Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-11-06
2004-03-16
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06706921
ABSTRACT:
The invention relates to a process for the preparation of acid-addition salts of the compounds of the formula I
in which R
1
, R
2
and R
3
, independently of one another, are alkyl having from 1 to 12 carbon atoms, characterised in that, in a step A, the compounds of the formula II
in which R
1
and R
2
are as defined above, and X is F, Cl, Br, alkyl- or arylsulfonate or perfluoroalkylsulfonate, are converted by conventional methods into the esters of the formula III
in which R
1
, R
2
and X are as defined above, and R
4
is alkyl having from 1 to 10 carbon atoms, and, in a step B, these are converted in the presence of alkylsulfinate into the compounds of the formula IV
in which R
1
, R
2
, R
3
and R
4
are as defined above, the resultant compounds of the formula IV are, in a step C, converted by reaction with guanidine into the corresponding compounds of the formula I, and, in a step D, these are treated with a suitable acid in order to form the acid-addition salt.
Sulfonylbenzoylguanidines are known and are described, for example, in EP 0 758 644 A1. These substances are inhibitors of the cellular Na
+
/H
+
antiproter, 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 ischemic 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 compounds of the formula I can be prepared, for example, as described in EP 0 758 644. The syntheses known hitherto are based on the introduction of alkylsulfone groups into the ring of a corresponding aromatic carboxylic acid and comprise a multiplicity of individual steps, in some cases with unsatisfactory yields. The known processes furthermore have reaction conditions which are disadvantageous for industrial production. Thus, for example, the introduction of alkylsulfone groups into the ring of an aromatic carboxylic acid by nucleophilic substitution of suitable leaving groups with alkylsulfanes followed by oxidation is problematic owing to the extreme and long-lasting odour nuisance by alkylsulfanes, even if they are liberated only in traces.
In the case of direct introduction of the alkylsulfonyl group into the ring of an aromatic carboxylic acid by nucleophilic substitution of suitable leaving groups by means of alkylsulfinate, temperatures of at least 120° C. are necessary, even if highly polar solvents are used, in order to achieve adequate reaction rates. It has been observed that although a slow decomposition reaction occurs in this temperature range, it increases greatly at elevated temperatures with high exothermicity. Owing to the considerable evolution of heat by this decomposition, there is a risk in large batches of the temperature management of the reaction going out of control. It is consequently not possible to use this reaction on an industrial scale for safety reasons.
The object of the present invention was therefore to provide an improved process for the preparation of the compounds of the formula I and their acid-addition salts which circumvents the above-mentioned problematic reaction steps and in addition provides better yields.
This object has been achieved by the process according to the invention having the features described herein. It has been found, surprisingly, that the exchange of the leaving group X in the esters of the formula III proceeds significantly more quickly or at lower temperature than in the case of the corresponding free acid which is employed in the processes of the prior art, resulting in a considerable improvement in yield. The process according to the invention therefore also enables inexpensive starting compounds with chlorine substituents on the aromatic ring as leaving groups to be used with very good results. It has furthermore been found that, in accordance with the process according to the invention, it is possible to carry out steps A and B and steps C and D one after the other without working up the reaction mixtures, enabling losses of yield and complex working steps to be avoided.
In the compounds of the formulae I, II, III and IV, the radicals have the following preferred meanings:
R
1
, R
2
, R
3
and R
4
are, independently, preferably methyl, ethyl, n-propyl, n-butyl or n-pentyl. Particular preference is given to methyl or ethyl, in particular methyl.
X is preferably F, CF
3
SO
2
or Cl, in particular Cl.
The process according to the invention is particularly suitable for the preparation of acid-addition salts of compounds of the formula I in which R
1
, R
2
and R
3
are simultaneously a methyl group (compounds of the formula IA). A very particularly preferred acid-addition salt is the hydrochloride.
The process is therefore particularly suitable for the preparation of the compound of the formula V:
The reaction in the process according to the invention is simple to carry out, the relevant starting compounds of the formula II being converted, in step A, into the corresponding esters by the conventional esterification methods known from the literature, such as, for example, acid-catalysed esterification using a corresponding alcohol, such as methanol or ethanol, in the presence of excess alcohol as solvent or in the presence of a suitable cosolvent, reaction of the carboxylic acid salts of compounds of the formula II with a suitable alkylating agent, such as, for example, dialkyl sulfate, or reaction of the free acids with orthoesters.
A further possible esterification reaction is conversion of the acid into an acid halide and subsequent reaction with a corresponding alcohol to give the ester.
The esterification is preferably carried out by reaction of the carboxylic acid salts of compounds of the formula II with alkylating agents, such as, for example, dialkyl sulfate, or reaction of the compounds of the formula II with an orthoester.
The reaction of the carboxylic acid salts with alkylating agents is advantageously carried out by preferably adding a dialkyl sulfate to the respective carboxylic acid salt dissolved in an inert solvent, the salt preferably being prepared in situ by addition of a base, such as, for example, alkali metal carbonate, hydrogencarbonate, hydroxide or alkoxide, in particular an alkoxide, such as, for example, potassium tert-butoxide, or a hydroxide, such as, for example,
Bartmann Ekkehard
Kirschbaum Michael
Kumar Shailendra
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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