Use of a thioester for preparing pharmaceutical compositions for the treatment of ischemia and reperfusion syndromes

Abstract: Use of compound of the formula: in which R is hydrogen or a C₁-C₆ alkyl group, or of the salts thereof, when R is H, with a pharmaceutically acceptable base for preparing pharmaceutical compositions for the treatment of ischemia and reperfusion syndromes.

Description: This invention relates to the use of a thioester for preparing pharmaceutical compositions for treating ischemia and reperfusion syndromes, to some new thioesters and pharmaceutical compositions containing them. More particularly, this invention relates to the use of a thioester of the formula in which R is hydrogen or a C 1 -C 6 alkyl group; and of the salts thereof, when R is H, with a pharmaceutically acceptable base. Thioesters of 2-(4-isobutylphenyl)-propionic acid with N-acetylcysteine are described in the European patent No. 0 052 910. 2-(R,S)-(4-isobutylphenyl)-propionic acid is a drug endowed with anti-inflammatory, analgesic and anti-pyretic activity, known as Ibuprofen. N-acetylcysteine is a known drug endowed with mucolytic activity. The thioesters described in European Patent No. 0 052 910 are endowed with anti-inflammatory, analgesic and anti-pyretic properties as well as with mucolytic activity and show, furthermore, an improved gastric tolerability in comparison to Ibuprofen. Other properties were not identified in the compounds described by the above-mentioned European patent. According to recent studies it results that Ibuprofen is also effective in protecting the ischemic myocardium during the post-ischemia period [A.M. Lefer et al., Advances in Shock Research, 3 , 133-141, (1980)]. It is known that infarction phenomenon in the different tissues is characterized by an anoxic or ischemic condition which may be followed by a necrosis or a recovery (either spontaneous or therapeutically induced) of the oxygenation (reperfusion phase); M. Bernier et al., Circulation Research, 58 , 331-340 (1986). A specific functional alteration may take place during the reperfusion phase according to the area concerned. For example, it is often a typical feature of the cardiac muscle during the reperfusion phase that it be afflicted by the occurence of arrhythmic phenomena, such as ectopic beat, tachycardia and fibrillation and by impairment of the contraction. The severity of these phenomena may be high and may also cause the death of the patient through arrhythmia or cardiac shock. We have now found that the compounds of formula I above and the salts thereof, when R is H, with pharmaceutically acceptable bases are useful in the treatment of ischemia and reperfusion syndromes. The composition of this invention has proved to be most effective and the compounds of formula I represent valuable means of treating ischemia and reperfusion syndromes. The preparation of the compounds of formula I is preferably carried out by reacting 2-(4-isobutylphenyl)-propionic acid or a suitable reactive derivative thereof with N-acetylcysteine or an ester thereof according to usual techniques. Typical examples of reactive derivates of 2-(4-isobutylphenyl)-propionic acid are the acid halides and the anhydrides. When starting from 2-(4-isobutylphenyl)-propionic acid the reaction is performed in the presence of a condensing agent such as dicyclohexylcarbodiimide a N-hydroxy-benzotriazole. The most preferred method comprises reacting 2-(4-isobutylphenyl)-propionic acid chloride with N-acetylcysteine or with an ester thereof in an inert solvent such as an ether, a hydrocarbon or a chlorinated hydrocarbon, in the presence of a tertiary amine such as trimethyl amine, triethyl amine or pyridine, at a temperature of between -10 and 30°C inclusive. N-acetylcysteine and the esters thereof may also be used in the form of a reactive derivative such as an S-trialkylsilyl derivative. When the base is pyridine, this can act also as a solvent. The preparation of the salts of the compounds of formula I is carried out according to usual techniques. Typical examples are the salts of alkali and alkaline-earth metals such as sodium, potassium, magnesium and calcium, and of organic bases such as 2-amino-ethanol, trihydroxymethylamino-methane, lysine and arginine. The activity of the compounds of formula I in preventing the injuries caused by ischemia or reperfusion has been tested in different experimental patterns with satisfactory results. For example, the prevention of arrhythmia from reperfusion has been tested in the anesthetized rat. In the said animal the reperfusion phase after obstruction (5 minutes) of the left coronary artery is distinguished by the occurrence of arrhythmic phenomena (ectopic beat, tachycardia and ventricular fibrillation) of varying degree, the result of which may be the death of the animal. The protective action of the compounds of this invention has been evaluated using this model. The parameters considered were the following: percentual incidence of ectopic beat, percentual incidence of ventricular tachycardia, percentual incidence of ventricular fibrillation. All the compounds of formula I tested showed an effective, preventive action on reperfusion arrhythmia and especially on ventricular fibrillations at doses af 2-6 mg/kg after oral administration. The compounds of formula I proved to be well tolerated in the mouse by oral route and in the narcotized rat by intravenous perfusion, they are tolerated as Ibuprofen by oral route and better than Ibuprofen by intravenous route: more particularly, the compounds of formula I show a lack of the negative inotropic property which is typical of Ibuprofen. Furthermore, tests for ulcerogenic activity, after repeated oral administration to the rat on an empty stomach, indicate that the compounds of formula I contrary to Ibuprofen, have poor ulcerogenic action. Data concerning the prevention of injuries caused by ischemia and reperfusion as well as the favourable systemic and topic gastric tolerability allow the conclusion to be made that the compounds of formula I are valuable drugs. Examples of therapeutic indications are myocardial infarction, prevention of arrhythmia due to reperfusion after thrombolysis or coronary by-pass operations, acute breathing syndrome in adults and injuries caused by cerebral ischemia events. For therapeutical purpose the compounds of formula I and the salts thereof, when R is hydrogen, with pharmaceutically acceptable bases are preferably incorporated in a pharmaceutical dosage form suitable for oral or intravenous administration. Depending on the desired administration route, the compositions according to this invention will be in the form of tablets, capsules, pills, grains and the like or of a liquid preparation ready for use or which is extemporaneously prepared by diluting a lyophilized composition. Besides one or more compounds of formula I, the compositions according to this invention comprise a carrier or an inert diluent either solid or liquid and, optionally, other additives suitable for pharmaceutical use, and are prepared according to usual techniques. Furthermore, for oral administration, slow-release compositions may also be used. The effective dose of the compounds formula I for the treatment of ischemia and reperfusion syndromes according to this invention, will vary, depending on various factors such as the individual response, the age, and the general condition of the patient as well as the intended administration route. In general, the effective dose will be from 0.2 to 4 g/day. In order to better illustrate this invention without however limiting it, the following example is given; H-NMR, IR spectra and elemental analysis are consistent with the indicated structure. EXAMPLE 1 N-acetyl-S-[2-(4-isobutylphenyl)-propionyl]-cysteine (Compound No. 1) N-acetylcysteine (16.3 g; 0.1 moles) was dissolved in anhydrous pyridine (100 ml) and de-aerated. To this solution, a solution of (R,S)-2-(4-isobutylphenyl)-propionyl chloride (25.2 g; 0.11 moles) in dichloromethane (25 ml) was added dropwise at -5°C. When the addition was over the cooling bath was taken off and the stirring was continued for 2 hours. The reaction mixture was then poured into 36% HCl (100 ml), cooled to 5°C and extracted with ethyl ether. After evaporating the ether an oily residue was obtained (31.3 g) that was purified by chromatography on silica gel, eluting with chloroform/methanol/acetic acid (95:5:2). The desired product (22 g) was so obtained as a colourless oil which crystallized from isopropyl ether. m.p. = 114-116°C; [α] 20 / D = 0 o (c=1%, EtOH).

Claims: Use of a compound of formula in which R is hydrogen or a C 1 -C 6 alkyl group, or of a salt thereof, when R = H, with a pharmaceutically acceptable base for preparing a pharmaceutical composition for the treatment of ischemia and reperfusion syndromes.

Inventors: CARENZI ANGELO, DELLA BELLA DAVIDE, FERRARI VITTORIO, CARENZI, ANGELO, DELLA BELLA, DAVIDE, FERRARI, VITTORIO
Applicants: ZAMBON SPA, ZAMBON S.P.A.
Application year: 1987
Main classification: A61K31
IPC codes: A61K31