Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-09-04
2004-01-06
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06673968
ABSTRACT:
The present invention relates to N-(4,5-bismethanesulfonyl-2-methyl-benzoyl)guanidine, hydrochloride hydrate, and to a process for the preparation of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride and the hydrochloride hydrate. N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride hydrate is an NHE-1 selective Na
+
/H
+
antiporter inhibitor.
Sulfonylbenzoylguanidines are known and are described, for example, in EP 0 758 644 A1. These substances are inhibitors of the cellular Na
+
/H
+
antiporter, i.e. they are active ingredients which inhibit the Na
+
/H
+
exchange mechanism of the cells (Düsing et al., Med. Klin. 1992, 87, 367-384,) and are consequently good antiarrhythmic agents which are suitable, in particular, for the treatment of arrhythmia occurring as a consequence of oxygen deficiency.
The substances exhibit a good cardioprotective action and are therefore particularly suitable for the treatment of acute myocardial infarction, infarction prophylaxis, post-infarction treatment, chronic cardiac insufficiency and for the treatment of angina pectoris. They furthermore counter all pathological hypoxic and ischaemic damage, enabling the illnesses caused primarily or secondarily thereby to be treated. These active ingredients are likewise highly suitable for preventive applications.
Owing to the protective action of these substances in pathological hypoxic or ischaemic situations, further possible applications arise therefrom in surgical interventions for protection of organs with temporarily reduced supply, in organ transplants for protection of the removed organs, in angioplastic vascular or cardiac interventions, in ischemia of the nervous system, in the therapy of shock states and for the prevention of essential hypertonia.
These compounds can furthermore also be employed as therapeutic agents in illnesses caused by cell proliferation, such as arteriosclerosis, diabetes and late complications of diabetes, tumour illnesses, fibrotic illnesses, in particular of the lungs, liver and kidneys, and organ hypertrophia and hyperplasia. In addition, the compounds are suitable for diagnostic use for the recognition of illnesses accompanied by increased activity of the NA
+
/H
+
antiporter, for example in erythrocytes, thrombocytes or leukocytes.
The compounds can therefore be used as medicament active ingredients in human and veterinary medicine. They can furthermore be used as intermediates for the preparation of further medicament active ingredients.
The invention had the object of finding a highly active compound having a very good oral absorption property.
N-(4,5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride hydrate has proven to be a highly suitable and highly active substance and is distinguished by a particularly good oral absorption property. N-(4, 5-Bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride hydrate is therefore preferably administered in oral form.
The absorption from the digestive tract after oral administration can be calculated by comparison of the concentrations of the administered active ingredient determined in the blood plasma after oral and intravenous administration (dose-standardised AUC
po
/AUC
iv
) [AUC=area under the curve]. The rat exhibited an absorption rate of 98% (of the orally administered radioactively labelled substance). Bioavailabilities of the hydrochloride hydrate of from 88% to 99% were found in dogs, and 75% and 96% in 2 monkeys. Since the absorption rate is at least equal to or greater than the bioavailability determined, very good absorption has thus also been found in these animal species.
The invention therefore relates to N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, hydrochloride hydrate. This invention is to be regarded as a selection invention to EP 0 758 644.
Since this substance is very promising, its preparation is of very considerable interest. The preparation of the free N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine base and its analogues has been described in EP 0 758 644 A1 cited above.
However, the known syntheses comprise a large number of individual steps, some of which have unsatisfactory yields and which also have environmentally polluting and hazardous reaction conditions, such as, for example, the reaction with methyl mercaptam or the oxidation of the thioether to give the sulfone.
There is therefore great interest in finding an improved process for the preparation of N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine, its hydrochloride and hydrochloride hydrate.
It was therefore likewise an object of the present invention to find a novel synthesis variant for the Na
+
/H
+
antiporter which is shorter and also more effective compared with conventional methods.
The invention relates to a process for the preparation of the benzoylguanidine derivative N-(4,5-bismethanesulfonyl-2-methylbenzoyl)-guanidine, hydrochloride of the formula I
in which Me is methyl, and of the hydrochloride hydrate, which is characterised in that firstly, by reaction of the starting compound of the formula II
in which
Me is a methyl group, and Q is fluorine or chlorine,
with a methanesulfinate in a nucleophilic substitution on the activated aromatic ring, the 4-methanesulfonyl group is introduced in a one-step reaction,
then, in the second step, the compound of the formula III
is converted into an acid chloride and reacted with guanidine to give N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine,
and, in the third step, converted into the hydrochloride of the formula I and/or its hydrochloride hydrate by reaction in aqueous HCl.
The starting compound of the formula II is prepared, for example, starting from 2-bromo-5chlorotoluene by halogen-metal exchange and CO
2
treatment to give 4-chloro-2-methylbenzoic acid followed by reaction of 4-chloro-2-methylbenzoic acid with chlorosulfonic acid, sodium sulfite and methyl iodide to give 4-chloro-2-methyl-5-methylsulfonylbenzoic acid or by reaction of 2-bromo-5-chlorotoluene with methanesulfonic acid and thionyl chloride in a Friedel-Crafts-like reaction in the presence of a Friedel-Crafts catalyst to give 4-chloro-2-methyl-4-methylsulfonylphenyl bromide followed by exchange of the bromine by a carboxyl group through a palladium-catalysed carbonylation reaction in an autoclave under superatmospheric pressure and at elevated temperature to give 4-chloro-2-methyl-5-methyl-sulfonylbenzoic acid. The reaction conditions selected are known from the literature (lit.: Houben-Weyl, Methoden der Organ. Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). However, it is also possible to use other processes which are known from the literature, but are not explained in greater detail here, for the preparation of compounds of the formula II.
The term methanesulfinate denotes an alkali metal salt of methanesulfinic acid, in particular sodium methanesulfinate or potassium methanesulfinate, or an alkaline earth metal salt of methanesulfinic acid, in particular calcium methanesulfinate or magnesium methanesulfinate. Particular preference is given to the use of sodium methanesulfinate.
The reaction of the compound of the formula II with a methanesulfinate, preferably sodium methanesulfinate, is carried out analogously to the method of A. Ulman et al., J. Org. Chem. 1989, 54, 4691-4692. The reaction is preferably carried out in a polar solvent and at reaction temperatures between 10 and 200°, preferably between 50 and 180°, particularly preferably between 80 and 140°. Particularly preferred solvents are dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or 1-methyl-2-pyrrolidone (NMP), very particularly preferably DMF or NMP. The methanesulfinate is generally employed in excess. Under the said reaction conditions, exclusively the 4,5-bismethanesulfonyl-2-methylbenzoic acid of the formula III is formed.
The guanidination of the compound of the formula III in step 2 is not restricted to the acid chloride method, in which, for example, the compou
Baumgarth Manfred
Bender Hans Markus
Gericke Rolf
Ladstetter Bernhard
Davis Brian
Merck Patent Gesellschaft mit beschränkter Haftung
Millen White Zelano & Branigan P.C.
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