MXPA99003433A - Use of condensated (hetaryl-substituted) 1-benzal-3-pyrazol derivates for treating special diseases of the cardiovascular and the central nervous systems - Google Patents

Abstract

The present invention relates to the new application of condensated (hetaryl-substituted) 1-benzal-3-pyrazol derivates of general formula (I), where R1 to R4 have the meanings given in the description, as drug products and new active substances, and more particularly to their use as vasodilators, possibly combined with organic nitrates and NO donors, possibly combined with compounds which inhibit the degradation of cGMP.

Description

Use of derivatives of l-benzyl-3- (substituted heteroaryl) - (fused pyrazole) for the treatment of special diseases of the cardiocirculatory system and the central nervous system DESCRIPTION OF THE INVENTION The present invention relates to the new use of l-benzyl-3- (substituted heteroaryl) - (fused pyrazole) derivatives, known in part, as medicaments, to new active substances, especially to their use as vasodilators, if any. in combination with organic nitrates and? O donors and eventually in combination with compounds that inhibit the degradation of cGMP. It is already known that derivatives of l-benzyl-3- (substituted heteroaryl) - (fused pyrazole) inhibit in vitro the stimulated aggregation of thrombocytes (see EP 667 345 Al, C.-C. Wu et al., Br. J. Pharmacol., 1995, 116: 1973-1978, F.-? Ko et al., Blood 1994-, 84: 4226-4233, S.-U. Yu et al., Blood 1996, 87: 3758. -3767). It was now surprisingly found that derivatives of l-benzyl-3- (substituted heteroaryl) - (fused pyrazole) of general formula (I) REF .: 29911 wherein R1 represents hydrogen, halogen, hydroxyl or (C -.- C3) alkyl or -alkoxy, Ra represents a radical of formula wherein R5 means hydrogen, halogen, carboxyl, (CL-C3) -alkyl, (Ci-Cj) -alkoxycarbonyl or a moiety of formula -CH2-OR6, wherein R6 means hydrogen or (C3.-C3) - alkyl, R3 and R4 together form a residue of formula wherein R7 signifies hydrogen, halogen, hydroxyl, (C3-C3) -alkyl or (CY-CJ) -alkoxy, and their isomeric forms and salts, show, together with their weak antiagregatory properties, a pronounced vasodilatory action, especially a drop in blood pressure. Therefore, they are suitable for the treatment of special diseases of the cardiocirculatory system, especially for the treatment of various forms of angina pectoris, myocardial infarction, heart failure, arteriosclerosis, apoplectic attack and hypertension. . The compounds according to the invention of the general formula (I) can also be present in the form of their salts. Mention may be made here, in general, of salts with organic or inorganic bases or acids. In the context of the present invention, physiologically acceptable salts are preferred. Physiologically innocuous salts can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Especially preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid , fumaric acid, maleic acid or benzoic acid. Physiologically innocuous salts can also be metal or ammonium salts of the compounds according to the invention if they possess a free carboxyl group. Especially preferred are, for example, sodium, potassium, magnesium or calcium salts, as well as ammonium salts derived from ammonia, or organic amines such as, for example, ethylamine, di- or, triethylamine, di- or, triethanolamine. , dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine. (CÍ-CJ) -alkyl, in the context of the invention, represents a linear or branched hydrocarbon radical having 1 to 3 carbon atoms. Mention may be made, for example, of methyl, ethyl, propyl and isopropyl. (CÍJ) -alkoxy, in the context of the invention, represents a linear or branched alkoxy radical having 1 to 3 carbon atoms. Mention may be made, for example, of methoxy, ethoxy, propoxy and isopropoxy. -alkoxycarbonyl, in the context of the invention, represents a linear or branched alkoxycarbonyl radical having 1 to 3 carbon atoms. Mention may be made, for example, of methoxycarbonyl, of ethoxycarbonyl, of p-op-oxo-c-a-b-i-o and of isopropoxycarbonyl. Preferably, compounds according to the invention of general formula (I) are used in which R 1 represents hydrogen, fluorine, chlorine, (C 3 -C 3) -alkyl or (Cj-C 3) -alkoxy, R 2 represents a radical of formula wherein R5 signifies hydrogen, chloro, carboxyl, (C3-C3) -alkyl, (Cx-C3) -alkoxycarbonyl or a moiety of formula -CH2-0Rβ, wherein R6 signifies hydrogen or methyl, R3 and R4 form together a residue of the formula in which R7 signifies hydrogen, fluorine, chlorine, (-Cj) -alkyl or (Cx-Ca) -alkoxy, and their isomeric forms and salts, for the treatment of special cardiocirculatory diseases. Particular preference is given to using compounds according to the invention of the general formula (I) in which R 1 represents hydrogen, fluorine, chlorine or methoxy, R 2 represents a radical of the formula wherein R5 signifies hydrogen, (CJ.-C3) -alkyl or a moiety of formula -CH2-OR6, wherein R6 signifies hydrogen or methyl, R3 and R4 together form a moiety of formula wherein R7 means hydrogen, chlorine, fluorine, methyl or methoxy, and their isomeric forms and salts, for the treatment of special cardiocirculatory diseases. The invention also relates to new substances that are indicated in the following table: Table The compounds according to the invention of general formula (I), known and new, can be prepared by customary methods, for example according to EP-667 345 Al. Furthermore, the invention preferably also comprises the combination of compounds according to the invention of general formula (I) and the new substances with organic nitrates and NO donors. In the context of the invention, organic nitrates and NO donors are, in general, substances that exert their therapeutic activity by releasing NO or NO compounds. Sodium nitroprusside (NPS), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-1 and analogous substances are preferred. The invention further comprises the combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are especially the inhibitors of phosphodiesterases 1, 2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11, pages 150 to 155.

By means of these inhibitors, the action of the compounds according to the invention is enhanced and the desired pharmacological effect is increased. The new and known compounds of general formula (I), to be used according to the invention, show a spectrum of pharmacologically valuable activity, not foreseeable. They induce, for example, a relaxation of the vessels and lead to a drop in blood pressure and an increase in coronary blood flow. Therefore, they are suitable for use in the treatment of special diseases of the cardiocirculatory system, such as, for example, the various forms of angina pectoris, myocardial infarction, heart failure, arteriosclerosis, apoplectic attack and hypertension. For the verification of cardiovascular activity, the following investigations were carried out: in in vitro investigations on cells of vascular origin, the influence on the formation of cGMP dependent on guanylate cyclase, with and without NO donor, was tested. The relaxing action on the blood vessels was determined on rings of rabbit aorta previously contracted with phenylephrine. The reductive action of blood pressure was investigated in narcotic rats.

Stimulation of the guanylate cyclase sol .. T- > 1 e in primary endothelial cells Cells of the primary endothelium of pig aorta were isolated by treatment with collagenase solution. The cells were then cultured in culture medium until confluency was reached. For investigations, a cell passage was made, planted in cell culture plates and subcultured until reaching confluence. For the stimulation of the endothelial guanylate cyclase, the culture medium was filtered in vacuo and the cells were washed once with Ringer's solution and incubated in stimulation buffer with or without NO donor (sodium nitroprusside, NPS, i μM) . Following this, the test substances (final concentration 1 μM) were pipetted onto the cells. At the end of the 10 minute incubation time, the buffer solution was vacuum filtered and the cells were lysed at -20 ° C for 16 hours. Next, radioimmunological-intracellular cGMP was determined.

In-vitro relaxing action on the blood vessels They are placed individually in 5 ml organ baths, under pretension, 1.5 mm wide rings of a rabbit isolated aorta with Krebs-Henseleit solution heated at 37 ° C, gasified with carbogén. The force of contraction is amplified and digitized, as well as registered in parallel in a continuous line recorder. To provoke a contraction, phenylephrine is added to the bath in increasing concentration in a cumulative manner. After several control cycles, the substance to be tested is investigated in each additional incremental dosing pass and the height of the contraction is compared with the height contraction reached in the last previous pass. From this, the concentration that is necessary to reduce the height of the control value by 50% (IC50) is calculated. The standard application volume assumes 5 μl. Table B Measurements of blood pressure in narcotized rats Male Wistar rats with a body weight of 300-350 g are anesthetized with thiopental (100 mg / kg, i.p.). After the tracheotomy, a catheter is inserted into the femoral artery to measure blood pressure. The substances to be tested are administered orally in the form of suspension in solution of tylose, in several doses, through a pharyngeal tube.

Table C The compounds described in the present invention also constitute substances active to combat diseases of the central nervous system which are characterized by alterations of the NO / cGMP system. They are especially suitable for eliminating cognitive deficiencies, for improving learning and memory abilities and for the treatment of Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system as states of anguish, tension and depression, sexual dysfunctions and sleep disturbances originating in the central nervous system as well as for the regulation of pathological alterations of food intake, stimulants and drugs. In addition, these active substances are also suitable for the regulation of cerebral circulation and therefore constitute effective agents for combating migraine. They are also suitable for prophylaxis and to combat the consequences of episodes of cerebral infarction (Apoplexia cerebri) such as strokes, cerebral ischemias and cranio-encephalic trauma. The compounds according to the invention can also be used to combat painful conditions. The present invention relates to pharmaceutical preparations which, together with pharmaceutically suitable non-toxic inert excipients, contain one or more of the compounds according to the invention or which are composed of one or more active substances according to the invention, as well as the processes for obtaining these preparations. The active substance (s) can also be in microencapsulated form, optionally in one or more of the excipients indicated above. The therapeutically active compounds should be present in the pharmaceutical preparations indicated above in a concentration of approximately 0.1 to 99.5% by weight of the total mixture, preferably of the 0.5 to 95%, approximately. The pharmaceutical preparations indicated above may also contain, in addition to the compounds according to the invention, other pharmaceutically active substances.

It has proven advantageous in general, both in medicine and in veterinary medicine, to administer the active substance (s) according to the invention in total amounts of from about 0.5 to about 500 mg / kg of body weight every 24 hours, preferably from 5 to 100 mg / kg, optionally in the form of several dosage units, to achieve the desired results. A dosage unit contains the active substance (s) according to the invention, preferably in amounts of about 1 to about 80 mg / kg of body weight, especially 3 to 30 mg / kg. Preparation examples Example 1 1- (2-fluorobenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole 0.8 g (2.5 mmol) of 1- (2-fluorobenzyl) -3- (5-formyl-2-furanyl) -indazole are suspended in 40 ml of propanol and added slowly at 0 ° C. 0.8 g of NaBH4. After stirring for 1 hour at room temperature, the clear solution is poured into water, extracted with ethyl acetate, the organic phase is dried with sodium sulfate, evaporated in vacuo and the residue is chromatographed on silica gel with toluene mixtures. (T) / ethyl acetate (EA) as eluents. 620 mg (77% of theory) of crystals are obtained. P.of f. (point of fire): 83 ° C. R £ (SiO 2, toluene / ethyl acetate 2: 1): 0.50. The examples in Tables 1, 2 and 3 were similarly prepared: Table 1: Melting point T ----- Í2--2: Tablai.

(H = hexane) Table 3 (rrn-tin.-ac-on .: It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (5)

1. Having described the invention as above, property is claimed as contained in the following re vindications:
2. Use of i-benzyl-3- (substituted heteroaryl) - (condensed pyrazole) derivatives of the general formula (I) wherein R 1 represents hydrogen, halogen, hydroxyl or (C 1 -C 3) -alkyl or (C-Cj) -alkoxy, R 2 represents a radical of formula wherein R5 means hydrogen, halogen, carboxyl, (C3-C3) -alkyl, (C3-C3) -alkoxycarbonyl or a moiety of formula -CH2-ORβ, wherein Rs means hydrogen or (C1.-C3) ) -alkyl, R3 and R4 together form a remainder of formula
3. Y wherein R7 signifies hydrogen, halogen, hydroxyl, (Ci-C,) -alkyl or (d- j) -alkoxy, and its isomeric forms and salts, for the preparation of medicaments for the treatment of special diseases of the cardiocirculatory system . Use of compounds of general formula (I) according to claim 1 for the preparation of medicaments for combating hypertension. Madijcareptas, cacscterxzscks pa-que capfcLenen catches of general test (1), according to claim 1, in combination with organic nitrates and NO donors. Use of compounds of general formula (I), according to claim 1, in combination with organic nitrates and NO donors for the preparation of medicaments for the treatment of cardiocirculatory diseases.
4. Use of compounds of general formula (I), according to claim 1, in combination with compounds that inhibit the degradation of cGMP for the preparation of medicaments for the treatment of cardiocirculatory diseases. New compounds of the group 1- (2-fluorobenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole, 1- (4-f-lorubbenzyl) -3- (5-hydroxymethyl-2-yl) -indazole , 3- (5-hydroxymethylfuran-2-yl) -1- (3-methoxybenzyl) -indazole, 1- (3-f-lucorbenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole, 3- ( 5-hydroxymethyl uran-2-yl) -1- (2-methoxybenzyl) -indazole, 1- (3-chlorobenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole, 6-fluoro-l- ( 2-f luporbenzyl) -3- (5-hydroxy-4-yl-ura-2-yl) -indazole, 6-f-lluor-3- (5-hydroxymethylfuran-2-yl) -1- (3-methoxy-benzyl) -indazole, 1 - (3-chlorobenzyl) -6-fluoro-3- (5-hydroxymethylfuran-2-yl) -indazole, l-benzyl-3- (5-methyl-furan-2-yl) -indazole, l-benzyl-3- ( 5-hydroxymethylthien-2-yl) -indazole, 4-fluoro-l- (2-fluorobenzyl) -3- (5-hydroxymethylfuran-2-yl) -indazole and
5. 5-fluoro-l- (2-fluorobenzyl) -3 - (5-Hydroxymethylfuran-2-yl) -indazole. Medicaments, characterized in that they contain a compound according to claim 6. Use of compounds of general formula (I), as defined in claim 1, for the preparation of a medicament for the treatment of diseases of the central nervous system. Use according to claim 8 for the treatment of cerebral infarcts.