Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-29
2001-09-25
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S319500
Reexamination Certificate
active
06294562
ABSTRACT:
Salts of ethyl 3-(2-(4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetylamino)-3-phenylpropionate
SUMMARY OF THE INVENTION
The present invention relates to ethyl 3-(2-(4-(4-(amino-imino-methyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenyl-propionate salts of the formula I,
in which HM is maleic acid, and to their physiologically tolerated salts, to processes for their preparation and to their use in pharmaceuticals.
STATE OF THE ART
Ethyl 3-(2-(4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetyiamino)-3-phenyipropionate hydrochlorides and their pharmacological properties have already been described in PCT application PCT/EP94/03491 (WO-A-95/14008). However, the hydrochloride salts of ethyl (S)-3-(2-((S)-4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionate, of ethyl (R)-3-(2-((R)-4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetylamino)-3-phenylpropionate, of ethyl (S)-3-(2-((R)-4-(4-(amino-imino-methyl) phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionate and of ethyl (R)-3-(2-((S)-4-(4-(amino-imino-methyl) phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenylpropionate suffer from the disadvantage that they are amorphous and cannot be obtained in the crystalline state. The above hydrochloride salts cannot, therefore, be purified by crystallization and can consequently scarcely be used as active compounds in pharmaceuticals, for whose constituents the legislator stipulates precisely defined degrees of purity, and as target products in the industrial synthesis of the pharmacologically active substances, in the processes for isolating and purifying which conditions have to be adhered to which are likewise precisely defined by the legal guidelines. Furthermore, on the basis of their physical and handling properties, the amorphous hydrochloride salts are not well suited for the galenic production of pharmaceutical preparations such as tablets.
The object of the present invention is, therefore, to prepare the ethyl 3-(2-(4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxoimidazolidin- -yl)-acetylamino)-3-phenylpropionates in a suitable, nonhygroscopic form, which makes it possible to adhere with ease to the degrees of purity required and meet the demands associated with industrial synthesis, as well as the galenic demands.
DETAILED DESCRIPTION
This object is achieved, surprisingly, by preparing the maleic acid salts of the ethyl 3-(2-(4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetylamino)-3-phenylpropionates, in particular the salts, which contain these ethyl esters and maleic acid in salt form (i.e. in form of an acid addition salt) in a molar ratio of approx. 1:1.
The present invention consequently relates to ethyl 3-(2-(4-(4-(amino-imino-methyl) phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionate salts of the formula I,
in which HM is maleic acid, in all stereoisomeric forms and mixtures thereof in any ratios, and to the physiologically tolerated salts thereof.
The compounds of the formula I are crystalline and nonhygroscopic and consequently possess advantages which it was not possible to foresee. They can be crystallized under defined conditions and be purified by recrystallization and are suitable for use in pharmaceuticals and for the galenic preparation of drug forms.
The present invention encompasses all the stereoisomers of the compounds of the formula 1, that is the isomer having an (S) configuration at the chiral center in the imidazolidine ring and an (S) configuration at the chiral center in the propionic acid unit, the isomer having an (R) configuration at the chiral center in the imidazolidine ring and an (S) configuration at the chiral center in the propionic acid unit, the isomer having an (S) configuration at the chiral center in the imidazolidine ring and an (R) configuration at the chiral center in the propionic acid unit and the isomer having an (R) configuration at the chiral center in the imidazolidine ring and an (R) configuration at the chiral center in the propionic acid unit. A preferred form is the isomer having an (S) configuration at the chiral center in the imidazolidine ring and an (S) configuration at the chiral center in the propionic acid unit, that is the ethyl (S)-3-(2-((S)-4-(4-(amino-imino-methyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetylamino)-3-phenyl-propionate salt of the formula Ia,
in which HB is maleic acid, and the physiologically tolerated salts thereof.
The present invention also encompasses all mixtures of two or more stereoisomers of the formula I in any quantity ratios.
In the novel compounds of the formula I, which contain ethyl 3-(2-(4-(4-(amino-imino-methyl) phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-acetylamino)-3-phenylpropionate and maleic acid in a molar ratio of approx. 1:1, one of the two COOH groups of maleic acid is neutralized by the basic amidino group and is present in salt form, that is as negatively charged carboxylate group (after protonation by the maleic acid the amidino group in the ethyl ester is then present as positively charged amidinium group). The second of the two COOH groups of the maleic acid can be present, in the novel compounds, in acid form, that is as a COOH group, or it can be present in salt form, that is as a carboxylate group. The present invention relates both to the hydrogen maleates, in which there is still present a COOH group and which are preferred, and to the physiologically tolerated salts which are derived therefrom and which are formed from them with organic or inorganic bases.
In this context, physiologically tolerated salts are, in particular, pharmaceutically utilizable or nontoxic salts. Cations which may be present in these salts are derived, for example, from alkali metals and alkaline earth metals such as sodium, potassium, magnesium or calcium, from ammonia or from physiologically tolerated organic amines such as triethylamine, ethanolamine or tris(2-hydroxyethyl)amine. The salts of the compounds of the formula I can be obtained directly in the preparation process which is described below by employing, for example, suitable salts of maleic acid in this process or by adding suitable bases. However, the salts can also be obtained by treating initially prepared hydrogen maleates of the formula I, in which a COOH group is still present, with suitable bases, for example alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates, alkaline earth metal oxides or amines. In this context, the COOH groups can either be converted completely, or only partially, into the salt form. The extent to which such a salt formation is carried out depends, for example, on the pH which is sought in association with the intended use. The conversion of free COOH groups
once again completely or only partially—into the salt form can also be effected only at the time when hydrogen maleates of the formula I are employed together with basic substances in the production of pharmaceutical preparations.
The compounds of the formula I can be prepared by carrying out an anion exchange with maleic acid and/or maleates using compounds of the formula II,
in which HV is any inorganic or organic acid which is different from maleic acid, in accordance with customary methods which are known to the skilled person. Examples of acids of the formula HV are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid or methanesulfonic acid. Examples of compounds of the formula II are the compounds of the formulae IIa and IIb,
in which HV in the formula II is hydrochloric acid and acetic acid, respectively. The starting compounds of the formula II can be prepared as described, by way of example, for the hydrochloride (salt with hydrochloric acid) or for the salt with acetic acid in PCT applications PCT/EP94/03491 and PCT/EP96/01572 (WO-A-96/33976). In this respect, the content of PCT applications PCT/EP94/03491 and PCT/
Beck Gerhard
Radau Manfred
Stilz Hans Ulrich
Hoechst Aktiengesellschaft
Morris Patricia L.
Perman & Green LLP
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