologically tolerable salts are preferably employed for this in the form of pharmaceutical preparations that are tailored with respect to their composition and the administration form to the medicinal effects desired in the specific case, for example in the form of solid preparations such as tablets or capsules or in the form of liquid preparations such as solutions for injections and infusions.
For the production of pharmaceutical preparations, it is often advantageous to employ a pharmaceutical active compound which contains an acidic group or a basic group in the form of a specific salt which has, for example, a more favorable solubility, a more favorable absorption behavior, a more favorable stability, or generally a more favorable property profile. The use of a specific salt, for example, can also have advantages in the preparation of the active compound or of the pharmaceutical preparations, or advantages with respect to adherence to the requirements of drug regulatory authorities. In particular for the production of solutions of pharmaceutical active compounds, especially of solutions which, as a solvent, contain only water or mainly water, it is often advantageous, for the obtainment of an adequate solubility, to employ a pharmaceutical active compound in the form of a suitable physiologically tolerable salt.
The hydrogen atom on that nitrogen atom of the thiourea group in the benzamide I which is bonded to the sulfonyl group has a relatively high acidity. The benzamide I can form salts with bases, for example metal salts, wherein a hydrogen atom is replaced by a monovalent metal ion or one equivalent of a polyvalent metal ion and which can be formally represented by formula II
wherein the cation M can be, for example, a monovalent metal cation or one equivalent of a polyvalent metal cation, for example a sodium ion, a potassium ion, or one equivalent of a calcium ion or magnesium ion. An advantageous salt for use in pharmaceutical preparations is the sodium salt of the benzamide I, which can be formally represented by formula III.
Formula III, however, is not to be understood as meaning that it shows, in each case for the solid or the dissolved sodium salt, the actual relative arrangement of the sodium ion and of the organic anion. The sodium ion can also be located in another position relative to the atoms in the anion; for example it can be coordinated to the sulfur atom of the thiourea group. The sodium salt of the benzamide I can, for example, likewise be represented by formula IV
which, however, in turn is not to be understood as meaning that the single bonds and double bonds indicated therein represent the actual bonding conditions, or it can be represented by the empirical formula C
9
H
21
ClN
3
NaO
5
S
2
.
The preparation of the benzamide I is carried out according to the details in U.S. Pat. Nos. 5,574,069 and 5,776,980 and corresponding publications, for example EP-A-612 724, by deprotonating 5-chloro-2-methoxy-N-(2-(4-methoxy-3-aminosulfonylphenyl)ethyl)benzamide in the aprotic solvent dimethylformamide using sodium hydride and then reacting it with methyl isothiocyanate. The isolation of the sodium salt of the benzamide I intermediately resulting here from the reaction mixture is not described, and the sodium salt is also not characterized in more detail. By pouring the reaction mixture into hydrochloric acid, the sodium salt is converted into the neutral sulfonylthiourea of formula I, which is isolated by filtration. The sodium salt itself can be isolated from the reaction mixture described in the prior art only with great difficulty. The salt remains clearly dissolved in the reaction mixture obtained. It is not possible to precipitate out a filterable solid by cooling or evaporation. On addition of nonpolar solvents such as, for example, diisopropyl ether, the reaction product precipitates in the form of an oil that is heavily contaminated and is unsuitable for use in pharmaceutical preparations and would only be usable after laborious purification operations. Moreover, in the process described in the prior art for the preparation of the sodium salt, sodium hydride is employed and hydrogen gas is released, which necessitates complicated precautions in terms of apparatus and safety measures for carrying out on a large industrial scale. It is an object of the present invention to make available, in a simple manner suitable for carrying out on a large industrial scale, the sodium salt of the benzamide I in a form suitable for pharmaceutical use.
It has now been found that the sodium salt of the benzamide I can be prepared in a solid crystalline form suitable for pharmaceutical use by reaction of the benzamide I with basic sodium compounds, for example sodium hydroxide or sodium alcoholates. Surprisingly, it turned out here that the solid crystalline sodium salt of the benzamide I can occur in a number of different crystal modifications, i.e., in polymorphic forms, which can be prepared specifically by adjustment of the reaction conditions and/or of the crystallization conditions and which differ in their physicochemical properties. Thus, these crystal modifications differ, for example, in their solubility, rate of dissolution, or behavior during pharmaceutical processing, and allow the production of pharmaceutical preparations having different property profiles starting from a single parent compound. The present invention thus relates to the crystalline sodium salt of 5-chloro-2-methoxy-N(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide and in particular to the individual polymorphic forms of the crystalline sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide which are characterized, for example, by their physicochemical data indicated below. The invention relates in particular to:
crystal modification 1 (polymorphic form 1) of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide which has X-ray reflections at the following diffraction angles 2Theta (in°) in the X-ray diffraction diagram using Cu K
&agr;1
radiation:
strong X-ray reflections: 8.95°;
medium-strong X-ray reflections: 7.10°, 11.35°, 12.15°, 15.40°, 22.80°, 23.00°, 23.50°;
crystal modification 2 (polymorphic form 2) of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminothiocarbonylaminosulfonylphenyl)ethyl)benzamide which has X-ray reflections at the following diffraction angles 2Theta (in°) in the X-ray diffraction diagram using Cu K
&agr;1
radiation:
strong X-ray reflections: 7.15°, 11.10°, 22.85°, 23.10°, 26.80°;
medium-strong X-ray reflections: 9.90°, 1
Englert Heinrich Christian
Gerlach Uwe
Metzenthin Tobias
Schneider Harald
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
O'Sullivan Peter
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