MXPA96006133A - Novel 1,1-bis(heteroazolyl)alkane derivatives and their use as neuroprotective agents - Google Patents

Abstract

The present invention relates to novel heterocyclic compounds having general fórmula (1), wherein:X1 and X2 are independently O, S or Se;Y1 and Y2 are independently C or N with the proviso that at least one of Y1 and Y2 is N;Y3 and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N;R1 and R2 each represent one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl, lower acyloxy-lower alkyl or CF3;and A is (a) or (b) geometrical and optical isomers and racemates thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof;having therapeutic activity, processes and intermediates for their preparation, pharmaceutical fórmulations containing said compounds and the medicinal use of said compounds.

Description

NEW 1, 1-BIS DERIVATIVES (HETEROAZO IDALCANO AND ITS USE AS NEUROPROTECTING AGENTS FIELD OF THE INVENTION The present invention relates to new heterocyclic compounds having therapeutic activity, with processes and intermediates for their preparation, with pharmaceutical formulations containing the compounds and the medical use of the compounds.

BACKGROUND OF THE INVENTION There is a large group of acute and chronic neuropsychiatric disorders for which safe and clinically effective treatments are currently not available. This diverse group of disorders encompasses a broad spectrum of initial events, which are characterized by the initiation of progressive processes that sooner or later lead to neuronal cell death and dysfunction. The attack, cerebral ischemia, trauma or a neurodegenerative disease such as the disease Alzheimer's or Parkinson's disease, all are commonly occurring conditions, which are associated with neurodegeneration of the brain and / or spine.

REF: 23530 The initiation of research into potential treatments of neurodegenerative disorders has involved the investigation of excitatory amino acid antagonists, inhibitors of lipid peroxidation, calcium channel antagonists, inhibitors of specific pathways of the arachidonic acid cascade, agonists layer opioids, adenocin agonists, PAF antagonists and other miscellaneous agents. Currently there is no consensus on the relative importance of the role played by the compounds belonging to any of these general classes. In a document on the reactions of the 2-halotiazoles with ketone enolates, J. F. Olfe et al. (J. Org. Chem. 1986, 5¿, 1184-1188) describe the bis (2-thiazolyl) derivatives of the following formula: In a document on the synthesis of 2-aroyloxazoles (Synthesis, 1984, 1048-1050), the following compound is described: No pharmacological activity is associated with any of the above compounds. The pattern of substitution of the above compounds places them outside the scope of the present invention. In the patent application DE 2801794 (US 4371734) a process for the preparation of thiazoles of the general formula is claimed: A specific example of thiazoles is 4-methyl-α- (4-phenyl-2-thiazolyl) -2-thiazolacetonitrile. The compounds are useful as intermediates in the preparation of certain coloring matters. No pharmacological action was attributed to the compounds. The definition of the groups R, and R2 places those compounds outside the scope of the present invention. In a paper on the synthesis of thiazoles labeled with deuterium, Russel and Metzger (Bull, Soc. Chim. Fr., 1962, 2075-2078) describe the isolation and partial characterization of 1,1-di (2-thiazolyl) ethanol. No pharmacological activity is associated with this compound. This compound is eliminated from the scope of the present invention by abandonment in claim 1.

THE PRESENT INVENTION A main objective of the present invention is to provide structurally novel heterocyclic compounds, which by virtue of their pharmacological profile are expected to be of value in the treatment of acute and chronic neuropsychiatric disorders, characterized by progressive processes that sooner or later late lead to the death of neuronal cells and dysfunction. Such disorders include seizures, cerebral ischemia; dysfunctions that result from trauma to the brain and / or the spine; hypoxia and anoxia, such as somnolence and including damage to the brain by hypoxic perinatal and neonatal asphyxia; dementia due to multiple infarctions; dementia due to AIDS; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, epilepsy, multiple sclerosis and amitrophic lateral sclerosis; cerebral dysfunction in connection with surgery involving extracorporeal circulation or in connection with surgery in the brain, including endarterectomy of the carotid arteries; and CNS dysfunctions as a result of exposure to neurotoxins or radiation. This utility is manifested, for example, by the ability of these compounds to inhibit delayed neuronal death in the model of bilateral occlusion in ischemic gerbils. The present invention relates to a compound having the general formula (1) wherein: X-j_ and X2 are independently O, S or Se; Y-j_ and Y2 are independently C or N with the proviso that at least one of Y1 and Y2 is N; Y3 and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N; R-j_ and R2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, lower hydroxyalkyl, lower acyloxy-alkyl wherein W is O, S, NH or N-lower alkyl, R3 is H, lower alkyl or lower acyl, or R3 is H, R4 is lower alkyl or perfluoro-lower alkyl, or R3 and R4 taken together form a ring where n is 2, 3 or 4, R5 and Rg independently are H or lower alkyl; geometrical and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof; with the proviso that 1,1-di (2-thiazolyl) ethanol is excluded. The term "pharmaceutically acceptable acid addition salts" is intended to include but not be limited to such salts as the hydrochloride, hydrobromide, iodohydrate, nitrate, acid sulfate, dihydrogen phosphate, ethanedisulfonate, esylate, fumarate, maleate and succinate. Preferred embodiments of this invention relate to compounds having the general formula (2) where xl and x2 are independently 0 or S; and, R1 # R2, R3 and R4 are as previously defined. More preferred embodiments of this invention relate to compounds having the general formula (3) where: xl and x2 ssn independently 0 or S; W is O, NH or N-lower alkyl; and R1 # R2, R3 and R4 are as previously defined. Analogous compounds wherein X-j_ and / or X2 are Se, for example, 1,1-bis (2-selenazolyl) -2,2,2-trifluoroethanol and 1,1-bis (2-selenazolyl) ethylamine are specifically included within the scope of the invention. Throughout the specification and the appended claims, a given chemical formula or name should embrace all geometric and optical isomers and their racemates, where such isomers exist, as well as their pharmaceutically acceptable acid addition salts and solvates thereof such as, for example, the hydrates. The following definitions should apply throughout the specification and the appended claims. Unless stated or otherwise indicated, the term "lower alkyl" means a linear or branched alkyl group having from 1 to 6 carbon atoms. Examples of the lower alkyl include straight, branched methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and pentyl and hexyl. Unless otherwise stated or indicated, the term "perfluoroalkyl lower" represents a linear or branched alkyl group having from 1 to 4 carbon atoms, fully substituted by fluorine. Examples of perfluoroalkyl groups include trifluoromethyl, pentafluoroethyl and heptafluoroisopropyl. Unless otherwise stated or indicated, the term "lower acyl" means a branched or linear acyl group having from 1 to 6 carbon atoms. Examples of the lower acyl include formyl, cetyl, propionyl, isobutyryl, valeryl, and pivaloyl. Unless otherwise stated or indicated, the term "lower hydroxyalkyl" represents a lower alkyl group as defined above, substituted by a hydroxy group. Examples of the lower hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl. Unless otherwise stated or indicated, the term "lower acyloxy-lower alkyl" means a lower alkyl group as defined above, substituted by an oxygen atom which itself carries a lower acyl group as was defined in the above. Examples of lower acyloxy-lower alkyl include acetoxy methyl, propionyloxymethyl, 1-acetoxyethyl and 2-acetoxyethyl. Unless otherwise stated or indicated, the term "lower alkoxy" represents a linear or branched alkoxy group having from 1 to 6 carbon atoms. Examples of the lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight chain or branched pentoxy and hexoxy. Unless otherwise stated or indicated, the term "lower alkoxy-lower alkyl" represents a lower alkyl group as defined above substituted by a lower alkoxy group as defined above. Examples of the lower alkoxy-lower alkyl include methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl. Among the most preferred compounds of the formula (1) according to the present invention are: 1,1-bis (4,5-dimethyl-2-thiazolyl) ethanol; 1,1-di (2-thiazolyl) -2,2,2-trifluoroethanol; and their pharmaceutically acceptable acid addition salts or solvates thereof. The present invention also relates to processes for preparing the compound having the formula (1). Throughout the following general description of such processes, it should be understood that, where appropriate, suitable protecting groups will be added to and subsequently eliminated from the various reagents and intermediates in a manner that will be readily understood by one skilled in the art of synthesis. organic Conventional procedures for using such protecting groups are described, for example, in "Protective Groups in Organic Synthesis," T. W. Greene, Wiley-Intercience, New York, 1981.

The compound wherein A is can be prepared by (a) reacting a compound of the general formula (4) with an organometallic derivative of the general formula (5) or (b) reacting a compound of the general formula (6) with an organometallic derivative of the general formula (7) or (c) reacting a compound of the general formula (8) with an organometallic derivative of the general formula R4M and the reaction mixture is stopped with a proton source (R3 is H) or an alkylating reagent (R3 is lower alkyl) or acylation (R3 is lower acyl), or (d), particularly in cases where R4 is perfluoroalkyl , reacting a compound of the general formula (8) with a derivative. silyl of the general formula R4SiMe3. Alternatively, the compound of the formula (1) where A is can be obtained first as in the above and then converted to the compound in which R3 is lower alkyl or lower acyl. Processes (a), (b) or (c) can be achieved, for example, by reacting together a ketone of structure (4) or (6) or (8) with a preformed organometallic derivative (5) or (7) or R4M respectively in a suitable anhydrous solvent such as diethyl ether, tetrahydrofuran or hexane or mixtures thereof. The reaction should be carried out at a suitable temperature, usually between -100 ° C and + 50 ° C and preferably under an inert atmosphere, usually nitrogen or argon. In a specific variation, a solution of the ketone of structure (4) or (6) or (8) in anhydrous diethyl ether or tetrahydrofuran is added in drops to the organometallic derivative (5) or (7) or R4M respectively, in anhydrous diethyl ether or tetrahydrofuran or hexane or mixtures thereof at a temperature of about -50 ° C to -78 ° C and under a nitrogen atmosphere. After a suitable period of time, the reaction mixture is allowed to warm to room temperature and then stopped by the addition of water or a lower alcohol. The required product (1) OH where A is c _ then it can be isolated and * Purify and characterize using standard techniques. Process (d) can be achieved, for example by treating a solution of the ketone (8) and the silyl derivative R4SiMe3 in a suitable anhydrous solvent such as diethyl ether or tetrahydrofuran with tetrabutylammonium fluoride. The reaction should be carried out at a suitable temperature, usually between -100 ° C and + 50 ° C and preferably under an inert atmosphere, usually nitrogen or argon. After a suitable period of time, the reaction mixture is allowed to reach room temperature and then treated with 6M hydrochloric acid. The required product (1) in which A is requendo product (1) where A is then can be isolated and purified and characterized using standard techniques. The ketones of formula (4) or (6) or (8) are either compounds which are commercially available or have been previously described in the literature, or compounds which can be prepared by the direct application of known methods. In this way, the present invention also refers to some new intermediates of the general formula (9), namely: where : Ri and R are as defined in R7 is perfluoroalkyl or and X-, and X2 are independently O, S or Se; with the proviso that the di (2-thiazolyl) ketone is excluded.

In the organometallic derivatives of the general formula (5) or (7) or R4M, M represents a metal residue such as Li or Mg-halogen. Such compounds are either commercially available or have been previously described in the literature, or can be prepared by the direct application of known methods of organometallic chemistry. The silyl derivatives of the formula R4SiMe3 are either commercially available, for example, CF3SiMe3, or have been described in the literature or can be prepared by direct application of known methods.

The compounds of the formula (1) wherein A is can be prepared by (a) the removal of H R3 from a compound of the formula (1) wherein A is where A is or (b) using a compound of the general formula (8) as the substrate for a standard alkene forming the reaction, such as the Wittig reaction, the Peterson reaction or the McMurry reaction.

The process (a) can be carried out, for example, by the treatment of a solution of a compound of the formula (1) WR where A is c 3 R * in a suitable inert solvent with an acid or a base or a reagent such as thionyl chloride or phosphorus oxychloride. The reaction should be carried out at a suitable temperature, usually between -20 ° C and the reflux temperature of the solvent. In a preferred variation, a solution of a compound of formula (1) OR where A is c 3 8n a solvent such as dichloromethane or chloroform from 0 ° C to 10 ° C is treated with an acid such as anhydrous hydrogen chloride or p-toluenesulfonic acid, or with thionyl chloride. Then the reaction is allowed to proceed at room temperature or above. The required product (1) in which A is then can be isolated and purified and characterized using standard techniques.

The compounds of formula (1) wherein A is can be prepared by (a) the use of a compound of the general formula (1) wherein as e | substrate for a • Ritter reaction, or (b) by the use of a compound of the general formula (1) wherein A is like the substrate for a Mitsunobu type reaction, or (c) reacting a compound of general formula (1) wherein A is with trimethylsilylazide, Mß3SiN3, in in the presence of a Lewis acid such as boron trifluoride diethyl ether to give an azide of the formula (1) wherein A is, and then reducing the azide using, for example, hydrogen in the presence of a palladium or platinum catalyst. Some compounds of the general formula (1) contain an asymmetric center and thus can exist in enantiomeric forms. These enantiomers can be separated using methods that are well known to those skilled in the art. Such methods include, for example, (i) direct separation by means of chiral chromatography, for example by CLAP using a chiral column; or (ii) recrystallization of the diastereoisomeric salts formed by reacting the base (1) with an optically active acid; or (iii) derivatization of the compound of the formula (1) by reaction with an optically active reagent, separation of the resulting diastereoisomeric derivatives for example, by crystallization or chromatography, followed by regeneration of the compound of the formula (1). Alternatively, the compounds of formula (1) can be obtained directly in an optically active form using a chemistry-based or enzymatic method of asymmetric synthesis.

Some compounds of general formula (1) wherein A is they can exist as the E and Z isomers (trans and cis). Such isomers can be separated using standard techniques, for example crystallization or chromatography, which will be readily apparent to one skilled in the art.

Pharmacology The neuroprotective properties of the compounds of formula (1) are exemplified by their ability to inhibit delayed neuronal death in the model of bilateral occlusion in ischemic gerbils. The animals used were mongolean gerbils (60-80 g). The drugs were dissolved in isotonic saline solution containing dimethyl sulfoxide. Ischemia was induced in the gerbils by occlusion of 5 minutes of both carotid arteries following the procedure described by R. Gilí, A. C. Foster and G. N. Woodruff, J. Neuroscience. 1987, 7, 3343-3349. The body temperature was maintained at 37 ° C throughout the experiment. Restoration of blood flow after occlusion was verified visually and animals were allowed to survive for 4 days. The extent of Neuronal degeneration in the hippocampus is then evaluated. Test compounds were administered (i.p.) as a single dose 60 minutes after occlusion. No administration was made before occlusion. The effectiveness of the compounds of the formula (1) in decreasing the damage to CA1 / CA2 hippocampal neurons in gerbils after ischemic damage clearly illustrates the utility of these compounds in preventing neurodegeneration. These compounds are therefore expected to be of value in the treatment of acute and chronic neuropsychiatric disorders characterized by progressive processes that sooner or later lead to neuronal cell death and dysfunction.

Pharmaceutical Formulations Administration in the novel method of the treatment of this invention may conveniently be oral, rectal, topical or parenteral at a dosage level for example, from about 0.01 to 1000 mg / kg, preferably from about 1.0 to 500 mg / kg. and especially from about 5.0 to 200 mg / kg and can be administered in a regimen of 1 to 4 doses or treatments per day. The dose will depend on the route of administration, with the preferred routes being oral administration or intravenous administration. It will be appreciated that the severity of the disease, the age of the patient and other factors normally considered by the attending physician, will influence the individual regimen and dose most appropriate for a particular patient. The pharmaceutical formulations comprising the compound of this invention may conveniently be tablets, pills, capsules, syrups, powder or granules for oral administration, sterile parenteral solutions or suspensions for parenteral administration; suppositories for rectal administration; or suitable topical formulations. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Desing", ME Aulton, Churchill Livingstone, 1988. To produce pharmaceutical formulations containing a compound according to the present invention in the form of dosage unit for oral application, the active substance can be mixed with an adjuvant / carrier for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, can be coated with a concentrated sugar solution which may contain eg "gum arabic, gelatin, talcum, titanium dioxide and the like." Alternatively, the tablet it can be coated with a polymer known to man skilled in the art, dissolved in an easily volatile organic solvent or a mixture of organic solvents.The coloring matters can be added to these coatings to easily distinguish between the tablets containing the active substances or different amounts of the active compounds For the preparation of soft gelatin capsules, the active substance can be mixed, for example, with vegetable oil or polyethylene glycol.The hard gelatine capsules can contain granules of the active substance using either the excipients mentioned in the above for tablets, for example, lactose , sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Also liquids or isólidos of the drug can be filled in hard gelatin capsule.

The dosage units for rectal application can be solutions or suspensions or they can be prepared in the form of suppositories, which comprise the active substance in mixture with a neutral fat base, or rectal gelatin capsules, which comprises the active substance in admixture with the vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.02% to about 20% by weight of the active substance described herein, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to man in the art. Solutions for parenteral applications by injection can be prepared in an aqueous solution of a pharmaceutically acceptable salt., 'soluble in water of the active substance, preferably in a concentration of about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents and may involve the use of agents that act on the surface to improve solubility. Conveniently they can be provided in various dose unit vials. Except where otherwise indicated, the initial materials needed for all preparations and examples were purchased commercially.

PREPARATION 1 4-methyl-2-trifluoroacetylthiazole N-Butyllithium (2.5 M solution in hexane 40.4 mL) is added in drops to a stirred solution of 4-methylthiazolo (10 g) in anhydrous tetrahydrofuran at -70 ° C under an atmosphere of dry nitrogen. After 30 minutes, ethyl trifluoroacetate (12 ml) is added dropwise. After a further 2 hours the mixture is allowed to warm to room temperature and is allowed to stir overnight. The saturated aqueous ammonium chloride solution is added and the organic phase is separated, dried and evaporated to dryness. The residue is purified by flash chromatography to give the corresponding hydrate for the title compound as a white solid. P.f. 77-81 ° C. 13 C NMR (d6-DMSO) 16.4, 91.1 (c J 32Hz), 116.3, 122.2 (c, J 287Hz), 152.0 and 166.6 ppm.

Found: C, '33 .8; H, 2.7; N, 6 6 CgH6F3N02S requires: C, 33.8; H, 2.8; N, 6.6%. Following the general method of Preparation 1 and using the appropriate thiazole, the compounds of Preparations 2 and 3 are prepared.

PREPARATION 2 4,5-Dimethyl-2-trifluoroacetylthiazole (as the corresponding hydrate) P.f. 84-86 ° C. Found: C, 37.15; H, 3.4; N, 5.9. 7HgF3N02S requires: C, 37.0; H, 3.55; N, 6.2% PREPARATION 3 2-trifluoroacetylthiazole (as the corresponding hydrate) P.f. 80-82 ° C. 13 C NMR (dg-DMSO) 91.7 (c, J 32Hz), 122.4, 122.7 (c, J 287Hz), 142.9 and 167.9 ppm.

PREPARATION 4 2-Acetyl-5- (2-methoxyethyl) -4-methylthiazole From 5- (2-methoxyethyl) -4-methylthiazole and ethyl acetate, following the procedure of Preparation 1. 13C NMR (CDC13) 15.1, 25.6 , 27.6, 58.7, 71.9, 137.9, 151.6, 163.0 and 191.5 ppm.

PREPARATION 5 - (2-methoxyethyl) -4-methyl-2-trifluoroacetylthiazole From 5- (2-methoxyethyl) -4-methylthiazole and ethyl trifluoroacetate, following the procedure of Preparation 1. 13C NMR (CDC13) 15.2, 27.8 , 58.6, 71.3, 116.2 (c, J 288Hz), 142.2, 154.1, 155.8 and 173.0 (c, J 36Hz) ppm.

PREPARATION 6 -methyl-2-trifluoroacetyloxazole 1-Trifluoroacetylimidazole (10 g) is added to a stirred solution of 4-methyl-2-trimethylsilyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258) (9.95 g) in diethyl ether (100 ml). at 0 ° C. After 20 hours, water is added. The organic phase is separated, dried and evaporated and the residue is purified by flash chromatography to give the title compound as the corresponding hydrate. 13 C NMR (dg-DMSO) 11.0, 89.5, (c, J 33Hz), 122.3 (c, J 287Hz), 136.0, 136.1 and 158.6 ppm.

PREPARATION 7 Bis (4-methyl-5-thiazolyl) ketone N-Butyllithium (2.5 M solution in hexane, 12.8 mL) is added in drops to a stirred solution of 4-methyl-2-trimethylsilylthiazole (5 g) in tetrahydrofuran / diethyl ether / pentane (4: 4: 1, 75 ml). ) at -100 ° C under an atmosphere of dry nitrogen. After 90 minutes, 4-methyl-5-thiazolecarbaldehyde (J. Amer. Chem. Soc., 1982, 104, 4934-4943) (4 g) is added. After a further 3 hours at -100 ° C, water is added and the mixture is heated to room temperature. A solution of saturated aqueous ammonium chloride is added and the organic phase is separated, dried and evaporated. The residue is crystallized from ethyl acetate to give bis (4-methyl-5-thiazolyl) methanol. This dichloromethane material is oxidized using manganese dioxide to give the title compound. NMR H1 (CDC13) 2.73 (6H, s) and 8.85 (2H, s) ppm.

PREPARATION 8 Bis (4-methyl-2-oxazolyl) ketone Trifosgen (2.9 g) in anhydrous dichloromethane (25 ml) is added in drops to a stirring solution of 4-methyl-2-trimethylsilyloxazole (10 g) in dichloromethane (50 ml) at 0 ° C. Then the mixture is stirred overnight at room temperature. A solution of saturated anhydrous ammonium chloride is added. The organic phase is separated, washed, dried and evaporated. Purification by flash chromatography then gives the title compound. 13 C NMR (CDC13) 11.7, 138.7, 140.2, 155.9 and 164.6 ppm.

EXAMPLE 1 1, 1-bis (4-methyl-2-thiazolyl) ethanol N-butyllithium (2.5M solution in hexane, 44.4 ml) is added in drops to a stirred solution of 4-methylthiazole in anhydrous tetrahydrofuran (100 ml) at -70 ° C under an atmosphere of dry nitrogen. After 30 minutes ethyl acetate (4 g) in tetrahydrofuran (25 ml) is added dropwise. After another hour, the mixture is allowed to warm to room temperature and then allowed to stir overnight. A saturated aqueous sodium hydrogen carbonate solution is added and the organic phase is separated. Then another processing in the usual way and crystallization from diethyl ether gives the title compound. P.f. 82-84 ° C 13 C NMR (CDCl 3) 17.0, 31.2, 76.1, 114.7, 152.2 and 174.4 ppm. The treatment with anhydrous hydrogen chloride in diethyl ether to give the corresponding hydrochloride P.f. 135 ° C (decomposition). 13 C NMR (dg-DMSO) 16.3, 28.9, 75.2, 115.6, 150.8 and 175.5 ppm. Following the general method of Example 1 and using the appropriate thiazole with the appropriate ether, the compounds of Examples 2 to 5 are prepared.

EXAMPLE 2 1. l-bis (4,5-dimethyl-2-thiazolyl) ethanol P.f. 143-144 ° C. 13 C NMR (CDCl 3) 11.2, 14.6, 30.8, 75.8, 127.5, 147.3 and 170.3 ppm. Found: C, 53.7; H, 5.95; N, 10.3. C12H16N2OS2 requires C, 53.7; H, 6.0; N, 10.4% hydrochloride, m.p. 146-147 ° C. Found: C, 47.2; H, 5.7; N, 9.0.

C12H16N2OS2-HCl requires C, 47.3; H, 5.6; N, 9.2%.

EXAMPLE 3 1, 1-bis (4,5-dimethyl-2-thiazolyl) -2, 2-dimethyl-1-propanol P.f. 91-92 ° C. 13 C NMR (CDC 13) 11.6, 15.1, 26.0, 40.5, 83.1, 127.7, 146.8 and 168.4 ppm. Hydrochloride, p.f. 160-162 ° C. Found: C, 51.8; H, 6.7; N, 7.9.

C15 22N2OS2-HCl requires C, 52.0; H, 6.7; N, 8.1%.

EXAMPLE 4 1, 1-bis (4,5-dimethyl-2-thiazolyl) -2-methyl-1-propanol P.f. 106-108 ° C. 13 C NMR (CDCl 3) 11.2, 14.6, 16.5, 40.0, 81.0, 127.2, 146.8 and 170.1 ppm.

Hydrochloride, p.'f. 169-171 ° C. Found: C, 50.5; H, 6.4; N, 8.4.

C14H20N2OS2-HC1 requires C, 50.5; H, 6.4; N, 8.%.

EXAMPLE 5 1, 1-bis- (4-methyl-2-thiazolyl) -2,2-dimethyl-l-propanol hydrochloride P.f. 190-193 ° C (decomposed) 13 C NMR (dg-DMSO) 16.5, 25.4, 40.0, 82.3, 115.6, 150.2 and 172.5 ppm. Found: C, 49.0; H, 6.1; N, 8.65. i3H18 2OS2 -HC1 requires C, 49.0; H, 6.0; N, 8.8%.

EXAMPLE 6 l.1-di (2-thiazolyl) ethanol N-Butyllithium (2.5M solution in hexane, 17.3 ml) is added in drops to a stirring solution of 2-bromothiazole. (6.5 g) in anhydrous diethyl ether (40 ml) at -70 ° C under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiazole (5 g) in diethyl ether (10 ml) is added in drops. After another hour, the mixture is allowed to warm to room temperature. After 1 hour, a saturated aqueous sodium acid carbonate solution is added and the organic phase is separated. Then another processing in the usual way gives the title compound. P.f. 146-147 ° C. 13 C NMR (CDC13) 31.4, 76.4, 120.3, 142.0 and 175.2 ppm. Found: C, 45.1; H, 3.5; N, 13.0, CgHgN2OS2 requires C, 45.2; H, 3.8; N, 13.2%. Hydrochloride, p.f. 137-140 ° C (decomposition). 13 C NMR (dg-DMSO) 28.8, 75.4, 120.6, 142.0 and 176.0 ppm. Following the general method of Example 6, the compounds of Examples 7 to 13 are prepared.

EXAMPLE 7 1- (4-methyl-2-oxazolyl) -1- (2-thiazolyl) ethanol From 2-bromothiazole and 2-acetyl-4-methyloxazole (J. Chem. Soc., Chem. Commun., 1984, 258). 13 C NMR (CDCl 3) 11.3, 27.9, 73.1, 119.9, 135.4, 136.4, 142.6, 164.6 and 174.1 ppm.

"EXAMPLE 8 1. 1-di- (2-thiazolyl) -2,2.2-trifluoroethanol From 2-bromothiazole and 2-trifluoroacetylthiazole. P.f. 113-115 ° C. 13 C NMR (dg-DMSO) 77.3 (c, J 30Hz), 122.8, 123.0 (c, J 286Hz), 142.7 and 166.1 ppm. Found: C, 36.25; H, 1.7; N, 10.5. CgH5F3N2OS2 requires C, 36.1; H, 1.9; N, 10.5%.

EXAMPLE 9 1, 1-bis (4,5-dimethyl-2-thiazolyl) -2.2.2-trifluoroethanol From 4,5-dimethylthiazole and 4,5-dimethyl-2-trifluoroacetylthiazole. P.f. 122-123.5 ° C .. • 13C NMR (dg-DMSO) 10.5, 14.4, 76.9 (c, J 30Hz), 123. 1 (c, J 286Hz), 129.0, 147.9 and 161.0 ppm.

EXAMPLE 10 1, 1-bis (4-me-il-2-thiazolyl) -2,2.2-trifluoroethanol From 4-methylthiazole and 4-methyl-2-trifluoroacetylthiazole and using anhydrous tetrahydrofuran as solvent. P.f. 140-142.5 ° C. 13C NMR (CDC13) 17.0, 77.5 (c, J 31Hz), 117.1, 122. 6 (c, J 284Hz), 152.5 and 163.9 ppm.

EXAMPLE 11 1, 1-bis (5- (2-methoxyethyl) -4-methyl-2-thiazolyl) ethanol From 5- (2-methoxyethyl) -4-methylthiazole and 2-acetyl-5- (2-methoxyethyl) -4-methylthiazole. P.f. 50-51 ° C. 13 C NMR (CDC 13) 14.8, 27.0, 30.8, 58.5, 72.4, 75.8, 129. 3, 147.6 and 171.3 ppm.

EXAMPLE 12 1. 1-bis (5- (2-methoxyethyl) -4-methyl-2-thiazolyl) -2.2.2-trifluoroethanol From 5- (2-methoxyethyl) -4-methylthiazole and 5- (2-methoxyethyl) -4 -methyl-2-trifluoroacetylthiazole. P.f. 68-69 ° C. 13 C NMR (dg-DMSO) 14.6, 26.0, 57.7, 71.4, 77.0 (c, J 30Hz), 123.1 (c, J 286Hz), 131.4, 148.1 and 162.0 ppm.

EXAMPLE 13 1- (2,4-dimethyl-5-thiazolyl) -1- (2-thiazolyl) ethanol 13 C NMR (CDC 13) 16.3, 18.7, 31.6, 73.6, 119.9, 136.4, 142.2, 148.3, 162.7 and 176.9 ppm.

EXAMPLE 14 1, 1-bis (4-methyl-5-thiazolyl) -2,2, 2-trifluoroethanol (Trifluoromethyl) trimethylsilane (494 μl) is added to a stirred solution of bis (4-methyl-5-thiazolyl) ketone. (500 mg) in anhydrous tetrahydrofuran (20 ml) at room temperature. After 1 hour, tetrabutylammonium fluoride (300 mg) is added. The mixture is stirred for 2 hours and then 3M hydrochloric acid is added. After 10 minutes the reaction mixture is adjusted to a pH of 10 by the addition of 5M potassium hydroxide. The organic phase is separated and then worked up in the usual way to give the title compound. 13 C NMR (dg-DMSO) 15.9, 73.7 (c, J 31Hz), 124.9 (c, J 285Hz), 128.0, 152.1 and 152.8 ppm.

EXAMPLE 15 1. 1-bis (4-methyl-2-oxazolyl) -2.2.2-trifluoroethanol Following the method of Example 14 and using bis (4-methyl-2-oxazolyl) ketone and dichloromethane as the solvent, the title compound is prepared. 13C NMR (CDC13) 14.7, 76.8 (c, J 32Hz), 125.9 (c, J 285Hz), 140.5, 140.8 and 160.1 ppm.

EXAMPLE 16 1- (2,4-dimethyl-5-thiazolyl) -1- (4-methyl-2-thiazolyl) ethanol N-Butyllithium (2.5M solution in hexane, 5.1 ml) is added in drops to a stirring solution of 4-methyl-2-trimethylsilylthiazole (from 4-methylthiazole, n-butyllithium and trimethylsilyl chloride) (2 g). in anhydrous tetrahydrofuran (40 ml) at -70 ° C under an atmosphere of dry nitrogen. After 30 minutes, 5-acetyl-2,4-dimethylthiazole (2 g) in tetrahydrofuran (10 ml) is added dropwise. After 1 hour the mixture is allowed to warm to room temperature.

After a further 2 hours, a saturated aqueous ammonium chloride solution is added. The organic phase is separated, washed, dried and evaporated. The residue is dissolved in tetrahydrofuran (2 mL) and tetrabutylammonium fluoride (640 mg) is added. The mixture is stirred overnight and then worked up in the usual way to give the title compound. 13 C NMR (CDC 13) 16.4, 17.0, 18.7, 31.5, 73.3, 114.4, 136.3, 148.2, 152.3, 162.6 and 175.7 ppm. Found: C, 51.7; H, 5.4; N, 10.8. C11H14N2OS2 requires C, 51.9; H, 5.55; N, 11.0%.

EXAMPLE 17 1, 1-bis (4,5-dimethyl-2-thiazolyl) -2,2,2-trifluoro-ethyl acetate Acetyl chloride (0.68 ml) is added to a solution of 1,1-bis (4,5-dimethyl-2-thiazolyl) -2,2,2-trifluoroethanol (1.54 g) and 4-dimethylaminopyridine (2 g) in dry dichloromethane (70 ml). The mixture is stirred at room temperature overnight and then washed with a saturated aqueous acidic carbonate solution. The organic phase is separated, dried and evaporated and the residue is purified by flash chromatography to give the title compound. P.f. 163-164 ° C. Found: C, 45.9; H, 4.0; N, 7.4. C14H15F3N202S2 requires C, 46.15; H, 4.15; N, 7.7%.

EXAMPLE 18 1, 1-di (2-thiazolyl) -2, 2, 2-trifluoroethyl acetate Starting from 1,1-di (2-thiazolyl) -2,2,2-trifluoroethanol using the method of Example 17. P.f. 82-84 ° C. 13C NMR (CDC13) 21.2, 81.4 (c, J 31Hz), 121.4 (c, J 284Hz), 122.5, 142.2, 161.1 and 167.5 ppm.

EXAMPLE 19 1-Azido-l- (2,4-dimethyl-5-thiazolyl) -1- (2-thiazolyl) ethane 1- (2,4-Dimethyl-5-thiazolyl) -1- (2-thiazolyl) ethanol (200 mg) is suspended in benzene (2 ml) at room temperature. Diphenylphosphoryl azide (212 μl) is added, followed by 1,8-diazabicyclo [5, 4, 0] undec-7-ene (152 μl). The mixture is stirred at room temperature for 72 hours and then diluted with ethyl acetate and water. Then work in the usual way including flash chromatography for the title compound. 13 C NMR (CDCl 3) 16.4, 18.9, 28.4, 64.9, 120.3, 132.4, 143.0, 149.4, 163.3 and 172.3 ppm.

EXAMPLE 20 1- (2,4-Dimethyl-5-thiazolyl) -1- (2-thiazolyl) ethylamine The product of Example 19 is hydrogenated in ethanol, in the presence of 10% palladium on carbon to give the title compound. 3-H NMR (CDCI3) 2.02, 2.08 and 2.61 (each 3H, s), 2.23 (2H, broad s) and 7.28 and 7.73 (each 1H, d, J 3Hz) ppm.

EXAMPLE 21 1, 1-di (2-thiazolyl) -2,2, 2- trifluoroethylmethylether 1, 1-di (2-thiazolyl) -2,2,2-trifluoroethanol is added (1 g) to a stirring suspension of sodium hydride (80%, 225 mg) in dry dimethoxyethane (50 ml) at 0 ° C. After minutes, methyl iodide (2.1 g) is added in drops. The mixture is allowed to warm to room temperature and is allowed to stir overnight. The mixture is concentrated by evaporation, then purified in a saturated aqueous sodium chloride solution and extracted with dichloromethane. The material thus obtained is purified by flash chromatography to give the title compound as a white solid (950 mg). P.f. 40-41 ° C. 13 C NMR (CDC13) 54.9, 82.9 (c, J 30Hz), 122.2, 122.8 (c, J 287Hz), 143.2 and 163.6 ppm. Found: C, 38.7; H, 2.4; N, 9.9. CgH7F3N2OS2 requires C, 38.6; H, 2.5; N, 10.0%.

EXAMPLE 22 1,1-di (5-thiazolyl) -2,2,2-trifluoroethanol N-Butyllithium (2.5M solution in hexane, 13.9 ml) is added in drops to a stirring solution of 2-tri-ethylsilylthiazole (5 g) in tetrahydrofuran / diethyl ether / anhydrous pentane (4: 4: 1, 75 ml). -100 ° C under an atmosphere of dry nitrogen. After 1 hour, trifluoroacetic anhydride (3 g) is added in drops in the above solvent mixture (15 ml). After a further 3 hours at -100 ° C, water is added and the mixture is heated to room temperature. A saturated aqueous ammonium chloride solution is added and the organic phase is separated, dried and evaporated. Flash chromatography followed by recrystallization from diethyl ether gives the title compound as a white solid. P.f. 109-110 ° C. 13 C NMR (CDCl 3) 74.5 (c, J 33Hz), 123.9 (c, J 286Hz), 138.1, 142.0 and 155.0 ppm. Found: C, 36.1; H, 1.9; N, 10.3. CgH5F3N2OS2 requires C, 36.1; H, 1.9; N, 10.5% EXAMPLE 23 l, l-di (4-thiazolyl) -2,2, 2-trifluoroethanol N-butyllithium (2.5M solution in hexane, 2.5 ml) is added in drops to a stirring solution of 4-bromo-2-trimethylsilylthiazole (Synthesis, 1986, 757) (1.5 g) in anhydrous diethyl ether (25 ml) at -78 ° C under an atmosphere of dry nitrogen. After 30 minutes, trifluoroacetic anhydride (300 μl) is added in drops. After another hour at -78 ° C, the mixture is warmed to room temperature. After 1 hour, hydrochloric acid (1M, 10 ml) is added and the mixture is stirred for 1 hour. Then the organic phase is separated. The material thus obtained is purified by flash chromatography to give the title compound as a white solid. P.f. 87-89 ° C. 13 C NMR (CDCl 3) 75.6 (c, J 31Hz), 118.6, 123.9 (c, J 286Hz), 152.4 and 152.6 ppm.

EXAMPLE 24 1- (4-methyl-2-thiazolyl) -1- (2-thiazolyl) -2,2.2-trifluoroethanol From 4-methylthiazole and 2-trifluoroacetylthiazole using the general method of Example 6. P.f. 89-90 ° C.

PHARMACEUTICAL EXAMPLES The following examples illustrate pharmaceutical compositions suitable for use in the method of the invention.

Composition 1 - Tablets Compound of Example 8 10 g Lactose 94 g Microcrystalline cellulose 86 g Polyvinyl pyrrolidone 8 g Magnesium stearate 2 g The compound of Example 8, lactose, cellulose and polyvinylpyrrolidone are screened and mixed. The magnesium stearate is screened and then mixed into the above mixture. The compression uses suitable punches then producing 1000 tablets each containing 10 mg of the active ingredient. If desired, the obtained tablets can then be film coated.

Composition 2 - Tablets Compound of Example 8 50 g Lactose 80 g Microcrystalline cellulose 20 g Potato starch 40 g Polyvinylpyrrolidone 8 g Magnesium stearate 2 g The compound of Example 8, lactose, cellulose and part of the starch are mixed and granulated with 10% starch paste. The resulting mixture is dried and mixed with residual starch, polyvinylpyrrolidone and sieved magnesium stearate. The resulting mixture is then compressed to give 1000 tablets, each containing 50 mg of the active ingredient.

Composition 3 - Capsules Compound of Example 8 100 g Pregelatinized starch 98 g Magnesium stearate 2 g The compound of Example 8 and the starch are screened, mixed together and then lubricated with the sieved magnesium stearate. The mixture is used to fill 1000 hard gelatin capsules of an appropriate size. Each capsule contains 100 mg of the active ingredient.

Composition 4 - Formulation for Invention Compound of Example 8 0.5 to 10 g Polyethoxylated castor oil 15 g Water for injection ad 100 g The sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted to that of maximum stability and / or facilitate the solution of the compound of the invention, using diluted acid or alkali or by the addition of suitable buffer salts. Antioxidants and metal chelating salts may also be included.

The solution is prepared, clarified and filled in appropriately sized bottles and sealed. The formulation is sterilized by heating in an autoclave. Alternatively, the solution can be sterilized by filtration and filled in sterile bottles under aseptic conditions. The solution can be packaged under a blanket of nitrogen.

Composition 5 - Formulation for Invention Compound of Example 8 0.5 to 10 g Polyethoxylated castor oil 15 g Propylene glycol 20 g Polyoxyethylene-polyoxypropylene block copolymer (Pluronic F68) 10 g Water for injection ad 100 g The compound of the invention is added to a mixture of polyethoxylated castor oil, propylene glycol and Pluronic F68. The mixture is heated gently until a clear solution is obtained. This solution is sterilized by heating in an autoclave or alternatively, by the filtration process. A concentrated sterile solution is thus obtained, which is suitable for dilution with sterile water to form a composition suitable for parenteral administration.

Composition 6 - "Formulation for Invention Compound of Example 8 0.5 to 10 g Hydroxypropyl-β-cyclodextrin 10 g Water for injection ad 100 g Water for injection is added to a mixture of the compound of the invention and hydroxypropyl-β-cyclodextrin. The mixture is stirred gently until a clear solution is obtained. The solution is filled into the bottles which are then sealed and sterilized by heating in an autoclave or alternatively by the filtration process.

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. Having described the invention as above, property is claimed as contained in the following:

Claims (13)

CLAIMS 1. A compound having the general formula (1) characterized in that: X-j_ and X2 are independently O, S or Se; Y-L and Y2 are independently C or N with the proviso that at least one of Y ^ and Y2 is N; Y3 and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N; R-j and R 2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxyalkyl, lower acyloxy-lower alkyl or CF3; wherein W is O, S, NH or N-lower alkyl, R3 is H, lower alkyl or lower acyl, or WR3 is H, R4 is lower alkyl or perfluoroalkyl lower, or R3 and R4 taken together form a ring where n is 2, 3 or 4, R5 and Rg independently are H or alkyl : er? or; 5 geometric and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof. with the proviso that 1, 1-di (2-thiazolyl) ethanol is
1. . J excluded.
2. The compound according to claim 1, characterized in that it has the general formula (2) _ wherein: X1 and X2 are independently 0 or S, and W, R1, R2, R3 and R4 are as defined in claim 1.
3. 3. The compound in accordance with 5 claim 1, characterized in that it has the general formula (3) wherein: X1 and X2 are independently 0 or S; i J is 0, NH or lower N-alkyl; and R1, R2, R3 and 4 are as defined in claim 1.
4. . A compound according to claim 15, characterized in that it is 1,1-bis (4,5-dimethyl-2-thiazolyl) ethanol; 1,1-di (2-thiazolyl) -2,2,2-trifluoroethanol; its acid addition salts and pharmaceutically acceptable solvates thereof.
5. 5. The process for preparing a compound according to claim 1, characterized in that , OR3 (I) in the case where A is 4 (a) reacting a compound of the general formula (4) with an organometallic derivative of the general formula (5) or (b) reacting a compound of the general formula (6) with an organometallic derivative of the general formula (7) or (c) reacting a compound of the general formula (8) with an organometallic derivative of the general formula R ^ M and the reaction mixture is stopped with a proton source (R3 is H) or an alkylating reagent (R3 is lower alkyl) or acylation (R3 is lower acyl), or (d), particularly in cases where R4 is perfluoroalkyl reacting a compound of the general formula (8) with a silyl derivative of the general formula R4SiMe3; (II) in the case where R3 is lower alkyl or lower acyl where compound A is obtainable first as in the above and then converted to the compound in which R3 is lower alkyl or lower acyl; (III) in the case where A is by (a) removal of HWR3 from a compound of the formula (1) WR3 where A is cC ^ or (b) by the use of a compound of general formula (8) as the substrate for a reaction to form a standard alkene; or (a) the use of a compound of general formula (1) wherein A is c as in the substrate for a Ritter reaction, or (b) by the use of a compound of the general formula (1) wherein OH A is C? as in the substrate for a reaction of itsunobu type R4 or (c) reacting a compound of the general formula (1) wherein A is with trimethylsilylazide and a Lewis acid, and then reduce the resulting azide,
6. A compound that has the general formula (9) in do X-j_ and X2 are independently 0, S or Se; and R1 and R2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxyalkyl, lower acyloxy-lower alkyl or CF3; with the proviso that di (2-thiazolyl) ketone is excluded.
7. 7. A pharmaceutical formulation containing a compound having the general formula (1) where: X-j_ and X2 are independently 0, S or Se; Y- ^ and Y2 are independently C or N with the proviso that at least one of Y-j_ and Y2 is N; Y3 and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N; R- ^ and R2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxyalkyl, lower acyloxy-lower alkyl or CF3; wherein W is 0, S, NH or N-lower alkyl, R3es H, lower alkyl or lower acyl, or R3 is H, R4 is lower alkyl or perfluoroalkyl lower, or R3 and R4 taken together form a ring wherein n is 2, 3 or 4, R5 and R6 independently are H or lower alkyl; geometric and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof, as an active ingredient and a pharmaceutically acceptable carrier.
8. 8. A compound that has the general formula where X-j_ and X are independently 0, S or Se; Y-j_ and Y are independently C or N with the proviso that at least one of Y _ and Y2 is N; Y and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N; R.j_ and R2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxyalkyl, lower acyloxy-lower alkyl or CF3; wherein is 0, S, NH or N-lower alkyl, R3es H, lower alkyl or lower acyl, or WR3 is H, R4 is lower alkyl or perfluoroalkyl lower, or R3 and R4 taken together form a ring wherein n is 2, 3 or 4, R5 and Rg independently are H or lower alkyl; geometric and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof, for use in therapy.
9. 9. A compound according to claim 8, for use as an agent for the treatment of acute and chronic neuropsychiatric disorders, characterized by progressive processes that sooner or later lead to neuronal cell death and dysfunction.
10. 10. The compound according to claim 9, for the treatment of attack, cerebral ischemia; dysfunctions that result from trauma to the brain and / or spine; hypoxia and anoxia; dementia due to multiple infarctions; dementia due to AIDS; neurodegenerative diseases; brain dysfunction in relation to surgery; and CNS dysfunctions as a result of exposure to eurotoxins or radiation.
11. 11. The use of a compound having the general formula (1) where x ^ and? 2 are independently O, S or Se; Y-j_ and Y2 are independently C or N with the proviso that at least one of Y- ^ and Y2 is N; Y3 and 4 are - "independently C or N with the proviso that at least one of Y and Y4 is N; Rl and R2 ca ^ a represents one or more groups independently selected from H, lower alkyl, lower alkoxy-alkyl lower, lower hydroxyalkyl, lower acyloxy-lower alkyl or CF3; wherein W is 0, S, NH or N-lower alkyl, R3 is H, lower alkyl or lower acyl, or WR3 is H, R4 is lower alkyl or perfluoroalkyl lower, or 3 and R4 taken together form a ring wherein n is 2, 3 or 4, R5 and R independently are H or lower alkyl; geometric and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof for the manufacture of a medicament for the treatment of acute and chronic neuropsychiatric disorders, characterized by progressive processes that will sooner or later lead to neuronal cell death and dysfunction.
12. 12. The use according to claim 11, for the manufacture of a medicament for the treatment of attack, cerebral ischemia; dysfunctions that result from trauma to the brain and / or spine; hypoxia and anoxia; dementia due to multiple infarctions; dementia due to AIDS; neurodegenerative diseases; brain dysfunction in relation to surgery; and CNS dysfunctions as a result of exposure to neurotoxins or radiation.
13. 13. A method for the treatment of acute and chronic neuropsychiatric disorders characterized by progressive processes that sooner or later lead to the death of neuronal cells and dysfunction by administration to a host in need of such treatment, a sufficient amount of a compound which has the general formula (1) where X ^ and X2 are independently 0, S or Se; Y-_ and Y2 are independently C or N with the proviso that at least one of Y-, and Y2 is N; Y3 and Y4 are independently C or N with the proviso that at least one of Y3 and Y4 is N; R-j and R 2 each represents one or more groups independently selected from H, lower alkyl, lower alkoxy-lower alkyl, hydroxyalkyl, lower acyloxy-lower alkyl or CF3; wherein W is 0, S, NH or N-lower alkyl, R3 is H, lower alkyl or lower acyl, or R3 is H, R4 is lower alkyl or perfluoroalkyl lower, or R3 and R4 taken together form a ring wherein n is 2, 3 or 4, R5 and R6 independently are H or lower alkyl; geometric and optical isomers and racemates thereof, where such isomers exist as well as their acid addition salts and pharmaceutically acceptable solvates thereof.