Thiazoleethanol, methods for their preparation, drug intermediates to obtain theatlanticwire.com

 

(57) Abstract:

The invention relates to new theatlanticwire.com General formula I, where R1means a sulfur atom, R2means hydrogen, -R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH(R8)-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-SO-, -CH2-CH2-CH2-SO2- and so on, R7means polyfluoroankyl or polyporales, R8means hydroxyl, R9means benzyl, R10means alkyl, -CH2HE-Sooma, -COOH or-CONH2their isomers, racemates, enantiomers and salts with inorganic or organic acid. Method of producing compounds of the formula I, in which the thiocyanate of an alkali metal or selenocyanate alkali metal is injected into the interaction with a derivative of formula II; or the compounds of formula I, in which2means hydrogen, -R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH(R8) and R8means hydroxyl, obtained by recovery of the corresponding compounds of formula I in which R2means hydrogen and R3-R4-R5-R6- on the rod, -R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-SO-, -CH2-CH2-SO2-CH2and so on, is obtained by oxidation of the corresponding compounds of formula I in which R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-S-, -CH2-CH2-S-CH2- obtained product is isolated and, if necessary, turn into salt. Drug with anticonvulsant effect, containing a compound of formula I or its pharmaceutically acceptable salt with an inorganic or organic acid and a pharmaceutically acceptable carrier. Derivative of the formula II in which R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-S - etc.,, R7means polyfluoroankyl or polyporales, R8means hydroxyl, R9means benzyl, R10means alkyl, -CH2OH, -COOMe, -COOH or-CONH2. Technical result: accepting new theatlanticwire.com. 4 C. and 5 C.p. f-crystals.

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The invention relates to compounds of formula (I)

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their isomers, racemates, enantiomers, their salts, processes for their receipt is on;

R2means a hydrogen atom or alkyl;

-R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CO-,

CH2-CH2-CH2-CH(R8)-, -CH2-CH2-CH2-Se-, -CH2-CH2-Se-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-SO, -CH2-CH2-CH2-SO2-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-,

-CH2-CH2-CO-CH2, -CH2-CH2-CH(R8)-CH2, -CH2-CH2-S-CH2-, -CH2-CH2-SO CH2-,

-CH2-CH2-SO2-CH2-, -CH2- (ALK)(ALK')-S-CH2-, -CH2- (ALK)(ALK')-SO-CH2-,

-CH2- (ALK)(ALK')-SO2-CH2-, -CH2-CH(R10)-S-CH2, -CH2-CH(R10)-SO-CH2-,

-CH2-CH(R10)-SO2-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-;

R7means polyfluoroankyl or polyporaceae;

R8means hydroxyl;

R9means a hydrogen atom, or alkyl, or benzo is LK' means alkyl.

In the above and the following definitions, unless otherwise stated, the alkyl radicals and the alkyl parts contain 1 to 6 carbon atoms in linear or branched chains.

From politcially radicals can be called trifluoromethyl, 2,2,2-trifluoromethyl, 1,1,2,2-tetraborates, perforated, performaer, performatic.

From poliferation radicals can be called triptoreline, perforators, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethoxy, 2,2,3,3,3-pentafluoropropane, partocracy, perforbalance.

Preferred polyporaceae and polyporaceae radicals are trifluoromethyl, triptoreline, pentaverate.

The invention relates also to the salts of joining compounds of formula (I) with inorganic and organic acids.

The compounds of formula (I) which contain one or more asymmetric centers, have isomeric forms; these isomers and mixtures form part of the invention. The racemates and enantiomers of these compounds are also part of the invention.

The compounds of formula (I) in which R1means a sulfur atom or selenium, R2means a hydrogen atom, -R3-R4-R5-R6- THE CH2-CH2-CH(R8)-, -CH2-CH2-CH2-Se-, -CH2-CH2-Se-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-,

-CH2-CH2-CO-CH2, -CH2-CH2-CH(R8)-CH2, -CH2-CH2-S-CH2-, -CN,-C (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-;

R8means hydroxyl, R9means a hydrogen atom or alkyl or benzyl and R10means alkyl, -Cooalk or-CONH2can be obtained by interaction of thiocyanate of an alkali metal or selenocyanate alkali metal derivative of the formula (II)

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in which R7has the same meanings as in the formula (I), and R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CO-, CH2-CH2-CH2-CH(R8)-, -CH2-CH2-CH2-Se-, -CH2-CH2-Se-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-, -CH2-CH2- (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-; R8means hydroxyl,

R9means a hydrogen atom, or alkyl, or benzyl and R10means alkyl, -Cooalk or CNH2; ALK and ALK' mean alkyl.

This reaction is usually carried out in the presence of bromine, chlorine, chloramine or bivalent copper chloride, in an organic solvent, such as acetic acid, at a temperature in the range of 15oC to the boiling temperature of the reaction medium. As a thiocyanate of an alkali metal or selenocyanate alkali metal, preferably using potassium thiocyanate or selenocyanate potassium.

Derivatives of the formula (II) are new compounds and as such form part of the invention.

The compounds of formula (I) in which R2means alkyl, can be obtained by alkylation of the corresponding compounds of formula (I) in which R2means a hydrogen atom.

This alkylation is carried out by any method that allows you to alkilirovanii imine function. Preferably operate using derivative is entrusted chlorine atom, bromine or iodine) or tosyloxy, in an inert organic solvent such as an aliphatic alcohol with 1 to 6 carbon atoms (for example, ethanol, propanol, butanol), ketone (e.g. acetone, methyl ethyl ketone and dimethylformamide, in the presence of a base such as a carbonate of an alkali metal (e.g. potassium carbonate) at a temperature in the range of 20oC to the boiling temperature of the reaction medium.

The compounds of formula (I) in which R2means a hydrogen atom or alkyl, R3-R4-R5-R6means a chain of formula-CH2-CH2-CH(R8)-CH2- or-CH2-CH2-CH2-CH(R8) and R8means hydroxyl, can also be obtained by recovering the corresponding compounds of formula (I) in which R2means a hydrogen atom or alkyl and R3-R4-R5-R6means a chain of formula-CH2-CH2-CO-CH2- or-CH2-CH2-CH2WITH-.

This reaction is carried out in any way, enabling you to navigate from the ketone to the alcohol. Usually work when using sodium borohydride in alcohol, such as methanol or ethanol, at a temperature of 0-25oC.

The compounds of formula (I) in which R2-CH2-SO, -CH2-CH2-CH2-SO2,

-CH2-CH2-SO CH2, -CH2-CH2-SO2-CH2-, -CH2- (ALK)(ALK')-SO CH2-, -CH2- (ALK)(ALK')-SO2-CH2-, -CH2-CH(R10)-SO CH2- or-CH2-CH(R10)-SO2-CH2- can be obtained by oxidation of the corresponding compounds of formula (I), in which the chain-R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-S-, -CH2-CH2-S-CH2, -CH2- (ALK)(ALK')-S-CH2- or-CH2-CH(R10)-S-CH2-.

This oxidation is carried out according to known methods of oxidation of sulfur-containing derivatives, such as the methods described by M. HUDLICKY, xidation in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, work by affecting organic nagkalat or salt of such acid (as nadirbaeva or natalibokova acid, in particular natantia acid, 3-chlormadinone acid, 4-nitromidazole acid, peracetic acid, CRYPTOMAGAZINE acid, nagarajuna acid, monongalia acid) or inorganic nagkalat or salt of such an acid (such as, for example, nationa acid or nadmerna Ki a temperature in the range from 0 to 25oC. you can Also use hydrogen peroxide or periodate (for example, periodate sodium) in an inert solvent such as a lower aliphatic alcohol, water or a mixture of these solvents at a temperature in the range from 0 to 20oC. you can Also work when using tert. -butylhydroperoxide in the presence of tetraisopropyl titanium or OksanaR(peroxymonosulfate potassium) in a lower aliphatic alcohol or a mixture of water and alcohol at a temperature of approximately 25oC.

The compounds of formula (I) in which R2means a hydrogen atom or alkyl, R3-R4-R5-R6means a chain of formula-CH2-CH(R10)-S-CH2-, where R10means the radical-CH2IT can be obtained by recovering the corresponding compounds of formula (1) in which R2means a hydrogen atom or alkyl, R3-R4-R5-R6means a chain of formula-CH2-CH(R10)-S-CH2-, where R10means the radical-Cooalk.

This reaction is carried out by any known method, allowing to obtain alcohol from the corresponding complex ester. Preferably operate using borgert sodium in alcohol, such as ethanol, at a temperature of the keel, -R3-R4-R5-R6means a chain of formula-CH2-CH(R10)-S-CH2-, where R10means the radical-COOH, can be obtained by hydrolysis of the corresponding compounds of formula (I) in which R2means a hydrogen atom or alkyl, R3-R4-R5-R6means a chain of formula-CH2-CH(R10)-S-CH2-, where R10means the radical-Cooalk.

This reaction takes place in any way, enabling you to navigate from a complex ester to the corresponding acid. Usually work when using an alkali metal hydroxide (e.g. sodium hydroxide) in an inert solvent, such as alcohol (e.g. methanol, ethanol) at a temperature in the range of 15oC to the boiling temperature of the reaction medium.

Derivatives of the formula (II), in which the chain-R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2and R7means polyfluoroankyl or politcially, can be obtained by exposure to 1,4-dehalogenating on Li-derived 4-polyphthalocyanine or 4-polyferrocenylsilane, amine function is protected, followed by removal of the protective group with NH.

This reaction Orme tert.-BUTYLCARBAMATE; in this case, the removal of the protective groups is carried out using triperoxonane acid, in an inert organic solvent such as a chlorinated solvent (e.g. chloroform, dichloromethane), at a temperature of about 20oC. Preferably using 1-chloro-4-iodobutane. Li-derivative is obtained by exposure to tert. -utility in pentane 4-polyphthalocyanines or 4-poliferation, amine function is protected, in tetrahydrofuran at a temperature of -78oC.

4-Polyphthalocyanines and 4-poliferation are industrial products or can be obtained by using or adapting methods described in J. Org. Chem. , 29, 1 (1964) and in U.S. patents 3920444, 2436100, the Federal Republic of Germany patent 2606982, European patents 205821 and 54391.

Derivatives of the formula (11), in which R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-S-, -CH2-CH2-CH2-Se-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-,

-CH2-CH2-S-CH2-, -CH2- (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, where R10means alkyl, -CH2-CH2-Se-CH2-, CH2-CH2-O-CH2-, -CH< / BR>
in which R7has the same meanings as in the formula (I), and R4-R5-R6means a chain of formula-CH2-CH2-S-, -CH2-CH2-Se-, -CH2-CH2-O-, -CH2-CH2-N(R9)-, -CH2-S-CH2- ,- (ALK)(ALK')-S-CH2-, -CH(R10)-S-CH2-, where R10means alkyl, -CH2-Se-CH2-, -CH2-O-CH2-, -CH2-N(R9)-CH2-, where R9has the same meanings as in the formula (I).

This reaction is usually carried out using a reducing agent such as alumalite lithium, in an inert organic solvent, such as tetrahydrofuran, at a temperature of about 20oWith, or complex of boron hydride with dimethyl sulfide in an inert solvent such as toluene at the boiling temperature of the reaction medium.

Derivatives of the formula (III), in which the chain-R4-R5-R6means a chain of formula-CH2-S-CH2- ,- (ALK)(ALK')-S-CH2-, -CH(R10)-S-CH2-, where R10means alkyl or-CH2-Se-CH2- can be obtained by cyclization of a derivative of formula (IV):

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in which the amine function, if necessary, protected and either Rb means a sulfur atom, each of RC, Rd and Re means the atom of water which means a hydrogen atom, and Re means alkyl.

Preferably the amine function is protected in the form of tert.-BUTYLCARBAMATE. When Re means alkyl, the cyclization is usually carried out using triperoxonane acid in an inert organic solvent such as a chlorinated solvent (e.g. chloroform, dichloromethane), at a temperature of about 20oWith, or using p-toluenesulfonic acid in toluene at the boiling temperature of the reaction medium. When Re denotes a hydrogen atom, the cyclization is preferably carried out in xylene by heating at the boiling temperature of the reaction medium.

Derivative of formula (IV) where Re denotes alkyl, can be obtained by exposure to sulfur or selenium, then the derived Gal-RRd-Cooalk, where Gal means a halogen atom, Rc and Rd have the above values, Li-derived 2-methyl-4-polyphthalocyanine or 2-methyl-4-polyporaceae-aniline, amine function is protected, preferably in the form of rubs. -BUTYLCARBAMATE, in tetrahydrofuran, at a temperature of from about -70oWith up to about 20oC. Li-derived 2-methyl-4-polyphthalocyanine or 2-methyl-4-polyporaceae-aniline, amine function is protected, is produced by exposure to tert.-utility 2-methyl-4-palift is a temperature of about -70oC. Derivatives of the formula (IV), where Re denotes a hydrogen atom, can be obtained by hydrolysis of the corresponding derivative of formula (IV), where Re denotes alkyl. This hydrolysis is usually carried out with sodium hydroxide in ethanol at a temperature in the range of 15oC to the boiling temperature of the reaction medium.

2-Methyl-4-polyphthalocyanines or 2-metyl-4-poliferation, the amine function of which is protected, can be obtained by exposure of iodomethane on Li-derived 4-polyphthalocyanine or 4-polyferrocenylsilane, the amine function of which is protected, in tetrahydrofuran at a temperature from about -70oWith up to about 20oC.

Derivatives of the formula (III), in which the chain-R4-R5-R6means a chain of formula-CH2-N(R9)-CH2and derivatives of the formula (II), in which the chain-R3-R4-R5-R6means a chain of formula-CH2-CO-N(R9)-CH2- can be obtained by exposure of chloroacetanilide on aniline of formula (V)

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in which R7and R9have the same meanings as in the formula (I), and by separating the two derivatives.

This reaction is usually carried out in an inert organic is mperature about 20oC.

Anilines of the formula (V) are obtained according to reaction scheme 1 (see the end of the description).

In these formulas, R7and R9have the same meanings as in the formula (I), and BOC means tert.-butoxycarbonyl. Operating conditions are described in more detail in example 8.

Derivatives of the formula (III), in which the chain-R4-R5-R6- means chain-CH2-O-CH2- can be obtained by application or adaptation of the method described E. TESTA and L. FONTANELLA, II Farmaco, 20, 323-335 (1965), according to the following reaction scheme 2 (see the end of the description).

In these formulas, R7has the same meanings as in the formula (I), Me denotes methyl and VI denotes butyl.

Derivatives of the formula (III), in which the chain-R4-R5-R6means a chain of formula-CH2-CH2-Se-, -CH2-CH2-Se-, -CH2-CH2-O-, -CH2-CH2-N(R9)-, can be obtained from the derivative of formula (VI)

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in which Rf denotes a radical, HE, SH, S or NH(R9), R7and R9have the same meanings as in the formula (I), by using or adapting methods described in the examples and X. HUANG, Synthesis, 851-852 (1984); W. C. LUMMA, etc. , J. Med.Chem., 24, 93-101 (1981); and E. J. JACOBSEH and other J. Med. Chem., 39, 158-175 (neh R. BELCHER and others, J. Chem.Soc., 3846 (1954); B. L. MYLARY, J. Med.Chem., 34, 108-122 (1991); D. W. COMBS, etc., J. Med.Chem., 35, 172-176 (1992); W. C. LUMMA, etc., J. Med.Chem., 24, 93-101 (1981); and A. V. ZEIGER, etc., J. Org.Chem., 42 (3), 542 (1977).

Derivatives of the formula (II) in which R3-R4-R5-R6means the radical-CH2-CH2-CH2-CO-, can be obtained by decarboxylation of a derivative of formula (VII)

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in which R7has the same meanings as in the formula (I), Rg means p-toluensulfonyl and Et means ethyl, with the subsequent removal of the protective group.

This reaction is usually carried out using hydrochloric acid in acetic acid at the boiling temperature of the reaction medium. Removing the protective groups are usually using magnesium shavings in a mixture of tetrahydrofuran with methanol at a temperature of about 20oC.

Derivative of formula (VII) can be obtained according to reaction scheme 3 (see end of description).

In these formulas, R7has the same meanings as in the formula (I), Rg means p-toluensulfonyl, Et means ethyl, and tBu means tert.-butyl. Operating conditions are described in more detail in example 1.

Derivatives of the formula (II) in which R3-R4-R5-R6means the radical-CH22means a hydrogen atom or alkyl and R3-R4-R5-R6means a chain of formula-CH2-CH2-CO-CH2- or-CH2-CH2-CH2WITH.

This reaction is carried out in any way, enabling you to navigate from the ketone to the alcohol. Usually work with sodium borohydride in alcohol, such as methanol or ethanol, at a temperature of 0-25oC.

Derivatives of the formula (II) in which R3-R4-R5-R6means a radical of the formula-CH2-CH2-CO-CH2- can be obtained by decarboxylation of a derivative of formula (VIII)

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in which R7has the same meanings as in the formula (I), tBu means tert.-butyl and Et means ethyl, with the subsequent removal of the protective group.

This reaction is usually carried out using hydrochloric acid in acetic acid at the boiling temperature of the reaction medium.

Derivatives of the formula (VIII) can be obtained according to reaction scheme 4 (see end of description), and in these formulas, R7has the same meanings as in the formula (I), Et denotes ethyl and tBu means tert.-butyl.10)-S-CH2-, where R10means the radical-CONH2can be obtained by exposure to ammonia on the corresponding derivative of formula (II) in which R3-R4-R5-R6means the radical CH2-CH(R10)-S-CH2-, where R10means radical Cooalk.

This reaction is usually carried out in an inert solvent, such as alcohol (e.g. ethanol) at a temperature of about 20oC.

Derivatives of the formula (II) in which R3-R4-R5-R6means the radical-CH2-CH(R10)-S-CH2-, where R10means radical Cooalk, can be obtained by recovering the derivative of formula (IX)

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in which R7has the same meanings as in the formula (I).

This reaction is preferably carried out with magnesium in an inert solvent such as an aliphatic alcohol with 1 to 6 carbon atoms (e.g. methanol) at a temperature of 40oC.

Derivative of formula (IX) can be obtained according to reaction scheme 5 (see the end of the description), and in these formulas, R7has the same meanings as in the formula (I), a1k means alkyl, BOC means tert.-butoxycarbonyl.

For professionals it is obvious that s groups to amine functions, to avoid secondary reactions. In particular, we work according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley Interscience Publication (1981), or Mac Omie, Protective Groups in Organic Chemistry, Plenum Press (1973). Amine functions can be protected, for example, methoxycarbonyl, ethnicalbanian, tert.-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichlorocarbanilide, trichloroacetyl, TRIFLUOROACETYL, chloroacetyl, triphenylmethyl, benzhydryl, benzyl, allyl, formyl, acetyl, benzyloxycarbonyl or its substituted derivatives, or can be protected in the form of tert.-BUTYLCARBAMATE or methylcarbamate, then regenerated using triperoxonane acid or hydrochloric acid in tetrahydrofuran, or in the form of benzylcarbamoyl, then regenerated by hydrogenation after the implementation of the method according to the invention.

The reaction mixture obtained various above-described methods, the process according to the classical physical methods, such as evaporation, extraction, distillation, chromatography, crystallization) or by a chemical method, such as the formation of salts).

The enantiomers of compounds of formula (I) containing at least one asimmetricheskie by chromatography on chiral stationary phase type (s,s) WHELCK-01, Chiracel OJor when using a chiral column according to W. H. PIRCLE and others, Asymmetric synthesis, vol. 1, Academic Press (1983).

The compounds of formula (I) in free base form, if necessary, can be converted into a salt of joining with an inorganic or organic acid by exposure to this acid in an organic solvent, such as alcohol, ketone, simple ether or a chlorinated solvent.

As examples of pharmaceutically acceptable salts can be called the salt of the merger with inorganic or organic acids, such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, ideational, theophyllinate, salicylate, methylene-bis-xinafoate, hydrochloride, sulfate, nitrate and phosphate.

The compounds of formula (I) have an interest pharmacological properties. These compounds are anticonvulsant drugs and interfere with glutamatergic conduct and, therefore, suitable for the treatment or prevention of any of ischemia (such as focal or total ischemia), resulting from violations of cerebral circulation, such as thromboembolic and gamorra is light or severe hypoglycemia. They are also suitable for treatment effects due to anoxia, as perinatal and evolved as a result of drowning, high pressure or spinal damage. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, horii's chorea, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis or other Mannaioni disease, Olivo-cerebellopontine atrophy and Parkinson's disease. These compounds can also be used against epileptic symptoms (epilepsy) and/or convulsive symptoms, for the treatment of traumatic brain or spinal injury, injury-related degeneration of the inner ear (R. PUJOL and others, Neuroreport, 3, 299-302 [1992]) or the retina (J. L. MONSINGER etc. , Exp. Neuol., 113, 10-17 [1991]), noise in the ears, anxiety (KEHNE and others, Eur.J.Pharmacol., 193, 283 [1991]), depression (TRULLAS and other Eur.J.Pharmacol., 185, 1 [1990]), schizophrenia (REYNOLDS, TIPS, 13, 116 [1992]), Tourette's syndrome, hepatic encephalopathy, sleep disorders, disorders related to attention deficit, disorders of hormonal conditions (excessive secretion of HG or HL, the secretion of corticosterone), as analgesics (DICKENSON and others , Neurosc. Letters, 121, 263 [1991]), anti-inflammatory is against migraines, cancer funds, and treatment of poisoning by neurotoxins or other substances - receptor agonists NMDA or AMPA, and neurological disorders associated with viral diseases such as viral meningitis and viral encephalitis, AIDS (LIPTON and others, Neuron, 7, 111 [1991]), rabies, measles and tetanus (BAGETTA, etc., Br.J.Pharmacol., 101, 76 [1990]). These compounds are also useful for the prevention, tolerance and dependence in relation to the withdrawal symptoms to drugs, alcohol and suppression of dependence and addiction in relation to opiates, barbiturates, amphetamines and benzodiazepines. They can also be used in the treatment of nedostatochnosty associated with mitochondrial abnormalities, such as mitochondrial myopathy, Leber's syndrome, Wernicke's encephalopathy, rett syndrome, homocysteinuria, hyperprolinemia, hydroxybutylidene, lead encephalopathy (chronic toxicity for lead) and the deficit sulfadoxine.

The activity of these products as anti-convulsants determine Mimi by the method of maximum electroshock. White CD1 mice injected test compound in saline solution for 10 minutes prior to the shock (75 mA; duration 0.04 seconds) with stories by pulling the limbs. If tonic spasm does not occur, the animal is considered protected, in this test, the compounds of formula (I) show ED50equal to or below 4 mg/kg.

The activity of these products as antiglutamate determine when the convulsions caused by glutamate, according to the manner similar to that described LAPIN I. P., J. Neural. Transmission, 54, 229-238 [1982], and injection of glutamate exercise intracerebroventricular according to the method similar to that described R. CHERMAT and P. SIMON, J. Pharmacol. (Paris), 6, 489-492 [1975]. Their ED50is the value below 10 mg/kg

The compounds of formula (I) have low toxicity. Their LD50(lethal dose causing death in 50% of mice) mouse is the value above 15 mg/kg intravenously.

For use in medicine, the compounds of formula (I) can be used in pure form or in the form of pharmaceutically acceptable salts, that is non-toxic in the doses.

Of particular interest are compounds of formula (I) in which R7means cryptometer or trifluoromethyl.

Preferred compounds of formula (I) are those in which R1means a sulfur atom, R2means a hydrogen atom, -R3-R4-R5-R6- means chain UB>2-CH(R8)-,

-CH2-CH2-CH2-Se-, -CH2-CH2-Se-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-SO-,

-CH2-CH2-CH2-SO2-, -CH2-CH2-CH2-O-, -CH2-CH2-CH2-N(R9)-, -CH2-CH2-CO-CH2,

-CH2-CH2-CH(R8)-CH2-, -CH2-CH2-S-CH2-, -CH2-CH2-SO CH2-, CH2-CH2-SO2-CH2-,

-CH2- (ALK)(ALK')-S-CH2-, -CH2-CH(R10S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-; R7means trifluoromethyl or triptoreline; R8means hydroxyl; R9means a hydrogen atom, or alkyl, or benzyl; R10means alkyl, -CH2HE is Cooalk, -COOH or-NN2; ALK denotes an alkyl or ALK' is alkyl; and their isomers, racemates, enantiomers and their salts.

Of particular interest are the following compounds of formula (I):

-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole[5,4,3-jk] [1] benzazepin-7-ol;

-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole[5,4,3-jk] [1] benzazepin;

-2-imino-9-triptime] benzodiazepin-7,7-dioxide;

-2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [1,5] benzodiazepin-7-oxide;

-2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [1,5] benzothiazepin;

-6-benzyl-2-imino-9-triptoreline-6,7-dihydro-4H-thiazol[3,4,5-kj] [1,4] benzodiazepine-5-he;

-6-benzyl-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole [3,4,5-kj][1,4]benzodiazepine;

-2-imino-9-triptoreline-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1] benzothiazepin;

-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1] benzothiazepin;

-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-triazole[3,4,5-de][4,1]benzo-diazepin-6,6-dioxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [1,5]benzo-diazepin-7,7-oxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [l, 5]benzodiazepin-6,6-dioxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [1,5] benzothiazepin;

-2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazole[5,4,3-jk] [1]benzazepin-7-ol;

-2-imino-9-triptoreline-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6,6-dioxide;

-2-imino-9-triptoreline-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-6-benzyl-2-imino-9-trifluoromethyl-6,7-dihydro-4H-thiazol[3,4,5-kj] [1,4] benzodiazepine-5-he;

-6-benzyl-2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-R> -5-carbarnoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H,7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-5-hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin;

their isomers, racemates, enantiomers and their salts.

Especially preferred are the following compounds:

-(R, S)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1] benzothiazepin-6-oxide;

-(+)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-(-)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-(R,S)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-(+)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-(-)-2-imino~ 5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

and their salts.

The following examples illustrate the invention without limiting its scope.

EXAMPLE 1

Within 10 minutes at a temperature of about 20oWith 1.2 g of bromine diluted in 10 ml of acetic acid is added dropwise to a solution of 1.7 g of potassium thiocyanate and 1.9 g (R,S)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1]BAE, poured on ice, alkalinized with 20% ammonium hydroxide solution and extracted with three times 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa) at a temperature of 40oC. the Residue (0.4 g) chromatographic on silica gel, elwira with ethyl acetate. The isolated product is treated with a mixture of 4 ml of diisopropyl ether and petroleum ether in a volume ratio of 50: 50 and thus receive the 0.15 g (R,S)-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole-[5,4,3-jk] [1] benzazepin-7-ol in the form of a cream solid color, melting at 167oC.

Analysis of C12H11F3N2O2S

Calculated, %: C Of 47.37, H 3,64, F 18,73, Of 9.21 N, O 10,52, S 10,54.

Found, %: C 47,76, N, 3,5, F 18,4, N, 9,1, S 10,6.

(R, S)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepin-5-ol may be obtained in the following way.

At a temperature of about 20oWith 1.08 g of magnesium turnings are added to a solution of 3.6 g (R,S)-1-(toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1]benzazepin-5-ol in 30 ml of tetrahydrofuran and 40 ml of methanol. The reaction mixture is stirred for 2 is functioning diethyl ether, filtered off, then washed three times in 40 ml of diethyl ether. The thus obtained filtrate pale yellow dried over magnesium sulfate, then evaporated under reduced pressure at a temperature of 50oC. are Thus obtained 1.9 g (R,S)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1]benzazepin-5-ol in the form of a cream solid color, melting at 110oC.

(R, S)-1-(Toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-lH-[1] benzazepin-5-ol may be obtained in the following way.

To a solution of 3.7 g of 1-(toluene-4-sulfonyl)-7-triptoreline-2,3-dihydro-1H, 4H-[1] benzazepin-5-it in 40 ml of ethanol is added in small portions 0.7 g sodium borohydride and incubated with stirring for two hours at a temperature of about 20oC. After the usual processing gain 3 g (R,S)-1-(toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepin-5-ol in the form of a solid beige color, melting at 160oC.

1-(Toluene-4-sulfonyl)-7-triptoreline-2,3-dihydro-1H, 4H-[1] benzazepin-5-he may storms obtained as follows.

To a solution of 2.2 g of ethyl ester of 5-oxo-1-(toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepine color and the reaction mixture is refluxed for 4 hours. Concentrate to dryness under reduced pressure, the obtained yellow oil is treated with 300 ml of diethyl ether and the resulting solution was washed with a saturated solution of sodium bicarbonate. After decanting, washing twice with 50 ml distilled water and saturated sodium chloride solution, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 60oC. are Thus obtained was 1.58 g of 1-(toluene-4-sulfonyl)-7-triptoreline-2,3-dihydro-lH, 4H-[1]benzazepin-5-it is in the form of a solid beige color, melting at 96oC.

Ethyl ester of 5-oxo-1-(toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepin-4-carboxylic acid can be obtained as follows.

To 275 ml of anhydrous toluene, brought to the boiling point under reflux in an argon atmosphere, add becomes 9.97 g of tert.-the butyl potassium, then injected dropwise a solution of 23 g of ethyl ester of 2-[(3-ethoxycarbonylphenyl)-(toluene-4-sulfonyl)amino] -5-cryptomaterial acid in 300 ml of anhydrous toluene. After the addition was finished, continue heating for one hour. After cooling, add the phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 60oC. the resulting residue is dissolved in 100 ml of boiling cyclohexane and after cooling appeared precipitate is filtered off and dried at a temperature of 40oWith under reduced pressure (70 PA). So get of 10.75 g of ethyl ester of 5-oxo-1-(toluene-4-sulfonyl)-7-triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepin-4-carboxylic acid in the form of a powder beige color, melting at 97oC.

Ethyl ester of 2-[(3-ethoxycarbonylphenyl)-(toluene-4-sulfonyl)amino]-5-cryptomaterial acid can be obtained as follows.

For 17 hours at a temperature of 80oWith a heated mixture of 5.5 g of ethyl ester of 2-(toluene-4-sulfonyl)amino]-5-cryptomaterial acid, 5.6 g of potassium carbonate, 3,18 g of ethyl ester of 4-pamakani acid in 30 ml of dimethylformamide. Concentrate to dryness under reduced pressure (2.2 kPa) at a temperature of 60oC. the Obtained brown oil was dissolved in ethyl acetate and the solution washed with distilled water, then a saturated solution of sodium chloride, dried over magnesium sulfate and then concentrated to dryness, ccarbonate)-(toluene-4-sulfonyl)amino]-5-cryptomaterial acid as a yellow oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), in M. D. (millionths): 1,10 (3H, t, J=6 Hz, CH3); of 1.30 (3H, t, J= 6 Hz, CH3); of 1.65 (2H, m, CH2); is 2.40 (5H, m, PINES2AND C6H5CH3); 3,45 and 3.70 (1H each, m, N2); 4,00 (2N, K, J=6 Hz, och2), 4,25 (2N, K, J=6 Hz, och2); 7,05 (1H, d, J=8 Hz, CH arene.); 7,40 (4 H, s, 4 CH of Totila); the 7.65 (1H, DD, J=8 and 2 Hz, CH arene.); of 7.70 (1H, d, J=2 Hz, CH arene.).

Ethyl ester of 2-(toluene-4-sulfonyl)amino-5-cryptomaterial acid can be obtained as follows.

To a solution of 17.5 g of ethyl ester of 2-amino-5-cryptomaterial acid In 70 ml of pyridine with stirring and at a temperature of about 20oTo add to 16.1 g of the acid chloride toluene-4-sulfonic acid. After stirring for 24 hours, concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 60oC. the Obtained brown oil was dissolved in ethyl acetate and the solution washed sequentially 2 N. hydrochloric acid, distilled water and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 50oC. the Obtained orange oil, obtaini acid in the form of a white powder, melting at 76oC.

Ethyl ester of 2-amino-5-cryptomaterial acid can be obtained as follows.

To 21 g of ethyl ester of 2-tert.-butoxycarbonylamino-5-cryptomaterial acid in 150 ml of dichloromethane added 55 ml triperoxonane acid. After incubation for four hours at a temperature of about 20oWith the resulting solution black color concentrate to dryness. The residue is treated with dilute sodium hydrogen carbonate solution and extracted with petroleum ether. The organic phase is washed with distilled water until neutral pH, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 50oC. are Thus obtained 14 g of ethyl ester of 2-amino-5-cryptomaterial acid as a brown oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: of 1.30 (3H, t, J=6 Hz, CH3); 4,30 (2N, K, J=6 Hz, och2); 6,85 (2H, s, NH2); 6,87 (1H, d, J=8 Hz, CH arene.); 7,30 (1H, DD, J=8 and 2 Hz, CH arene.); at 7.55 (1H, d, J=2 Hz, CH arene.),

Ethyl ester of 2-tert. -butoxycarbonylamino-5-cryptomaterial acid can be obtained as anhydrous tetrahydrofuran, supported in an argon atmosphere at a temperature of -78oWith, within 1 hour, poured 200 ml of 1.5 M solution of tert. -utility in pentane. After the natural rise in temperature to about -20oWith the environment is maintained with stirring for 2.5 hours. The reaction medium is again cooled to -78oAnd for once poured 75 ml diethylmalonate. After 16 hours at a temperature of about 20oWith added 100 ml of aqueous saturated solution of ammonium chloride and 250 ml of diethyl ether. After decanting, the aqueous phase is again extracted with twice 200 ml of diethyl ether. The organic extracts are combined, washed with distilled water and aqueous saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The obtained red oil was dissolved in petroleum ether and the solution is filtered through silica gel, washing with petroleum ether.

Concentrated to dryness of the filtrate gives a red oil, which crystallizes. After recrystallization from 50 ml of hexane gain of 21.5 g of ethyl ester of 2-tert.-butoxycarbonylamino-5-cryptomaterial acid in the form of a cream solid color, melting at 82oC.

Within 10 minutes and at a temperature of 0oTo a solution of 47 g of di-tert.-BUTYLCARBAMATE in 100 ml of anhydrous tetrahydrofuran is poured to the solution 32,75 g of 4-triphtalocyaninine in 150 ml of anhydrous tetrahydrofuran. The reaction medium is stirred at a temperature of 80oC for three hours, then concentrated to dryness. Get a white crystalline product, which is again dissolved in 300 ml of ethyl acetate. The solution is washed three times with distilled water, dried over magnesium sulfate and concentrated to dryness. By powdering in petroleum ether, filtration and drying under reduced pressure (70 PA) at a temperature of 20oTo obtain 35.5 g of tert.-butyl ether 4-triftormetilfullerenov acid in a solid white color, melting at 110oC.

EXAMPLE 2

Follow the procedure of example 1, but using 0.7 bromine in 5 ml of acetic acid, 1 g 7 triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepine and of 1.46 g of potassium thiocyanate in 15 ml of acetic acid. Selected a thick orange oil chromatographic on silica gel, elwira a mixture of ethyl acetate with petroleum ether in a volume ratio of 70:30. Receives a yellow oil, which was dissolved in diisopropyl color filter, then dried in vacume (70 PA) at a temperature of 40oC. Thus obtain 0.52 g of 2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole [5,4,3-jk] [1] benzenedimethanamine in a solid white color, melting at 270oC (with decomposition).

Analysis: C12H12ClF3N2OS

Calculated, %: C 44,38, H 3,72, Cl 10,92, F 17,55, N 8,63, O 4,93, S 9,87.

Found, %: C 44,3, H 3,5, Cl 10,9, F 17,7, N 9,1.

7 Triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepin can be obtained as follows.

To a solution of 2.3 g of tert.-butyl ether 7 triptoreline-2,3,4,5-tetrahydro-1H-[1]benzazepin-1-carboxylic acid in 25 ml of dichloromethane add 5 ml triperoxonane acid. After incubation for 1 hour at a temperature of about 20oWith the obtained red solution is concentrated to dryness under reduced pressure. The residue is treated with dilute sodium hydrogen carbonate solution and extracted with diethyl ether. The organic phase is washed with distilled water, then a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.2 kPa) at a temperature of 50oC. Thereby obtaining 1.3 g of brown oil,Oseni 70:30. After evaporation under reduced pressure allocate 1,14 g 7 triptoreline-2,3,4,5-tetrahydro-1H-[1] benzazepine in the form of a pasty solid substances used in this form in the next stage.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: between 1,50 and 1.70 (4H, m, 2 of CH2); 2,60 (2H, m6H5CH2); 2,90 (2H, m, NCH2); to 5.40 (1H, s, NH); between 6,80 and to 7.00 (3H, m, 3 of CH arene.).

tert.-Butyl ester of 7-triptoreline-2,3,4,5-tetrahydro-lH- [1]benzazepin-1-carboxylic acid can be obtained as follows.

Supported in an argon atmosphere at a temperature of -78oWith the solution 5,54 g of tert. -butyl ester 4-triftormetilfullerenov acid in 60 ml of anhydrous tetrahydrofuran for 1 hour add 32 ml of a 1.5 M solution of tert. -utility in pentane. The reaction mixture was then stirred for 2.5 hours at a temperature of about -20oC. her Again cooled to a temperature of -78oWith and within 15 minutes, poured dropwise to 2.65 ml of 1-chloro-4-iodobutane. The reaction mixture is brought to a boil and boil for 5 hours. After cooling, add 50 ml of aqueous saturated solution of ammonium chloride and extracted three times with aqueous saturated solution of sodium chloride, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The oil obtained (6,65 g) chromatographic on silica gel, elwira a mixture of petroleum ether and dichloromethane in a volume ratio of 50:50. Thus obtain 2.3 g of tert.-butyl ether 7 triptoreline-2,3,4,3-tetrahydro-1H-[1] benzazepin-1-carboxylic acid as a yellow oil.

1H-NMR spectrum (200 MHz; hexacyanometallate; temperature = 20oC), M. D.: between 1,65 and 1,90 (4H, m, 2 CH); 2,70 (2H, m6H5CH2); 3,50 (2H, t, J=6 Hz, NCH2); between 7,05 and 7.35 (3H, m, 3 of CH arene.).

EXAMPLE 3

Follow the procedure of example 1, but use of 2.38 g of bromine in 5 ml of acetic acid, 3.2 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-lH-[1] benzazepine and 5 g of potassium thiocyanate in 35 ml of acetic acid. Selected brown oil chromatographic on silica gel, elwira with ethyl acetate. Receives a yellow oil, which was dissolved in 15 ml of diisopropyl ether, to which was added 1 ml of 1.94 N. solution methansulfonate in isopropanol. The resulting white precipitate is filtered off, then dried under vacuum (70 PA) at a temperature of 50oC. Thus 0.7 g of 2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazole-[5,4,3-jk] -[1]benzazepines: C13H15F3N2O3S

Calculated, %: C 42,38, H 4,1, F 15,2, 7,5 N, O And 13.3, S 17,41.

Found, %: C 42,4, N. 3,9, F 15,2, 7,5 N, S 17,4.

7-trifluoromethyl-2,3,4,5-tetrahydro-1H-[1] benzazepin can be obtained as in example 2, but from 5 g of tert.-butyl ester of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-1-carboxylic acid in 50 ml of dichloromethane and 5 ml triperoxonane acid. Thus obtained 3,3 g of 7-trifluoromethyl-2,3,4,5-tetrahydro-1H- [1]benzazepine in the form of a red oil, used in this form in the next stage.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D. : between and 1,60 1,90 (4H, m, 2CH2); to 2.75 (2H, t, J=6 Hz, C6H5CH2); 3,00 (2H, t, J=6 Hz, NCH2); 5,90 (1H, ush.c, NH); make 6.90 (1H, d, J=8 Hz, CH arene.); 7,28 (1H, DD, J=2 and 8 HZ, CH arene.); 7,33 (1H, d, J=2 Hz, CH arene.).

tert. -Butyl ester 7-trifluoromethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-1-carboxylic acid can be obtained, as in example 2, but out of 26.1 g of tert.-butyl ether 4-triftormetilfullerenov acid in 300 ml of anhydrous tetrahydrofuran, 160 ml of a 1.5 M solution of tert.-utility and 24 g of 1-chloro-4-iodobutane. Obtain 36 g of brown oil, which chromatographic on silica gel, elwira mix the petrol is iformity-2,3,4,5-tetrahydro-1H-[1]benzazepin-1-carboxylic acid in the form of a greenish oil, used in this form in the next stage.

EXAMPLE 4

To a solution of 1 g of 2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol-[3,4,5-ef]-[1,5]benzodiazepine in 20 ml of dichloromethane for 15 minutes and at a temperature of about 20oWith added dropwise a solution of 1.55 g of 3-chlormadinone acid (purity 80%) in 10 ml of dichloromethane, and the mixture is then stirred for 24 hours at the same temperature. Then add 100 ml of 1 M aqueous solution of sodium bicarbonate and stirred for 1 hour at the same temperature. After separation of the phases the aqueous phase is extracted with twice 50 ml of dichloromethane and the combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product (1.4 g) chromatographic under nitrogen pressure (150 kPa) on 30 g of silica gel (20-45 μm) contained in a column 2 cm in diameter, elwira with ethyl acetate. Received the product in the amount of 300 mg was dissolved in 35 ml of absolute ethanol, to which add 69 μl methansulfonate. After stirring for 1 hour at a temperature of about 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in isopropanol, filtered off, about the,21 g of 2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef] [1,5] benzothiazepin-7,7-dioxymethylene in a solid white color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O6S3< / BR>
Calculated, %: C 33,17, H 3,02, F 13,12, N 6,45, O 22,10, S 22,14.

Found, %: C 33,20, N 2,71, F 12,7, N 6,30, S 22,1.

EXAMPLE 5

To a solution of 1 g of 2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol-[3,4,5-ef] [1,5]benzodiazepine in 30 ml of dichloromethane for 15 minutes and at a temperature of about 0oWith added dropwise a solution of 770 mg of 3-chlormadinone acid (purity 80%) in 5 ml of dichloromethane and the mixture is then stirred for 1 hour at the same temperature. After that, add 35 ml of 1 M aqueous solution of sodium bicarbonate and stirred for 1 hour at a temperature of 20oC. After separation of the phases the aqueous phase is extracted with 15 ml of dichloromethane and the combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The product obtained is suspended in 20 ml of diisopropyl ether, filtered off, washed with diisopropyl ether and dried under reduced pressure. Received the product in the quantity 716 mg dissolved in 70 ml of absolute ataea at a temperature of about 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in isopropanol, filtered off, washed with isopropanol and diisopropyl ether and dried under reduced pressure. So get 0,70 g of 2-imino-9-triptoreline-5,6-dihydro-2H,4H-thiazol[3,4,5-ef][1,5] benzodiazepin-7-Oxymetazoline in the form of a cream solid color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O5S3< / BR>
Calculated, %: C 34,45, H 3,13, F 13,62, N 6,69, O 19,12, S 22,99.

Found, %: C 34,44, H 2,86, F 13,37, N Of 6.68, S 22,8.

EXAMPLE 6

Follow the procedure of example 1, but using 0.4 ml of bromine in 5 ml of acetic acid, 2 g of 8-triptoreline-2,3,4,5-tetrahydro[1,5]benzothiazepine and 1.71 g of potassium thiocyanate in 24 ml of acetic acid. The resulting crude product chromatographic under nitrogen pressure (150 kPa) on 40 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50. Dissolve 0.5 g of the obtained product (obtained from a total of 1.5 g) in 80 ml of ethanol, to which add 0,117 ml methansulfonate. After stirring for 16 hours at a temperature of 20oWith Rastogi ether, filtered off, washed with diisopropyl ether and dried under poniendo pressure (2 kPa) at a temperature of 20oC. are Thus obtained 0.56 g of 2-imino-9-triptoreline-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef][1,5]benzodiazepines.alternate in a solid beige color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, Of 6.96 N, O 15,9, S 23,9.

Found, %: C 35,8, H, 3,0, F 14,3, N 7,00, S 23,8.

8 Triptoreline-2,3,4,5-tetrahydro[1,5]benzothiazepin can be obtained as follows.

To 21,4 ml to about 0.5 M solution of lithium aluminum hydride in tetrahydrofuran, supported in an argon atmosphere at a temperature of 5oWith in 15 minutes is added dropwise a solution of 2.5 g of 8-triptoreline-2,3-dihydro-5H-[1,5]benzothiazepin-4-it in 25 ml of tetrahydrofuran. The reaction mixture was then stirred for two hours at a temperature of 20oWith and consistently add 500 ml of distilled water, 100 ml of ethyl acetate and 100 ml of saturated solution of sodium chloride. After decanting, the aqueous phase is extracted with three times 50 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and con,5]benzothiazepine in the form of a yellow oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: 1,95 (2H, m, CH2); 3,00 (2H, m, SCH2); 3,30 (2H, m, NCH2); 5,90 (1H, m, NH); 6,85 (1H, d, J=8 Hz, CH arene.); of 7.00 (1H, d, J=8 Hz, CH arene.); for 7.12 (1H, s, CH arene.).

8 Triptoreline-2,3-dihydro-5H-[1,5] benzo-diazepin-4-one can be obtained as follows.

To a suspension of 11.5 g of 2-amino-6-cryptomaterial in 115 ml of distilled water is added 70 g of potassium hydroxide in pastilles portions of about 10, the Mixture is then stirred for 16 hours at the boil under reflux. After cooling to a temperature of 20oTo add to 16.4 g of ethyl ester of 3-bromopropionic acid, then 30 ml of distilled water and the medium is stirred for 16 hours at the same temperature. The mixture was then acidified with concentrated hydrochloric acid at a temperature of about 5oC, extracted with three times 50 ml of ethyl acetate. The organic extracts are combined, washed three times with distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting crude product chromatographic under nitrogen pressure (150 kPa) on 250 g of silica gel (20-45 μm) contained in Colo is up 2.5 g solid white, which again suspended in diisopropyl ether, filtered off, washed with diisopropyl ether and dried under reduced pressure (2 kPa). Thus obtained 1.6 g of 8-triptoreline-2, 3-dihydro-5H-[1,5] benzothiazepin-4-it is in the form of a solid white color, melting at 188oC.

2-Amino-6-cryptomaterial can be obtained by the method described by L. M. Yagupolskii and others, GOH, 33 (7), 2301 (1963).

EXAMPLE 7

Follow the procedure of example 1, but using 1.2 g of bromine in 2 ml of acetic acid, 2.5 g of 4-benzyl-7-triptoreline-4,5-dihydro-lH,2H-[1,4]benzodiazepine-3-one and 1.6 g of potassium thiocyanate in 25 ml of acetic acid. The resulting product chromatographic under nitrogen pressure (150 kPa) on 75 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira with ethyl acetate. Dissolve 0.6 g of the obtained product (obtained from generally 2.25 g) in 45 ml of ethanol, to which add 0.1 ml of methansulfonate. After stirring for three hours at a temperature of 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in diethyl ether, filtered off, washed with diethyl ether and dried under reduced pressure (2 kPa) at ,4] benzodiazepine-5-onmeasureitem in the form of a cream solid color melting at a temperature above 260oC.

Analysis: C19H18F3N3O5S2< / BR>
Calculated, %: C 46,62, H 3,71, F 11,64, N 8,58, O 16,34, S 13,10.

Found, %: C 46,5, H 3,4, F 11,3, 8,5 N, S 12,61.

EXAMPLE 8

Follow the procedure of example 1, but using 4.15 g of bromine in 5 ml of acetic acid and 8.3 g of 4-benzyl-7-triptoreline-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine in 120 ml of acetic acid and 10 g of potassium thiocyanate. Obtain 2.7 g of a brown oil, which chromatographic consistently on silica gel, then deactivated neutral aluminum oxide with 10% water, elwira in both cases a mixture of ethyl acetate with cyclohexane in a volume ratio of 50: 50. Received the product in the quantity of 0.68 g dissolved in 45 ml of ethanol, to which add 0,23 ml methansulfonate. After stirring for two hours at a temperature of 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in ethanol, filtered off, washed with ethanol and then diethyl ether and dried under reduced pressure (2 kPa) at a temperature of 20oC. Obtain 0.32 g of 6-benzyl-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole[3,4,5-kj] [1,4]benzodiazepine in the form of a solid substance is 3O7S3< / BR>
Calculated, %: C 42,02, H To 4.23, F Becomes 9.97, N 7,35, O 19,59, S Equal To 16.83.

Found, %: C 41,2, H 4.2, F 9,3, N, 7,2, S 16,5.

4-Benzyl-7-triptoreline-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine can be obtained, as in example 6, but using 95 ml to about 0.35 M solution of lithium aluminum hydride in tetrahydrofuran and 6 g of 4-benzyl-7-triptoreline-4,5-dihydro-1H, 3H-[1,4]benzodiazepine-2-it in 40 ml of anhydrous tetrahydrofuran. Obtain 4.8 g of 4-benzyl-7-triptoreline-2,3,4,5-tetrahydro-lH-[1,4]benzodiazepine as colorless oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: a 2.75 (2H, m, NCH2); 3,00 (2H, m, NCH2); to 3.58 (2H, s, CH2); 3,63 (2H, s, CH2); the 5.65 (1H, t, J=2 Hz, NH); to 6.80 (1H, d, J=2 Hz, CH); make 6.90 (1H, d, J=8 Hz, CH); 7,00 (1H, DD, J=8 and 2 Hz, CH); 7,30 (5H, m, 5 CH, aryl).

4-Benzyl-7-triptoreline-4,5-dihydro-1H, 3H-[1,4] benzodiazepine-2-he 4-benzyl-7-triptoreline-4,5-dihydro-1H, 2H-[1,4] benzodiazepine-3-one can be obtained as follows.

Supported at temperature of 20oC to a solution of 15.1 g of 2-benzylamino-4-triphtalocyaninine in 350 ml of diethyl ether is added 16.5 g of chloroacetanilide, then 350 ml of aqueous saturated solution of sodium bicarbonate. The reaction is vivane and the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa). The residue after evaporation was dissolved in 300 ml of a mixture of tetrahydrofuran with isopropanol in a volume ratio of 50:50, to which add to 17.6 g of tert.-butoxide potassium, and stirred for 1 hour at a temperature of about 20oC. After acidification with 12 ml of acetic acid and diluting with 350 ml of distilled water and extracted with twice 100 ml of ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa). The oil obtained is treated with 50 ml of a mixture of cyclohexane to ethyl acetate in a volume ratio of 75:25, from which it appears solid. It is filtered off, washed with 10 ml of the same mixture and receive 6,04 g of 4-benzyl-7-triptoreline-4,5-dihydro-1H, 3H-[1,4]benzodiazepine-2-it is in the form of a solid white color, melting at 178oC. the Filtrate is concentrated to dryness under vacuum (2 kPa) and the residue chromatographic on 160 g of silica (20-45 μm) contained in a column with a diameter of 3.5 cm, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50. So get 5,72 g of 4-benzyl-7-triptoreline-4,5C.

2-Benzylamino-4-cryptomaterial can be obtained as follows.

To 97 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran, supported in an argon atmosphere at a temperature of 20oWith add 100 ml of anhydrous 1,4-dioxane is then added dropwise a solution of 15 g of N-benzyl-2-amino-5-triphtalocyaninine in 70 ml of anhydrous 1,4-dioxane and the mixture is stirred for 24 hours while boiling under reflux. After hydrolysis at a temperature of 5oWith by slowly adding 20 ml of distilled water appeared insoluble part is filtered off, washed with distilled water, then with ethyl acetate and remove. The filtrate is decanted and the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product chromatographic under nitrogen pressure (150 kPa) on 150 g of silica gel (20-45 μm) contained in a column with a diameter of 3.5 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 75:25. So get 7,39 g 2-benzylamino-4-triphtalocyaninine in the form of a colorless oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), memorial plaques: to 2.65 (1H, s, NH); 3C, CH arene.); between then 7.20 and 7.50 (5H, m, 5 aromatic CH).

N-Benzyl-2-amino-5-cryptomaterial can be obtained as follows.

A solution of 5 g of N-benzyl-2-tert.-butoxycarbonylamino-5-triphtalocyaninine in 25 ml triperoxonane acid was incubated for 16 hours at a temperature of about 20oWith, then concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in ethyl acetate and the solution washed successively twice 15 ml of distilled water and 15 ml of aqueous saturated solution of sodium bicarbonate, and then concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in pentane, filtered and dried under reduced pressure (2 kPa). So get 3,55 g of N-benzyl-2-amino-5-triphtalocyaninine in the form of a cream solid color, melting at 143oC.

N-benzyl-2-tert. -butoxycarbonylamino-5-cryptomaterial can be obtained as follows.

Supported in an argon atmosphere at a temperature of -10oWith a solution of 20 g of 2-tert.-butoxycarbonylamino-5-cryptomaterial acid and 16.9 g of 1-hydroxybenzotriazole and 6.8 g of benzylamine 400 ml be the owls at the same temperature, then for 16 hours at a temperature of about 20oC. After cooling to a temperature of 0oWith the insoluble part is filtered off, washed with ethyl acetate and the filtrate is concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in 60 ml of ethyl acetate and the solution washed with twice 25 ml of aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product is again suspended in a mixture of petroleum ether-pentane in a volume ratio of 50:50, is filtered off, washed with a mixture of petroleum ether with pentane and dried under reduced pressure (2 kPa). So get of 21.7 g of N-benzyl-2-tert.-butoxycarbonylamino-5-triphtalocyaninine in the form of a cream solid color, melting at 144oC.

2-tert.-Butoxycarbonylamino-5-cryptomaterial acid can be obtained as follows.

Supported at -70oC in an atmosphere of argon 29 g of tert.-butyl ether 4-triftormetilfullerenov acid in 300 ml of anhydrous tetrahydrofuran is added dropwise within 1 hour to 168 ml of a 1.5 M solution of tert.-butelli and small amounts add an excess of solid carbon dioxide, dried over anhydrous tetrahydrofuran. The mixture is stirred for 16 hours at a temperature of about 20oWith, then add 500 ml of aqueous saturated solution of ammonium chloride and 200 ml of ethyl acetate. The aqueous phase is extracted with twice 200 ml of ethyl acetate and the organic extracts are combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in a mixture of petroleum ether-pentane in a volume ratio of 50: 50, filtered off, washed with pentane and dried under reduced pressure (2 kPa). So get to 31.7 g of 2-tert.-butoxycarbonylamino-5-cryptomaterial acid in the form of a cream solid color, melting at 204-208oC.

EXAMPLE 9

Follow the procedure of example 1, but using 1.5 g of bromine in 5 ml of acetic acid, 2,34 g 7 triptoreline-1,2,3,5-tetrahydro[4,1]benzothiazepine, 2.5 g of potassium thiocyanate and 20 ml of acetic acid. Received the product in a number of 3.42 g chromatographic under nitrogen pressure (150 kPa) on 80 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50. The resulting product specify by th product (0.66 g) was dissolved in 30 ml of ethanol, to which add 0.15 ml of methansulfonate. After stirring for 16 hours at a temperature of 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The obtained product is recrystallized from 10 ml of ethanol Diisopropylamine ether in a volume ratio of 75: 25. Thus obtain 0.28 g of 2-imino-9-triptoreline-4,5-dihydro-2H,7H-thiazole[3,4,5-de] [4,1]-benzodiazepine in a solid yellow color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, Of 6.96 N, O 15,9, S 23,9.

Found, %: C 35,6, H, 3,0, F 14,1, N, 6,9, S 23,7.

7 Triptoreline-1,2,3,5-tetrahydro[4,1]benzothiazepin can be obtained as follows.

Follow the procedure of example 6, but using 3.4 g of 7-triptoreline-1,5-dihydro-3H-[4,1] benzothiazepin-2-it in 25 ml of anhydrous tetrahydrofuran, 15,5 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran and 15 ml of anhydrous 1,4-dioxane. So get 2,34 g 7 triptoreline-1,2,3,5-tetrahydro[4,1]benzothiazepine in the form of a yellowish oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D. : 2,80 (2H, m, SCH2); to 3.25 (2H, m, NCH

Supported at -70oC in argon atmosphere 10.3 g of tert. -butyl ester 4-triftormetilfullerenov acid in 150 ml of anhydrous tetrahydrofuran is added dropwise within 1 hour and 47 ml of a 1.5 M solution of tert. -utility in pentane. The mixture is stirred for two hours at -20oC, cooled to -70oTo add 1.1 g of sulfur, and then stirred for 1 hour at -20oC. the Mixture is cooled to -70oTo add to 5.4 g methylpropanoate, then stirred for 16 hours at a temperature of about 20oC. After hydrolysis with 50 ml of distilled water and extracted with three times 50 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in 50 ml of dichloromethane, then add 15 ml triperoxonane acid. After stirring for two hours at a temperature of about 20oThe mixture is concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in 40 ml ethyl acetate and the solution is washed with 40 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (Lam and dried under reduced pressure (2 kPa). So get of 3.45 g of 7-triptoreline-1,5-dihydro-3H-[4,1]benzothiazepin-2-it is in the form of a cream solid color, melting at 190oC.

tert. -Butyl ester 2-methyl-4-triftormetilfullerenov acid can be obtained as follows.

Supported at -70oIn an argon atmosphere to a solution of 20 g of tert. -butyl ester 4-triftormetilfullerenov acid in 250 ml of anhydrous tetrahydrofuran is added dropwise within 1 hour 106 ml of a 1.5 M solution of tert. -utility in pentane. The mixture is stirred for 4 hours at -20oC, cooled to a temperature of -10oTo add 10.3 g of iodomethane, then stirred for 16 hours at a temperature of about 20oC. After hydrolysis with 100 ml of distilled water, extracted with three 60 ml ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in petroleum ether, filtered off, washed with the same solvent and dried under reduced pressure (2 kPa). So get of 15.1 g of tert.-butyl ether of 2-methyl-4-triptorelineC.

EXAMPLE 10

Follow the procedure of example 1, but using 1.6 g of bromine in 5 ml of acetic acid, 2.3 g of 7-trifluoromethyl-1,2,3,5-tetrahydro [4, 1]-benzodiazepine, 2.1 g of potassium thiocyanate and 30 ml of acetic acid. After recrystallization from absolute ethanol to 1.15 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]-benzodiazepines.alternate in a solid white color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O3S3< / BR>
Calculated, %: C 37,3, H 3,39, F 14,75, N 7,25, O 12,42, S 24,89.

Found, %: C 37,2, H 3.2, F 14.4V, N, 7,2, S 24,6.

7-Trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin can be obtained as follows.

Follow the procedure of example 6, but using 3.6 g of 7-trifluoromethyl-1,5-dihydro-3H-[4,1] benzothiazepin-2-it in 50 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous 1,4-dioxane and 17.5 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran. Thereby obtaining 2.4 g of 7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepine in a solid beige color, melting at 94oC.

7-Trifluoromethyl-1,5-dihydro-3H-[4,1]benzothiazepin-2-it can be obtained as follows.

A mixture of 14.3 smetana and 15 ml triperoxonane acid is stirred for 3.5 hours at a temperature of about 20oC. the Mixture is concentrated to dryness under reduced pressure (2 kPa), the obtained product is dissolved in 40 ml of N,N-dimethylformamide and within three hours refluxed. The mixture is concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in 50 ml of ethyl acetate and the solution washed with twice 100 ml of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in diisopropyl ether, filtered off, washed with a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50 and dried under reduced pressure (2 kPa). Obtain 3.7 g of 7-trifluoromethyl-1, 5-dihydro-3H-[4,1] benzothiazepin-2-it is in the form of a solid beige color, melting at 239oC.

Methyl ether (2-tert.-butoxycarbonylamino-5-triftormetilfullerenov) acetic acid can be obtained as follows.

Supported at -70oIn an argon atmosphere of 13.7 g of tert. -butyl ester 2-methyl-4-triftormetilfullerenov acid in 180 ml of anhydrous tetrahydrofuran is added dropwise within 1 hour and 15 minutes 67 ml of a 1.5 M solution of tert.-utility in pentane. A mixture of n is 6 grams of sulfur, then stirred for 1 hour at -20oC. the Mixture is cooled to a temperature of -40oTo add 7.6 g of methylpropanoate, then stirred for 16 hours at a temperature of about 20oC. After hydrolysis with 300 ml of distilled water and extracted twice with generally 160 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in petroleum ether and the solution is filtered, then concentrated to dryness under reduced pressure (2 kPa). Obtain 14.3 g of methyl ester of 2-tert.-butoxycarbonylamino-5-triftormetilfullerenov acid in a solid yellow color, melting at 54oC.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: 1,45 (N, with, (CH3)3); to 3.25 (2H, s, S2CO); OF 3.60 (3H, s, och3); 4,00 (2H, s, SCH2-aryl); 7,60 (2H, m, 2 of CH arene.); the 7.85 (1H, d, J=7 Hz, CH arene.); cent to 8.85 (1H, s, NH).

Methyl ether (2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)acetic acid can also be obtained in the following way.

To a suspension of 5.2 g of sodium hydride (who derivekey in nitrogen atmosphere, poured 14 g of methylthioribose and then stirred for 1 hour 30 minutes at a temperature of about 20oC. then poured the solution of 37.8 g of tert.-butyl ester 2-methyl bromide-4-triftormetilfullerenov acid in 30 ml of dimethylformamide and stirred so for 16 hours. The reaction mixture is concentrated to dryness under vacuum (2 kPa) and the resulting paste is treated with 200 ml of distilled water and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa). Oil in the amount of 32.6 g chromatographic 360 g of silicon dioxide (20-45 μm) contained in a column of diameter 4 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 90:10. Thus obtain 15.2 g of methyl ester of (2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)-acetic acid in a solid yellow color, melting at 54oC.

tert. -Butyl ester 2-methyl-4-triftormetilfullerenov acid was obtained as follows.

Supported at -70oC in an atmosphere of argon and 30 g of tert.-butyl ether 4-triftormetilfosfinov tert. -utility in pentane. The mixture is stirred for 4 hours at -20oC, again cooled to a temperature of -70oTo add to 16.4 g of iodomethane, then stirred for 16 hours at a temperature of about 20oC. After hydrolysis with 300 ml of distilled water and extracted twice with generally 160 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product is suspended in petroleum ether, filtered off, washed with the same solvent and dried under reduced pressure (2 kPa). So get to 20.5 g of tert.-butyl ether of 2-methyl-4-triftormetilfullerenov acid in a solid beige color, melting at 101oC.

tert.-Butyl ester 2-methyl bromide-4-triftormetilfullerenov acid can be obtained as follows.

A mixture of 40 g of tert.-butyl ether of 2-methyl-4-triftormetilfullerenov acid, 26 g of N-bromosuccinimide and 1.5 g of benzoyl peroxide in 290 ml of carbon tetrachloride is brought to a boil and cover the lamp Mazdasol 100 watts for 4 hours. The formed succinimide of utilitaruluiincorporat sodium, then 200 ml of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum (2 kPa). The oil is treated with petroleum ether and the resulting crystals filtered off. So get to 37.9 g of tert.-butyl ester 2-methyl bromide-4-triftormetilfullerenov acid in a solid white color, melting at 98oC.

EXAMPLE 11

Follow the procedure of example 4, but using 6,35 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole-[3,4,5-de][4,1]benzothiazepine and 15.1 g of 3-chlormadinone acid (purity 80%) in 130 ml of dichloromethane. Thus obtain 4.12 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de] [4,1] benzothiazepin-6,6-dioxymethylene in the form of a white powder, melting at above 260oC.

Analysis: C12H13F3N2O5S3< / BR>
Calculated, %: C 34,45, H 3,13, F 13,62, N 6,69, S 22,99,

Found, %: C 34,46, H 2,94, F 13,17, N Of 6.71, S Of 23.11.

EXAMPLE 12

Follow the procedure of example 5, but using 230 mg of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepine and 198 mg of 3-chlormadinone acid (purity 80%) in 8 ml dichloromethane. Thus obtained 210 mg of (R,S)-2-imino-9-trifluoromethyl-4,5-dihydro what.

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, N Of 6.96, S 23,9.

Found, %: C 36,2, H 2,9, F 13,9, N, 7,0, S 23,5.

EXAMPLE 13

Dissolve 400 mg of (R,S) -2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de)[4,1]benzothiazepin-6-oxide in 160 ml of dichloromethane and Inuktitut on 700 g of chiral stationary phase type (S,S) WHELCK-01contained in a column with a diameter of 60 mm and a length of 400 mm, elwira a mixture of dichloromethane with n-heptane and methanol in a volume ratio of 50:50:2 with a flow rate of 70 ml/min Receive 200 mg of (+)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole(3,4,5-de)[4,1] benzothiazepin-6-oxide ([]D20=+27,7o1o; c=0,2%, methanol) and 200 mg of (-)-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de)[4,1] benzothiazepin-6-oxide ([]D20=-28,2o1o; 0=0,2%, methanol).

Dissolve 200 mg of (+)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3, 4, 5-de)[4,1] benzothiazepin-6-oxide in 30 ml of ethanol with 70 mg of methansulfonate and stirred for 16 hours at a temperature of about 20oC. the Medium is then concentrated to dryness under vacuum (2 kPa) and the clear coat is treated with 1.0 ml of acetone. The solid is filtered off, washed twice in 2 ml of acetone. Obtain 240 mg of the (+)white society, melting at 230o(Melting with the formation of the adhesive melt).

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, N Of 6.96, S 23,9.

Found, %: C 35,51, H 2,78, F 14,26, N 6,75, S 23,95.

[]D20=+73,1o1,1o(C=0.5%, methanol)

Dissolve 200 mg of (-)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-triazole(3,4,5-de)[4,1] benzothiazepin-6-oxide in 30 ml of ethanol with 70 mg of methansulfonate and stirred for 16 hours at a temperature of about 20oC. the Medium is then concentrated to dryness under vacuum (2 kPa) and the clear coat is treated with 10 ml of acetone. The solid is filtered off, washed twice in 2 ml of acetone and obtain 230 mg of (-)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de)[4,1] benzothiazepin-6-Oxymetazoline in a solid white color, melting at 235o(Melting with the formation of the adhesive melt).

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, N Of 6.96, S 23,9.

Found, %: C 35.70 Barm, H 3,14, F 13,30, N 6,91, S 24,23.

[]D20=-74,2o1,2o(C=0.5%, in methanol).

EXAMPLE 14

It cooled to a tempera-ef) [1,5] -benzodiazepine in 20 ml of dichloromethane added to 0.92 g of 3-chlormadinone acid (purity 80%). The mixture is stirred for 1.5 hours at the same temperature. After chromatography with elution by ethyl acetate and processing methansulfonate obtain 0.88 g of 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef) [1,5] -benzodiazepin-7-Oxymetazoline in a solid white color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O4S3< / BR>
Calculated, %: C 35,82, H 3,26, F 14,16, Of 6.96 N, O 15,9, S 23,9.

Found, %: C 35,7, H 3,3, F 13,8, N, 6,9, S 24,0.

EXAMPLE 15

Follow the procedure of example 4, but using 1 g of 2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef)[1,5]-benzothiazepine and 2.2 g of 3-chlormadinone acid (purity 80%) in 20 ml of dichloromethane. So get 789 mg of 2-imino-9-trifluoromethyl-5,6-dihydro-2H,4H-thiazol[3,4,5-ef)[1,5]-benzodiazepin-6,6-dioxymethylene in the form of a white powder, melting at above 260oC.

Analysis: C12H13F3N2O5S3< / BR>
Calculated, %: C 34,45, H 3,13, F 13,62, N 6,69, S 22,99.

Found, %: C 34,16, H 3,17, F 13.56MHz, N 6,75, S 23,23.

EXAMPLE 16

Follow the procedure of example 1, but using 6.3 g of bromine in 20 ml of acetic acid, 9 g 8-trifluoromethyl-2,3,4,5-tetrahydro[1,5]benzothiazepin the population of nitrogen (50 kPa) on 90 g of silica gel (20-45 μm), contained in a column 3 cm in diameter, elwira mixture of ethylacetate with cyclohexane in a volume ratio of 50:50. Dissolve 4.4 g of the obtained product (obtained from generally 5.7 g) in 80 ml of ethanol, to which add 1.5 ml of methansulfonate. So get 5 g of 2-imino-9-trifluoromethyl-5,6-dihydro-3H, 4H-thiazol[3,4,5-ef)[1,5] -benzodiazepines.alternate in a solid white color, melting at a temperature above 260oC.

Analysis: C12H13F3N2O3S3< / BR>
Calculated, %: C 37,3, H 3,39, F 14,75, N 7,25, O 12,42, S 24,89.

Found, %: C 37,4, H, 3,0, F 14,7, 7,3 N, S 25,3.

8-Trifluoromethyl-2,3,4,5-tetrahydro[1,5] benzothiazepin-triptorelin can be obtained as follows.

To a solution of 13 g of tert.-butyl ester 8-trifluoromethyl-2,3,4,5-tetrahydro[1,5]-benzodiazepin-5-carboxylic acid in 30 ml dichloromethane added a solution of 15 ml triperoxonane acid. The mixture is stirred for 1 hour at a temperature of about 20oWith, then concentrated to dryness under reduced pressure (2 kPa). The obtained product is dissolved in 60 ml of ethyl acetate and the solution washed with distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). contained in a column of diameter 4 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 75:25. The resulting product is suspended in petroleum ether and filtered. Get 9 g 8-trifluoromethyl-2,3,4,5-tetrahydro[1,5] benzodiazepines.percocet in a solid orange color, melting at 60oC.

tert.-Butyl ester 8-trifluoromethyl-2,3,4,5-tetrahydro [1,5]-benzodiazepin-5-carboxylic acid can be obtained as follows.

Supported at -70oIn an argon atmosphere to a solution of 20 g of tert. -butyl ester 4-triftormetilfullerenov acid in 250 ml of anhydrous tetrahydrofuran is added dropwise to/for 1 hour 102 ml of a 1.5 M solution of tert. -utility in pentane. The mixture is stirred for 4 hours at -20oC, cooled to -60oWith add 2.5 g of sulfur, and then stirred for 45 minutes at -20oC. the Mixture is cooled to -60oTo add the 15.6 g of 1-chloro-3-iodopropane, then stirred for 16 hours at a temperature of about 20oWith over 7 hours at boiling temperature under reflux, and then for 48 hours at a temperature of about 20oC. hydrolyzing the Mixture through the organic extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa). The resulting product chromatographic under nitrogen pressure (150 kPa) on 450 g of silica gel (20-45 μm) contained in a column of diameter 6 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 90:10. Thereby obtaining 13 g of tert.-butyl ester 8-trifluoromethyl-2,3,4,5-tetrahydro[1,5] benzodiazepin-5-carboxylic acid as a pale yellow oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: 1,50 (N, with, (CH3)3); of 1.95 (2H, m, CH2); 3,05 (2H, t, J=6 Hz, SCH2); 3,70 (2H, t, J=6 Hz, CH2CL); of 7.60 (1H, DD, J=8 and 2 Hz, CH arene.); of 7.75 (1H, d, J=2 Hz, CH arene.); the 7.85 (1H, d, J=8 Hz, CH arene.); at 8.60 (1H, s, NHCO).

EXAMPLE 17

Follow the procedure of example 1, but using 0,660 g of bromine in 5 ml of acetic acid, 1 g (R,S)-3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepine, 0,864 g of potassium thiocyanate and 15 ml of acetic acid. Before alkalizing using ammonium hydroxide insoluble portion removed by filtration, washed with ethyl acetate. The resulting product chromatographic under nitrogen pressure (150 kPa) at 40 g

silica gel (20-45 μm) contained in a column with a diameter of 1.5 cm, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50. The resulting product Y for 16 hours at a temperature of about 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product proscout in acetone, filtered off, washed with acetone, then diisopropyl ether and dried for 16 hours in air in a ventilated fume hood. So get 0,834 g (R, S)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1] benzodiazepines.alternate in a solid white color, melting at a temperature above 260oC.

Analysis: C12H15F3N2O3S3< / BR>
Calculated, %: C 38,99, H Of 3.78, F 14,23, N 7,00, O 11,99, S To 24.02.

Found, %: C 39,05, H 3,45, F 13,94, N 7.03 Is, S 24,37.

Dissolve 425 mg (R,S)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzodiazepines.alternate in a mixture of 25 ml of ethanol, 0.5 ml of triethylamine and 200 ml of n-heptane and Inuktitut on 700 g of stationary phase CHIRACEL OJ (20 μm) contained in a column with a diameter of 60 mm and a length of 400 mm Elwira a mixture of n-heptane with isopropanol and triethylamine in a volume ratio of 90:10:0,1 with a flow rate of 90 ml/min Receive 150 mg of (+)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepine in a solid beige color, melting at 102oWITH

{[]D20

Found, %: C 47,59, H 3,24, F 18,44, N 8,99, S 20,92}.

and 150 mg of (-)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de) [4,1]-benzodiazepine in a solid beige color, melting at 102oWITH

{[]D20=-103,1o1,6o; (C=0.5%, methanol);

Analysis: C12H11F3N2S2< / BR>
Calculated, %: C 47,36, H 3,64, F 18,73, N 9,20, S 21,07.

Found, %: C 47,64, H 3,24, F 18,37, N 8,97, S 20,93}.

(R, S)-3-Methyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepin can be obtained as follows.

To a solution of 4.5 g (R,S)-3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin-2-it in 120 ml of toluene is added dropwise to 16.5 ml of 2 M solution of a complex of boron hydride with dimethyl sulfide in toluene and all together for 1.5 hours refluxed. After returning to a temperature of 20oWith the environment handle and peremeshivayte within 15 minutes with a saturated solution of sodium bicarbonate, then extracted with twice ethylacetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). Product chromatographic under nitrogen pressure (150 kPa) on the lines a ratio of 80:20. So get of 2.36 g (R, S)-3-methyl-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepine in the form of a colorless oil, which crystallizes in the form of white crystals, melting at 62oC.

(R, S)-3-Methyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin-2-it can be obtained as follows.

A solution of 13.6 g of methyl ester of (R,S)-2-(2-amino-5-triftormetilfullerenov)propionic acid, 2 g of 4-toluenesulfonic acid and 200 ml of toluene is refluxed for 48 hours. After returning to a temperature of about 20oWith add aqueous saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The resulting product chromatographic under nitrogen pressure (150 kPa) on 150 g of silica gel (20-45 μm) contained in a column with a diameter of 3.5 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 50: 50, then pure ethyl acetate. Thus obtained 4.5 g (R, S)-3-methyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin-2-it is in the form of a solid beige color, melting at 220oC.

To a solution of 17.3 g of methyl ester of (R,S)-2-(2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)propionic acid in 200 ml of dichloromethane added at once 20 g triperoxonane acid and stirred for 16 hours at a temperature of about 20oC. After concentration to dryness under reduced pressure (2 kPa) and the residue after evaporation is treated with ethyl acetate and aqueous saturated solution of sodium bicarbonate. The alkaline phase is extracted again with ethyl acetate and the combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). So get to 13.6 g of methyl ester of (R,S)-2-(2-amino-5-triftormetilfullerenov)propionic acid as a brown oil, which is used in this form.

Methyl ester of (R, S)-2-(2-tert. -butoxycarbonylamino-5-triftormetilfullerenov) propionic acid can be obtained as described in example 10, but based on 15 g of tert.-butyl ether of 2-methyl-4-triftormetilfullerenov acid in 210 ml of anhydrous tetrahydrofuran, 91 ml of a 1.5 M solution of tert.-utility in pentane, to 1.75 g of sulfur and 11 g of methyl ester of (R, S)-2-bromopropionic acid. Thus obtain 17.3 g is a transparent yellow oil, used in this manner.

EXAMPLE 18

Follow the procedure of example 1, but using 0,76 g of bromine in 6 ml of acetic acid, 1.3 g (R,S)-3-carbarnoyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepine, 0,912 g of potassium thiocyanate and 11 ml of acetic acid. To alkalizing the ammonium hydroxide insoluble part is filtered off, washed with ethyl acetate. The resulting product chromatographic under nitrogen pressure (150 kPa) on 30 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 90:10. The resulting product in an amount of 560 mg will recrystallized from 5 ml of acetonitrile and thus emit 390 mg (R,S)-5-carbarnoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-triazole[3,4,5-de][4,1]benzothiazepine in a solid white color, melting at a temperature of about 114oC.

Analysis: C12H10F3N3S2< / BR>
Calculated, %: C 43,43, H 3,02, F 17,1, N 12,61, O 4,80, S 19,24.

Found, %: C 42,83, H 2,79, F 16,68, N 12,3, S 19.01 In.

(R, S)-3-Carbarnoyl-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin can be obtained as follows.

Dissolve 3 g of methyl ester of (R,S)-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin-3-carboxylic it is their 16 hours. Wednesday concentrated to dryness under reduced pressure and the dry extract chromatographic under nitrogen pressure (150 kPa) on 35 g of silica gel (20-45 μm) contained in a column 2 cm in diameter, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50, then pure ethyl acetate. Thus obtained 1.3 g (R,S)-3-carbarnoyl-7-trifluoromethyl-1,2,3,5-tetrahydro [4,1]benzothiazepine in the form of an orange oil.

1H-NMR spectrum (250 MHz; hexacyanometallate; temperature = 27oC), M. D.: the 3.5 and 3.9 (1H each, m, NCH2); 3,6-and 4,6 (1H each, d, J= 16 Hz, SCH2); 3,6 (1H, DD, J=4 and 12 Hz, SCH); at 6.4 (1H, m, NH); 6,8 (1H, d, J= 7 Hz, CH arene.); of 7.1 and 7.5 (1H each, s, CONH2); 7,28 (1H, d, J=7 Hz, CH arene.); to 7.32 (1H, s, CH arene.).

Methyl ester of (R, S)-7-trifluoromethyl-1,2,3,5-tetrahydro [4,1]benzothiazepin-3-carboxylic acid can be obtained as follows.

A mixture of 4.7 g of methyl ester of 7-trifluoromethyl-1,5-dihydro[4,1]benzothiazepin-3-carboxylic acid, 15,55 g of magnesium shavings and 150 ml of methanol is brought to a temperature of about 40oC. When the reaction begins, bath removed and the reaction proceeds by itself at boiling under reflux. At the end of education phlegmy Wednesday is brought to a temperature of about 0oAnd debateroom. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). So get of 3.07 g of methyl ester of (R,S)-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzothiazepin-3-carboxylic acid as a brown oil.

1H-NMR spectrum (250 MHz; hexacyanometallate; temperature = 27oC), M. L.: between 3.6 and 4.1 (7H, m, N2+S+1/2S2+CO3); 4,4 (1H, d, J= 16 Hz, 1,2 SCH2); and 6.5 (1H, m, NH); 6,8 (1H, d, J=7 Hz, CH arene.); 7,28 (1H, d, J=7 Hz, CH arene.); to 7.32 (1H, s, CH arene.).

Methyl ether 7-trifluoromethyl-1,5-dihydro[4,1]benzothiazepin-3-carboxylic acid can be obtained as follows.

To a solution 7,05 g of methyl ester of 3-dimethylamino-2-(2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)acrylic acid in 75 ml of dichloromethane is added slowly to 9.25 g triperoxonane acid and all together is stirred for 24 hours at a temperature of about 20oC. Environment concentrated to dryness under reduced pressure (2 kPa) and the residue is treated with 100 ml of aqueous saturated solution of sodium bicarbonate and extracted once with 200 ml of ethyl acetate. The organic extract is dried over magnesium sulfate, ochiltree-1,5-dihydro[4,1] benzothiazepin-3-carboxylic acid in the form of a solid orange color, melting at 260oC.

Methyl ester of 3-dimethylamino-2-(2-tert.-butoxycarbonyl-amino-5-triftormetilfullerenov)acrylic acid can be obtained as follows.

To a solution of 11.3 g of methyl ester of (2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)acetic acid in 230 ml of anhydrous 1,2-dimethoxyethane poured 15.6 g of tert.-Butylochka-bis(dimethylamino)methane. The medium is refluxed for two hours, then stirred for 48 hours at a temperature of about 20oC. the Medium is then hydrolized with 150 ml aqueous saturated solution of sodium bicarbonate and extracted with 200 ml of ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The residue (12.1 g) chromatographic under nitrogen pressure (150 kPa) on 400 g of silica gel (20-45 μm) contained in a column with a diameter of 4.5 cm, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 80:20. So get 7,05 g of methyl ester of 3-dimethylamino-2-(2-tert.-butoxycarbonylamino-5-trifluoromethyl-benzylmethyl)acrylic acid in the form of a cream solid color.

1); 2,95 (6N, s, N(CH3)2; of 3.60 (3H, s, och3); of 3.80 (2H, s, S2); 7,30 (1H, d, J=2 Hz, CH arene.); to 7.50 (1H, DD, J=2 and 7 Hz, CH arene. ); the 7.65 (1H, s, CH ethylene); of 7.90 (1H, d, J=7 Hz, CH arene.); of 8.90 (1H, s, NH).

EXAMPLE 19

Follow the procedure of example 1, but using 0.34 g of bromine in 3 ml of acetic acid, 0.55 g of 3,3-dimethyl-7-trifluoromethyl-1,2-dihydro-5H-[4,1]benzothiazepine, 0.45 g of potassium thiocyanate and 10 ml of acetic acid. The resulting product chromatographic under nitrogen pressure (150 kPa) on 40 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira a mixture of ethyl acetate with cyclohexane to volume ratio of 50:50. Received the product in the amount of 610 mg dissolved in 10 ml of ethanol, to which add 0,22 g methansulfonate. After stirring for 16 hours at a temperature of about 20oThe solution is concentrated to dryness under reduced pressure (2 kPa). The resulting product proscout in a mixture of acetone with diisopropyl ether in a volume ratio of 65: 35, filtered off, washed with acetone, then diisopropyl ether and dried for 16 hours in air in a ventilated fume hood. So get 0,595 g of 5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H, 7H-thiazole-[3,4,5-de] [4,1]benzothiazepine in the form of a solid white3S3< / BR>
Calculated, %: C 40,57, H 4,13, F Of 13.75, N 6,76, O 11,58, S 23,21.

Found, %: C 40,23, H 3,63, F 13,46, N Of 6.65, S 23,6.

3,3-Dimethyl-7-trifluoromethyl-1,2~ dihydro-5H-[4,1]benzothiazepin can be obtained as follows.

To a solution of 1.6 g of 3,3-dimethyl-7-trifluoromethyl-1,5-dihydro [4,1]benzothiazepin-2-it in 80 ml of anhydrous toluene is added dropwise to 7.3 ml of 2 M solution of a complex of boron hydride with dimethyl sulfide in toluene together and refluxed for 1 hour. After returning to a temperature of 20oC environment handle and stirred for 30 minutes with saturated aqueous sodium bicarbonate, then extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). Product chromatographic under nitrogen pressure (150 kPa) on 100 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 80:20. Thus obtained 0.55 g of 3,3-dimethyl-7-trifluoromethyl-1,2-dihydro-5H-[4,1] benzothiazepine in the form of white crystals, melting at 142oC.

3,3-Dimethyl-7-trifluoromethyl-1,5-dihydro[4,1]benzathine)-2-methylpropionic acid in 40 ml of xylene is refluxed for 72 hours. The medium is then concentrated to dryness under reduced pressure (2 kPa) and the residue chromatographic under nitrogen pressure (150 kPa) at 155 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 75:25. The resulting product is treated and elaborate with diisopropyl ether and filtered, then washed with diisopropyl ether, and dried under reduced pressure. Thus obtain 1.47 g of 3,3-dimethyl-7-trifluoromethyl-1,5-dihydro[4,1] benzothiazepin-2-it is in the form of a cream solid color, melting at 210oC.

2-(2-Amino-5-triftormetilfullerenov)-2-methylpropionate acid can be obtained as follows.

A solution of 2.55 g of methyl ester of 2-(2-amino-5-triftormetilfullerenov)-2-methylpropionic acid, of 0.59 g of potassium hydroxide in pastilles (purity 85%) in 30 ml of absolute ethanol is stirred at a temperature of about 20oC for 5 days. The medium is then acidified with 18 ml of about 5 M solution of hydrogen chloride in isopropanol and the medium is then concentrated to dryness under reduced pressure (2 kPa). The residue is treated with ethyl acetate and the insoluble part is filtered off, referat under nitrogen pressure (150 kPa) on 50 g of silica gel (20-45 μm), contained in a column 2 cm in diameter, elwira a mixture of ethyl acetate with methanol in a volume ratio of 95:5. Produce a product that is treated with petroleum ether, and the product is filtered off, washed with petroleum ether and dried. Thus obtained 2.2 g of 2-(2-amino-5-triftormetilfullerenov)-2-methylpropionic acid in the form of a cream solid color, melting at 113oC.

Methyl ester 2-(2-amino-5-triftormetilfullerenov)-2-methylpropionic acid can be obtained as follows.

A solution of 9.2 g of methyl ester of 2-(2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)-2-methylpropionic acid, 10.3 g triperoxonane acid and 100 ml of dichloromethane is stirred for 72 hours at a temperature of about 20oC. Environment concentrated to dryness under reduced pressure (2 kPa) and the residue is treated with 250 ml of aqueous saturated solution of sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) to give oil, which chromatographic under nitrogen pressure (150 kPa) on 80 g of silica gel (Ni 75:25. So get 5 g of methyl ester of 2-(2-amino-5-triftormetilfullerenov)-2-methylpropionic acid as a yellow oil.

1H-NMR spectrum (300 MHz; hexacyanometallate; temperature = 27oC), M. D.: 1,49 (6N, s, 2 CH3); 3,6 (3H, s, och3); 3,8 (2H, S, SCH2); 5,6 (2H, S, NH2); to 6.75 (1H, d, J=7 Hz, CH arene.); of 7.25 (1H, d, J=7 Hz, CH arene.); to 7.35 (1H, s, CH arene.).

Methyl ester 2-(2-tert.-butoxycarbonylamino-5-triftormetilfullerenov)-2-methylpropionic acid can be obtained as described in example 10, but 15 g of tert.-butyl ether of 2-methyl-4-triftormetilfullerenov acid in 210 ml of anhydrous tetrahydrofuran, 91 ml of a 1.5 M solution of tert. -utility in pentane, to 1.75 g of sulfur and 11.9 g of methyl ester of 2-bromo-2-methylpropionic acid. So get of 9.2 g of methyl ester of 2-(2-tert. -butoxycarbonylamino-5-trifloromethyl-sulfanyl)-2-methylpropionic acid as a colourless oil.

1H-NMR spectrum (250 MHz; hexacyanometallate; temperature = 27oC), M. D. : 1,56 (6N, s, 2 CH3); 1,57 (N, with, (CH3)3); 3,6 (3H, s, och3); as 4.02 (2H, s, SCH2); the 7.65 (1H, d, J=7 Hz, CH arene.); of 7.75 (2H, m, 2 of CH arene.); 8,9 (1H, s, NH).

EXAMPLE 20

(R, S)-5-HYDR="ptx2">

To a solution of 2.5 g of methyl ester of (R,S)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de)[4,1]benzothiazepin-5-carboxylic acid in 25 ml of absolute ethanol, supported in an argon atmosphere, add 300 mg of sodium borohydride and all together refluxed for 5 hours. The medium is then stirred for 16 hours at a temperature of about 20oWith, and then hydrolyzing with 50 ml of distilled water and extracted with 50 ml ethyl acetate. The organic extract is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa). The oil obtained chromatographic under nitrogen pressure (150 kPa) on 30 g of silica gel (20-45 μm) contained in a column 2.5 cm in diameter, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 50:50. The obtained solid is treated with diisopropyl ether, filtered off, dried under reduced pressure (2 kPa). So get 40 mg (R, S)-5-hydroxy-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de)[4,1] benzothiazepine in the form of a solid vaguely colored substance, melting at 167oC.

Analysis: C12H11F3N2OS2< / BR>
Calculated, %: C 44,99, H 3.46 in, F 1 is the measure of 1, but use of 1.66 g of bromine in 5 ml of acetic acid, 3 g of methyl ester of (R,S)-7-trifluoromethyl-1,2,3,5-tetrahydro[4,1] benzothiazepin-3-carboxylic acid, 2.2 g of potassium thiocyanate and 30 ml of acetic acid. The resulting product chromatographic under nitrogen pressure (150 kPa) on 80 g of silica gel (20-45 μm) contained in a column with a diameter of 3.5 cm, elwira a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50. Thereby obtaining 2.5 g of methyl ester of (R,S)-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole(3,4,5-de) [4,1] benzothiazepin-5-carboxylic acid in the form of butter.

EXAMPLE 22

Follow the procedure of example 1, but use of 1.47 g of bromine in 5 ml of acetic acid, 2 g of 7-trifluoromethyl-1,2,3,5-tetrahydro[4,1]benzoxazepine, 3 g of potassium thiocyanate and 50 ml of acetic acid. After chromatography was carried out on silica gel with elution with a mixture of ethyl acetate with cyclohexane in a volume ratio of 50:50 and processed by methansulfonate get to 1.79 g of 2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole(3,4,5-de)[4,1] benzodiazepines.alternate in the form of a whitish solid, melting at a temperature of about 258oC.

Analysis: C12H13F3N2O4S2< / BR>
Calculated, %: C 38,92, H 3,54, F 15,39, N 7,56, O 17,28, S 17,31.

Chen as follows.

To a suspension 2,22 g of 7-trifluoromethyl-1,5-dihydro-3H-[4,1]benzoxazepin-2-it in 100 ml of toluene is added dropwise in an argon atmosphere and at a temperature of about 20oWith 15 ml of 2 n solution of a complex of boron hydride with dimethyl sulfide in tetrahydrofuran. Reaction medium was then heated to boiling and boiled for 1 hour and 45 minutes. After cooling to a temperature of 20oWith a hydrolyzing reaction medium with 100 ml of saturated solution of sodium bicarbonate, then extracted with twice 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, and then concentrated in a rotary evaporator, after powdering of the residue in petroleum ether to obtain 2 g of 7-trifluoromethyl-1,2,3,5-tetrahydro-[4,1] benzoxazepine in the form of a yellowish solid, melting at about 85oC.

7-Trifluoromethyl-1,5-dihydro-3H-[4,1]benzoxazepin-2-it can be obtained as follows.

To a solution 2,95 g of 2-chloro-N-(2-hydroxymethyl-4-triptoreline)ndimethylacetamide in 330 ml of tetrahydrofuran in an argon atmosphere and at a temperature of about 5oTo add to 2.9 tert.-the butyl potassium. After stirring for 1 hour at this temperature, the reaction medium was hydrolized with 30 ml sasisekharan magnesium, then concentrate to dryness in a rotary evaporator. After powdering of the residue in a mixture of diethyl ether and petroleum ether to obtain 2.2 g of 7-trifluoromethyl-1,5-dihydro-3H-[4,1] benzothiazepin-2-it is in the form of a solid white color, melting at a temperature of about 183oC.

2-Chloro-N-(2-hydroxymethyl-4-triptoreline)ndimethylacetamide can be obtained as follows.

To a solution 5,54 g 2-amino-5-triftormetilfullerenov in 100 ml of dichloromethane and 6 ml of triethylamine, in an argon atmosphere and at a temperature of about 5oTo add to 2.1 ml chloroacetanilide in the form of a solution in 20 ml of dichloromethane. The reaction medium is stirred for three hours at a temperature of 5oWith, then for 18 hours at room temperature. Then it was poured into 100 ml of saturated solution of sodium bicarbonate, then extracted with 200 ml diethyl ether. The organic phase is dried over magnesium sulfate, and then concentrated in a rotary evaporator. After chromatography was carried out on silica gel, elwira with a mixture of cyclohexane to ethyl acetate in a volume ratio of 65: 35 and powdering of the residue in a mixture of diethyl ether and petroleum ether, to obtain 4 g of 2-chloro-N-(2-hydroxymethyl-4-triptoreline)ndimethylacetamide methylphenylethyl can be obtained as follows.

To a solution of 7.3 g of 2-amino-5-triftorperasin acid in 250 ml of tetrahydrofuran in an argon atmosphere and at a temperature of about 5oTo add to 7.3 g of sodium borohydride, and then 24 ml of chlorotrimethylsilane. After stirring for 44 hours at room temperature, the reaction medium is cooled to a temperature of about 5oWith, and then hydrolyzing with 100 ml of distilled water and extracted twice with diethyl ether (400 ml, then 150 ml). The combined organic phases are washed with 100 ml of 1 n sodium hydroxide solution, then dried over magnesium sulfate and concentrated in a rotary evaporator. Thus obtained 7.9 g of 2-amino-5-triftormetilfullerenov in a solid white color, melting at 70oC.

2-Amino-5-triftorperasin acid can be obtained according to the method described by M. L. Carmellino and other Eur.J.Meci.Chem.Chim. Ther., 29 (10), 743 (1994).

Medicinal product according to the invention is formed by a compound of the formula (I) or the salt of such compounds in pure form or in the form of a composition in which the compound or its salt is associated with any other pharmaceutically compatible product, which may be inert or physiologically actioncasino.

As solid compositions for oral administration can be used in tablets, pills, powders (gelatin capsules, starch wafers or pellets. In these compositions, the active principle according to the invention are mixed in a stream of argon with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions can also contain diluents and other substances, for example one or more lubricants such as magnesium stearate or talc, a colorant, a shell (pills) or lacquer.

As liquid compositions for oral administration can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions can also include diluents and other substances, for example wetting, sweetening, thickening agents, flavoring agents or stabilizers.

Sterile compositions for parenteral administration can preferably be an aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or carrier can ispolzovanie esters for injection, as, for example, etiloleat, or other suitable organic solvents. These compositions can also contain additives, in particular wetting, isotonic components, emulsifiers, dispersing agents and stabilizers. Sterilization can be done in several ways, for example by asamisimasa filtering, including the composition of the sterilizing agent, by irradiation or by heating. They can also prepare in the form of sterile solid compositions, which at the time of use can be dissolved in sterile water or any other sterile environment for injection.

Compositions for rectal injection are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The composition for external use may constitute, for example, creams, lotions, lotions for the eyes, the liquid for rinsing the mouth and applications to the gums, nasal drops or aerosols.

In human therapy, the compounds according to the invention is particularly suitable for the treatment and/or prevention of convulsions and diseases associated with glutamatergic Premia), resulting from violations of cerebral circulation, such as thromboembolic and hemorrhagic shock, cardiac arrest, hypotension, surgery on the heart, blood vessels or lungs, or severe hypoglycemia; for treatment effects due to anoxia, which is perinatal or evolved as a result of drowning, high pressure or spinal damage; to treat or prevent the development of neurodegenerative diseases, horii's chorea, Alzheimer's disease and other dementias, amyotrophic lateral sclerosis or other Mannaioni disease, Olivo-cerebellopontine atrophy and Parkinson's disease; against epileptic symptoms (epilepsy) and/or convulsive symptoms; for the treatment of traumatic brain or spinal injury, injury-related degeneration of the inner ear or of the retina, tinnitus, anxiety, depression, schizophrenia, Tourette's syndrome, hepatic encephalopathy, sleep disorders, disorders related to attention deficit, disorders of hormonal conditions (excessive secretion of HG or HL, the secretion of corticosterone), as analgesics, anti-inflammatory drugs, protivoanemi, and neurological disorders associated with viral diseases such as viral meningitis and viral encephalitis, AIDS, rabies, measles and tetanus. These compounds are also useful for the prevention, tolerance and dependence in relation to symptoms of withdrawal syndrome when drug or alcohol dependence and for the suppression of dependence and addiction in relation to opiates, barbiturates, amphetamines and benzodiazepines. They can also be used in the treatment of nedostatochnosty associated with mitochondrial abnormalities, such as mitochondrial myopathy, Leber's syndrome, Wernicke's encephalopathy, rett syndrome, homocysteinuria, hyperprolinemia, hydroxybutylidene, lead encephalopathy (chronic intoxication with lead) and the deficit sulfadoxine.

Doses depend on the desired effect, the duration of treatment and the route of administration; they are usually 10-100 mg per day orally for an adult with usual doses, reaching 5-50 mg of active substance.

In General, the physician determines the appropriate dosage depending on the age, weight and all other factors relating to the patient.

The following examples illustrate to the s with doses of 50 mg of active product, having the following composition mg:

The compound of formula (I) - 50

Cellulose - 18

Lactose - 55

Colloidal silicon dioxide is 1

Sodium salt of carboxymethyl amylum - 10

Talc - 10

Magnesium stearate - 1

EXAMPLE B

The usual way to prepare tablets with a dose of 50 mg of active product having the following composition mg:

The compound of formula (I) - 50

Lactose - 104

Cellulose - 40

Polyvidone - 10

Sodium salt of carboxymethyl amylum - 22

Talc - 10

Magnesium stearate - 2

Colloidal silicon dioxide - 2

A mixture of hydroxymethylcellulose, glycerol, titanium dioxide (72-3,5-24,5) to the total mass of one of the finished film-coated tablets - 245

THE EXAMPLE IN

Prepare a solution for injection containing 10 mg of active product and having the following composition:

The compound of formula (I), 10 mg

Benzoic acid 80 mg

Benzyl alcohol - 0.06 ml

Sodium benzoate - 80 mg

Ethanol 95% - 0.4 ml

Sodium hydroxide - 24 mg

Propylene glycol - 1,6 ml

Water to a total volume of 4 PIM

1. Thiazoleethanol formula (I)

< / BR>
in which R1means a sulfur atom;

R2means a hydrogen atom;

-R3-R4-R<8)-, -CH2-CH2-CH2-S-, -CH2-CH2-CH2-SO-, -CH2-CH2-CH2-SO2-,

-CH2-CH2-S-CH2-, -CH2-CH2-SO-CH2-, -CH2-CH2-SO2-CH2-, -CH2- (ALK) (ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-;

R7means polyfluoroankyl or polyporaceae;

R8means hydroxyl;

R9means benzyl;

R10means alkyl, -CH2HE-Sooma, -COOH or-CONH2;

Ala means alkyl;

ALK' is alkyl;

with these definitions, the alkyl radicals and the alkyl parts contain 1 to 6 carbon atoms in linear or branched chains; and their isomers, racemates and enantiomers and their salts with inorganic or organic acid.

2. The compounds of formula (I) under item 1, in which R7means triptoreline or trifluoromethyl, their isomers, racemates, enantiomers and their salts with inorganic or organic acid.

3. The compounds of formula (I) under item 1, selected from the following compounds:

-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-T2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazole[5,4,3-jk][1]benzazepin;

-2-imino-9-triptoreline-5,6-dihydro-2H,4H-thiazol[3,4,5-ef][1,5]benzothiazepin-7,7-dioxide;

-2-imino-9-triptoreline-5,6-dihydro-2H,4H-thiazol[3,4,5-ef][1,5]benzodiazepin-7-oxide;

-2-imino-9-triptoreline-5,6-dihydro-2H,4H-thiazol[3,4,5-ef][1,5]benzothiazepin;

-6-benzyl-2-imino-9-triptoreline-6,7-dihydro-4H-thiazol[3,4,5-kj] [1,4] benzodiazepine-5-he;

-6-benzyl-2-imino-9-triptoreline-4,5,6,7-tetrahydro-2H-thiazole[3,4,5-kj][1,4]benzodiazepine;

-2-imino-9-triptoreline-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin;

-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin;

-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6,6-dioxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef][1,5]benzodiazepin-7-oxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef][1,5]benzothiazepin-6,6-dioxide;

-2-imino-9-trifluoromethyl-5,6-dihydro-2H, 4H-thiazol[3,4,5-ef][1,5]benzothiazepin;

-2-imino-9-trifluoromethyl-4,5,6,7-tetrahydro-2H-thiazole[5,4,3-jk] [1]benzazepin-7-ol;

-2-imino-9-triptoreline-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6,6-dioxide;

-2-imino-9-triptoreline-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-6-benzyl-2-imino-9-trifluoromethyl-6,7-dihydro-4H-thiazol[3,4,5-kj] [1,4] benzo is Ino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de][4,1] benzothiazepin;

-5-carbarnoyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-5,5-dimethyl-2-imino-9-trifluoromethyl-2H, 4H, 7H-thiazole[3,4,5-de][4,1]benzothiazepin;

-5-hydroxymethyl-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin;

their isomers, racemates, enantiomers and their salts with inorganic or organic acid.

4. The compounds of formula (I) under item 1, selected from the following compounds:

-(R,S)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-(+)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-(-)-2-imino-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de][4,1]benzothiazepin-6-oxide;

-(R,S)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H,7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-(+)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

-(-)-2-imino-5-methyl-9-trifluoromethyl-4,5-dihydro-2H, 7H-thiazole[3,4,5-de] [4,1]benzothiazepin;

and their salts.

5. The method of obtaining compounds of formula (I) under item 1, in which R1means a sulfur atom, R2means a hydrogen atom, -R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, SN2
- (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-; R8means hydroxyl, R9means benzyl, and R10means alkyl, -Sooma or-CONH2, ALK denotes alkyl, ALK' is alkyl, wherein the thiocyanate of an alkali metal or selenocyanate alkali metal is injected into the interaction with a derivative of formula (II)

< / BR>
in which R7has the same meanings as in paragraph 1;

-R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, CH2-CH2-CH2-CH(R8)-, -CH2-CH2-CH2-S-, -CH2-CH2-S-CH2-, -CH2- (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-;

R8means hydroxyl;

R9means benzyl;

R10means alkyl, -Sooma or-CONH2;

Ala means alkyl;

ALK' is alkyl;

the product is isolated and, if necessary, turn it into salt.

6. The method of obtaining compounds of formula (I) p.-CH2-CH2-CH(R8) and R8means hydroxyl, wherein restore the corresponding compound of formula (I) in which R2means a hydrogen atom, and R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CO-, the product is isolated and, if necessary, turn it into salt.

7. The method of obtaining compounds of formula (I) under item 1, in which R2means a hydrogen atom, and R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-SO-, -CH2-CH2-CH2-SO2-, -CH2-CH2-SO-CH2-, -CH2-CH2-SO2-CH2-, wherein oxidizing the corresponding compound of formula (I), in which the chain-R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-S-, -CH2-CH2-S-CH2-,

the product is isolated and, if necessary, turn it into salt.

8. Drug with anticonvulsant effect, containing the active principle and a pharmaceutically acceptable carrier, characterized in that it comprises as an active beginning at least one compound according to any one of paragraphs.1-4 or proizvodnye formula (II)

< / BR>
in which R3-R4-R5-R6means a chain of formula-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-S-, -CH2-CH2-S-CH2-, -CH2- (ALK)(ALK')-S-CH2-, -CH2-CH(R10)-S-CH2-, -CH2-CH2-O-CH2-, -CH2-CH2-N(R9)-CH2- or-CH2-CO-N(R9)-CH2-; R7means polyfluoroankyl or polyporaceae;

R8means hydroxyl;

R9means benzyl;

R10means alkyl, -Sooma, -COOH or-CONH2;

Ala means alkyl;

ALK' is alkyl.

 

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ororor< / BR>
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