MXPA00001528A - Heterocyclic vinylethers against neurological disorders - Google Patents

Abstract

The invention is concerned with the use of compounds of general formula (I), wherein R signifies halogen or lower alkyl;n signifies 0-3;R1 signifies lower alkyl;cycloalkyl;benzyl optionally substituted by hydroxy, halogen, lower alkoxy or lower alkyl;benzoyl optionally substituted by amino, lower alkylamino or di-lower alkylamino;acetyl or cycloalkyl-carbonyl;and (A) signifies an aromatic 5-membered residue which is bonded via a N-atom and which contains further 1-3 N atoms in addition to the linking N atom, as well as their pharmaceutically acceptable salts as therapeutically active substances, especially for the control or prevention of acute and/or chronic neurological disorders.

Description

HETEROCYCLIC VINYL ETHERS AGAINST NEUTRAL OGIC DISORDERS Description of the invention: The present invention relates to heterocyclic vinyl ethers of the general formula: where: R represents halogen or lower alkyl; n means 0-3; R1 means lower alkyl; cycloalkyl; benzyl optionally substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl optionally substituted by amino, lower alkylamino or dialkylamino lower; acetyl or cycloalkyl carbonyl; and T denotes a 5-membered aromatic residue which is linked through an N atom and which contains 1-3 additional N atoms in addition to the N-binder atom, as well as its pharmaceutically acceptable salts for the treatment or the prevention of diseases. Some triazole derivatives which are included in formula I have been known for a long time.

They are described, eg. , in European Application No. 079 856 for REF; 32612 their use as active substances for the agrochemical control of pests, preferably for the control or prevention of an attack by microorganisms. In addition, the imidazolyl and triazolyl vinyl ethers of Formula I, described in DE 3417468 and DE 2839388, have fungicidal and bactericidal activity in animals and / or humans. It has surprisingly been found that the compounds of the general formula I are antagonists and / or agonists of the metabotropic glutamate receptors. In the central nervous system (CNS) the transmission of stimuli is done by the interaction of a neurotransmitter, which is sent by a neuron, with a neuroreceptor. L-glutamic acid, the neurotransmitter most commonly present in the CNS, plays a critical role in a large number of physiological processes. The stimulus receptors that depend on glutamate are divided into two main groups. The first major group forms ion channels controlled by ligands. Metabotropic glutamate receptors (mGluR) belong to the second major group, and also belong to the family of G-protein coupled receptors. Currently eight different members of these mGluRs are known and of these some even have subtypes. Based on structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity for low molecular weight chemical compounds, these eight receptors can be subdivided into three subgroups: mGluRl and mGluR5 belong to group I, mGluR2 and mGluR3 belong to the Group II and mGluR4, mGluR6, mGluR7 and mGluRd belong to group III. Ligands of the metabotropic glutamate receptors belonging to the second group can be used for the treatment or prevention of acute and / or chronic neurological disorders such as a restricted brain function caused by bypass or transplant operations, a poor supply of blood to the brain , spinal cord damage, head injury, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Other related indications that can be treated are Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye damage, retinopathy, cognitive disorders, idiopathic parkinsonism or parkinsonism caused by medications as well as conditions that lead to functions with glutamate deficiency, such as, for example. , muscle spasms, seizures, migraine, urinary incontinence, nicotine addiction, psychosis, opiate addiction, anxiety, vomiting, chronic pain, dyskinesia, depression and pain. The objects of the present invention are the compounds of formula 1 and their pharmaceutically acceptable salts as therapeutically active substances but the prediction of medicaments, as well as medicaments based on new compounds, new compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances for the control or prevention of diseases of the type mentioned above. New compounds of formula I are especially those in which R and R 1 have the meaning given above and A means a 5-membered aromatic ani-kyl which is attached through an N atom and which contains 1 or 3 carbon atoms. N in addition to the N-binder atom or where R has the meaning given above, A means a 5-membered aromatic ring which is linked through an N atom and which contains 3 additional N atoms in addition to the N-binder atom and R 1 means cycloalkyl. The term "lower alkyl" used in the present disclosure denotes straight or branched chain saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like. The term "cycloalkyl" denotes cyclic saturated hydrocarbon residues with 3-7 carbon atoms in the ring, such as, for example, cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "lower alkoxy" denotes lower alkyl residues in the sense of the above definition that are linked through an oxygen atom. The term "halogen" includes fluorine, chlorine, bromine and iodine. In the scope of the present invention, those compounds of the general formula I wherein R means chlorine, n is 1 or 2, R 1 means lower alkyl, cyclohexyl or benzyl and A means a 5-membered aromatic ring that is attached through of an N atom and containing 2 or 3 additional N atoms in addition to the N-binder atom for use as therapeutically active substances. The following are examples of preferred compounds of the general formula I: 1- [2- (2, -dichloro-phenyl) -2-cyclohexyloxy-vinyl] -1H [1, 2,] triazole, 1- [2- (2 , 4-dichloro-phenyl) -2-benzyloxy-vinyl) -lH-tetrazoJ. ^ 2- [2- (4-chloro-phenyl) -2-butoxy-vinyl) -2H-tetrazole, 1- [2- ( 4-chloro-phenyl) -2-butoxy-vinyl] -1H [1,2, 4] -triazoI and l- [2- (2,6-dichloro-phenyl) -2-butoxy-vinyl] -1H- [ 1, 2,4] triazole. The novel compounds of the general formula I can be prepared according to the invention by alkylating or acylating a compound of the formula wherein R, n and 2L- ^ have the meanings given above, and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt. If desired, a functional group in a compound of formula I can be converted to a different functional group; in particular, the amino groups can be alkylated to lower alkylamino or dialkylamino lower groups or -hydroxy groups can be alkylated. These procedures are familiar to any person skilled in the art. In the alkylation or acylation, an acetophenone derivative of formula II is reacted with a suitable alkylating or acylating agent, preferably with benzyl bromide, benzoyl chloride, acetyl cyclohexyl triflate chloride, cyclopropyl chloride, isopropyl bromide, n-butyl, 4-methoxybenzyl chloride, isopropyl triflate, 4-dimethylaminobenzoyl chloride, benzyl chloride or the like. This reaction is carried out according to known methods, preferably in the presence of sodium hydride. As solvent, especially THF (tetrahydrofuran) and DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone) are used in the ratio 3: 1. This processing variant is described in detail in the Example Ib). The pharmaceutical salts can be produced rapidly according to methods known per se, taking into account the nature of the compound to be converted into a salt. Inorganic or organic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid , p-toluenesulfonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds containing the alkali or alkaline earth metals, for example, sodium, potassium, calcium, magnesium, or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds. Scheme I below illustrates the preparation of the compounds of formula I, starting with the known compounds of formulas III and IV.

Scheme 1 In this Scheme R, n and (A have the meanings described above, X means halogen, preferably chlorine or bromine A compound of formula IV can preferably be a triazole, tetrazole, or imidazole of the general formulas The compounds of the general formulas II, III and IV are known or can be prepared according to methods known per se. The following Table I shows a selection of compounds tested for use as therapeutically active substances in a mGluR affinity test (see pages 14 and 15): r s Q / 6 4-CH3 i-Prop R7 2,6-Cl Benzyl > S8 2,4-Cl n-Bu T / 9 4-C1 n-Bu N * a N. ü / 10 2,6-Cl i-Prop V / ll 2,4-Cl 4-Benzyl Methoxy - * W / 12 2,4-Cl Benzoyl X / 13 2,4-Cl i-Prop v »and / 14 2,4-Cl 4-Benzyl. Dimethylamino TC « z / 15 2,4-Cl Benzyl A 1- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -1H- [1,2,4] triazole B 1- [2- (2,4-dichloro-phenyl) -2 -isobutoxy-vinyl] -1H- [1,2,4] triazole C 1- [2- (2,4-dichloro-phenyl) -2-butoxy-2-vinyl] -1H- [1,2,4] triazole D 1- [2- (2, 4, 6-trichloro-phenyl) -2-isopropoxy-vinyl] -1H [1,2, 4] triazole E 1- [2- (2,4-dichloro-phenyl) -2-methoxy-vinyl] -1H- [1,2, 4] triazole F 1- [2- (4-bromo-phenyl) -2-butoxy-vinyl] -1H- [1,2,4] triazole G 1- [2- (2, -difluoro-phenyl) -2-isopropoxy-vinyl] -1H- [1,2, 4] triazole H 1- [2- (4-fluoro-phenyl) -2-isopropoxy-vinyl ] -1H- [1, 2, 4] triazole I 1- [2- (phenyl) -2-isopropoxy-vinyl] -1H- [1,2,4] triazole J 1- [2- (4-chloro- phenyl) -2-butoxy-vinyl] -1H- [1,2,4] triazole K 1- [2- (2,6-dichloro-phenyl) -2-butoxy-vinyl] -1H- [1,2, 4] triazole L 1- [2- (2,4-dichloro-phenyl) -2-benzyloxy-vinyl] -1H- [1,2,4] triazole M 1- (2,4-dichloro-phenyl) acid ester ) -2- [1,2,4] triazol-1-yl-vinyl-benzoic N Ester of acid 1- (2, 4-dichloro-phenyl) -2- [1,2,4] triazol-1-yl-vinyl-acetic acid OR 1- [2- (2,4-dichloro-phenyl) -2-cyclohexyloxy-vinyl] -1H - [1,2,4] triazole P 1- (2,4-dichloro-phenyl) -2- [1,2,4] triazol-1-yl-vinyl-cyclopropanecarboxylic acid ester 1- 1- 2- ( 4-tolyl) -2-isopropoxy-vinyl] -1H- [1,2, 4] triazole R 1- [2- (2,6-dichloro-phenyl) -2-benzyloxy-vinyl] -2H-tetrazole S 2 - [2- (2,4-dichloro-phenyl) -2-butoxy-vinyl] -2H-tetrazole T 2- [2- (4-chloro-phenyl) -2-butoxy-vinyl] .- 2H- [1 , 2,4] tetrazole U 2- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -2H-tetrazole V 2- [2- (2,4-dichloro-phenyl) -2- (4-methoxy-benzyloxy-vinyl] -2H-tetrazole W 1- (2,4-dichloro-phenyl) -2-tetrazol-1-yl-vinylbenzoic acid ester X 1- [2- (2,4-dichloro- phenyl) -2-isopropoxy-vinyl] -1H-tetrazole and 1- (2,4-dichloro-phenyl) -2-tetrazol-1-yl-vinyl-4-dimethylaminobenzoic acid 1- [2- (2 , 4-dichloro-phenyl) -2-benzyloxy-vinyl] -1H-tetrazole AA 1- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -1H-imidazole BB 1- [2- (2, 4- dichloro-phenyl) -2-butoxy-vinyl] -lH-imidazole As mentioned above, the compounds of formula I and its pharmaceutically acceptable salts are antagonists and / or agonists of the metabotropic glutamate receptor and can be used for the treatment or prevention of acute and / or chronic neurological disorders. The ligation of the compounds of formula I according to the invention to the metabotropic glutamate receptors of group II was determined in vitro. The preparations were tested according to the test indicated below: The GTPy35S test was used to determine the affinity of a compound for group II mGluR. Membranes that adhere to the rat mGluR2 receptor were used. These were stimulated with 10 μM of 1S, 3R-ACPD. The Ki values of the compounds to be tested are given. The Ki value is defined by the following formula IC?. = 50 wherein the IC5o values are those concentrations of the compounds to be tested in μM with which 50% of the effect of 1S, 3R-ACPD is antagonized. [L] is the concentration of 1S, 3R-ACPD and the EC50 value is the concentration of IS, 3R-ACPD in nN that produces approx. 50% stimulation Table 2 Activity on mGluR Compound No / K ,. [μM M] Example No. m-GluR2 A 1.17 B 0.64 C 1.40 D 2.70 E 11.00 F 0.66 G 7.60 H 10.00 I 12.70 Activity on iriGluR Compound No / Ki [μM M] Example No. m -GluR2 J 0.60 K 0.60 L / l 0.43 M / 2 1.20 N / 3 4.70 0/4 0.10 P / 5 2.40 Q / 6 6.10 R / 7 2.00 S / 8 1.00 T / 9 0.32 U / 10 2.00 V / ll 1.00 W / 12 0.90 X / 13 1.30 Y / 14 1.40 Z / 15 0.27 AA / 16 7.71 BB / 17 4.30 The compounds of formula I and the pharmaceutically acceptable salts thereof can be used as medicaments, e.g. , in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. , in the form of coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be performed rectally, for example. , in the form of suppositories, parenterally, by e. , in the form of injectable solutions. The compounds of formula I and the pharmaceutically acceptable salts thereof can be processed with inorganic or organic, pharmaceutically inert carriers for the production of pharmaceutical preparations. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, I do not know. they generally require vehicles, however, in the case of soft gelatine capsules. Water, polyols, sucrose, invert sugar, glucose and the like are, for example, suitable vehicles for the production of solutions and syrups. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used for aqueous injectable solutions of water-soluble salts of compounds of the formula I, but in general they are not necessary. Suitable carriers for suppositories are, for example, natural or hydrogenated oils, fatty waxes, liquid or semi-liquid polyols and the like. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically useful substances. As mentioned above, medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also subject of the present invention, in addition also a process for the production of such medicaments., characterized in that a form of galenic administration is given to one or more compounds of formula I or pharmaceutically acceptable salts thereof, and if desired, one or more therapeutically useful substances, together with one or more therapeutically inert carriers. The dosage can vary within wide limits and will be adapted, of course, to the individual requirements in each particular case. In general, the effective dose for oral or parenteral administration is between 0.01-20 mg / kg / day, with a dose of 0.1-10 mg / kg / day being preferred for all the indications described. The daily dose for an adult human of 70 kg of body weight is therefore between 0.7-1400 mg per day, preferably between 7 and 700 mg per day. The following Examples are intended to illustrate the preparation of the new specific compounds in greater detail.

Example 1 1- [2-2- (2,4-dichloro-phenyl) -vinyl] -2-benzyloxy-1H- [1,2,4] riazole a) 10 g (44.8 mmol) of 2 were added , 2 ', 4' -trichloroacetophenone in portions at room temperature to a solution of 9.3 g (134 mmol) of triazole in 50 ml of dimethylformamide and stirred at 80 ° C for 16 hours. The reaction mixture was added to 100 ml of 2N sodium hydroxide solution and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate / methanol 100: 5). 2.8 g (25%) of 1-2, 4 were obtained. { dichlorophenyl) -2- [1, 2, 4] triazol-1-yl-ethanone as a yellow-brown solid. b) 670 mg (2.62 mmoles) of 1- (2,4-dichlorophenyl) -2- [1,2, 4] triazol-1-yl-ethanone in 12 ml of tetrahydrofuran and 4 ml of 1, 3- were added dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone to a suspension of 171 mg (3.92 mmol) of sodium hydride (55% in mineral oil) in 15 ml of tetrahydrofuran and 5 ml of 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU) and stirred at room temperature for 3 hours. Then 396 mg (5.24 mmol) of benzyl bromide were added and the mixture [stirred] was stirred at room temperature for another 16 hours. The tetrahydrofuran was removed under vacuum, the residue was added to 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulfate and the diethyl ether was removed in vacuo. The crude product was purified by chromatography. Column on silica gel (diethyl ether / pentane 1: 4). In addition to the fractions mixed with the C-alkylation product, 65 mg was obtained (7%) of 1- [2- (2,4-dichloro-phenyl) -2-benzyloxy-vinyl] -1H- [1, 2, 4] triazole as a colorless oil. [M + H] + = 345.347. EXAMPLE 2 1- (2,4-Dichloro-phenyl) -2- [1, 2,] riazole-1-vinylbenzoic acid ester Analogously to Example la, b, after reacting 1- (2, -dichlorophenyl) ) -2- [1, 2, 4] -triazol-1-yl-ethanone with benzoyl chloride was obtained 1- (2, -dichloro-phenyl) -2- [1, 2, 4] triazole- 1-pure vinylbenzoic. After reacting with oxalic acid, a salt of composition C? 7H N302Cl2.2C2H2? 4 with a melting point of 130 ° C was obtained. EXAMPLE 3 1- (2,4-Dichloro-phenyl) -2- [1, 2, 4] triazol-1-yl-vinylacetic acid ester Analogously to Example la, b, after reacting 1- (2, -dichlorophenyl) -2- [1, 2, 4] -triazol-1-yl-ethanone with benzoyl chloride, the ester of l- (2,4-dichloro-phenyl) -2- [1, 2, ] triazol-1-yl-vinyl-acetic acid as a white solid with mp 127 ° C.

EXAMPLE 4 1- [2- (2,4-dic-gold-phenyl) -2-cyclohexyloxy-vinyl-lH- [1,2,4] triazole. Analogously to Example la, b, after reacting 1- ( 2,4-dichlorophenyl) -2- [1, 2, 4] -triazol-1-yl ethanone with cyclohexyl triflate was obtained 1- [2- (2, -dichloro phenyl) -1-cyclohexyloxy-vinyl-1H- [ 1, 2, 4] triazole as a white solid with mp 84 ° C.

EXAMPLE 5 1- (2,4-Dichloro-phenyl) -2- [1, 2, 4] triazol-1-yl-vinyl-cyclopropanecarboxylic acid ester Analogously to Example la, b, after reacting 1- (2,4-dichlorophenyl) -2- [1, 2, 4] -triazol-1-yl-ethanone with cyclopropyl chloride gave the ester of l- (2,4-dichloro-phenyl) -2- [1 , 2,4] triazol-1-yl-vinylcyclopropanecarboxylic acid as a white solid with pfl08cC.

EXAMPLE 6 1- [2- (4-Tolyl) -2-isopropoxy-vinyl] -lH- [1,2,4] triazole Analogously to Example la, b, after reacting 1- (4-methylphenyl) -2- [1, 2, 4] -triazol-1-yl-ethanone with isopropyl bromide was obtained 1- [.2- (4-tolyl > -isopropoxy-vinyl] -1H- [1, 2, 4 ] triazole After reacting with acid in dioxane, a salt of the composition Ci4H17 30. HCl [M + H] + = 243 was obtained.

EXAMPLE 7 1- [2- (2,6-Dichloro-phenyl) -2-benzyloxy-vinyl] -1H- [1, 2, 4] triazole Analogously to Example la, b, after reacting 1- ( 2,6-dichlorophenyl) -2- [1, 2, 4] -triazol-1-yl-ethanone with benzyl chloride gave 1- [2- (2,6-dichloro-phenyl) -vinyl] -2-benzyloxy -lH- [1, 2, 4] triazole. After reacting with oxalic acid, a salt of composition Ci H? 3N30Cl2 was obtained. C H20 which decomposed to > 71 ° C.

EXAMPLE 8 2- [2- (2,4-dichloro-phenyl) -2-butoxy-vini] -2H- [1,2, 4] tetrazole a) A solution of 15.9 g (71 mmol) of 2, 2 ' , 4-trichloroacetophenone in 100 ml of methylene chloride was slowly added dropwise while cooling with ice to a solution of 4.98 g (71 mmol) of tetrazole and 14.4 (142 mmol) of triethylamine in 100 ml of methylene chloride and heated under reflux- for 16 hours. The reaction mixture was added to 100 ml of water and extracted three times with 100 ml of methylene chloride each time. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate / hexane 1: 1). 4.75 g (26%) of l- (2,4-dichloro) -2-tetrazol-1-yl-ethanone and 7.80 g (43%) of 1- (2,4-dichlorophenyl) -2-tetrazole were obtained. 2-yl-ethanone. b) Analogously to Example Ib, after reacting 1- (2,4-dichlorophenyl) -2-tetrazol-2-yl-ethanone with n-butyl bromide, 2- [2- (2,4-dichloro-phenyl) was obtained ) -2-butoxy-vinyl] -2H- [1, 2, 4] tetrazole as a colorless oil. [M + H] + = 313.

EXAMPLE 9 2- [2- (4-Chloro-phenyl) -2-butoxy-vinyl] -2H- [1,2, 4] etrazole Analogously to Example 7a, b, after reacting 1- (4- chlorophenyl) -2-tetrazol-2-yl-ethanone with n-butyl bromide gave 2- [2- (4-chloro-phenyl) -2-butoxy vinyl] -2H-tetrazole as a colorless oil. [M + H] + = 279.

EXAMPLE 10 2- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -2H-tetrazole Analogously to Example 7a, b, after reacting 1- (2,4-dichlorophenyl) - 2-Tetrazol-2-yl-ethanone with isopropyl bromide gave 2- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -2H-tetrazole as a colorless oil. [M] + = 299.

EXAMPLE 11 2- [2- (2,4-dichloro-phenyl) -2- (4-methoxy-benzyloxy) -vinyl] -2H-tetrazole Analogously to Example 7a, b, after reacting 1- (2 , 4-dichlorophenyl) -2-tetrazol-2-yl-ethanone with 4-methoxybenzyl chloride gave 2- [2- (2,4-dichloro-phenyl) -2- (4-methoxy-benzyloxy) -vinyl] - 2H-tetrazol comp colorless oil. [M + H] + = 376.

EXAMPLE 12 1- (2,4-Dichloro-enyl) -2-tetrazol-1-yl-vinyl-benzoic acid ester Analogously to Example 7a, b, after reacting 1- (2,4-dichlorophenyl) ) -2-tetrazol-1-yl-ethanone with benzoyl chloride, 1- (2,4-dichloro-phenyl) -2-tetrazol-1-yl-vinyl-benzoic acid ester was obtained as a colorless oil. [M] + = 360 EXAMPLE 13 1- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl] -lH-tetrazole Analogously to Example 7a, b, after reacting 1- (2,4-dichlorophenyl) - 2-tetrazol-1-yl-ethanone with isopropyl triflate was obtained 1- [2- (2,4-dichloro-phenyl) -2-isopropoxy-vinyl-1H-tetrazole as a white powder with mp 82 ° C.

EXAMPLE 14 1- (2,4-Dichloro-phenyl) -2-tetrazol-1-yl-vinyl-4-dimethylamino-benzoic acid ester Analogously to Example 7a, b, after reacting 1- (2, 4-dichlorophenyl) -2-tetrazol-1-yl-ethanone with 4-dimethylamino-benzoyl chloride was obtained 1- (2,4-dichloro-phenyl) -2-tetrazol-1-yl-vinyl-4-ester -dimethylaminbenzoic acid as colorless crystals with mp 135 ° C.

EXAMPLE 15 1- [2- (2,4-Dichloro-phenyl) -2-benzyloxy-vinyl] -lH-tetrazole Analogously to Example 7a, b, after reacting 1- (2,4-dichlorophenyl) - 2-tetrazol-1-yl-ethanone with benzyl chloride was obtained 1- (2, -dichloro-phenyl) -2-benzyloxy-vinyl-1H-tetrazole as colorless crystals with mp. 92 ° C.

EXAMPLE 16 1- [2 (2, 2-Dichloro-phenyl) -2-isopropoxy-vinyl] -lH-imidazole a) Analogously to Example la, after reacting 2, 2 ', 4' -trichloroacetophenone with imidazole obtained 1- (2,4-dichlorophenyl) -2- (1H-imidazole) -1-yl-ethanone. b) Analogously to Example Ib, after reacting 1- (2,4-dichlorophenyl) -2- (lH-imidazole) -1-yl-ethanone with isopropyl bromide, 1- [2- (2, 4-dichloro-phenyl) -2-isopropoxy-vinyl] -lH-imidazole which was isolated as a salt of composition C? 4H? 4Cl2N20. HCl with m.p. 184-186 ° C. Example 17 1- [2- (2, 4-dichloro-phenyl) -2-butoxy-vinyl] -lH-imidazole Analogously to Example 16a, b after reacting 1- (2,4-dichlorophenyl) -2 - (lH-imidazole) -1-yl-ethanone with n-butyl bromide was obtained 1- [2- (2,4-dichloro-phenyl) -2-butoxy-vinyl] -IH-imidazole which was isolated as a salt of the composition C? 5H? 6Cl2N20.HCl with mp 205-207 ° C.

EXAMPLE A Tablets of the following composition are produced in the usual manner: mg / tablet Active ingredient 100 Lactose powder 95 White corn starch 35 Polyvinylpyrrolidone Carboxymethyl starch of Na 10 Magnesium stearate Tablet weight 250 EXAMPLE B Tablets of the following composition are produced in a conventional manner: mg / tablet Active ingredient 200 Lactose powder 100 White corn starch 64 Polyvinylpyrrolidone 12 Carboxymethyl starch of Na 20 Magnesium stearate Tablet weight 400 Example C Capsules of the following mg / capsule compositions are produced Active ingredient 50 Lactose crist. 60 Microcrystalline cellulose 34 Talcum 5 Magnesium stearate 1 Weight of the capsule filling 150 With the active ingredient having a suitable particle size, the crystalline lactose and the microcrystalline cellulose are mixed homogeneously with each other, sieved and lu-ego added by mixing talc and magnesium stearate. The finished mixture is filled into hard gelatin capsules of suitable size.

It is noted that in relation to this date, the best method known to the applicant for carrying out said invention is that which is clear from the present description of the invention.

Claims (11)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The use of compounds of the general formula: where : R means halogen or lower alkyl; n means 0-3; R1 means lower alkyl; cycloalkyl; benzyl optionally substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl optionally substituted by amino, lower alkylamino or lower dialkyl amino; acetyl or cycloalkyl carbonyl; and Z / si.sgnniiffiicca a 5-membered aromatic residue that is linked through an N atom and containing 1-3 additional N atoms in addition to the N-binder atom as well as its pharmaceutically acceptable salts for the production of drugs for the control or prevention of acute and / or chronic neurological disorders.

2. The use of compounds of general formula I according to claim 1, wherein: R means chlorine, n means 1 or 2, R1 means lower alkyl, cyclohexyl or benzyl and? ^) means a 5-membered aromatic ring that is linked through an N atom and contains 2 or 3 additional N atoms in addition to the N-binder atom.

3. The use of: 1- [2- (2,4-dichloro-phenyl) -2-cyclohexyloxy-vinyl] -1H [1, 2, 4] triazole, 1- [2- (2,4-dichloro-phenyl) -2-benzyloxy-vinyl] -lH-tetrazole, 2- [2- (4-chloro-phenyl) -2-butoxy-vinyl] -2H-tetrazole, l- [2- (4-chloro-phenyl) -2-butoxy-vinyl] -lH [l, 2,4] -triazole and 1- [2- (2,6-dichloro-phenyl) -2-butoxy- vinyl] -1H- [1,2,4] triazole according to claim 2.

4. The compounds of the general formula I, characterized in that they have the meanings given in claim 1 and Q. ? ^) means a 5-membered aromatic ring that is linked through an N atom and contains 3 additional N atoms in addition to the N-binder atom.

5. The compounds of the general formula I, characterized in that R and A? they have the indicated meanings according to claim 1 and R 1 is cycloalkyl.

6. 1- [2- (2,4-dichloro-phenyl) -2-cyclohexyloxy-vinyl) -1H- [1, 2,4] triazole according to claim 5.

7. A process for the preparation of compounds according to claims 4 to 6, characterized in that it comprises alkylating or acylating a compound of the formula: wherein R, n and have the meanings given in claim 1, and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt.

8. The compounds according to claims 4 to 6 for use as therapeutically active substances.

9. The use of compounds according to claims 4 to 6 in the control or prevention of diseases especially for the control or prevention of acute and / or chronic neurological disorders and, respectively, for the production of corresponding drugs.

10. A medicament characterized in that it contains one or more compounds according to claims 4 or 5 and a therapeutically inert excipient.

11. A medicament according to claim 10 for the control or prevention of diseases, especially for the control or prevention of acute and / or chronic neurological disorders. SUMMARY OF THE INVENTION The invention relates to the use of compounds of 1 general formula (I): wherein: R represents halogen or lower alkyl; n means 0-3; R means lower alkyl; cycloalkyl; benzyl optionally substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl optionally substituted by amino, lower alkylamino or lower alkylamino; acetyl or cycloalkyl-carbonyl and v ^ i - ^ means a 5-membered aromatic residue which is linked through an N atom and which contains 1-3 additional N atoms in addition to the N-binder atom as well as • also its pharmaceutically acceptable salts as substances therapeutically active, especially for the control or prevention of acute and chronic neurological disorders.