New phenol derivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

 

The technical field to which the invention relates

The present invention relates to a new derivative of phenol, which is characterized by a high concentration of unchanged compound in the urine, and also has a noticeable uricosuric effect, or its pharmaceutically acceptable salt, or hydrate or their MES, and a drug containing the specified derivative as an active ingredient.

Background of invention

Uric acid is formed as a result of catabolism of purine, which is formed by the cleavage of nucleic acids and adenosine triphosphate (ATP), which is a source of energy of a living organism, with subsequent oxidation metabolized purine (xanthine) by xanthine oxidase or antiaging. In humans, uric acid (dissociation constant pKa=5,75) represents the final metabolite of purine present in the body in the form of free uric acid or salt.

Uric acid is usually excreted in the urine, and if the production of uric acid exceeds its removal, and the content of uric acid in the blood increases, there is hyperuricemia. If over a long period of excess uric acid in the blood exceeds the upper limit of solubility (approximately 7 mg/DL), in the sediment issue which gives crystal lithate (usually sodium salt).

Crystal lithate is deposited in cartilage or joints with sediment, leading, thus, to the formation of gouty nodes. When this is induced acute gouty arthritis and develops chronic gouty arthritis.

If crystalline lithate precipitates in the urine, there is kidney damage (gouty kidney), such as interstitial nephritis, kidney stones, etc. With the purpose of correcting hyperuricemia after remission of the acute attack of gouty arthritis medication exercise jointly with maintaining a positive quality of life.

Prevention of acute gouty arthritis, gouty kidney, urolithiasis, etc. is very important to perform the correction of hyperuricemia and appropriate to regulate the content of uric acid.

It is believed that hyperuricemia is complicated by the diseases associated with lifestyle, such as obesity, hyperlipidemia, abnormal glucose tolerance and hypertension with high pressure (see non-patent document 1 (pages 7-9)). Increasing the concentration of urate in serum is characterized by positive correlation with mortality due to cardiovascular diseases. Since a high concentration of lithate is in the serum increases mortality due to cardiovascular diseases, it is assumed that the increase of uric acid concentration in serum independently and significantly associated with risk of death due to cardiovascular disease (see non-patent document 2).

It is also assumed that the concentration of urate in serum is a high risk factor for myocardial infarction and hemorrhage in the brain (see non-patent document 3). Until now it was reported that hyperuricemia is associated with obesity, hyperlipidemia, dyslipidemia, abnormal glucose tolerance, diabetes mellitus, metabolic syndrome, kidney disease (e.g., renal insufficiency, proteinuria, end-stage renal failure (ESRD), etc.), cardiovascular diseases (e.g. hypertension, ischemic heart disease, disease of the carotid arteries, endothelial dysfunction, arteriosclerosis, cardiac hypertrophy, cerebrovascular disease and so on) or is a risk factor for these diseases (see non-patent documents 2-11). It was also reported that the concentration of uric acid is increased in cerebrospinal fluid in vascular dementia (see non-patent document 12).

In these circumstances, it is assumed that the reduction of the content of urate in the blood can delay the onset of kidney disease, and can reduce the risk of heart is a rule-vascular diseases (see non-patent documents 5, 8, 13 and 14), and reported that the treatment should also apply in the case of asymptomatic hyperuricemia (see non-patent document 14).

Accordingly, it is believed that the reducing amount of urate in the blood when the above-mentioned diseases is effective for the treatment or prophylaxis of these diseases, but it is also important from the point of view of prevention of recurrence of myocardial infarction and maintain kidney function.

The main factor in the increase in the content of urate in the blood includes enhanced products and insufficient excretion of uric acid. It is believed that the method of suppressing the production of uric acid or accelerate the excretion of uric acid is effective for reducing the amount of urate in the blood. It is known that with the first mechanism of action of the drug (inhibitor of production of uric acid) includes allopurinol, whereas with the latter the mechanism of action of the drug (uricosuric drug) includes benzbromarone, probenecid, connection, JP-A-2006-176505 (patent document 1), etc.

Japanese guidelines for treatment of hyperuricemia and gout, as a General rule prescribes that in the case of treatment of hyperuricemia uricosuric drugs used in patients with inadequate excretion of uric acid as inhibitors of the production of uric acid used in patients with avicennae production of uric acid, respectively (see non-patent document 1 (pages 31-32)).

It is reported that in Japan, patients with insufficient excretion of uric acids make up approximately 60% of all patients with hyperuricemia and patients of mixed type with insufficient excretion and increased production of uric acids make up approximately 25% of all patients with hyperuricemia (non-patent document 15). It is also reported that a lack of uric acid excretion is observed in approximately 85% of patients with gout, and even in patients with increased production of uric acid the average uric acid excretion is significantly lower than in healthy people, and a lack of uric acid excretion is assumed to be normal in all patients with gout (non-patent document 16).

Accordingly, when hyperuricemia (especially gout) is an important treatment for patients with insufficient excretion of uric acid, and the significance of the existence of uricosuric drugs is especially great.

Among the main uricosuric drugs probenecid is almost never used, because it has a weak effect and definitely causes gastrointestinal disorders and interacts with other drugs; however, it was reported about serious liver damage by benzbromarone, which is has a strong uricosuric effect and is often used in Japan as a uricosuric drugs (see non-patent document 17).

Benzbromarone or its analogue is characterized by mitochondrial toxicity, for example, inhibition of the activity of enzyme complexes of the respiratory chain of the mitochondria, uncoupling effect, inhibition of respiration, inhibition of β oxidation of fatty acids, decreased membrane potential of mitochondria, apoptosis, production of reactive oxygen species, etc., and mitochondrial toxicity is presumably involved in the induction of liver damage (see non-patent documents 18 and 19). Active metabolite of benzbromarone, 6-hydroxybenzamide, is also characterized by toxicity to mitochondria.

In addition, benzbromarone has an inhibitory effect on cytochrome P450 (CYP), which is an enzyme metabolizing drugs, and is characterized by a particularly strong inhibitory effect on CYP2C9, and presumably cause pharmacokinetic drug interaction (see non-patent documents 20 and 21).

In JP-A-2006-176505 (patent document 1) described nitrogen-containing compound with condensed rings, which has an inhibitory action on URAT1 as type vector lithate, and has a structure similar to the structures of the compounds of the present invention. However, this connection does not have sufficient effect, but the second actionable uricosuric drug developed was not.

Recently, results were obtained that uricosuric effect depends on the concentration of the drug with such action, in the urine, then there is a uricosuric drug shows efficacy of a drug in the excretion of urine (see patent document 2, non-patent documents 22 and 23).

Accordingly, it is assumed more powerful, effective uricosuric drug that is excreted in the urine in large quantities. However, the above-mentioned existing uricosuric drugs are characterized by a very low concentration in the urine, and it is impossible to say, which is achieved satisfactory activity.

As for the excretion of drugs from urine, it may be the case, when injected drug is excreted as unchanged compound "as is", and the case when the drug is converted to an active metabolite, and then displayed. In the latter case, there is a risk that due to individual differences in the production of the active metabolite may increase its quantity. To obtain a stable drugs and security more desirable is a prescription medication that is output in the form of unchanged compound.

Thus, it is desirable to develop a medicinal product which is characterized by a high concentration of unchanged compound in the urine, and the region is significant uricosuric effect and high safety compared with existing uricosuric drugs.

The list of cited documents

Patent documents

Patent document 1: JP-A-2006-176505

Patent document 2: WO 2005/121112

Non-patent documents

Non-patent document 1: Guidelines for the Management of Hyperuricemia and Gout (First Edition) pp. 7-9, and pp. 31-32, Gout and Nucleic Acid Metabolism, Vol. 26, Supplement 1, 2002, Japanese Society of Gout and Nucleic Acid Metabolism

Non-patent document 2: JAMA 283: 2404-2410 (2000)

Non-patent document 3: Stroke 37: 1503-1507 (2006)

Non-patent document 4: Nephrology 9: 394-399 (2004)

Non-patent document 5: Semin. Nephrol. 25: 43-49 (2005)

Non-patent document 6: J. Clin. Hypertens. 8: 510-518 (2006)

Non-patent document 7: J. Hypertens. 17: 869-872 (1999)

Non-patent document 8: Curr. Med. Res. Opin. 20: 369-379 (2004)

Non-patent document 9: Curr. Pharm. Des. 11: 4139-4143 (2005)

Non-patent document 10: Hypertension 45: 991-996 (2005)

Non-patent document 11: Arch. Intern. Med. 169: 342-350 (2009)

Non-patent document 12: J. Neural. Transm. Park Dis. Dement. Sect. 6: 119-126 (1993)

Non-patent document 13: Am. J. Kidney Dis. 47: 51-59 (2006)

Non-patent document 14: Hyperuricaemia and Gout 9: 61-65 (2001)

Non-patent document 15: Nippon Rinsho 54: 3230-3236 (1996)

Non-patent document 16: Nippon Rinsho 54: 3248-3255 (1996)

Non-patent document 17: J. Hepatol. 20: 376-379 (1994)

Non-patent document 18: J. Hepatol. 35: 628-636 (2001)

Non-patent document 19: Hepatology 41: 925-935 (2005)

Non-patent document 20: the Journal of Saitama Medical University (J. Saitama. Med. School) 30: 187-194 (2004)

Non-patent document 21: Drug Metab. Dispos. 31: 967-971 (2003)

Non-patent is a document 22: Proceedings of the 42nd Annual Meeting of the Japanese Society of Gout and Nucleic Acid Metabolism, p. 59 (2009)

Non-patent document 23: ACR 2008 Annual Scientific Meeting, No. 28

A brief description of the invention

The technical problem

The aim of the present invention is to provide new compounds and a pharmaceutical preparation, which have a visible uricosuric effect.

The solution

To achieve the above objectives of the invention the present invention have conducted intensive studies and found a new derivative of phenol with high security and noticeable uricosuric effect, making thereby the present invention.

Thus, the present invention relates to a new derivative of phenol represented by the following General formula (1):

[Chemical formula 1]

,

where R1and R2are the same or different and represent a lower alkyl group, lower alkenylphenol group, lower alkylamino group, a lower alkoxygroup, halogenation group, halogenlampe, alkylsulfanyl group, alkylsulfonyl group, alkylsulfonyl group, substituted lower alkyl karbamoilnuyu group, nitrogen-containing saturated heterocyclic N-carbonyl group, a halogen atom, a cyano or a hydrogen atom, R3represents a lower alkyl gr the PPU, halogenating group, halogen atom, hydroxyl group or hydrogen atom, and X represents a sulfur atom, -S(=O)- or-S(=O)2and its pharmaceutically acceptable salts and their hydrates and their MES and containing pharmaceutical compositions.

In the present description "lower alkyl group" represents a C1-6alkyl group, and may be any of the non-branched, branched and cyclic lower alkyl group, and alkyl group, consisting of combinations thereof. The same should apply to the alkyl portions of the substituents containing an alkyl fragment [lower alkoxygroup, substituted lower alkyl carnemolla group, alkylsulfonyl group and so on]. Examples of C1-6alkyl groups include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, n-hexoloy group, cyclopropyl group, cyclobutyl group, etc., Examples of the lower alkoxygroup include a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, cyclopropane, n-butoxypropyl, isobutoxy, tert-butoxypropyl, n-phenoxypropan, n-hexyloxy, etc., Examples of the lower halogenlampe include cryptometer and crypto is ethoxypropan. Examples of the lower halogenoalkanes groups include triptorelin group, triptorelin group, etc., Examples of the lower alkylsulfonyl groups include methylsulfonyl group, ethylsulfonyl group, isopropylphenyl group, etc., Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and iodine atom. Examples of substituted lower alkyl carbamoyl groups include methylcarbamoyl group, ethylcarbitol group, dimethylcarbamoyl group, diethylcarbamoyl group, etc. are Examples of nitrogen-containing saturated heterocyclic N-carbonyl group include pyrrolidin-1-ylcarbonyl group, thiazolidin-3-ylcarbonyl group, 1-oxothiazolidine-3-ylcarbonyl group, 1,1-dioxothiazolidine-3-ylcarbonyl group, etc., Examples of the lower alkenylphenol group include vinyl group, propenyloxy group, etc., Examples of the lower alkenylphenol groups include etinilnoy group, propenyloxy group, etc., Examples of the lower alkylsulfonyl groups include methylsulfonyl group, ethylsulfinyl group, etc., Examples of the lower alkylsulfonyl groups include methylsulfonyl group, ethylsulfonyl group, etc.

The lower alkyl group represented by R1preferably represents an ethyl group, isopropyl group, n-boutelou group, tert-boutelou group, cyclopropyl group or cyclobutyl group. Lower halogenation group preferably represents triptorelin group. Lowest alkoxygroup preferably represents a methoxy group. Lowest halogenlampe preferably represents cryptometer. Alkylsulfonyl group preferably represents methylsulfonyl group, ethylsulfonyl group or isopropylacetanilide group. Alkylsulfonyl group preferably represents methylsulfonyl group. The halogen atom is preferably a fluorine atom or a chlorine atom. Substituted lower alkyl carnemolla group preferably represents dimethylcarbamoyl group. Saturated nitrogen-containing heterocyclic N-carbonyl group preferably represents pyrrolidin-1-ylcarbonyl group, thiazolidin-3-ylcarbonyl group, 1-oxothiazolidine-3-ylcarbonyl group or 1,1-dioxothiazolidine-3-ylcarbonyl group. Lower Alchemilla group preferably represents etinilnoy group. Lower alkylsulfonyl group preferably represents methylsulfinyl group. R2preferably represents a fluorine atom, a chlorine atom, a cyano, methylsulfonyl group or three is tomatillo group. X preferably represents a sulfur atom or-S(=O)2-. R3preferably represents a hydroxyl group, triptorelin group or a hydrogen atom.

More preferably, as examples can be represented by compounds in which X represents-S(=O)2-, R1represents a chlorine atom, a lower alkyl group, lower alkoxygroup, cryptometer, alkylsulfonyl group or triptorelin group, R2represents a cyano, chlorine atom, fluorine atom, methylsulfonyl group or triptorelin group, and R3represents a hydrogen atom or a hydroxyl group.

In particular, the compounds preferably are 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-l,3-benzothiazole, 3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole 3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(5-tert-butyl-4-hydroxy-3-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole, 3-(3-cyano-5-ethinyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole or pharmaceutically acceptable salt, or a hydrate or MES.

As for the compounds of the present invention, there may be isomers. For example, there may be geometric isomers, optical isomers or diastereoisomers. Any individual isomer of these isomers, any mixtures of the isomers, racemates, etc. fall under the scope of the present invention.

Depending on the type of the substituent of the compounds of the present invention can form a basic additive salt or acid additive salt. Specific limitations on the type of salt does not exist, and its examples include without limitation metal salts such as sodium salt, potassium salt and calcium salt; basic additive salts such as ammonium salts and salts of organic amines; salts of inorganic acids, such as hydrochloride, sulfates and nitrates; organic acid salts such as para-toluensulfonate, methanesulfonate and salt wines is Oh acid.

Compounds of the present invention and their salts may exist in the form of a hydrate or of MES, and these substances also fall under the scope of the present invention. Examples of hydrates include 1/2 hydrate, monohydrate, dihydrate etc.

The prodrug as an equi-join of a new derivative of phenol represented by the General formula (1) according to the present invention, or its pharmaceutically acceptable salt, or hydrate or MES, also falls under the scope of the present invention. "Prodrug" means a compound which is converted to compound (1) on the mechanism of metabolismin vivoi.e. the connection, which causes enzymatic oxidation, restore or hydrolysisin vivoor causes hydrolysis of the acid gastric juice, and is converted thereby to compounds of General formula (1). Examples of prodrugs of General formula (1) include compounds in which the phenolic hydroxyl group modified acyl group, alkyl group, etc., for example, acetylated and pualeilani connection.

These compounds can be synthesized from compound (1) in a known manner. The prodrug of compound (1) may be a prodrug, which is converted to compound (1) under the conditions described in "Soyaku Called", pp. 204-208, published in 2004 by Tokyo Called Dojin Co. Ltd.

Particular restrictions on the method of synthesis of compounds of the present invention does not exist, and, for example, they can be synthesized in accordance with the following stages. In this case, sometimes they can be retrieved efficiently from the point of view of methods of synthesis, by introducing a suitable protective group into the functional group of the source materials or intermediate compounds, depending on the type of functional group. Examples of such functional groups include an amino group, a hydroxy-group, carboxypropyl, etc. If the synthesis is carried out by introducing a protective group into the functional group, the desired compound can be obtained by removing the appropriate protective group at appropriate stages of the synthesis. Examples of such protective groups and ways to protect and unprotect include those described, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis (Fourth Edition)", and so on

The beneficial effects of the present invention

A new derivative of a phenol of the present invention or its pharmaceutically acceptable salt, or a hydrate or MES, characterized by a high concentration of unchanged compound in the urine, and also has excellent uricosuric effect and is excellent in terms of safety, and therefore applicable as a drug to speed up the excretion of uric acid; medications to reduce uric to the slots and/or concentration of uric acid in the blood and/or tissue; medicines for use in the prevention and/or treatment of a disease associated with uric acid in the blood and/or tissue; medicines for use in the prophylaxis and/or treatment of hyperuricemia; and medicines for use in the prophylaxis and/or treatment of diseases associated with hyperuricemia and/or diseases associated with hyperuricemia.

Brief description of drawings

In Fig. 1 presents the General formula reflecting a new derivative of a phenol of the present invention.

Description of embodiments

A typical method for the synthesis of novel phenol derivatives represented by the following General formula (1) according to the present invention will be described below.

<a method of obtaining a>

First stage: the acid chloride (3) can be synthesized from the intermediate carboxylic acid (2) as the starting material in an organic solvent using thionyl chloride, pentachloride phosphorus, trichloride phosphorus oxychloride phosphorus, oxalicacid etc.

Second stage: 2,3-dihydro-1,3-benzothiazole (5), substituted R3may be obtained by interaction of 2-aminobenzamide (4), substituted R3with an aqueous solution of formalin, or equivalent formal is degidi, such as paraformaldehyde.

Third stage: the amide Compound (6) can be synthesized by condensation synthesized in the first stage of the acid chloride, in which the phenol is protected, and synthesized at the second stage 2,3-dihydro-1,3-benzothiazole substituted R3in the presence of a conventional base.

Fourth stage: If R1, R2and R3connection amide (6) represent the functional groups are not affected by the oxidation process, the sulfoxide or sulfon can be obtained by conventional oxidation of organic peroxyacids, such as perchlorobenzene acid or peracetic acid, hydrogen peroxide, and catalyst. If R1represents a functional group that is affected by the oxidation process, for example, alkylsulfonyl group and so on, the sulfone derivative can be synthesized simultaneously carrying out oxidation. In the case of synthesis of a derivative in which R1represents alkylsulfonyl group derived can be obtained from the compounds in which R1is a halogen, such as iodine, with the use of combination reaction or so on

Fifth stage: with regard to unprotect protected hydroxyproline group, the target product (1) can be synthesized, for example, in the us what the conditions unprotect, described in "Protective Groups in Organic Synthesis (Fourth Edition)" (written by Greene and Wuts). For example, if the protective group is a methyl group, the target product (1) can be obtained by heating at least an equivalent amount of lithium chloride in N,N-dimethylformamide. In the case of the benzyl groups of the target product (1) can be obtained by carrying out the catalytic hydrogenation in the presence of a catalyst, such as palladium.

The intermediate connection carboxylic acid (2) used in the first stage, can be synthesized from the appropriate starting compounds by carrying out the following common reaction process represented by the following diagram

The method of synthesis i) the Method of synthesis of ester of 4-hydroxybenzoic acid, substituted in the 3-d position: for Example, with regard to compounds in which R5is cryptometer, the connection (11), in which R5is cryptometer and which is a starting material for the synthesis method (ii) can be synthesized by acetylation of 2-cryptomaterial (8) with acetic anhydride or similar, for the rearrangement of Fris using triftormetilfullerenov acid or similar, followed by the protection hidroxil the th group and esterification by californai reaction.

The method of synthesis ii) using the following methods of connection, in which R6represents a halogen atom, and R5represents a cyano, triptorelin group or cryptometer, can be synthesized from complex ester of 4-hydroxybenzoic acid (11), substituted in the 3 position.

For example, the intermediate compound of ester (13), in which R6represents a halogen atom, and R5represents a cyano, can be synthesized by halogenation of ester 3-cyano-4-hydroxybenzoic acid (11) conventional halogenation agent such as N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-jodatime (NIS), with the subsequent implementation of the interaction of the phenolic hydroxy-group with dimethylsilanol acid, benzylbromide, etc. in the presence of a common base, thereby fulfilling protection with R4(a methyl group, benzyl group, or so on). Thus obtained intermediate compound of ester (13) was subjected to conventional hydrolysis with obtaining the intermediate carboxylic acid (14). For example, in the following conditions hydrolysis of the intermediate compound of carboxylic acid can be synthesized by interaction with the room is the temperature value or by heating under reflux in an organic solvent, water or in a solvent, mixed with an organic solvent, in the presence of an appropriate reaction amount of acid or base. Examples of the acid include hydrochloric acid, sulfuric acid, Hydrobromic acid, triperoxonane acid, etc., and examples of the base include sodium hydroxide, lithium hydroxide, etc.,

As to intermediate compounds of ester (13-1), in which R6is an atom of iodine, the iodine atom can be converted to a functional group that can be introduced by conventional reaction combinations.

For example, the intermediate compound of ester (15-1), in which R7represents an alkyl group, alkylamino group or alkylsulfonyl group, can be synthesized from intermediate compounds of ester (13-1-1), in which R5represents cyano, and R6is an atom of iodine, in the presence of a catalyst, such as palladium or Nickel, with the use of organoboron compounds, alkyne, diallyldisulfide, etc., in Addition, received in this document is derived alkyne can be converted to a derived alkene, derivative of alkyl, etc., by conducting a conventional catalytic reduction using palladium kata is Isadora, gaseous hydrogen, etc. in Addition, the intermediate connection of ester (15-2), in which R5represents cyano, and R7represents triptorelin group, can be synthesized by interaction of intermediate compounds of ester (13-1-1) methylbenzylphosphonate when heated in the presence of copper iodide. In addition, carrying out the reactions of combinations possible in the case of compound (12-1), which has no protective group, R4. The intermediate connection of ester (15) in which protected phenolicresin group, is subjected to conventional hydrolysis with obtaining the intermediate carboxylic acid (16).

The method of synthesis iii) If R8represents a functional group that is not affected by subsequent reaction, for example, alkyl group, triptorelin group, alkoxygroup or so on, the relay connection carboxylic acid (23) can be synthesized using phenol (17), substituted R8in the 2nd position as the original substance.

The hydroxyl group of phenol, substituted R8in the 2nd position, defended methoxymethyl group or so on, were literally organolithium reagent (n-butyllithium, second-butyllithium, METI is lithium, and so on) and formulirovalis N,N-dimethylformamide (DMF), and then removed the protective group of the hydroxyl group with obtaining salicylaldehyde (19), substituted in the 3 position. The compound (21) can be obtained by conducting the synthesized hydroxyl group in the para-position, by protecting a hydroxyl group and by protecting the formyl group. 3-Formyl-4-alkoxybenzyl acid (22), substituted R8in 5th position, can be synthesized by adding magnesium and the activating agent to obtain a Grignard reagent, interaction with carbon dioxide, and subsequent removal of the protection in acidic conditions. The intermediate connection carboxylic acid (23), substituted by cyano in the 3rd position can be synthesized by interaction of 3-formyl-4-alkoxybenzyl acid (22) with hydroxylamine to obtain the oxime, followed by reaction of dehydration of the oxime, turning, thereby, formyl group in the cyano.

In addition, the intermediate connection carboxylic acid (26), substituted carbamoyl group at the 3rd position, can be synthesized by converting a carboxylic acid (22) to complex ether and oxidation of the formyl group with obtaining carboxylic acid (24), through the implementation of the interaction of carboxylic acids with amine in the presence of a condensing agent and subsequent hydrolysis words the aqueous ether.

Synthesized by the above methods, compounds of General formula (1) can be isolated and purified in a free form or salt form by conventional chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various types of chromatography, etc. in Addition, optical isomers, stereoisomers and positional isomers of the compounds can be appropriately selected by the method of fractional recrystallization method of separation on chiral column method of education diastereoisomers etc.

Pharmaceutical composition containing as the active(s) ingredient(s) substance(a) selected(s) from the group consisting of compounds represented by General formula (1) and its pharmaceutically acceptable salts and their hydrates and their MES can be used "as is" or can be used in the form of a composition containing one, or two, or more pharmaceutical additives. The pharmaceutical composition can be used in any dosage form and can be applied in the form of tablets, pills, capsules, powders, liquefied granules, granules, solutions, suspensions, syrups, injectable preparations, external preparations, suppositories, etc.

The types of pharmaceutical additives special ogran what values does not exist, if a pharmaceutical composition comprising as active ingredient a substance(a) selected(s) from the group consisting of compounds represented by General formula (1) and its pharmaceutically acceptable salts and their hydrates and their MES, is used in the form of the aforementioned pharmaceutical composition, and may use bases, fillers, lubricants, coating substances, enrobing means, wetting substances, binders, disintegrating agents, solvents, solubilization, dissolving agents, contributing to the dissolution agents, suspendida substances, dispersing agents, emulsifiers, surfactants, isotonic substances, buffering agents, pH regulators, soothing agents, antiseptics, preservatives, stabilizers, antioxidants, colorants, sweeteners, etc. individually or in a suitable combination.

Examples of bases include kaolin, cocoa butter, corn starch, dried gel of aluminum hydroxide, crystalline cellulose, methylcellulose, hydroxypropylcellulose, macrogol, etc., Examples of fillers include lactose, sucrose, starch, D-mannitol, corn starch, crystalline cellulose, cellulose derivatives (hydroxypropylcellulose, carmellose calcium, hydroxypropylcellulose with a low degree of substitution, and so on), the easier the Yu anhydrous silicic acid, phosphate calcium, etc. are Examples of lubricants include magnesium stearate, calcium stearate, talc, titanium oxide, etc., Examples of the coating substances include carmellose calcium, titanium oxide, aluminum stearate, talc, etc., Examples of enrobing means include sucrose, lactose, gelatin, paraffin, crystalline cellulose, etc., Examples of the wetting substances include glycerin, urea, macrogol, etc., Examples of binders include crystalline cellulose, sucrose, powdered Arabian gum, Argent sodium, carboximetilzellulozu, starch, sucrose, purified gelatin, dextrin, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, carboximetilzellulozu, hydroxyethyl cellulose, hydroxypropylcellulose, hypromellose, pullulan, polyvinyl alcohol, polyvinylpyrrolidone, etc., examples of the powder include sucrose, lactose, starch, agar powder, crospovidone, carboxymethylcellulose, carboximetilkrahmal sodium, carmellose, hypromellose, citric anhydride, lauryl sodium dihydrophosphate calcium, etc., Examples of solvents include purified water, water for injection, ethanol, glycerin, propylene glycol, macrogol, sesame oil, corn oil, hydrochloric acid, acetic acid, etc., Examples of solubilization including the Ute glycerin, polyxystra, Polysorbate, macrogol, etc., examples of the solvent agents include, in addition to be used as the above-mentioned solvents, sodium hydroxide, sodium carbonate, meglumin, etc. are Examples of promoting dissolution agents include hydrochloric acid, acetic acid, citric acid, sodium citrate, aspartic acid, sodium hydroxide, ethanol, propylene glycol, D-mannitol, benzoate sodium, benzyl benzoate, urea, triethanolamine, Polysorbate, polyvinylpyrrolidone, macrogol, etc., Examples of promoting suspendirovanie substances include Arabian gum, benzalkonium chloride, kaolin, carmellose, sodium lauryl sulfate, lauramidopropyl acid, glycerylmonostearate, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, etc. are Examples of contributing to the dispersion of substances include sodium citrate, light aluminum oxide, titanium oxide, zinc stearate, Polysorbate, macrogol, dextrin, hydroxypropylcellulose with a low degree of substitution, hydroxypropylcellulose, etc., Examples of emulsifiers include benzalkonium chloride, glycerin, propylene glycol, cetanol, lecithin, lanolin, sodium lauryl sulfate, etc., Examples of surfactants include squalene, C is tonal, polyoxyethyleneglycol ether, lauromacrogol, etc. are Examples of isotonic substances include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc., Examples of buffering agents include buffer solutions such as phosphate, acetate, carbonate, citrate buffers, etc., examples of the pH regulators include inorganic acids such as hydrochloric acid and phosphoric acid and their salts, organic acids such as acetic acid, citric acid and lactic acid and their salts, etc., Examples of sedatives include creatinine, benzyl alcohol, etc., Examples of antiseptics include esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid, etc., Examples of preservatives include benzoic acid, esters of peroxybenzoyl acid, sorbic acid, etc., Examples of stabilizers include taurine, amino acids, esters of peroxybenzoyl acid, benzyl alcohol, crystalline cellulose, macrogol, etc., examples of the antioxidant include sulfite, ascorbic acid, etc., Examples of dyes include food dyes (β-carotene, Riboflavin), etc. are Examples of sweeteners include aspartame, sucrose, D-sorbitol, maltose, etc., Examples of flavorings include the bitter essence, bitter basis, and so on

Novo is a derivative of a phenol of the present invention is characterized by a high concentration of unchanged compound in the urine and has a remarkable uricosuric effect, therefore, a new derivative of phenol or its pharmaceutically acceptable salt, or a hydrate or MES applicable as a drug to regulate the reabsorption of uric acid and accelerate the excretion of uric acid; medications to reduce uric acid and/or concentration of uric acid in the blood and/or tissue; medicines for use in the prevention and/or treatment of a disease associated with uric acid in the blood and/or tissue; medicines for use in the prophylaxis and/or treatment of hyperuricemia; and medicines for use in the prophylaxis and/or treatment of diseases associated with hyperuricemia and/or diseases associated with hyperuricemia.

For the term "disease associated with uric acid in the blood and/or tissue or a disease associated with hyperuricemia and/or disease accompanied by hyperuricemia" special restrictions do not exist, unless the disease is a associated with uric acid disease, regardless of whether the relationship is direct or indirect, or if it is assumed that the disease associated with uric acid and/or disease complicated by these diseases. Their examples include gout, mackaman the th disease, obesity, hyperlipidemia, abnormal glucose tolerance, diabetes mellitus, metabolic syndrome, kidney disease, bleeding in the brain and/or cardiovascular disease, and may also be included complications of these diseases.

For the subject with gout special restrictions do not exist, unless it is a painful condition that meets diagnostic criteria or is consistent with them. For example, included subjects with at least one painful condition from among gouty site, gouty arthritis and gouty kidney. Examples of kidney disease include, without limitation renal failure, albuminuria, nephritis, uremia, ESRD, etc., Examples of cerebrovascular diseases include, without limitation acute ischemic stroke, dementia, etc., Examples of cardiovascular diseases include, without limitation, hypertension, ischemic heart disease, disease of the carotid arteries, arteriosclerosis, cardiac hypertrophy, thrombosis, endothelial dysfunction and/or cardiovascular disease (angina, myocardial infarction, etc).

In addition, a new derivative of phenol according to the present invention can be used in combination with other drugs and/or preventive agents from you is ukazannyh diseases, and applicable for the effective treatment of these diseases. A new derivative of phenol according to the present invention is applicable, because it can supressive the increase in the content of lithate in the blood when used in combination with a drug that increases the level of lithate in the blood (e.g., antihypertensive diuretic, anti-TB medication, lipid-lowering medication, anti-inflammatory analgesic, Antiasthmatic agent, immunosuppressive medicine, an antimetabolite, an anti-cancer drug, etc). It is assumed that a substance capable of reducing of urate in the blood (allopurinol), effective from neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, etc.,), pancreatitis and apnea during sleep. Thus, a new derivative of a phenol of the present invention or its pharmaceutically acceptable salt, or a hydrate or MES, can also be used for the prevention and/or treatment of neurodegenerative diseases, digestive system diseases, such as pancreatitis, and respiratory diseases such as apnea during sleep.

Dose and number of doses of the compounds of the present invention or pharmaceutical compositions containing these modifications is to be placed, can be appropriately selected depending on the symptoms, age and sex of the patient, the dosage form and type of drugs used in combination, etc., for Example, the daily dose for adults can usually be selected in the range from 0.1 to 1000 mg, preferably from 1 to 500 mg, and above dose can be entered once a day or in several stages in the form of individual portions. The pharmaceutical composition of the present invention may be introduced separately or may be introduced in combination with other drugs that have the same and/or different efficiency.

Examples

The present invention will be specifically described by way of examples, but the present invention is not limited to the subsequent examples.

Values abbreviations used in the examples are as follows:

1H-NMR spectrum, the proton nuclear magnetic resonance, CDCl3: deuterated chloroform, DMSO-d6: deuterated dimethyl sulfoxide, CD3OD: deuterated methanol, Hz: Hertz, J: the interaction constant, m: multiplet, cept: septet, Quint: quintet, kV: Quartet, dt: doublet of triplets, DD: doublet of doublets, DDD: double doublet of doublets, t: triplet, d: doublet, s: singlet, user.from: broadened singlet, M: molar concentration, n: normal concentration. Which means Mr spectrum of nuclear magnetic resonance at 270 MHz, and as an internal standard tetramethylsilane was used (TMS). MS means mass spectrometry, and as a way ionization apparatus used with ionization elektrorazpredelenie (ESI).

Example 1: 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 2,3-dihydro-1,3-benzothiazole

37% formalin (5,2 ml) was diluted with water (80 ml) was added diisopropyl ether (80 ml) and 2-aminobenzoyl (7,84 g) and then stirred the mixture at room temperature for 30 minutes. The organic layer was separated, and the aqueous layer was extracted diisopropyl ether. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (c).

(b) Synthesis of 3,5-dichloro-4-methoxybenzanilide

To 3,5-dichloro-4-methoxybenzoic acid (8,81 g) was added toluene (170 ml), N,N-dimethylformamide (5 drops) and thionyl chloride (6.0 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, the obtained residue was subjected to azeotropic distillation with toluene, and then used for the synthesis of (c).

(c) Synthesis of 3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole was dissolved in whom hloroform (50 ml), was added to the solution triethylamine (17,4 ml) and 3,5-dichloro-4-methoxybenzophenone, and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (d).

(d) Synthesis of 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3,5-Dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (230 ml) to the solution at 0°C was added 70% meta-chloroperbenzoic acid (43,25 g), and then the mixture was stirred at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (13,25 g) as a colourless crystalline substance.

(e) SYN the ez 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3,5-Dichloro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1,00 g) was dissolved in N,N-dimethylformamide (5 ml), was added lithium chloride (570 mg) and then stirred the mixture at 130°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from ethanol to obtain specified in the connection header (749 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): to 5.35 (2H, s), 7,44 (1H, DD, J=7,6, 7,6 Hz), 7,74 (2H, s), 7,76 (1H, DD, J=8,4, a 7.6 Hz), of 7.90 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=8,4 Hz), 11,04 (1H, user.C). MS (m/z): 356 (M-H)-, 358 (M+2-H)-.

Example 2: 3-(3,5-dichloro-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole

3-(3,5-dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in N,N-dimethylformamide (6 ml) was added to a solution of lithium chloride (374 mg) and then stirred the mixture at 120°C for 16 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried to the anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the title compound (214 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): are 5.36 (2H, s), 7.03 is-7,13 (2H, m), 7,31-7,37 (1H, m) to 7.50 (1H, user.C) the 7.65 (2H, s), 10,89 (1H, user.C). MS (m/z):324 (M-H)-, 326 (M+2-H)-.

Example 3: 3-(3,5-dichloro-4-hydroxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-(3,5-dichloro-4-methoxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

3-(3,5-Dichloro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in chloroform (10 ml) was added to a solution of 70% meta-chloroperbenzoic acid (320 mg) and the mixture was stirred at 0°C for 10 minutes. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1) to obtain the specified title compound (336 mg) as a colourless crystalline substance.

(b) Synthesis of 3-(3,5-dichloro-4-hydroxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

3-(35-Dichloro-4-methoxybenzoyl)-1-oxo-2,3-dihydro-1,3-benzothiazole (336 mg) was dissolved in N,N-dimethylformamide (6 ml), was added to a solution of lithium chloride (400 mg) and then stirred the mixture at 120°C for 16 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from ethyl acetate/methanol to obtain specified in the title compound (220 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): 5,07 (2H, s), 7,38 (1H, DD, J=7,6, 7,6 Hz), of 7.70 (1H, DDD, J=8,3, to 7.6, 0.8 Hz), 7,73 (2H, s), of 8.00 (1H, d, J=8,3 Hz), 8,07 (1H, d, J=7,6 Hz), 11,06 (1H, user.C). MS (m/z): 340(M-H)-, 342(M+2-H)-.

Example 4: 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 1-methoxyethoxy-2-cryptomelane

2-Triptoreline (50,00 g) was dissolved in N,N-dimethylformamide (100 ml) was added to a solution of potassium carbonate (85,14 g) and chloromethylation ether (34,7 ml), and then the mixture was stirred under cooling for 1 hour. To the reaction solution were added water and then was extracted with a mixture of n-hexane. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent of othona and under reduced pressure to obtain specified in the connection header (64,13 g) as a colorless oily substance.

(b) Synthesis of 2-hydroxy-3-triftormetilfullerenov

1 Methoxyethoxy-2-triptoreline (64,13 g) was dissolved in tetrahydrofuran (500 ml) under a stream of argon at -70°C for 45 minutes was added to the solution 2,77 M solution of n-utility in n-hexane (123 ml) and then stirred the mixture for 1 hour. Was added N,N-dimethylformamide (28,5 ml) and then stirred at room temperature for 30 minutes. Added 4n hydrochloric acid (310 ml) and then stirred at 60°C for 19 hours. Organic solvent drove away under reduced pressure, and was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (59,16 g) as a yellow crystalline substance.

(c) Synthesis of 5-bromo-2-hydroxy-3-triftormetilfullerenov

2-Hydroxy-3-triftormetilfosfinov (59,16 g) was dissolved in acetonitrile (500 ml) was added to a solution of N-bromosuccinimide (57,56 g) and then stirred the mixture at 0°C for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. Races shall foretell drove away under reduced pressure, and washed the resulting crystalline substance n-hexane (50 ml) to obtain specified in the connection header (63,98 g) as a pale yellow crystalline substance.

(d) Synthesis of 5-bromo-2-methoxy-3-triftormetilfullerenov

5-Bromo-2-hydroxy-3-triftormetilfosfinov (63,98 g) was dissolved in N,N-dimethylformamide (130 ml), water cooling was added to a solution of potassium carbonate (65,79 g) and dimethylsiloxy acid (31,6 ml) and then stirred the mixture at room temperature for 3 hours. To the reaction solution were added water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (66,19 g) as a brown crystalline substance.

(e) Synthesis of 5-bromo-1-diethoxylate-2-methoxy-3-cryptomelane

5-Bromo-2-methoxy-3-triftormetilfosfinov (66,19 g) was dissolved in n-hexane (130 ml) and triethylorthoformate (51 ml) was added to a solution of Amberlyst-15 (6,62 g), and then the mixture was heated under reflux for 3 hours. The reaction solution was filtered, and then drove away the solvent under reduced pressure to obtain specified in the connection header (82,81 g) in VI is e brown oily substance.

(f) Synthesis of 3-formyl-4-methoxy-5-triftorperasin acid

To magnesium (5,97 g) was added tetrahydrofuran (230 ml) and 5-bromo-1-diethoxylate-2-methoxy-3-triptoreline (31,55 g) and then stirred the mixture at room temperature for 90 minutes. The reaction solution was cooled to 0°C and was stirred for 1 hour in an atmosphere of carbon dioxide, and then was added 2n hydrochloric acid (240 ml) and the mixture was stirred at room temperature for 16 hours. Organic solvent drove away under reduced pressure, and then was extracted with a mixture of diisopropyl ether. The organic layer was extracted by adding 1N sodium hydroxide (100 ml) and then twice washed aqueous layer diisopropyl ether. The reaction mixture was acidified by adding thereto 4n hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (50,05 g) as a brown solid.

(g) Synthesis of 3-cyano-4-methoxy-5-triftorperasin acid

3-Formyl-4-methoxy-5-triftorperasin acid (58,04 g) was dissolved in formic acid (290 ml) was added to a solution of hydroxylamine hydrochloride (17,07 g), and Agrawal the mixture under reflux for 19 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (15.62 wide g) as a brown solid.

1H-NMR δ (DMSO-d6): to 4.23 (3H, s), with 8.33 (1H, d, J=2.1 Hz), 8,55 (1H, d, J=2.1 Hz). MS (m/z: 244 (M-H)-.

(h) Synthesis of 3-cyano-4-methoxy-5-triftormetilfullerenov

3-cyano-4-methoxy-5-triftorperasin acid (8,10 g) was added toluene (160 ml), N,N-dimethylformamide (5 drops) and thionyl chloride (4,80 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, the obtained residue was subjected to azeotropic distillation with toluene, and then used for the synthesis of (i).

(i) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (5,00 g) and 37% formalin (3.0 ml) by the same method of synthesis as described in example 1 was dissolved in chloroform (50 ml), was added to the solution triethylamine (11,1 ml) and 3-cyano-4-methoxy-5-cryptomathematical, and then stirred the mixture at room temperature for 1 hour. The solvent drove conditions of reduced pressure, added water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (j).

(j) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (200 ml) was added to a solution of 70% meta-chloroperbenzoic acid (21,40 g), and then the mixture was stirred at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (4,08 g) as a pale yellow solid.

(k) Synthesis of 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (4,08 g) was dissolved in N,N-DIMET formamide (40 ml), was added to a solution of lithium chloride (1,74 g) and then stirred the mixture at 70°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the connection header (2,22 g) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): lower than the 5.37 (2H, s), 7,44 (1H, DD, J=7,8, and 7.8 Hz), to 7.77 (1H, DDD, J=7,9, and 7.8, 1.3 Hz), to $ 7.91 (1H, DD, J=7,8, 1.3 Hz), of 8.09 (1H, d, J=7.9 Hz), 8,10 (1H, d, J=2.1 Hz), of 8.27 (1H, d, J=2.1 Hz). MS (m/z): 381 (M-H)-.

Example 5: 3-(3-Cyano-4-hydroxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole (232 mg) was dissolved in N,N-dimethylformamide (3 ml) was added to a solution of lithium chloride (108 mg) and then stirred the mixture at 70°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced D. the effect, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the title compound (131 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): 5,38 (2H, s),? 7.04 baby mortality-7,14 (2H, m), 7,32-7,38 (1H, m), 7,55 (1H, usher.), with 8.05 (1H, d, J=2.1 Hz), by 8.22 (1H, d, J=2.1 Hz). MS (m/z): 349 (M-H)-.

Example 6: 3-(3-Cyano-4-hydroxy-5-trifloromethyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole (594 mg) was dissolved in chloroform (10 ml) was added to a solution of 70% meta-chloroperbenzoic acid (433 mg) and then stirred the mixture at 0°C for 5 minutes. Organic solvent drove away under reduced pressure, then was added 1N sodium hydroxide, and washed precipitated precipitated crystalline substance 1N sodium hydroxide and water to form a indicated in the title compound (619 mg) as a colourless crystalline substance.

(b) Synthesis of 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1-oxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-1-oxo-2,3-dihydro-1,3-benzothiazole (619 mg) was dissolved in N,N-dimethylformamide (5 ml) was added to a solution of lithium chloride (276 mg), and stirred the mixture at 70°C for 3 hours. To the obtained reactions is nomu the solution was added 1N hydrochloric acid, and then the reaction mixture is extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (494 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 5,09 (1H, d, J=13,0 Hz), further 5.15 (1H, d, J=13,0 Hz), 7,40 (1H, DD, J=7,5, 7.5 Hz), 7,72 (1H, DDD, J=7,5, to 7.5, 1.0 Hz), of 8.06 (1H, d, J=7.5 Hz), of 8.09 (1H, d, J=7.5 Hz), to 8.12 (1H, d, J=1,8 Hz), 8,30 (1H, d, J=1,8 Hz). MS (m/z): 365 (M-H)-.

Example 7: 3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-chloro-5-cyano-4-hydroxybenzoate

Methyl-3-cyano-4-hydroxybenzoate (2.00 g) was dissolved in chloroform (15 ml) and methanol (5 ml) was added to a solution of N-chlorosuccinimide (3,62 g) and 4n hydrochloric acid in ethyl acetate (6.8 ml) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, was added a mixture of methanol and water in a ratio of 9/1, and then washed precipitated precipitated crystalline substance with water and isopropyl alcohol to obtain specified in the title compound (1.27 g) as a colourless crystalline substance.

(b) Synthesis of methyl 3-chloro-5-cyano-4-methoxybenzoate

Methyl-3-chloro-5-cyano-4-hydroxybenzoate (1.27 g) is astoral in N,N-dimethylformamide (20 ml), was added to a solution of potassium carbonate (5,00 g) and dimethylsiloxy acid (1.70 ml) and then stirred the mixture at room temperature for 18 hours. The reaction solution was filtered, added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (of 1.03 g) as a colourless crystalline substance.

(c) Synthesis of 3-chloro-5-cyano-4-methoxybenzoic acid

Methyl-3-chloro-5-cyano-4-methoxybenzoate (1,02 g) was dissolved in tetrahydrofuran (15 ml) and water (6 ml) was added to a solution of the monohydrate of lithium hydroxide (759 mg) and then stirred the mixture at room temperature for 90 minutes. The organic solvent is kept off, and the aqueous layer was washed with n-hexane. The aqueous layer was acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (946 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 4,43 (3H, s), 8,55 (2H, s) 14,00 (1H, user.C). MS (m/z): 210 (M-H)- , 212 (M+2-H)-.

(d) Synthesis of 3-chloro-5-cyano-4-methoxybenzanilide

To 3-chloro-5-cyano-4-methoxybenzoic acid (932 mg) was added toluene (9,3 ml), N,N-dimethylformamide (0,03 ml) and thionyl chloride (0,38 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the connection header (993 mg) as a brown solid.

(e) Synthesis of 3-(3-chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (810 mg) and 37% formalin (0,53 ml) by the same method of synthesis as described in example 1 was dissolved in dichloromethane (15 ml), was added to the solution triethylamine (1.90 ml) and 3-chloro-5-cyano-4-methoxybenzophenone (993 mg) and then stirred the mixture at room temperature for 1.5 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain specified in the compound (580 mg) as a yellow oily substance.

(f) Synthesis of 3-(3-chloro-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (187 mg) was dissolved in dichloromethane (2 ml) was added to a solution of 70% meta-chloroperbenzoic acid (607 mg). After stirring the mixture at room temperature for 5 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (183 mg) as a pale yellow solid.

(g) Synthesis of 3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (180 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (87 mg) and then stirred the mixture at 100°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas received about who headed the remainder of the from n-hexane/chloroform to obtain specified in the title compound (146 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): 5,32 (2H, s), 7,44 (1H, DDD, J=8,4, 7,3, 0.8 Hz), of 7.75 (1H, DDD, J=8,6, and 7.3, 1.4 Hz), 7,88 (1H, DD, J=8,4, and 1.4 Hz), to 7.99 (1H, d, J=2.2 Hz), 8,00 (1H, d, J=2.2 Hz), of 8.06 (1H, d, J=8.6 Hz). MS (m/z): 347 (M-H)-.

Example 8: 3-(3-chloro-5-cyano-4-hydroxybenzoyl)-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (213 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (111 mg) and then stirred the mixture at 100°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was purified by the method of column chromatography on silica gel (ethyl acetate/methanol = 10/1), and then vykristallizovyvalas from n-hexane/chloroform to obtain specified in the title compound (68 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): lower than the 5.37 (2H, s), 7,01-7,16 (2H, m), 7,33 (1H, DD, J=6,5, 2.2 Hz), was 7.45 (1H, d, J=7,0 Hz), 7,79 (1H, s), 7,81 (1H, s). MS (m/z): 315 (M-H)-.

Example 9: 3-(3-tert-butyl-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl-3-tert-butyl-4-hydroxybenzoate

Methyl-4-hydroxybenzoate (3.0 g) was dissolved in methanesulfonic acid (15 ml), was added to a solution of 2-bromo-2-methylpropan (11,1 ml) and then stirred the mixture at 70°C for 16 hours. To the resulting reaction solution was added methanol (20 ml), and then the reaction mixture was stirred at 50°C for 3 hours. Added 1N potassium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with aqueous 10% potassium carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 3/1) to obtain specified in the connection header (1,83 g) as a pale yellow crystalline substance.

(b) Synthesis of methyl-3-tert-butyl-4-hydroxy-5-identity

Methyl-3-tert-butyl-4-hydroxybenzoate (1,83 g) was dissolved in dichloromethane (24 ml) and methanol (3 ml) was added to a solution of N-jodatime (2,08 g) and triftormetilfullerenov acid (3 ml) and then stirred the mixture at room temperature for 15 minutes. To the reaction solution was added water, and then separated the organic layer. The organic layer was washed with 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in C is the coupling head (2,77 g) as a brown crystalline substance.

(c) Synthesis of methyl-3-tert-butyl-5-iodine-4-methoxybenzoate

Methyl-3-tert-butyl-4-hydroxy-5-identit (2,77 g) was dissolved in N,N-dimethylformamide (50 ml) was added to a solution of potassium carbonate (12.0 g) and dimethylsiloxy acid (4,1 ml) and then stirred the mixture at room temperature for 16 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (2,77 g) as a brown crystalline substance.

(d) Synthesis of methyl-3-tert-butyl-5-cyano-4-methoxybenzoate

Methyl-3-tert-butyl-5-iodine-4-methoxybenzoate (2,77 g) was dissolved in N,N-dimethylformamide (30 ml) was added to a solution of copper cyanide (965 mg) and then stirred the mixture at 150°C for 2.5 hours. To the resulting reaction solution was added 10% potassium carbonate, and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 3/1) to obtain the indicated what about the title compound (1.48 g) as a yellow oily substance.

(e) Synthesis of 3-tert-butyl-5-cyano-4-methoxybenzoic acid

Methyl-3-tert-butyl-5-cyano-4-methoxybenzoate (1.48 g) was dissolved in methanol (20 ml), tetrahydrofuran (5 ml) and water (5 ml) was added to a solution of the monohydrate of lithium hydroxide (753 mg) and then stirred the mixture at room temperature for 2 hours. To the resulting reaction solution was added 10% hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.18 g) as a pale yellow crystalline substance.

1H-NMR δ (CDCl3): of 1.41 (9H, s), 4.26 deaths (3H, s), 8,23 (1H, d, J=2.2 Hz), of 8.25 (1H, d, J=2.2 Hz).

(f) Synthesis of 3-tert-butyl-5-cyano-4-methoxybenzanilide

3-tert-butyl-5-cyano-4-methoxybenzoic acid (586 mg) was added toluene (10 ml), N,N-dimethylformamide (2 drops) and thionyl chloride (0,27 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (630 mg) as a brown oily substance.

(g) Synthesis of 3-(3-tert-butyl-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzo is eazol, synthesized from 2-aminobenzamide (943 mg) and 37% formalin (or 0.57 ml) in the same way as described in example 1 was dissolved in chloroform (15 ml), was added to the solution triethylamine (1.04 million ml) and 3-tert-butyl-5-cyano-4-methoxybenzophenone (630 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain the specified title compound (904 mg) as a yellow oily substance.

(h) Synthesis of 3-(3-tert-butyl-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-tert-Butyl-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (452 mg) was dissolved in chloroform (9 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1,02 g), and then the mixture was stirred at room temperature for 16 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then extracted the mixture with ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (439 mg) as a pale yellow oily substance.

1H-NMR δ (CDCl3): of 1.36 (9H, s), 4,27 (3H, s), is 4.93 (2H, s), 7,37 (1H, DDD, J=7,8, and 7.1, 1.3 Hz), 7,58 (1H, DDD, J=8,2, to 7.1, 1.3 Hz), the 7.65 (1H, d, J=2.3 Hz), of 7.70 (1H, d, J=2.3 Hz), 7,72 (1H, d, J=2.3 Hz), 7,76-7,80 (1H, m).

(i) Synthesis of 3-(3-tert-butyl-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-tert-Butyl-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (364 mg) was dissolved in N,N-dimethylformamide (4 ml) was added to a solution of lithium chloride (401 mg) and then stirred the mixture at 120°C for 16 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the title compound (299 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 1.37 (9H, s), to 5.35 (2H, s), the 7.43 (1H, DD, J=7,4, 7,4 Hz), 7,73 (1H, d, J=2.1 Hz), of 7.75 (1H, DDD, J=7,4, ,4, 1.2 Hz), 7,88-to 7.93 (2H, m), 8,01 (1H, d, J=8,2 Hz), 11,23 (1H, user.C). MS (m/z): 369 (M-H)-.

Example 10: 3-(3-cyano-4-hydroxy-5-isopropylbenzyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 5-bromo-2-hydroxy-3-isopropylbenzaldehyde

2-Hydroxy-3-isopropylbenzaldehyde (20,19 g) was dissolved in acetonitrile (160 ml) at 0°C was added to a solution of N-bromosuccinimide (17,80 g) and then stirred the mixture at room temperature for 4 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (25,88 g) as a yellow oily substance.

(b) Synthesis of 5-bromo-3-isopropyl-2-methoxybenzaldehyde

5-Bromo-2-hydroxy-3-isopropylbenzaldehyde (25,88 g) was dissolved in N,N-dimethylformamide (100 ml), water cooling was added to a solution of potassium carbonate (27,64 g) and dimethylsiloxy acid (9.5 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sulfate intothree is. The solvent drove under reduced pressure to obtain specified in the connection header (26,76 g) as a brown oily substance.

(c) Synthesis of 5-bromo-1-diethoxylate-3-isopropyl-2-methoxybenzoyl

5-Bromo-3-isopropyl-2-methoxybenzaldehyde (26,76 g) was dissolved in n-hexane (50 ml) and triethylorthoformate (22 ml) was added to a solution of Amberlyst-15 (2,68 g), and then the mixture was heated under reflux for 4 hours. The reaction solution was filtered, and then drove away the solvent under reduced pressure to obtain specified in the connection header (31,55 g) as a brown oily substance.

(d) Synthesis of 3-formyl-5-isopropyl-4-methoxybenzoic acid

To magnesium (2,43 g) was added tetrahydrofuran (100 ml), 5-bromo-1-diethoxylate-3-isopropyl-2-methoxybenzoyl (31,55 g) and 0.97 M solution methylacrylamide in tetrahydrofuran (15 ml) and then stirred the mixture at room temperature for 2 hours. The reaction solution was cooled to 0°C and stirred in the atmosphere of carbon dioxide for 30 minutes, then was added 2n hydrochloric acid (100 ml) and stirred the reaction mixture at room temperature for 16 hours. Organic solvent drove away under reduced pressure, and then was extracted with a mixture of diisopropyl ether. The organic layer was extracted is by adding thereto 1N sodium hydroxide (100 ml), and then the aqueous layer was twice washed with diisopropyl ether. The aqueous layer was acidified by addition of 4n hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (15,85 g) as a brown solid.

(e) Synthesis of 3-cyano-5-isopropyl-4-methoxybenzoic acid

3-Formyl-5-isopropyl-4-methoxybenzoic acid (15,85 g) was dissolved in formic acid (80 ml) was added to a solution of hydroxylamine hydrochloride (of 5.45 g) and the mixture was heated under reflux for 19 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (15.62 wide g) as a brown solid.

1H-NMR δ (DMSO-d6): to 1.21 (6H, d, J=6.9 Hz), 3,29 (1H, sevent, J=6.9 Hz), Android 4.04 (3H, s), 8,10 (1H, s). MS (m/z): 218 (M-H)-.

(f) Synthesis of 3-cyano-5-isopropyl-4-methoxybenzanilide

3-cyano-5-isopropyl-4-methoxybenzoic acid (658 mg) was added toluene (7 ml), N,N-dimetilformamid (2 drops) and thionyl chloride (0.33 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (710 mg) as a brown oily substance.

(g) Synthesis of 3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (1,25 g) and 37% formalin (or 0.83 ml) in the same way as described in example 1 was dissolved in chloroform (7 ml), was added to the solution triethylamine (1.25 ml) and 3-cyano-5-isopropyl-4-methoxybenzophenone (710 mg) and then stirred the mixture at room temperature for 2 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain specified in the connection header (1,02 g) as a yellow oily substance.

(h) Synthesis of 3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-isopropyl-4-methoxime the zoilus)-2,3-dihydro-1,3-benzothiazole (501 mg) was dissolved in chloroform (5 ml), was added to a solution of 70% meta-chloroperbenzoic acid (996 mg), and then the mixture was stirred at room temperature for 18 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 3/1) to obtain the specified title compound (439 mg) as a brown amorphous substance.

(i) Synthesis of 3-(3-cyano-4-hydroxy-5-isopropylbenzyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-isopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (434 mg) was dissolved in N,N-dimethylformamide (5 ml) was added to a solution of lithium chloride (496 mg) and then stirred the mixture at 100°C for 20 hours. To the resulting reaction solution was added 1N hydrochloric acid, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure the Oia, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (351 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 1.18 (6H, d, J=6.8 Hz), the 3.35 (1H, sevent, J=6,8 Hz), of 5.34 (2H, s), the 7.43 (1H, DDD, J=7,8, and 7.8, 0.8 Hz), of 7.75 (1H, DDD, J=8,4, and 7.8, 1.3 Hz), 7,76 (1H, d, J=2.3 Hz), 7,87 (1H, d, J=2.3 Hz), of 7.90 (1H, DD, J=7,8, 0.8 Hz), 8,00 (1H, d, J=8,4 Hz). MS (m/z): 355 (M-H)-.

Example 11: 3-(3-cyano-5-cyclobutyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 1-cyclobutyl-2-methoxyethoxymethyl

2-Cyclobutanol (871 mg) was dissolved in N,N-dimethylformamide (5 ml), at 0°C was added to a solution of 60% sodium hydride (1.30 grams). After stirring the mixture for 30 minutes was added chloromethylation ether (2.1 ml), and the mixture was stirred for 14 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 10/1) to obtain the specified title compound (1.13 g) as a colorless oily substance.

(b) Synthesis of 3-cyclobutyl-2-hydroxybenzaldehyde

1-Cyclobutyl-2-label methoxybenzo (1.18 g) was dissolved in tetrahydrofuran (11 ml), and under a stream of argon at -60°C for 15 minutes was added to a solution of 1.01 M solution of sec-utility in cyclohexane (8,7 ml) and then stirred the mixture for 2 hours. Was added N,N-dimethylformamide (0,90 ml) and the mixture was stirred at the same temperature for 2 hours. At room temperature was added 4n hydrochloric acid (15 ml) and then stirred the mixture at 60°C for 20 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 20/1) to obtain the specified title compound (0.95 g) as a colorless oily substance.

(c) Synthesis of 5-bromo-3-cyclobutyl-2-hydroxybenzaldehyde

3-Cyclobutyl-2-hydroxybenzaldehyde (to 2.29 g) was dissolved in acetonitrile (30 ml), at 0°C was added to a solution of N-bromosuccinimide (5.10 g), and then stirred the mixture at room temperature for 4 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline, and then the land is over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (d).

(d) Synthesis of 5-bromo-3-cyclobutyl-2-methoxybenzaldehyde

5-Bromo-3-cyclobutyl-2-hydroxybenzaldehyde was dissolved in N,N-dimethylformamide (30 ml), water cooling was added to a solution of potassium carbonate (10,79 g) and dimethylsiloxy acid (3,7 ml) and then stirred the mixture at room temperature for 14 hours. The reaction solution was filtered, added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 20/1) to obtain the specified title compound (1.27 g) as a yellow oily substance.

(e) Synthesis of 5-bromo-3-cyclobutyl-1-diethoxylate-2-methoxybenzoyl

5-Bromo-3-cyclobutyl-2-methoxybenzaldehyde (1,15 g) was dissolved in n-hexane (5 ml) and triethylorthoformate (0,93 ml) was added to a solution of Amberlyst-15 (115 mg), and then the mixture was heated under reflux for 3 hours. The reaction solution was filtered, and then drove away the solvent under reduced pressure to obtain specified in the header Conn is in (1,33 g) as a yellow oily substance.

(f) Synthesis of 3-cyclobutyl-5-formyl-4-methoxybenzoic acid

To magnesium (106 mg) was added tetrahydrofuran (3.5 ml), 5-bromo-3-cyclobutyl-1-diethoxylate-2-methoxybenzoyl (1,33 g) and 0.97 M solution methylacrylamide in tetrahydrofuran (1,32 ml) and then stirred the mixture at room temperature for 1.5 hours. The reaction solution was cooled to 0°C and stirred in the atmosphere of carbon dioxide for 15 hours, then was added 2n hydrochloric acid (10 ml) and the mixture was stirred at room temperature for 1 hour. Organic solvent drove away under reduced pressure, and then was extracted with diisopropyl ether. The organic layer was extracted by adding 1N sodium hydroxide, and then the aqueous layer was twice washed with diisopropyl ether. The aqueous layer was acidified by addition of 4n hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (458 mg) as a brown solid.

(g) Synthesis of 3-cyano-5-cyclobutyl-4-methoxybenzoic acid

3-Cyclobutyl-5-formyl-4-methoxybenzoic acid (458 mg) was dissolved in formic acid (2.5 ml), was added to the solution hydroch Oric hydroxylamine (163 mg), and then mixture was heated under reflux for 19 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (404 mg) as a brown solid.

1H-NMR δ (CDCl3): 1,82-2,48 (6H, m), 3,76 (1H, quintet, J=8.7 Hz), 4,15 (3H, s), 8,18 (1H, d, J=2.2 Hz), to 8.20 (1H, d, J=2.2 Hz). MS (m/z): 230 (M-H)-.

(h) Synthesis of 3-cyano-5-cyclobutyl-4-methoxybenzanilide

3-cyano-5-cyclobutyl-4-methoxybenzoic acid (190 mg) was added toluene (2.0 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,07 ml), and stirred the mixture at 60°C for 3 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (204 mg) as a brown oily substance.

(i) Synthesis of 3-(3-cyano-5-cyclobutyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (153 mg) and 37% formalin (0.10 ml) in the same way as described in example 1 was dissolved in dichloromethane (3 ml), was added to the solution triethylamine (0,34 ml) and 3-cyano-5-C is clopotel-4-methoxybenzophenone (204 mg), and then the mixture was stirred at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (j).

(j) Synthesis of 3-(3-cyano-5-cyclobutyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-cyclobutyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (4 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1,62 g). After stirring the mixture at room temperature for 28 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (156 mg) as a yellow solid.

(k) Synthesis of 3-(3-cyano-5-cyclobutyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(5-Cyano-3-cyclobutyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (150 mg) was dissolved in N,N-d is methylformamide (1.5 ml), was added to a solution of lithium chloride (248 mg) and then stirred the mixture at 120°C for 2.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (95 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): 1,72-to 2.18 (4H, m), 2,25-2,39 (2H, m), of 3.77 (1H, quintet, J=8.7 Hz), to 5.35 (2H, s), 7,44 (1H, DD, J=7,6, 7,6 Hz), to 7.77 (1H, DD, J=8,4, a 7.6 Hz), 7,79 (1H, d, J=2.2 Hz), 7,87 (1H, d, J=2.2 Hz), to $ 7.91 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=8,4 Hz). MS (m/z): 367 (M-H)-.

Example 12: 3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-cyano-4-methoxy-5-trimethylsilylmethylamine

Methyl-3-cyano-5-iodine-4-methoxybenzoate (2,13 g) was dissolved in tetrahydrofuran (30 ml) was added to a solution of triethylamine (10 ml), copper iodide (256 mg), tetrakis(triphenylphosphine)palladium (777 mg) and trimethylsilylacetamide (858 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, and purified the resulting residue by column method chromium is adopted on silica gel (n-hexane/ethyl acetate = 4/1) to obtain specified in the connection header (2,03 g) as a brown oily substance.

(b) Synthesis of methyl 3-cyano-5-ethinyl-4-methoxybenzoate

Methyl-3-cyano-4-methoxy-5-trimethylsilylethynyl (2,03 g) was dissolved in tetrahydrofuran (20 ml) was added to a solution of aqueous 1N solution of sodium hydroxide (8 ml) and then stirred the mixture at room temperature for 10 minutes. The solvent is kept under reduced pressure, was added 1N hydrochloric acid, and was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (1,37 g) as a colourless crystalline substance.

(c) Synthesis of methyl 3-cyano-5-ethyl-4-methoxybenzoate

Methyl-3-cyano-5-ethinyl-4-methoxybenzoate (475 mg) was dissolved in tetrahydrofuran (10 ml) was added to a solution of 5% palladium on carbon (150 mg) and then stirred the mixture in an atmosphere of hydrogen at room temperature for 30 minutes. The reaction solution was filtered, then drove the solvent under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 5/1) to obtain the specified title compound (480 mg) as a colourless crystalline substance.

(d) Synthesis of 3-cyano-5-ethyl-4-methoxybenzoic the second acid

Methyl-3-cyano-5-ethyl-4-methoxybenzoate (480 mg) was dissolved in tetrahydrofuran (6 ml) and water (2 ml) was added to a solution of the monohydrate of lithium hydroxide (370 mg) and then stirred the mixture at room temperature for 5 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (403 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 1,50 (3H, t, J=7.5 Hz), 3,01 (2H, square, J=7.5 Hz), 4,36 (3H, s), 8,40 (1H, d, J=2.1 Hz), to 8.41 (1H, d, J=2.1 Hz). MS (m/z): 204 (M-H)-.

(e) Synthesis of 3-cyano-5-ethyl-4-methoxybenzanilide

3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg) was added toluene (3.5 ml), N,N-dimethylformamide (0.01 ml) and thionyl chloride (0.15 ml) and then stirred the mixture at 60°C for 14 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (387 mg) as a brown oily substance.

(f) Synthesis of 3-(3-cyano-5-ethyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-amino soltera (318 mg) and 37% formalin (of 0.21 ml) in the same way, as described in example 1 was dissolved in dichloromethane (6 ml), was added to the solution triethylamine (0,71 ml) and 3-cyano-5-ethyl-4-methoxybenzophenone (387 mg) and then stirred the mixture at room temperature for 1.5 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain the specified title compound (498 mg) as a yellow oily substance.

(g) Synthesis of 3-(3-cyano-5-ethyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-ethyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (366 mg) was dissolved in dichloromethane (7 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1.20 g). After stirring the mixture at room temperature for 14 hours was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure Poluchenie specified in the title compound (309 mg) as colorless solids.

(h) Synthesis of 3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-ethyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (309 mg) was dissolved in N,N-dimethylformamide (3 ml) was added to a solution of lithium chloride (443 mg) and then stirred the mixture at 120°C for 2.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (257 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): to 1.15 (3H, t, J=7,6 Hz), 2,68 (2H, square, J=7,6 Hz), of 5.34 (2H, s), the 7.43 (1H, DD, J=7,6, 7,6 Hz), 7,74 (1H, d, J=2.2 Hz), of 7.75 (1H, DD, J=8,4, a 7.6 Hz), 7,88 (1H, d, J=2.2 Hz), of 7.90 (1H, d, J=7,6 Hz), of 8.00 (1H, d, J=8,4 Hz), br11.01 (1H, user.C). MS (m/z): 341 (M-H)-.

Example 13: 3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-cyano-5-cyclopropyl-4-methoxybenzoate

Methyl-3-cyano-4-hydroxy-5-identit (1,00 g) was dissolved in 1,4-dioxane (15 ml) was added to a solution of potassium carbonate (1.31 g), cyclopropylboronic acid (325 mg) and dichloride, [1,3-bis-(2,6-diisopropylaniline-2-ilidene](3-chloropyridin)palladium (108 mg), and then the mixture was stirred under a stream of argon at 95°C for 22 hours. The reaction solution was filtered, drove away the solvent under reduced pressure, and then purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain the specified title compound (348 mg) as pale-yellow crystalline substance.

(b) Synthesis of 3-cyano-5-cyclopropyl-4-methoxybenzoic acid

Methyl-3-cyano-5-cyclopropyl-4-methoxybenzoate (491 mg) was dissolved in tetrahydrofuran (7.5 ml) and water (2.5 ml) was added to a solution of the monohydrate of lithium hydroxide (359 mg) and then stirred the mixture at room temperature for 20 hours. Organic solvent drove away under reduced pressure, and the aqueous layer was washed with n-hexane. To the aqueous layer was added 1N hydrochloric acid, and was extracted with a mixture of ethyl acetate under acidic conditions. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (394 mg) as a pale brown crystalline substance.

1H-NMR δ (DMSO-d6): 0,74-of 0.79 (2H, m), 1,03-1,10 (2H, m), 2,13-of 2.23 (1H, m) 4,06 (3H, s), the 7.65 (1H, d, J=2.0 Hz), of 8.04 (1H, d, J=2.0 Hz). MS (m/z): 216 (M-H)-.

(c) Synthesis of 3-cyano-5-cyclopropyl-methoxybenzanilide

3-cyano-5-cyclopropyl-4-methoxybenzoic acid (200 mg) was added toluene (2 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0.10 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (d).

(d) Synthesis of 3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (346 mg) and 37% formalin (0,23 ml) in the same way as described in example 1 was dissolved in chloroform (3 ml), was added to the solution triethylamine (0,38 ml) and 3-cyano-5-cyclopropyl-4-methoxybenzophenone, and then stirred at room temperature for 2 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (e).

(e) Synthesis of 3-(3-cyano-5-cyclopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-cyclopropyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (5 ml), we use the and to a solution of 70% meta-chloroperbenzoic acid (422 mg), and then the mixture was stirred at room temperature for 16 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate/methanol to obtain specified in the title compound (147 mg) as a colourless crystalline substance.

(f) Synthesis of 3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-cyclopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (142 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (163 mg) and then stirred the mixture at 100°C for 23 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain indicated the data in the title compound (115 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 0,69 to 0.75 (2H, m), 0,94-a 1.01 (2H, m), 2.05 is-to 2.15 (1H, m), and 5.30 (2H, s), 7,41 (1H, d, J=2.1 Hz), the 7.43 (1H, DD, J=7,8, and 7.8 Hz), of 7.75 (1H, DDD, J=8,4, and 7.8, 1.2 Hz), to 7.84 (1H, d, J=2.1 Hz), of 7.90 (1H, d, J=7.8 Hz), 8,02 (1H, d, J=8,4 Hz). MS (m/z): 353 (M-H)-.

Example 14: 3-(3-cyano-5-ethinyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-cyano-5-ethinyl-4-methoxybenzoic acid

Methyl-3-cyano-5-ethinyl-4-methoxybenzoate (640 mg) was dissolved in tetrahydrofuran (6 ml) and water (3 ml) was added to a solution of the monohydrate of lithium hydroxide (495 mg) and then stirred the mixture at room temperature for 3 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (610 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): 4,20 (3H, s), 4.72 in (1H, s), 8,17 (1H, d, J=2.1 Hz), 8,24 (1H, d, J=2.1 Hz). MS (m/z): 200 (M-H)-.

(b) Synthesis of 3-cyano-5-ethinyl-4-methoxybenzanilide

3-cyano-5-ethinyl-4-methoxybenzoic acid (610 mg) under cooling on ice, was added toluene (6 ml), N,N-dimethylformamide (1 drop) and oxacillin (0,32 ml), and stirred the mixture at room temperature is round for 1.5 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (c).

(c) Synthesis of 3-(3-cyano-5-ethinyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (570 mg) and 37% formalin (0,38 ml) in the same way as described in example 1 was dissolved in dichloromethane (10 ml), was added to the solution triethylamine (1.2 ml) and 3-cyano-5-ethinyl-4-methoxybenzophenone, and then stirred the mixture at room temperature for 2.5 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 5/1) to obtain the specified title compound (283 mg) as a yellow oily substance.

(d) Synthesis of 3-(3-cyano-5-ethinyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-ethinyl-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (344 mg) was dissolved in dichloromethane (5 ml) and added to a solution of 70% meta-chloroperbenzoic the strong acid (1,94 g). After stirring the mixture at room temperature for 16 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (199 mg) as a yellow oily substance.

(e) Synthesis of 3-(3-cyano-5-ethinyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-ethinyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (197 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (239 mg) and then stirred the mixture at 100°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was purified by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1), and then vykristallizovyvalas from n-hexane/acetone to obtain specified in the title compound (102 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): 4,58 1H, C) to 5.35 (2H, s), 7,44 (1H, DD, J=7,6, 7,6 Hz), 7,76 (1H, DD, J=8,4, a 7.6 Hz), to $ 7.91 (1H, d, J=8,4 Hz), to 7.93 (1H, d, J=2.4 Hz), of 8.04 (1H, d, J=2.4 Hz), with 8.05 (1H, d, J=7,6 Hz). MS (m/z: 337 (M-H)

Example 15: 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-bromo-4-hydroxybenzoate

Methyl-4-hydroxybenzoate (25,00 g) was dissolved in chloroform (225 ml) and methanol (25 ml), the solution was added dropwise a solution of bromine (8.5 ml) in chloroform (30 ml) and then stirred the mixture for 2 hours. The reaction solution was diluted with chloroform, washed with water, aqueous 10% sodium thiosulfate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (37,81 g) as a colourless crystalline substance.

(b) Synthesis of methyl 3-cyano-4-hydroxybenzoate

Methyl-3-bromo-4-hydroxybenzoate (37,81 g) was dissolved in N,N-dimethylformamide (250 ml) was added to a solution of copper cyanide (22,03 g). After stirring the mixture at 150°C for 16 hours to the solution while cooling on ice, was added potassium carbonate (68,00 g) and chloromethylation ether (14,8 ml) and then stirred the mixture for 2 hours. The reaction solution was filtered, added water, and then extracted the reaction mixture with ethyl acetate. After three times doba is ing water to the organic layer, stirring the mixture, filtering the mixture and separation of the organic layer, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and dissolving the resulting residue in chloroform (30 ml). To the solution was added triperoxonane acid (30 ml) and then stirred the mixture at room temperature for 2 hours. The solvent is kept under reduced pressure, and washed the remainder a mixture of n-hexane and ethyl acetate in a ratio of 2/1 with obtaining specified in the connection header (6,53 g) as a pale yellow crystalline substance.

(c) Synthesis of methyl 3-cyano-4-hydroxy-5-identity

Methyl-3-cyano-4-hydroxybenzoate (6,47 g) was dissolved in chloroform (80 ml) and methanol (10 ml) was added to a solution of N-jodatime (8,63 g) and triftormetilfullerenov acid (2.5 ml) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, and washed the remainder of the water to receive specified in the connection header (11,29 g) as a pale yellow crystalline substance.

(d) Synthesis of methyl 3-cyano-5-iodine-4-methoxybenzoate

Methyl-3-cyano-4-hydroxy-5-identit (of 11.29 g) was dissolved in N,N-dimethylformamide (230 ml), was added to the solution to rbonate potassium (49,20 g) and dimethylsiloxy acid (17,0 ml), and then the mixture was stirred at room temperature for 18 hours. After filtration of the reaction mixture was added water, and was collected in the precipitate crystalline substance by filtration to obtain specified in the connection header (8,99 g) as a pale yellow crystalline substance.

(e) Synthesis of 3-cyano-5-iodine-4-methoxybenzoic acid

Methyl-3-cyano-5-iodine-4-methoxybenzoate (8.00 g) was dissolved in tetrahydrofuran (100 ml) and water (50 ml) was added to a solution of the monohydrate of lithium hydroxide (to 4.23 g) and then stirred the mixture at room temperature for 4 hours. Organic solvent drove away under reduced pressure, and the aqueous layer was washed with n-hexane. The aqueous layer was acidified by adding 2n hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (7,26 g) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): to 4.38 (3H, s), 8,58 (1H, d, J=2.0 Hz), 8,86 (1H, d, J=2.0 Hz), 13,89 (1H, user.C). MS (m/z):302 (M-1)-.

(f) Synthesis of 3-cyano-5-iodine-4-methoxybenzanilide

3-cyano-5-iodine-4-methoxybenzoic acid (512 mg) was added toluene (5 ml), N,N-dimethylformamide (1 drop) and tio is illore (0.15 ml), and stirred the mixture at 60°C for 15 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (527 mg) as a pale yellow solid.

(g) Synthesis of 3-(3-cyano-5-iodine-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (317 mg) and 37% formalin (of 0.21 ml) in the same way as described in example 1 was dissolved in dichloromethane (6 ml), was added to the solution triethylamine (0,70 ml) and 3-cyano-5-iodine-4-methoxybenzophenone (527 mg) and then stirred the mixture at room temperature for 14 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 5/1) to obtain the specified title compound (435 mg) as a yellow oily substance.

(h) Synthesis of 3-(3-cyano-5-iodine-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-iodine-4-methoxybenzoyl)-2,3-dihydro-1,3-benzo is eazol (196 mg) was dissolved in dichloromethane (4 ml), and was added to a solution of 70% meta-chloroperbenzoic acid (495 mg). After stirring the mixture at room temperature for 2 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and then purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1) to obtain the specified title compound (106 mg) as a pale yellow oily substance.

(i) Synthesis of 3-(3-cyano-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-5-iodine-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (106 mg) was dissolved in N,N-dimethylformamide (1 ml) was added to a solution of lithium chloride (40 mg) and then stirred the mixture at 100°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (100 mg) as a yellow oily substance.

1H-NMR δ (DMSO-d6 ): to 5.35 (2H, s), the 7.43 (1H, DD, J=7,8, and 7.3 Hz), 7,76 (1H, DD, J=8,4, 7,3 Hz), of 7.90 (1H, d, J=7.8 Hz), 8,02 (1H, d, J=2.2 Hz), of 8.04 (1H, d, J=8,4 Hz), of 8.27 (1H, d, J=2.2 Hz).

(j) Synthesis of 3-(3-cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (334 mg) was dissolved in N,N-dimethylformamide (3.5 ml) was added to a solution of 2,2'-bipyridine (11 mg), zinc powder (95 mg), Nickel bromide (16 mg) and dimethyl disulfide (0.04 ml) and then stirred the mixture at 80°C for 1 hour. After filtration of the reaction mixture were added 1N hydrochloric acid, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and dissolving the resulting residue in N,N-dimethylformamide (3 ml). To the solution was added potassium carbonate (298 mg) and dimethylsiloxy acid (0,13 ml) and then stirred the mixture at room temperature for 1 hour. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silicagel is e (n-hexane/ethyl acetate = 2/1) to obtain the specified title compound (142 mg) as a pale yellow oily substance.

(k) Synthesis of 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (142 mg) was dissolved in N,N-dimethylformamide (1 ml) was added to a solution of lithium chloride (64 mg) and then stirred the mixture at 100°C for 1.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (95 mg) as a yellow crystalline substance.

1H-NMR δ (DMSO-d6): the 2.46 (3H, s), of 5.34 (2H, s), 7,45 (1H, DD, J=7,6, and 7.3 Hz), to 7.68 (1H, d, J=2.2 Hz), to 7.77 (1H, DD, J=8,4, a 7.6 Hz), 7,82 (1H, d, J=2.2 Hz), to $ 7.91 (1H, d, J=7,3 Hz), 8,08 (1H, d, J=8,4 Hz). MS (m/z): 359 (M-H)-.

Example 16: 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-(3-cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (163 mg) was dissolved in dichloromethane (4 ml) was added to a solution of 70% meta-chloroperbenzoic acid 480 mg). After stirring the mixture at room temperature for 18 hours the solution was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (142 mg) as a pale yellow solid.

(b) Synthesis of 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (138 mg) was dissolved in N,N-dimethylformamide (1 ml) was added to a solution of lithium chloride (58 mg) and then stirred the mixture at 70°C for 3 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (69 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): 3,26 (3H, s), are 5.36 (2H, s), 7,40 (1H, DD, J=7,6 Hz and 7.6 Hz), 7,73 (1H, DD, J=8,1, 7,6 Hz), 7,88 (1H,d, J=8.1 Hz), 7,92 (1H, d, J=7,6 Hz), 8,11 (2H, s). MS (m/z): 391 (M-H)-.

Example 17: 3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (7 mg) was dissolved in tetrahydrofuran (0.5 ml) and water (0.5 ml), was added to the solution Oxon (6 mg) and then stirred the mixture at room temperature for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (6 mg) as pale-yellow crystalline substance.

1H-NMR δ (CDCl3): is 2.88 (3H, s), 4,96 (2H, s), 7,33 (1H, DD, J=7,6, 7,4 Hz), EUR 7.57 (1H, DD, J=8.0 a, 7,4 Hz), to 7.67 (1H, d, J=8.0 Hz), 7,72 (1H, d, J=7,6 Hz), 7,89 (1H, s), 7,94 (1H, s). MS (m/z): 375 (M-H)-.

Example 18: 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-chloro-4-hydroxy-5-triftoratsetata

Methyl-4-hydroxy-3-triptoreline (1.40 g) was dissolved in chloroform (14 ml) and methanol (3 ml) was added to a solution of N-chlorosuccinimide (1.70 g) and triftormetilfosfinov (40 μl), and then the mixture was stirred at room temperature for 16 hours. The solvent is kept under reduced pressure, was added 10% sodium thiosulfate, and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.26 g) as a brown solid.

(b) Synthesis of methyl 3-chloro-4-methoxy-5-triftoratsetata

Methyl-3-chloro-4-hydroxy-5-triptoreline (1.26 g) was dissolved in N,N-dimethylformamide (6 ml) was added to a solution of potassium carbonate (3.42 g) and dimethylsiloxy acid (1,40 ml) and then stirred the mixture at room temperature for 2 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain specified in the connection header (639 mg) as a colorless oily substance.

(c) Synthesis of 3-chloro-4-methoxy-5-triftorperasin acid

Methyl-3-chloro--methoxy-5-triptoreline (634 mg) was dissolved in tetrahydrofuran (4 ml) and water (4 ml), was added to a solution of the monohydrate of lithium hydroxide (396 mg) and then stirred the mixture at room temperature for 2 hours. Organic solvent drove away under reduced pressure, and then washed aqueous layer was n-hexane. The aqueous layer was acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (579 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 3.97 (3H, s), 8,08 (1H, d, J=2.1 Hz), compared to 8.26 (1H, d, J=2.1 Hz), 13,69 (1H, usher.). MS (m/z): 253 (M-H)-, 255 (M+2-H)-.

(d) Synthesis of 3-chloro-4-methoxy-5-triftormetilfullerenov

To 3-chloro-4-methoxy-5-triftorperasin acid (300 mg) were added toluene (3 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,13 ml), and stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (e).

(e) Synthesis of 3-(3-chloro-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (442 mg) and 37% formalin (to 0.29 ml) in the same way that is described in example 1, was dissolved in chloroform (8 ml), was added to the solution triethylamine (0,49 ml) and 3-chloro-4-methoxy-5-cryptomathematical, and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (f).

(f) Synthesis of 3-(3-chloro-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (5 ml) was added to a solution of 70% meta-chloroperbenzoic acid (726 mg), and then the mixture was stirred at room temperature for 18 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by column method chromium is adopted on silica gel (n-hexane/ethyl acetate = 3/1) to obtain the specified title compound (74 mg) as a colourless crystalline substance.

(g) Synthesis of 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (74 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (77 mg) and then stirred the mixture at 70°C for 22 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from diethyl ether to obtain specified in the title compound (65 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): are 5.36 (2H, s), 7,44 (1H, DDD, J=7,8, and 7.8, 0.8 Hz), to 7.77 (1H, DDD, J=8,2, to 7.8, 1.3 Hz), 7,86 (1H, d, J=2.1 Hz), to $ 7.91 (1H, DD, J=7,8, and 0.8 Hz), of 8.06 (1H, d, J=2.1 Hz), 8,07 (1H, d, J=8,2 Hz). MS (m/z): 390 (M-H)-.

Example 19: 3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-chloro-5-fluoro-4-methoxybenzanilide

To 3-chloro-5-fluoro-4-methoxybenzoic acid (295 mg) was added toluene (3 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0.15 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, poluchenii residue was subjected to azeotropic distillation with toluene and used for the synthesis of (b).

(b) Synthesis of 3-(3-chloro-5-fluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (346 mg) and 37% formalin (0,23 ml) in the same way as described in example 1 was dissolved in chloroform (3 ml), was added to the solution triethylamine (0,38 ml) and 3-chloro-5-fluoro-4-methoxybenzophenone, and then stirred the mixture at room temperature for 90 minutes. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 8/1) to obtain the specified title compound (356 mg) as a pale yellow oily substance.

(c) Synthesis of 3-(3-chloro-5-fluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-fluoro-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (348 mg) was dissolved in chloroform (7 ml) was added to a solution of 70% meta-chloroperbenzoic acid (739 mg), and then the mixture was stirred at room temperature for 16 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept in terms of the reduced pressure, added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (313 mg) as a colourless crystalline substance.

(d) Synthesis of 3-(3-chloro-5-fluoro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-fluoro-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (307 mg) was dissolved in N,N-dimethylformamide (6 ml) was added to a solution of lithium chloride (163 mg) and then stirred the mixture at 100°C for 16 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1) to obtain the specified title compound (296 mg) as a pale yellow amorphous product.

1H-NMR δ (DMSO-d6): to 5.35 (2H, s), the 7.43 (1H, DD, J=7,4, 7,4 Hz), to 7.59 (1H, DD, J=11,1, 1.8 Hz), to 7.61 (1H, s), 7,76 (1H, DDD, J=8,4, to 7.4, 1.2 Hz), of 7.90 (1H, d, J=7,4 Hz), 8,02 (1H, d, J=8,4 Hz), 11,35 (1H, usher. is). MS (m/z): 340 (M-H)-, 342 (M+2-H)-.

Example 20: 3-(3,5-debtor-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3,5-debtor-4-methoxybenzanilide

To 3,5-debtor-4-methoxybenzoic acid (310 mg) was added toluene (3 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,14 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (347 mg) as a brown oily substance.

(b) Synthesis of 3-(3,5-debtor-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (316 mg) and 37% formalin (of 0.21 ml) in the same way as described in example 1 was dissolved in dichloromethane (3 ml) was added to a solution of diisopropylethylamine high (0.56 ml) and 3,5-debtor-4-methoxybenzophenone (347 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder on the I synthesis (c).

(c) Synthesis of 3-(3,5-debtor-4-methoxybenzoyl)-2,3-dihydro-1,1-dioxo-1,3-benzothiazole

3-(3,5-Debtor-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (8 ml), was added to a solution of 70% meta-chloroperbenzoic acid (2,01 g). After stirring the mixture at room temperature for 5 hours was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (453 mg) as colorless solids.

(d) Synthesis of 3-(3,5-debtor-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3,5-Debtor-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (453 mg) was dissolved in N,N-dimethylformamide (4 ml) was added to a solution of lithium chloride (559 mg) and then stirred the mixture at 100°C for 16 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and the obtained residue was purified by the method of column chromatography on silica gel (n-hexane/e is ylacetic = 1/1), and then vykristallizovyvalas from diethyl ether to obtain specified in the title compound (270 mg) as a colourless crystalline substance.

1H-NMR δ (CD3OD): 5,14 (2H, s), 7,32 (2H, d, J=8,3 Hz), 7,40 (1H, DD, J=7,8, and 7.3 Hz), 7,66 (1H, DD, J=8,4, 7,3 Hz), to 7.77 (1H, d, J=7.8 Hz), 7,83 (1H, d, J=8,4 Hz). MS (m/z): 324 (M-H)-.

Example 21: 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-chloro-4-hydroxy-5-identity

Methyl-3-chloro-4-hydroxybenzoate (12,31 g) was dissolved in dichloromethane (100 ml) and methanol (12 ml) was added to a solution of N-jodatime (15,59 g) and triftormetilfullerenov acid (2 ml) and then stirred the mixture at room temperature for 2 hours. The solvent is kept under reduced pressure, and washed the remainder water (100 ml) to obtain specified in the connection header (to 20.52 g) as a colourless crystalline substance.

(b) Synthesis of methyl 3-chloro-5-iodine-4-methoxybenzoate

Methyl-3-chloro-4-hydroxy-5-identit (3.00 g) was dissolved in N,N-dimethylformamide (20 ml) was added to a solution of potassium carbonate (3.98 g) and dimethylsiloxy acid (1,82 ml) and then stirred the mixture at room temperature for 5 hours. The reaction solution was filtered, added water, and then extracted the reaction mixture with ethyl acetate. The organic layer is washed with water and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (2,96 g) as a pale yellow crystalline substance.

(c) Synthesis of 3-chloro-5-iodine-4-methoxybenzoic acid

Methyl-3-chloro-5-iodine-4-methoxybenzoate (2,96 g) was dissolved in tetrahydrofuran (23 ml) and water (7 ml) was added to a solution of the monohydrate of lithium hydroxide (1.52 g) and then stirred the mixture at room temperature for 19 hours. After distillation of the organic solvent and the mixture was acidified by adding 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (2,74 g) as a colourless crystalline substance.

1H-NMR δ (CDCl3): of 3.95 (3H, s), 8,11 (1H, DD, J=2.2 Hz, 0.5 Hz), 8,42 (1H, DD, J=2.2 Hz, 0.5 Hz). MS (m/z): 311 (M-H)-.

(d) Synthesis of 3-chloro-5-iodine-4-methoxybenzanilide

To 3-chloro-5-iodine-4-methoxybenzoic acid (2,74 g) was added toluene (27 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,76 ml) and then stirred the mixture at 60°C for 15 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene with the teachings specified in the connection header (3,05 g) as a yellow solid.

(e) Synthesis of 3-(3-chloro-5-iodine-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (1.65 g) and 37% formalin (1,09 ml) in the same way as described in example 1 was dissolved in dichloromethane (15 ml) was added to a solution of diisopropylethylamine (3.0 ml) and 3-chloro-5-iodine-4-methoxybenzophenone (3,05 g) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from a mixture of n-hexane and ethyl acetate in a ratio of 1/1 with obtaining specified in the connection header (2,44 g) as a pale yellow solid.

(f) Synthesis of 3-(3-chloro-5-iodine-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-iodine-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (200 mg) was dissolved in tetrahydrofuran (5 ml) and added to a solution of 70% meta-chloroperbenzoic acid (462 mg). After stirring the mixture at room temperature for 1.5 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The PR is anceschi layer washed with 1N sodium hydroxide and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (96 mg) as a colorless oily substance.

(g) Synthesis of 3-(3-chloro-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-5-iodine-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (922 mg) was dissolved in N,N-dimethylformamide (6 ml) was added to a solution of lithium chloride (421 mg) and then stirred the mixture at 120°C for 2.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.19 g) as a brown oily substance.

1H-NMR δ (CDCl3): to 4.98 (2H, s), 7,30-7,92 (6H, m).

(h) Synthesis of 3-(3-chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1.19 g) was dissolved in N,N-dimethylformamide (9 ml) was added to a solution of 2,2'-bipyridine (32 mg), zinc powder (262 mg), Nickel bromide (45 mg) and dimethyl disulfide (0,09 ml) and then stirred the mixture at 80°C for 1.5 hours. PEFC is filtering the reaction mixture was added 1N hydrochloric acid, and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and dissolving the resulting residue in N,N-dimethylformamide (6 ml). To the solution was added potassium carbonate (828 mg) and dimethylsiloxy acid (0,38 ml) and then stirred the mixture at room temperature for 14 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 3/1) to obtain the specified title compound (203 mg) as a yellow crystalline substance.

(i) Synthesis of 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (203 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (258 mg) and then stirred the mixture at 120°C for 20 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. Org the organic layer washed with 1N hydrochloric acid and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/diethyl ether to obtain specified in the title compound (169 mg) as a brown crystalline substance.

1H-NMR δ (DMSO-d6): of 2.44 (3H, s), of 5.34 (2H, s), 7,38 (1H, s), the 7.43 (1H, DD, J=7,8, and 7.6 Hz), 7,54 (1H, s), 7,76 (1H, DD, J=8,6, and 7.8 Hz), of 7.90 (1H, d, J=7,6 Hz), 8,02 (1H, d, J=8.6 Hz), 10,54 (1H, s). MS (m/z): 368 (M-H)-.

Example 22: 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-(3-chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (828 mg) was dissolved in dichloromethane (10 ml) was added to a solution of 70% meta-chloroperbenzoic acid (2,13 g) and then stirred the mixture at room temperature for 16 hours. Added 1N sodium hydroxide, precipitated precipitated crystalline substance was washed 1N sodium hydroxide, water and methanol to obtain specified in the header of the compound (589 mg) as colorless solids.

(b) Synthesis of 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (586 mg) was dissolved in N,N-dimetil is mamide (4 ml), was added to a solution of lithium chloride (241 mg) and then stirred the mixture at 120°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid, precipitated precipitated crystalline substance was washed with water, and then vykristallizovyvalas from n-hexane/chloroform to obtain specified in the title compound (310 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): to 3.34 (3H, s), to 5.35 (2H, s), 7,44 (1H, DD, J=7,6, and 7.3 Hz), 7,76 (1H, DD, J=8,4, 7,3 Hz), to $ 7.91 (1H, d, J=7,6 Hz), to 7.99 (1H, d, J=2.2 Hz), 8,03 (1H, d, J=8,4 Hz), of 8.09 (1H, d, J=2.2 Hz). MS (m/z): 400 (M-H)-.

Example 23: 3-(3-chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (51 mg) was dissolved in tetrahydrofuran (0.5 ml) and water (0.5 ml), was added to the solution Oxon (43 mg) and then stirred the mixture at room temperature for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/diethyl ether to obtain specified in the title compound (45 mg) as a brown Crist is lifescope substances.

1H-NMR δ (DMSO-d6): 2,82 (3H, s), to 5.35 (2H, s), the 7.43 (1H, DD, J=7,6, and 7.3 Hz), of 7.75 (1H, DD, J=7,8, and 7.6 Hz), 7,81 (1H, d, J=1.6 Hz), 7,86-8,02 (2H, m), to 7.93 (1H, d, J=1.6 Hz). MS (m/z): 384 (M-H)-.

Example 24: 3-(4-hydroxy-3-methylsulphonyl-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl-4-hydroxy-3-iodine-5-triftoratsetata

Methyl-4-hydroxy-3-triptoreline (916 mg) was dissolved in dichloromethane (15 ml) was added to a solution of N-jodatime (1.06 g) and triperoxonane acid (5 ml) and then stirred the mixture at room temperature for 1 hour. After removal of the solvent under reduced pressure was added 10% sodium thiosulfate, and extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.44 g) as a brown solid.

(b) Synthesis of methyl-4-hydroxy-3-methylsulfanyl-5-triftoratsetata

Methyl-4-hydroxy-3-iodine-5-triptoreline (1.26 g) was dissolved in N,N-dimethylformamide (12 ml) was added to a solution of 2,2'-bipyridine (57 mg), zinc powder (476 mg), Nickel bromide (80 mg) and dimethyl disulfide (172 mg) and then stirred the mixture at 130°C for 1 hour. After filtration of the reaction mixture dobavlyali hydrochloric acid, and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain the specified title compound (276 mg) as a colourless crystalline substance.

(c) Synthesis of methyl 4-methoxy-3-methylsulfanyl-5-triftoratsetata

Methyl-4-hydroxy-3-methylsulfanyl-5-triptoreline (327 mg) was dissolved in N,N-dimethylformamide (6 ml) was added to a solution of potassium carbonate (1.70 g) and dimethylsiloxy acid (0.35 ml) and then stirred the mixture at room temperature for 1 hour. After filtration of the reaction mixture were added 1N hydrochloric acid, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (344 mg) as a colorless oily substance.

(d) Synthesis of 4-methoxy-3-methylsulfanyl-5-triftorperasin acid

Methyl-4-methoxy-3-methylsulfanyl-5-triptoreline (303 mg) was dissolved in tetrahydrofuran (3 ml) and water (1.5 ml), obavljale to a solution of the monohydrate of lithium hydroxide (215 mg), and then the mixture was stirred at room temperature for 1 hour. After distillation of the organic solvent, the aqueous layer was acidified by adding 1N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain specified in the title compound (277 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 2.56 (3H, s) to 3.89 (3H, s), of 7.90 (1H, d, J=1.7 Hz), 8,00 (1H, d, J=1.7 Hz), 13,49 (1H, user.C). MS (m/z): 265 (M-N)-.

(e) Synthesis of 4-methoxy-3-methylsulfanyl-5-triftormetilfullerenov

To 4-methoxy-3-methylsulfanyl-5-triftorperasin acid (277 mg) was added toluene (7 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,12 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (f).

(f) Synthesis of 3-(4-methoxy-3-methylsulfanyl-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (346 mg) and 37% formalin (0,23 ml) in the same way as described in example 1 was dissolved in chloroform (4 ml), was added to the solution triethylamine (0,43 ml) and 4-methoxy-methylsulfanyl-5-cryptomathematical, and then the mixture was stirred at room temperature for 1 hour. After removal of the solvent under reduced pressure was added water and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (g).

(g) Synthesis of 3-(4-methoxy-3-methylsulphonyl-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Methoxy-3-methylsulfanyl-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole synthesized at the stage (f), was dissolved in chloroform (8 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1,34 g), and then the mixture was stirred at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. After removal of the solvent under reduced pressure was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1) to obtain the specified zag is lowke compound (310 mg) as a colourless crystalline substance.

(h) Synthesis of 3-(4-hydroxy-3-methylsulphonyl-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Methoxy-3-methylsulphonyl-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (305 mg) was dissolved in N,N-dimethylformamide (3 ml) was added to a solution of lithium chloride (288 mg) and then stirred the mixture at 70°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (288 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 5.34 (2H, s), 5,71 (3H, user.C) the 7.43 (1H, DD, J=7,6, 7,6 Hz), of 7.75 (1H, DD, J=8,4, a 7.6 Hz), of 7.90 (1H, d, J=7,6 Hz), 8,02 (1H, d, J=8,4 Hz) to 8.14 (1H, d, J=1.9 Hz), of 8.25 (1H, d, J=1.9 Hz). MS (m/z): 434(M-H)-.

Example 25: 3-(5-tert-butyl-4-hydroxy-3-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl-3-tert-butyl-4-hydroxy-5-methylsulfonylbenzoyl

Methyl-3-tert-butyl-4-hydroxy-5-identit (1,00 g) was dissolved in N,N-dimethylformamide (10 ml) was added to a solution of 2,2'-bipyridine (47 mg), zinc powder (391 mg), Nickel bromide (66 mg) and dimethyl disulfide (142 mg) and then stirred the mixture at 130° for 1 hour. After filtration of the reaction mixture were added 1N hydrochloric acid, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 12/1) to obtain the specified title compound (382 mg) as a pale yellow oily substance.

(b) Synthesis of methyl-3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl

Methyl-3-tert-butyl-4-hydroxy-5-methylsulfonylbenzoyl (377 mg) was dissolved in N,N-dimethylformamide (7 ml) was added to a solution of potassium carbonate (818 mg) and dimethylsiloxy acid (0,32 ml) and then stirred the mixture at room temperature for 20 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (344 mg) as a pale yellow oily substance.

(c) Synthesis of methyl-3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl

Methyl-3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl (344 mg) was dissolved in whom hloroform (7 ml), was added to a solution of 70% meta-chloroperbenzoic acid (884 mg) and then stirred the mixture at room temperature for 3 hours. After removal of the solvent under reduced pressure was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (387 mg) as a colourless crystalline substance.

(d) Synthesis of 3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl acid

Methyl-3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl (382 mg) was dissolved in tetrahydrofuran (4 ml) and water (2 ml) was added to a solution of the monohydrate of lithium hydroxide (320 mg) and then stirred the mixture at room temperature for 5 hours. After distillation of the organic solvent, the aqueous layer was acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain specified in the title compound (372 mg) as a colourless crystalline substance.

1H-NMR δ (CDCl3): USD 1.43 (9H, s), of 3.32 (3H, s) to 3.99 (3H, s), 826 (1H, d, J=2.2 Hz), 8,32 (1H, d, J=2.2 Hz). MS (m/z): 285 (M-H)-.

(e) Synthesis of 3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl

3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl acid (200 mg) was added toluene (4 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (80 μl) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (f).

(f) Synthesis of 3-(3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (182 mg) and 37% formalin (87 μl) in the same way as described in example 1 was dissolved in chloroform (4 ml), was added to the solution triethylamine (0,29 ml) and 3-tert-butyl-4-methoxy-5-methysulfonylmethane, and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/etelaat is = 4/1) to obtain the specified title compound (246 mg) as a pale yellow amorphous product.

(g) Synthesis of 3-(3-tert-butyl-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-tert-Butyl-4-methoxy-5-methylsulfonylbenzoyl)-2,3-dihydro-1,3-benzothiazole (241 mg) was dissolved in chloroform (5 ml) was added to a solution of 70% meta-chloroperbenzoic acid (410 mg), and then the mixture was stirred at room temperature for 16 hours and was suppressed by the addition of 10% sodium thiosulfate. After removal of the solvent under reduced pressure was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (236 mg) as a colorless amorphous product.

(h) Synthesis of 3-(3-tert-butyl-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-tert-Butyl-4-methoxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (232 mg) was dissolved in N,N-dimethylformamide (5 ml) was added to a solution of lithium chloride (225 mg) and then stirred the mixture at 130°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water, 1N hydrochloric acid and saturated SOLEV the m solution, and then was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1) to obtain the specified title compound (201 mg) as a colorless amorphous product.

1H-NMR δ (DMSO-d6): of 1.40 (9H, s), 3,42 (3H, s) 5,33 (2H, s), the 7.43 (1H, DD, J=7,6, 7,6 Hz), of 7.75 (1H, DDD, J=8,3, to 7.6, 1.3 Hz), 7,80 (1H, d, J=2.2 Hz), to $ 7.91 (1H, d, J=7,6 Hz), of 7.97 (1H, d, J=8,3 Hz), to 7.99 (1H, d, J=2.2 Hz), 10,06 (1H, user.C). MS (m/z): 422 (M-H)-.

Example 26: 3-(4-hydroxy-3-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of ethyl-4-benzyloxy-3-methoxy-5-triftoratsetata

Ethyl-4-hydroxy-3-methoxy-5-triptoreline (583 mg) was dissolved in N,N-dimethylformamide (5 ml), at 0°C was added to a solution of 60% sodium hydride (132 mg). After stirring the mixture for 30 minutes to the solution was added benzylbromide (0,31 ml) and then stirred the mixture for 14 hours. To the reaction solution was added water, and then extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 7/1) is obtaining specified in the header of the compound (704 mg) as a yellow oily substance.

(b) Synthesis of 4-benzyloxy-3-methoxy-5-triftorperasin acid

Ethyl-4-benzyloxy-3-methoxy-5-triptoreline (704 mg) was dissolved in tetrahydrofuran (6 ml) and water (2 ml) was added to a solution of the monohydrate of lithium hydroxide (333 mg) and then stirred the mixture at 60°C for 3 hours. After distillation of the organic solvent and the mixture was acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the header of the compound (606 mg) as a colourless crystalline substance.

1H-NMR δ (CDCl3): 4,00 (3H, s), a total of 5.21 (2H, s), 7,33-rate of 7.54 (5H, m), a 7.85 (1H, s), of 8.00 (1H, s). MS (m/z): 325 (M-H)-.

(c) Synthesis of 4-benzyloxy-3-methoxy-5-triftormetilfullerenov

To 4-benzyloxy-3-methoxy-5-triftorperasin acid (601 mg) was added toluene (6 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0.16 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the header of the compound (657 mg) as a yellow oily substance.

(d) Synthesis of 3-(4-benzyloxy-3-methoxy-5-trifloromethyl)-2,3-dihydro-1,3 benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (346 mg) and 37% formalin (0,23 ml) in the same way as described in example 1 was dissolved in dichloromethane (3 ml) was added to a solution of diisopropylethylamine (0.63 ml) and 4-benzyloxy-3-methoxy-5-cryptomathematical (657 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain the specified title compound (578 mg) as a yellow oily substance.

(e) Synthesis of 3-(4-benzyloxy-3-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole (578 mg) was dissolved in dichloromethane (10 ml) and added to a solution of 70% meta-chloroperbenzoic acid (1,94 g). After stirring the mixture at room temperature for 4 hours) was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is amywali 1N sodium hydroxide and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (574 mg) as a colorless oily substance.

(f) Synthesis of 3-(4-hydroxy-3-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (574 mg) was dissolved in tetrahydrofuran (6 ml) was added to a solution of 5% palladium on carbon (310 mg) and then stirred the mixture at room temperature for 22 hours in an atmosphere of hydrogen. The reaction solution was filtered, then drove the solvent under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (353 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 3,93 (3H, s), to 5.35 (2H, s), the 7.43 (1H, DD, J=8,1, 7,3 Hz), 7,47 (1H, s), 7,54 (1H, s), 7,76 (1H, DD, J=7,3, 7,3 Hz), of 7.90 (1H, d, J=7,3 Hz), 8,02 (1H, d, J=8.1 Hz), is 10.68 (1H, s). MS (m/z): 386 (M-H)-.

Example 27: 3-(3-dimethylcarbamoyl-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-formyl-4-methoxy-5-triftoratsetata

3-Formyl-4-methoxy-5-triftorperasin acid (5,00 g) was dissolved in methanol (30 ml) was added to a solution of hydrochloride of 1-ethyl-3-(3-dimethylamine is propyl)carbodiimide (4,25 g), and then the mixture was stirred at room temperature for 90 minutes. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain specified in the connection header (2,98 g) as a colourless crystalline substance.

(b) Synthesis of compound 1-methyl ester 4-methoxy-5-cryptomaterial acid

Methyl-3-formyl-4-methoxy-5-triptoreline (1.50 g) was dissolved in acetonitrile (15 ml) and aqueous 5% citric acid solution was added to a solution of 2-methyl-2-butene (2.00 g) and sodium chlorite (776 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and washed the resulting crystalline substance n-hexane with the teachings specified in the connection header (1,15 g) as a colourless crystalline substance.

(c) Synthesis of methyl-3-dimethylcarbamoyl-4-methoxy-5-triftoratsetata

Complex 1-methyl ester 4-methoxy-5-cryptomaterial acid (500 mg) was dissolved in dichloromethane (10 ml) was added to a solution of dimethylamine hydrochloride (440 mg), the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.56 g) and triethylamine (3,00 ml) and then stirred the mixture at room temperature for 4 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (356 mg) as pale-yellow crystalline substance.

(d) Synthesis of 3-dimethylcarbamoyl-4-methoxy-5-triftorperasin acid

Methyl-3-dimethylcarbamoyl-4-methoxy-5-triptoreline (348 mg) was dissolved in tetrahydrofuran (3 ml) and water (1.5 ml) was added to a solution of the monohydrate of lithium hydroxide (191 mg) and then stirred the mixture at room temperature for 1 hour. Organic solvent drove under reduced pressure and acidified by adding 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. Organic SL the St was washed with saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (341 mg) as a colourless crystalline substance.

1H-NMR δ (CDC13): only 2.91 (3H, s) 3,18 (3H, s), of 3.96 (3H, s), by 8.22 (1H, d, J=2.3 Hz), 8,35 (1H, DD, J=2,3, 0.6 Hz). MS (m/z): 290 (M-H)-.

(e) Synthesis of 3-dimethylcarbamoyl-4-methoxy-5-triftormetilfullerenov

3-dimethylcarbamoyl-4-methoxy-5-triftorperasin acid (333 mg) was added toluene (3 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,13 ml) and then stirred the mixture at 60°C for 6 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (f).

(f) Synthesis of 3-(3-dimethylcarbamoyl-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (214 mg) and 37% formalin (0,14 ml) in the same way as described in example 1 was dissolved in chloroform (4 ml), was added to the solution triethylamine (0,47 ml) and 3-dimethylcarbamoyl-4-methoxy-5-cryptomathematical, and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is amywali 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (g).

(g) Synthesis of 3-(3-dimethylcarbamoyl-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Dimethylcarbamoyl-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (8 ml) was added to a solution of 70% meta-chloroperbenzoic acid (718 mg), and then the mixture was stirred at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1) to obtain the specified title compound (298 mg) as a pale yellow amorphous product.

(h) Synthesis of 3-(3-dimethylcarbamoyl-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Dimethylcarbamoyl-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-Digi the ro-1,3-benzothiazole (291 mg) was dissolved in N,N-dimethylformamide (3 ml), was added to a solution of lithium chloride (279 mg) and then stirred the mixture at 120°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (257 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 2,96 (6H, s), of 5.39 (2H, s), the 7.43 (1H, DD, J=7,6, 7,6 Hz), 7,55 (1H, DDD, J=8,4, to 7.6, 1.3 Hz), 7,79 (1H, d, J=2.1 Hz), of 7.90 (1H, d, J=7,6 Hz), to 7.93 (1H, d, J=2.1 Hz), 8,02 (1H, d, J=8,4 Hz), 11,27 (1H, s). MS (m/z): 427 (M-H)-.

Example 28: 3-(4-hydroxy-3-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of complex 2-triftormetilfullerenov ether acetic acid

2-Triptoreline (20,00 g) was dissolved in chloroform (160 ml), was added to the solution triethylamine (34,0 ml) and acetic anhydride (12,4 ml) and then stirred the mixture at room temperature for 3 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure is obtaining specified in the connection header (23,76 g) as a pale yellow oily substance.

(b) Synthesis of 1-(4-hydroxy-3-triptoreline)ethanone

Complex 2-cryptomaterial ether acetic acid (10,00 g) was dissolved in triftormetilfullerenov acid (10.0 ml) and stirred solution at room temperature for 16 hours. The reaction solution was poured into ice water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and washed the resulting crystalline substance n-hexane to obtain specified in the connection header (4,47 g) as a colourless crystalline substance.

(c) Synthesis of 1-(4-methoxyethoxy-3-triptoreline)ethanone

1-(4-Hydroxy-3-triptoreline)alanon (a 2.01 g) was dissolved in N,N-dimethylformamide (20 ml) was added to a solution of potassium carbonate (2.70 g) and chloromethylation ether (1,10 ml) and then stirred the mixture at room temperature for 1 hour. To the reaction solution was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (2,33 g) as a pale yellow mA is sanitago substances.

(d) Synthesis of methyl-4-hydroxy-3-cryptomaterial

1-(4-Methoxyethoxy-3-triptoreline)alanon (2,33 g) was dissolved in methanol (20 ml) was added to a solution of 5M solution of sodium methoxide in methanol (9,40 ml) and N-bromosuccinimide (5.10 g), and then stirred the mixture at room temperature for 30 minutes. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, was added 4n hydrochloric acid in ethyl acetate (20 ml) and then stirred the mixture at room temperature for 30 minutes. The reaction solution was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.42 g) as a colourless crystalline substance.

(e) Synthesis of methyl 4-benzyloxy-3-triftoratsetata

Methyl-4-hydroxy-3-cryptomaterial (936 mg) was dissolved in N,N-dimethylformamide (10 ml) was added to a solution of potassium carbonate (1.29 g) and benzylbromide (0,58 ml) and then stirred the mixture at room temperature for 24 hours. To the reaction rastv the ru was added water, and the reaction mixture is extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain the specified title compound (1.70 g) as a yellow crystalline substance.

(f) Synthesis of 4-benzyloxy-3-triftorperasin acid

Methyl-4-benzyloxy-3-triptoreline (1,38 g) was dissolved in tetrahydrofuran (10 ml) and water (5 ml) was added to a solution of the monohydrate of lithium hydroxide (1,49 g) and then stirred the mixture at room temperature for 20 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.25 g) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): 5,38 (2H, s), 7,31-7,51 (6H, m) to 8.12 (1H, d, J=2.1 Hz), 8,19 (1H, d, J=8,6, and 2.1 Hz), 13,12 (1H, user.C). MS (m/z): 269 (M-H)-.

(g) Synthesis of 4-benzyloxy-3-triftormetilfullerenov

To 4-benzyloxy-3-trif what normativizing acid (444 mg) was added toluene (5 ml), N,N-dimethylformamide (2 drops) and thionyl chloride (0.16 ml) and then stirred the mixture at 60°C for 20 hours. The solvent is kept under reduced pressure, and the obtained product was then subjected to azeotropic distillation with toluene and used for the synthesis of (h).

(h) Synthesis of 3-(4-benzyloxy-3-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (282 mg) and 37% formalin (0,19 ml) in the same way as described in example 1 was dissolved in chloroform (6 ml), was added to the solution triethylamine (of 0.62 ml) and 4-benzyloxy-3-cryptomathematical, and then stirred the mixture at room temperature for 1.5 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain the specified title compound (356 mg) as a pale yellow oily substance.

(i) Synthesis of 3-(4-benzyloxy-3-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-trif normativity)-2,3-dihydro-1,3-benzothiazole (600 mg) was dissolved in chloroform (10 ml), was added to a solution of 70% meta-chloroperbenzoic acid (1.04 g), and then the mixture was stirred at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1) to obtain the specified title compound (495 mg) as a colourless crystalline substance.

(j) Synthesis of 3-(4-hydroxy-3-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (490 mg) was dissolved in tetrahydrofuran (5 ml) and methanol (5 ml) was added to a solution of 20% palladium hydroxide on coal (100 mg) and then stirred the mixture at room temperature for 6 hours in an atmosphere of hydrogen. After filtration of the reaction mixture is kept off the solvent under reduced pressure, and then vykristallizovyvalas the resulting residue from diethyl ether to obtain specified in the title compound (397 mg) as colorless to istoricheskogo substances.

1H-NMR δ (DMSO-d6): of 5.29 (2H, s), 7,14 (1H, d, J=8,4 Hz), 7,41 (1H, DDD, J=8,2, to 7.8, 0.9 Hz), 7,72 (1H, DDD, J=8,5, to 7.3, 1.3 Hz), 7,80 (1H, DD, J=a 8.4 and 2.2 Hz), 7,84-7,88 (2H, m), to $ 7.91 (1H, d, J=8,2 Hz), 11,35 (1H, user.C). MS (m/z): 356 (M-H)-.

Example 29: 3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 4-benzyloxy-3-chloro-5-methoxybenzonitrile

To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg) was added toluene (5.4 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0.16 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (578 mg) as a yellow solid.

(b) Synthesis of 3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (347 mg) and 37% formalin (0,23 ml) in the same way as described in example 1 was dissolved in dichloromethane (3 ml) was added to a solution of diisopropylethylamine (0.63 ml) and 4-benzyloxy-3-chloro-5-methoxybenzoate (578 mg) and then stirred the mixture at room temperature for 1.5 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N hydroxide is m sodium and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 6/1) to obtain the specified title compound (498 mg) as a pale yellow oily substance.

(c) Synthesis of 3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-chloro-5-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (498 mg) was dissolved in dichloromethane (10 ml) and added to a solution of 70% meta-chloroperbenzoic acid (1.22 g). After stirring the mixture at room temperature for 16 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (521 mg) as a pale yellow oily substance.

(d) Synthesis of 3-(3-chloro-4-hydroxy-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(4-Benzyloxy-3-chloro-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (519 mg) was dissolved in tetrahydrofuran (5 ml) was added to a solution of 20% palladium hydroxide on coal (101 mg) and then stirred the mixture at room Tempe is the atur for 21 hours in an atmosphere of hydrogen. After filtration of the reaction mixture, the solvent is kept under reduced pressure, and then vykristallizovyvalas the resulting residue from chloroform to obtain specified in the title compound (185 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 3,88 (3H, s), of 5.34 (2H, s), 7,27 (1H, s), 7,35 (1H, s), the 7.43 (1H, DD, J=7,6 Hz and 7.6 Hz), of 7.75 (1H, DD, J=8,4, a 7.6 Hz), of 7.90 (1H, d, J=7,6 Hz), to 7.99 (1H, d, J=8,4 Hz). MS (m/z): 352 (M-H)-.

Example 30: 3-[4-hydroxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 4-methoxy-3-(pyrrolidin-1-carbonyl)-5-triftoratsetata

Complex 1-methyl ester 4-methoxy-5-cryptomaterial acid (4.35 g) was dissolved in dichloromethane (50 ml) was added to a solution of pyrrolidine (1.10 g) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2,99 g) and then stirred the mixture at room temperature for 16 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/3)to obtain specified in the connection header (1,33 g) as a brown oily substance.

(b) Synthesis of 4-methoxy-3-(pyrrolidin-1-carbonyl)-5-triftorperasin acid

Methyl-4-methoxy-3-(pyrrolidin-1-carbonyl)-5-triptoreline (1,33 g) was dissolved in tetrahydrofuran (8 ml) and water (4 ml) was added to a solution of the monohydrate of lithium hydroxide (708 mg) and then stirred the mixture at room temperature for 1 hour. Organic solvent drove away under reduced pressure, and washed aqueous layer diisopropyl ether. The aqueous layer was acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (790 mg) as a colorless amorphous product.

(c) Synthesis of 4-methoxy-3-(pyrrolidin-1-carbonyl)-5-triftormetilfullerenov

To 4-methoxy-3-(pyrrolidin-1-carbonyl)-5-triftorperasin acid (785 mg) was added toluene (8 ml) and oxacillin (0,64 ml) and then stirred the mixture at room temperature for 22 hours. The solvent is kept under reduced pressure, and used the resulting product for the synthesis of (d).

(d) Synthesis of 3-[4-methoxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzodiaz is l, synthesized from 2-aminobenzamide (464 mg) and 37% formalin (0,31 ml) in the same way as described in example 1 was dissolved in chloroform (10 ml), was added to the solution triethylamine (1,03 ml) and 4-methoxy-3-(pyrrolidin-1-carbonyl)-5-cryptomathematical, and then stirred the mixture at room temperature for 2 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/2) to obtain the specified title compound (778 mg) as a pale yellow amorphous product.

(e) Synthesis of 3-[4-methoxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-[4-Methoxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-2,3-dihydro-1,3-benzothiazole (773 mg) was dissolved in chloroform (15 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1.22 g), and then the mixture was stirred at room temperature for 16 hours and was suppressed by the addition of 10% sodium thiosulfate. After removal of the solvent under reduced gallerygallery 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (720 mg) as a white amorphous product.

(f) Synthesis of 3-[4-hydroxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-[4-Methoxy-3-(pyrrolidin-1-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (715 mg) was dissolved in N,N-dimethylformamide (7 ml) was added to a solution of lithium chloride (649 mg) and then stirred the mixture at 120°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (654 mg) as a colorless amorphous product.

1H-NMR δ (DMSO-d6): to 1.86 (4H, usher.), 3,45-of 3.60 (4H, t, J=6.5 Hz), lower than the 5.37 (2H, s), the 7.43 (1H, DDD, J=7,8, and 7.8, 0.8 Hz), 7,76 (1H, DDD, J=8,4, and 7.8, 1.3 Hz), of 7.90 (2H, usher.), 8,03 (1H, d, J=8,4 Hz), 12,29 (1H, s). MS (m/z): 453 (M-H)-.

Example 31: 3-[4-hydroxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,-dihydro-1,3-benzothiazole

(a) Synthesis of 3-formyl-4-methoxy-5-triftormetilfullerenov

To 3-formyl-4-methoxy-5-triftorperasin acid (2,05 g) was added toluene (20 ml), N/N-dimethylformamide (2 drops) and thionyl chloride (0,70 ml) and then stirred the mixture at 60°C for 6.5 hours. The solvent is kept under reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the connection header (2,42 g) as a brown oily substance.

(b) Synthesis of 3-(3-formyl-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (1.55 g) and 37% formalin (1.0 ml) in the same way as described in example 1 was dissolved in dichloromethane (15 ml) was added to a solution of diisopropylethylamine (2.7 ml) and 3-formyl-4-methoxy-5-cryptomathematical (2,42 g) and then stirred the mixture at room temperature for 14 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/e is ylacetic = 5/1) to obtain the specified title compound (1.44 g) as a yellow oily substance.

(c) Synthesis of 3-(3-diethoxylate-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

3-(3-Formyl-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole (277 mg) was dissolved in ethanol (1.5 ml) and triethylorthoformate (0.16 ml) was added to a solution of Amberlyst-15 (27 mg), and then the mixture was heated under reflux for 3.5 hours. The reaction solution was filtered, and then drove away the solvent under reduced pressure to obtain specified in the title compound (326 mg) as a yellow oily substance.

(d) Synthesis of 3-(3-formyl-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Formyl-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole (326 mg) was dissolved in dichloromethane (6 ml) was added to a solution of 70% meta-chloroperbenzoic acid (754 mg). After stirring the mixture at room temperature for 2 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was dissolved in ethyl acetate (3 ml) was added to a solution of 4n hydrochloric acid in ethyl acetate (0,74 ml) and then stirred the mixture at room temperature for 2 hours. Re clanny the solution was washed with water and saturated saline solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (248 mg) as a pale yellow oily substance.

(e) Synthesis of 5-(1,1-dioxo-2,3-dihydro-1,3-benzothiazol-3-carbonyl)-2-methoxy-3-triftorperasin acid

3-(3-Formyl-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (248 mg) was dissolved in methanol (2.5 ml) and aqueous 10% citric acid solution (2.5 ml) was added to a solution of 2-methyl-2-butene (0.33 ml) and sodium chlorite (84 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with aqueous 10% sodium thiosulfate solution and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (277 mg) as a pale yellow oily substance.

(f) Synthesis of 3-[4-methoxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

5-(1,1-Dioxo-2,3-dihydro-1,3-benzothiazol-3-carbonyl)-2-methoxy-3-triftorperasin acid (277 mg) was dissolved in dichloromethane (3 ml) was added to a solution of thiazole is in (0.10 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (238 mg), and then the mixture was stirred at room temperature for 19 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1) to obtain the specified title compound (138 mg) as a colorless oily substance.

(g) Synthesis of 3-[4-hydroxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-[4-Methoxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (138 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (118 mg) and then stirred the mixture at 120°C for 1.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform-Poluchenie specified in the title compound (47 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): a 3.06 (2H, user.C) of 3.77 (2H, user.C), 4,58 (2H, user.C) 5,38 (2H, s), the 7.43 (1H, DD, J=7,6, and 7.3 Hz), 1,16 (1H, DD, J=8,4, 7,3 Hz), 7,82-of 8.00 (2H, m), of 7.97 (1H, s), of 8.04 (1H, d, J=8,4 Hz), to 11.52 (1H, user.C). MS (m/z):471 (M-H)-.

Example 32: 3-[4-hydroxy-3-(1-oxo-1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-[4-Hydroxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (67 mg) was dissolved in tetrahydrofuran (0.5 ml) and water (0.5 ml), was added to the solution Oxon (45 mg) and then stirred the mixture at room temperature for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (46 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 2,98-3,15 (2H, m), 3,94-4,06 (1H, m), 4,22 (1H, user.C) br4.61 (2H, s), 5,32 (2H, s), 7,42 (1H, DD, J=7,6, 7,6 Hz), 7,74 (1H, DD, J=8,4, a 7.6 Hz), 7,86 (1H, d, J=7,6 Hz), 7,88 (1H, d, J=2.2 Hz), 7,98 (1H, d, J=2.2 Hz), 8,01 (1H, d, J=8,4 Hz). MS (m/z): 487 (M-H)-.

Example 33: 1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidin-3-carbonyl)-4-hydroxy-5-trifloromethyl]-2,3-d the hydro-1,3-benzothiazole

(a) Synthesis of 1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidin-3-carbonyl)-4-methoxy-5-trifloromethyl]-2,3-dihydro-1,3-benzothiazole

3-[4-Methoxy-3-(1,3-thiazolidin-3-carbonyl)-5-trifloromethyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in chloroform (10 ml) and added to a solution of 70% meta-chloroperbenzoic acid (1,21 g). After stirring the mixture at room temperature for 20 hours was added 1N sodium hydroxide, and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (266 mg) as a colorless oily substance.

(b) Synthesis of 1,1-dioxo-3-[3-(1,1-dioxo-1,3-thiazolidin-3-carbonyl)-4-hydroxy-5-trifloromethyl]-2,3-dihydro-1,3-benzothiazole

1,1-Dioxo-3-[3-(1,1-dioxo-1,3-thiazolidin-3-carbonyl)-4-methoxy-5-trifloromethyl]-2,3-dihydro-1,3-benzothiazole (260 mg) was dissolved in N,N-dimethylformamide (2.5 ml) was added to a solution of lithium chloride (200 mg) and then stirred the mixture at 120°C for 1.5 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline, and then dried to the anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (120 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): 3,50 (2H, t, J=6.8 Hz), 3,86-to 4.14 (2H, m), with 4.64 (2H, s), of 5.39 (2H, s), 7,44 (1H, DD, J=8,1, 7,6 Hz), to 7.77 (1H, DD, J=8,1, 7,6 Hz), 7,88 (1H, s), to $ 7.91 (1H, d, J=8.1 Hz), 8,01 (1H, s), of 8.06 (1H, d, J=8,1 Hz). MS (m/z): 503 (M-H)-.

Example 34: 3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of methyl 3-cyano-4-methoxybenzoate

Methyl-3-cyano-4-hydroxybenzoate (1,00 g) was dissolved in N,N-dimethylformamide (5 ml) was added to a solution of potassium carbonate (1.56 g) and dimethylsiloxy acid (0,70 ml) and then stirred the mixture at room temperature for 1 hour. After filtration of the reaction mixture was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (923 mg) as a yellow solid.

(b) Synthesis of 3-cyano-4-methoxybenzoic acid

Methyl-3-cyano-4-methoxybenzoate (879 mg) was dissolved in tetrahydrofuran (8 ml) and water (4 ml) was added to a solution of the monohydrate of hydrox is Yes lithium (772 mg), and then the mixture was stirred at room temperature for 1 hour. Organic solvent drove under reduced pressure and acidified by adding 2n hydrochloric acid, and then was collected in the precipitated crystalline substance by filtration to obtain specified in the header of the compound (754 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): 4,00 (3H, s), of 7.36 (1H, DD, J=6,6, 3.0 Hz), 8,18 (1H, d, J=3.0 Hz), to 8.20 (1H, DD, J=6,6, and 2.1 Hz), 13,17 (1H, user.C). MS (m/z): 176 (M-H)-.

(c) Synthesis of 3-cyano-4-methoxybenzanilide

3-cyano-4-methoxybenzoic acid (1.78 g) was added toluene (20 ml), N,N-dimethylformamide (3 drops) and thionyl chloride (1,14 ml) and then stirred the mixture at 60°C for 16 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (d).

(d) Synthesis of 3-(3-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (1.89 g) and 37% formalin (1.25 ml) in the same way as described in example 1 was dissolved in chloroform (20 ml), was added to the solution triethylamine (2,08 ml) and 3-cyano-4-methoxybenzophenone, and then stirred the mixture at room temperature for 2 hours. Organic solvent drove in conditions of decreased what about the pressure and were extracted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (e).

(e) Synthesis of 3-(3-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (50 ml) was added to a solution of 70% meta-chloroperbenzoic acid (9,19 g) and then stirred the mixture at room temperature for 20 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (2.30 g) as a pale yellow solid.

(f) Synthesis of 3-(3-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (2.30 g) was dissolved in N,N-dimethylformamide (25 ml) was added to a solution of lithium chloride (2,97 g) and then stirred the mixture at 130°C for 12 hours. To the resulting re is klonoa the solution was added 1N hydrochloric acid, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (g).

(g) Synthesis of 3-(3-cyano-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (27 ml) and methanol (3 ml) was added to a solution of N-jodatime (1,79 g) and triftormetilfullerenov acid (5 drops), and then stirred the mixture at room temperature for 15 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the connection header (1,30 g) as a colourless crystalline substance.

(h) Synthesis of 3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in N,N-dimethylformamide (5 ml), doba is ranged to a solution of 2,2'-bipyridine (18 mg), zinc powder (149 mg), Nickel bromide (25 mg) and diatinguished (70 mg) and then stirred the mixture at 110°C for 1 hour. After filtration of the reaction mixture were added 1N hydrochloric acid, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was purified by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1), and then vykristallizovyvalas from diethyl ether/ethyl acetate to obtain specified in the title compound (63 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): to 1.22 (3H, t, J=7,3 Hz), 2,96 (2H, square, J=7,3 Hz), to 5.35 (2H, s), 7,44 (1H, DD, J=7,6, 7,6 Hz), to 7.77 (1H, DDD, J=8,3, to 7.6, 1.3 Hz), 7,79 (1H, d, J=1,8 Hz), 7,88-7,94 (2H, m), 8,07 (1H, d, J=8,3 Hz). MS (m/z): 373 (M-H)-.

Example 35: 3-(3-cyano-4-hydroxy-5-isopropylaminomethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-hydroxy-5-Ioganson)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (1,03 mg) was dissolved in N,N-dimethylformamide (10 ml) was added to a solution of 2,2'-bipyridine (37 mg), zinc powder (306 mg), Nickel bromide (52 mg) and diisopropylamide (176 mg) and then stirred the mixture at 110°C for 1 hour. After filtration of the reaction mixture were added 1N hydrochloric acid, and was extracted with actionnow a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 2/1) to obtain the specified title compound (153 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): of 1.23 (6H, d, J=6.6 Hz), of 3.46 (1H, sevent, J=6.6 Hz), to 5.35 (2H, s), 7,44 (1H, DD, J=7,4, 7,4 Hz), 7,76 (1H, DDD, J=8,4, to 7.4, 1.3 Hz), of 7.90 (1H, d, J=2.1 Hz), to $ 7.91 (1H, d, J=7,4 Hz), 7,98 (1H, d, J=2.1 Hz), of 8.04 (1H, d, J=8,4 Hz), made 11.32 (1H, user.C). MS (m/z): 387 (M-H)-.

Example 36: 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 1-methoxyethoxy-2-cryptomaterial

2-Cryptomaterial (10,00 g) was dissolved in N,N-dimethylformamide (50 ml) was added to a solution of potassium carbonate (15,52 g) and chloromethylation ether (4,70 ml) and then stirred the mixture at room temperature for 1 hour. To the reaction solution were added water and then was extracted with a mixture of n-hexane. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (12,21 g) as a colorless oily substance.

(b) Synthesis of 2-Ki-the Roxy-3-triphtalocyaninine

1 Methoxyethoxy-2-cryptomaterial (12,21 g) was dissolved in tetrahydrofuran (120 ml) under a stream of argon at -60°C for 15 minutes was added to a solution of 1.59 M solution of n-utility in n-cyclohexane (40 ml) and then stirred the mixture for 1 hour. To the solution was added N,N-dimethylformamide (6.30 ml) and then stirred the mixture at room temperature for 30 minutes. To the solution was added 2n hydrochloric acid (100 ml) and then stirred the mixture at 60°C for 15 hours. Organic solvent drove away under reduced pressure, and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (10,38 g) as a colourless crystalline substance.

(c) Synthesis of 5-bromo-2-hydroxy-3-triphtalocyaninine

2-Hydroxy-3-triphtalocyaninine (10,38 g) was dissolved in dichloromethane (100 ml) was added to a solution of N-bromosuccinimide (9,41 g) and then stirred the mixture at room temperature for 30 minutes. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 10% sodium thiosulfate and saturated Sol is the first solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (14,27 g) as a brown solid.

(d) Synthesis of 5-bromo-2-methoxy-3-triphtalocyaninine

5-Bromo-2-hydroxy-3-cryptomaterial (of 5.00 g) was dissolved in N,N-dimethylformamide (25 ml) was added to a solution of potassium carbonate (4,85 g) and dimethylsiloxy acid (2.5 ml) and then stirred the mixture at room temperature for 16 hours. To the reaction solution was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (5,22 g) as a brown oily substance.

(e) Synthesis of 5-bromo-1-diethoxylate-2-methoxy-3-cryptomaterial

5-Bromo-2-methoxy-3-triphtalocyaninine (5,22 g) was dissolved in n-hexane (15 ml) and triethylorthoformate (4,4 ml) was added to a solution of Amberlyst-15 (522 mg), and then the mixture was heated under reflux for 3 hours. The reaction solution was filtered, and then drove away the solvent under reduced pressure to obtain specified in the connection header (to 6.19 g) in the form of coric is avago oily substance.

(f) Synthesis of 3-formyl-4-methoxy-5-cryptomaterial acid

To magnesium (403 mg) was added tetrahydrofuran (16 ml), 5-bromo-1-diethoxylate-2-methoxy-3-cryptomaterial (to 6.19 g) and 0.97 M solution methylacrylamide in tetrahydrofuran (0,42 ml) and then stirred the mixture at room temperature for 1 hour. The reaction solution was cooled to 0°C and was stirred for 45 minutes in an atmosphere of carbon dioxide. Added 4n hydrochloric acid (25 ml) and then stirred the mixture at room temperature for 30 minutes. Organic solvent drove away under reduced pressure, and the mixture was extracted with diisopropyl ether. The organic layer was extracted by adding 1N sodium hydroxide (100 ml) and the aqueous layer was twice washed with diisopropyl ether. The aqueous layer was acidified by addition of 4n hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (4,22 g) as a brown solid.

(g) Synthesis of 3-cyano-4-methoxy-5-cryptomaterial acid

3-Formyl-4-methoxy-5-triftormyetil acid (4,22 g) was dissolved in formic acid (20 ml) was added to a solution of the hydroxylamine hydrochloride (1.22 g), and then mixture was heated under reflux for 16 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the connection header (of 3.97 g) as a brown solid.

1H-NMR δ (DMSO-d6): 4,17 (3H, s), 8,10-to 8.14 (1H, m), of 8.28 (1H, d, J=2.0 Hz), 13,73 (1H, user.C). MS (m/z): 260 (M-H)-.

(h) Synthesis of 3-cyano-4-methoxy-5-cryptomaterial

3-cyano-4-methoxy-5-cryptomaterial acid (500 mg) was added toluene (10 ml), N,N-dimethylformamide (3 drops) and thionyl chloride (0,28 ml) and then stirred the mixture at 60°C for 6 hours. The solvent is kept under reduced pressure, and the obtained residue was subjected to azeotropic distillation with toluene and used for the synthesis of (i).

(i) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzoyl (359 mg) and 37% formalin (in 0.24 ml) in the same way as described in example 1 was dissolved in chloroform (10 ml), was added to the solution triethylamine (0,80 ml) and 3-cyano-4-methoxy-5-cryptomaterial, and C is the mixture was stirred at room temperature for 17 hours. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (j).

(j) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (15 ml) was added to a solution of 70% meta-chloroperbenzoic acid (1.98 g), and then the mixture was stirred at room temperature for 6 hours and was suppressed by the addition of 10% sodium thiosulfate. The solvent is kept under reduced pressure, was added a 1N solution of sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the header of the compound (631 mg) as a pale yellow solid.

(k) Synthesis of 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-tripterococcus the l)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (300 mg) was dissolved in N,N-dimethylformamide (4 ml), was added to a solution of lithium chloride (309 mg) and then stirred the mixture at 100°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the title compound (184 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): lower than the 5.37 (2H, s), 7,42 (1H, DDD, J=7,3, 7,3, 0.7 Hz), to 7.77 (1H, DDD, J=8,4, to 7.3, 1.3 Hz), 7,88-of 7.96 (2H, m), 8,04-8,11 (2H, m). MS (m/z): 397 (M-H)-.

Example 37: 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of complex 2-cryptomaterial ether acetic acid

2-Cryptomaterial (10,00 g) was dissolved in chloroform (30 ml), was added to the solution triethylamine (6,11 ml) and acetic anhydride (6,37 ml) and then stirred the mixture at room temperature for 2 hours. To the resulting reaction solution was added 10% potassium carbonate, and then the mixture was extracted with chloroform. The organic layer is washed with aqueous 5% citric acid solution and saturated saline, and then dried over anhydrous sulphate of soda is I. The solvent drove under reduced pressure to obtain specified in the connection header (is 11.39 g) as a colorless oily substance.

(b) Synthesis of 1-(4-hydroxy-3-trifloromethyl)ethanone

Complex 2-cryptomaterial ether acetic acid (is 11.39 g) was dissolved in triftormetilfullerenov acid (10 ml) and then stirred solution at room temperature for 2.5 hours. The reaction solution was poured into ice water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 3/1) to obtain specified in the connection header (4,55 g) as a colourless crystalline substance.

(c) Synthesis of 1-(4-methoxyethoxy-3-trifloromethyl)ethanone

1-(4-Hydroxy-3-trifloromethyl)alanon (1.55 g) was dissolved in N,N-dimethylformamide (20 ml) was added to a solution of potassium carbonate (1,46 g) and chloromethylation ether (0,64 ml) and then stirred the mixture at room temperature for 1 hour. To the reaction solution was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water insystem salt solution, and then was dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.54 g) as a colorless oily substance.

(d) Synthesis of methyl-4-methoxyethoxy-3-cryptomaterial

1-(4-Methoxyethoxy-3-trifloromethyl)alanon (540 mg) was dissolved in methanol (30 ml) was added to a solution of sodium methoxide (1.10 g) and N-bromosuccinimide (1,09 g) and then stirred the mixture at room temperature for 30 minutes. To the reaction solution was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (590 mg) as a yellow crystalline substance.

(e) Synthesis of methyl-4-hydroxy-3-cryptomaterial

Methyl-4-methoxyethoxy-3-cryptomaterial (590 mg) was dissolved in chloroform (10 ml), was added to the solution triperoxonane acid (5 ml) and then stirred the mixture at room temperature for 1 hour. To the solution was added water, and then was extracted with a mixture of chloroform. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent drove the conditions of low pressure, and washed the resulting residue n-hexane to obtain specified in the title compound (346 mg) as a colourless crystalline substance.

(f) Synthesis of methyl 3-chloro-4-hydroxy-5-cryptomaterial

Methyl-4-hydroxy-3-cryptomaterial (2,05 g) was dissolved in chloroform (20 ml) and methanol (3 ml) was added to a solution of N-chlorosuccinimide (1.39 g) and triftormetilfullerenov acid (0.05 ml) and then stirred the mixture at 50°C for 19 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (2.64 g) as a yellow solid.

(g) Synthesis of methyl 3-chloro-4-methoxy-5-cryptomaterial

Methyl-3-chloro-4-hydroxy-5-cryptomaterial (2.64 g) was dissolved in N,N-dimethylformamide (15 ml) was added to a solution of potassium carbonate (3,60 g) and dimethylsiloxy acid (1,64 ml) and then stirred the mixture at room temperature for 1 hour. To the reaction solution was added water, and extracted the reaction mixture with ethyl acetate. The organic layer was washed with water and saturated saline, and then sushiland anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 9/1) to obtain the specified title compound (1.70 g) as a colorless oily substance.

(h) Synthesis of 3-chloro-4-methoxy-5-cryptomaterial acid

Methyl-3-chloro-4-methoxy-5-cryptomaterial (1.70 g) was dissolved in tetrahydrofuran (12 ml) and water (6 ml) was added to a solution of the monohydrate of lithium hydroxide (1,00 g), and the mixture was stirred at room temperature for 2 hours. The solvent is kept under reduced pressure, was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (1.51 g) as a colourless crystalline substance.

1H-NMR δ (CDCl3): Android 4.04 (3H, s), to 7.93 (1H, s), 8,10 (1H, d, J=1.9 Hz). MS (m/z): 269 (M-H)-.

(i) Synthesis of 3-chloro-4-methoxy-5-cryptomaterial

To 3-chloro-4-methoxy-5-cryptomaterial acid (401 mg) was added toluene (4 ml), N,N-dimethylformamide (1 drop) and thionyl chloride (0,13 ml) and then stirred the mixture at 60°C for 13 hours. The solvent drove in the conditions of reduced pressure, and then spent azeotropic distillation with toluene to obtain specified in the title compound (436 mg) as a brown oily substance.

(j) Synthesis of 3-(3-chloro-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole

2,3-Dihydro-1,3-benzothiazole synthesized from 2-aminobenzamide (278 mg) and 37% formalin (of 0.18 ml) in the same way as described in example 1 was dissolved in dichloromethane (6.5 ml) was added to a solution of diisopropylethylamine (0,50 ml) and 3-chloro-4-methoxy-5-cryptomaterial (436 mg) and then stirred the mixture at room temperature for 1 hour. The solvent is kept under reduced pressure, adding water and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (k).

(k) Synthesis of 3-(3-chloro-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-trifloromethyl)-2,3-dihydro-1,3-benzothiazole was dissolved in chloroform (10 ml) was added to a solution of 70% meta-chloroperbenzoic acid (to 2.57 g) and then stirred the mixture at room temperature for 22 hours. Added 1H hydroxide on the matter, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 4/1) to obtain the specified title compound (420 mg) as a colorless oily substance.

(l) Synthesis of 3-(3-chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-methoxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (420 mg) was dissolved in N,N-dimethylformamide (5 ml) was added to a solution of lithium chloride (421 mg) and then stirred the mixture at 120°C for 14 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/ethyl acetate to obtain specified in the title compound (182 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): are 5.36 (2H, s), 7,44 (1H, DD, J=7,6, 7,0 Hz), to 7.67 (1H, user.C) 7,76 (1H, DD, J=8,1, 7,6 Hz), 7,82 (1H, q, j =2.2 Hz), to $ 7.91 (1H, d, J=7,0 Hz), 8,03 (1H, d, J=8.1 Hz), to 11.52 (1H, user.C). MS (m/z): 406 (M-H)-.

Example 38: 3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

37% formalin (0,22 ml) was diluted with water (6 ml) was added to a solution of diethyl ether (6 ml), triethylamine (0,37 ml) hydrochloride and 2-amino-4-trifloromethyl (611 mg) and then stirred the mixture at room temperature for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with saturated saline and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and used the remainder for the synthesis of (b).

(b) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

5-Trifluoromethyl-2,3-dihydro-1,3-benzothiazole was dissolved in dichloromethane (5 ml), was added to the solution triethylamine (of 0.56 ml) and 3-cyano-4-methoxy-5-cryptomathematical (839 mg) and then stirred the mixture at room temperature for 1.5 hours. Was added water and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sulfate on the model. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 8/1) to obtain the specified title compound (479 mg) as a pale yellow amorphous product.

(c) Synthesis of 3-(3-cyano-4-methoxy-5-trifloromethyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (520 mg) was dissolved in chloroform (8 ml), at 0°C was added to a solution of 70% meta-chloroperbenzoic acid (2.37 g). After stirring the mixture at room temperature for 40 hours was added 1N sodium hydroxide, precipitated precipitated crystalline substance was then collected by filtration and washed with 1N sodium hydroxide and water. Then the filtrate was extracted with ethyl acetate, the organic layer washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained product was combined with a crystalline substance, collected by filtration, and then washed with a mixture of a mixture of n-hexane and ethyl acetate in a ratio of 1/1 with obtaining specified in the title compound (459 mg) as a colourless crystalline substance.

(d) Synthesis of 3-(3-cyano-4-hydroxy-5-reformational)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

3-(3-Cyano-4-methoxy-5-trifloromethyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (459 mg) was dissolved in N,N-dimethylformamide (4.5 ml) was added to a solution of lithium chloride (169 mg) and then stirred the mixture at 70°C for 1 hour. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (411 mg) as a colourless crystalline substance.

1H-NMR δ (DMSO-d6): vs. 5.47 (2H, s), 7,81 (1H, d, J=8.1 Hz), 8,10 (1H, s), 8,21 (1H, d, J=8.1 Hz), of 8.28 (1H, s), 8,43 (1H, s). MS (m/z): 449 (M-H)-.

Example 39: 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

(a) Synthesis of 3-(3,5-dichloro-4-methoxybenzoyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

Hydrochloride of 2-amino-4-trifloromethyl (502 mg) and 5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole synthesized from 37% formalin (of 0.18 ml) and triethylamine (0,30 ml) in the same way as described in example 38 was dissolved in dichloromethane (5 ml), was added to the solution triethylamine (0,30 ml) and 3,5-dichloro-4-methoxybenzophenone (354 mg, and then the mixture was stirred at room temperature for 2 hours. Was added water and was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and purified the resulting residue by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 8/1) to obtain the specified title compound (223 mg) as a colorless oily substance.

(b) Synthesis of 3-(3,5-dichloro-4-methoxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole

3-(3,5-Dichloro-4-methoxybenzoyl)-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (223 mg) was dissolved in chloroform (5 ml), at 0°C was added to a solution of 70% meta-chloroperbenzoic acid (805 mg). After stirring the mixture at room temperature for 20 hours was added 1N sodium hydroxide, and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and saturated saline, and then dried over anhydrous sodium sulfate. The solvent drove under reduced pressure to obtain specified in the title compound (211 mg) as pale-yellow crystalline substance.

(c) Synthesis of 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-5-cryptomate the-2,3-dihydro-1,3-benzothiazole

3-(3,5-Dichloro-4-methoxybenzoyl)-1,1-dioxo-5-trifluoromethyl-2,3-dihydro-1,3-benzothiazole (209 mg) was dissolved in N,N-dimethylformamide (2 ml) was added to a solution of lithium chloride (106 mg) and then stirred the mixture at 120°C for 2 hours. To the resulting reaction solution was added 1N hydrochloric acid and then was extracted with a mixture of ethyl acetate. The organic layer is washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, and vykristallizovyvalas the resulting residue from n-hexane/chloroform to obtain specified in the title compound (167 mg) as a pale yellow crystalline substance.

1H-NMR δ (DMSO-d6): 5,46 (2H, s), 7,76 (2H, s), 7,80 (1H, d, J=8.1 Hz), to 8.20 (1H, d, J=8.1 Hz), to 8.41 (1H, s) to 11.11 (1H, user.C). MS (m/z): 424 (M-H)-, 426 (M+2-H)-.

Example 40: 3-(3-chloro-4-hydroxy-5-trifloromethyl)-5 or 6-hydroxy-1,1-dioxo-2,3-dihydro-1,3-benzothiazole

3-(3-Chloro-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (941 mg) obtained in example 18, suspended in a 15.7 ml of 0.5% solution of methylcellulose (0.5% of MC), has introduced a suspension of eight male rats Wistar/ST in the amount of 1.8 ml each, and immediately after the introduction of the collected urine for 6.5 hours. Received urine (28 ml) was acidified by adding hydrochloric acid and then was extracted with et is lacerata. The obtained organic layer was washed with saline, and then dried over anhydrous sodium sulfate. The solvent is kept under reduced pressure, the obtained residue was purified by the method of column chromatography on silica gel (n-hexane/ethyl acetate = 1/1), and then vykristallizovyvalas from n-hexane/ethyl acetate to obtain specified in the title compound (36 mg).

1H-NMR δ (DMSO-d6): of 5.34 (2H, s), to 7.09 (1H, d, J=2.6 Hz), to 7.15 (1H, DD, J=9,0, 2.6 Hz), 7,82 (1H, d, J=1.9 Hz), of 7.90 (1H, d, J=9.0 Hz), 8,02 (1H, d, J=1.9 Hz), 10,34 (1H, s), 11,38 (1H, user.C). MS (m/z): 406 (M-H)-, 408 (M+2-H)-.

In the following table 1 lists the values of R1, R2, R3and X corresponding to the above examples, with reference to the compound represented by General formula (1).

Table 1
ExamplesR1R2R3X
Example 1ClCl-SO2
Example 2ClCl- S
Example 3ClCl-SO
Example 4CF3CN-SO2
Example 5CF3CN-S
Example 6CF3CN-SO
Example 7ClCN-SO2
Example 8ClCN-S
Example 9tBuCN-SO2
Example 10iPrCN-SO2
Example 11cBuCN-SO2
Example 12EtCN-SO2
Example 13cPrCN-SO2
Example 14C≡CHCN-SO2
Example 15S-MeCN-SO2
Example 16SO2MeCN-SO2
Example 17SOMeCN-SO2
Example 18CF3Cl-SO2
Example 19FCl-SO2
Example 20FF-SO2
Example 21S-MeCl-SO2
Example 22SO2MeCl-SO2
Example 23SOMeCl-SO2
Example 24SO2MeCF3-SO2
Example 25SO2MetBu-SO2
Example 26CF3OMe2-S 2
Example 27CF3CONMe-SO2
Example 28CF3--SO2
Example 29OMeCl-SO2
Example 30CF3-SO2
Example 31CF3-SO2
Example 32CF3-SO2
Example 33CF3-SO2
Example 34S-EtCN-SO2
Example 35S-iPrCN-SO2
Example 36OCF3CN-SO2
Example 37OCF3Cl-SO2
Example 38CF3CN5-CF3SO2
Example 39ClCl5-CF3SO2
Example 40CF3Cl5 - or 6-OHSO2

Test example 1: Uricosuric effect in the model with pyrazinamide for rats

7-8-week old male rats Wistar/ST (4 rats the group), not receiving food for 16 hours, oral pyrazinamide was administered, suspended in 0.5% solution of methylcellulose (0.5% of MS), at a dose of 400 mg/kg After 30 minutes of oral was administered the test substance suspended in 0.5% MC, at a dose of 30 mg/kg, and collected urine within 1 hour after 2-3 hours after injection. At the beginning of the urine collection and after collection of urine in rats force caused urination by pressing on the abdomen of the rat. Using the set of measured concentration of uric acid and creatinine in the urine, and used the ratio of the concentration of uric acid to creatinine concentration as an indicator of uricosuric action. The effect of each test substance were expressed as percentage of the control.

Test example 2: the Concentration of unchanged compound in the urine of rats

Two male rats Wistar/ST and had no food for 16 hours, orally was administered the test substance suspended in 0.5% MC, at a dose of 3 mg/kg Immediately after the introduction of the collected urine for 4 hours. After collection of urine remaining in the bladder urine was fully excretionary by pressing on the abdomen of the rat. The concentration of unchanged compound in the urine was measured by the method of HPLC and represented as the molar concentration (μm).

The results of the above test are presented below in table 2.

Table 2
ExamplesUricosuric action (control = 100)The concentration of unchanged compound in the urine (µm)
Example 11699,8
Example 420151,8
Example 51361,1
Example 7178125
Example 1218715,8
Example 13172a 3.9
Example 14164119
Example 1520468,6
Example 182021
Example 1912955,2
P the emer 21 1201,9
Example 2714630,6
Example 3420823,5
Example 351401,5
Example 3818016,4
Benzbromarone1140
Probenecid111
171 (100 mg/kg)
0

As described above, a new derivative of phenol represented by the General formula (1), its pharmaceutically acceptable salt and hydrate and MES, characterized by uricosuric effect, equal to 20%-108%, and also have excellent efficiency compared to existing drug, which is characterized uricosuric effect, equal to 11%-14%. A new derivative of phenol represented by the General formula (1), its pharmaceutically acceptable salt and hydrate and MES, an excellent the fact that in comparison with an existing drug for which the excretion of the unchanged compound in urine is not detected, neizmenenennom of the present invention showing the efficacy of a drug, as the unchanged compound clearly excreted in the urine. Accordingly, a new derivative of phenol represented by the General formula (1), its pharmaceutically acceptable salt and hydrate and MES, are characterized by a high concentration of unchanged compound in the urine, and also have excellent uricosuric effect and are extremely safe, and thus applicable as a drug to speed up the excretion of uric acid; medications to reduce uric acid and/or concentration of uric acid in the blood and/or tissue; medicines for use in the prophylaxis and/or treatment of disease, associated with uric acid in the blood and/or tissue; medicines for use in the prophylaxis and/or treatment of hyperuricemia; and medicines for use in the prophylaxis and/or treatment of diseases associated with hyperuricemia and/or diseases associated with hyperuricemia.

Example composition (pill)
Connection example 15 mg
Lactose70 mg
Cook Rosny starch 21 mg
Hydroxypropylcellulose3 mg
Magnesium stearate1 mg
Total100 mg

After weighing the above components in a ratio corresponding to the composition, to produce a powder for pressing by wet granulation. To obtain tablets this powder is pressed so that each tablet contained 5 mg of the compound of example 1.

Compounds of the present invention are characterized by a high concentration of unchanged compound in the urine, and also have excellent uricosuric effect and are excellent in terms of safety, and therefore applicable as a drug to speed up the excretion of uric acid; medications to reduce uric acid and/or concentration of uric acid in the blood and/or tissue; medicines for use in the prevention and/or treatment of a disease associated with uric acid in the blood and/or tissue; medicines for use in the prophylaxis and/or treatment of hyperuricemia; and medicines for use in the prophylaxis and/or treatment of diseases associated with hyperuricemia and/or disease, accompanied by hyperuricemia.

1. A new derivative of phenol represented by the following General formula (1):

where R1represents a C1-C6 alkyl group, C1-C6 alkylamino group, C1-C6 halogenating group, C1-C6 alkylsulfonyl group, or halogen atom,
R2represents a cyano group or a halogen atom,
R3represents a hydrogen atom, and
X represents-S(=O)2,
characterized in that the compound is chosen from the group consisting of:
3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-4-hydroxy-5-trifloromethyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-chloro-5-cyano-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-5-ethyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-5-cyclopropyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-5-ethinyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-4-hydroxy-5-methylsulfonylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
3-(3-cyano-5-ethylsulfanyl-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole,
or its pharmaceutically acceptable salt.

2. The drug is characterized by a high concentration of unchanged compound in the urine and possess uricosuric de is predetermined, containing as active ingredient the compound under item 1 or its pharmaceutically acceptable salt.

3. Drug under item 2, which is represented in the form of pharmaceutical compositions, containing one, two or more additives for the preparation of composition.

4. Drug under item 2 or 3 to accelerate the excretion of uric acid.

5. Drug under item 2 or 3 to reduce the amount of uric acid and/or concentration of uric acid in the blood and/or tissue.

6. Drug under item 2 or 3 for use in the prevention and/or treatment of a disease associated with uric acid in the blood and/or tissue.

7. Drug under item 2 or 3 for use in the prophylaxis and/or treatment of hyperuricemia, diseases associated with hyperuricemia and/or diseases associated with hyperuricemia.

8. Drug under item 2 or 3 for use in the prevention and/or treatment of gout, kidney stones, obesity, hyperlipidemia, dyslipidemia, abnormal glucose tolerance, diabetes mellitus, metabolic syndrome, kidney disease and/or cardiovascular diseases.

9. Drug under item 8, where gout includes as a painful condition of at least one of gouty nodules, gouty arthritis and podagricescoy kidney.

10. Drug under item 8, wherein the cardiovascular disease is a hypertension, a disease of the carotid arteries, arteriosclerosis, thrombosis, endothelial dysfunction, cerebrovascular disease and/or heart disease.

11. Drug under item 2 or 3 for use in the prophylaxis and/or treatment of complications of the disease according to any one of paragraphs.6-10.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of controlling infection of useful plants with phytopathogenic microorganisms or prevention thereof, wherein a compound of formula I or a composition thereof, which contains said compound as an active ingredient, is deposited on plants, on a parts thereof or place where said plants grow, where the compound of formula I is substitutes are as defined in claim 1.

EFFECT: obtaining a compound for controlling infection of useful plants with phytopathogenic microorganisms.

26 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.

EFFECT: compounds act as modulators of gamma-secretase.

31 cl, 14 tbl, 3147 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), where A is C-R1b; R1a, R1b, R1c, R1d, R1e, R2, R3, R4, R5 and n are as described in claim 1 of the invention, as well as pharmaceutically acceptable salts thereof. Described also is a pharmaceutical composition having activity as glucocorticoid receptor modulators.

EFFECT: novel compounds are obtained and described, which are glucocorticoid receptor antagonists and useful for treating and/or preventing diseases such as diabetes, dyslipidaemia, obesity, hyptension, cardiovascular diseases, adrenal gland malfunction or depression.

24 cl, 210 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I): X denotes a single bond or a binding group selected from -CO, -SO2-, -CS- or -CH2-; Y denotes a single bond or a divalent binding group obtained from a cyclic structure selected from benzene, pyridine, pyrimidine, pyrazole, imidazole, thiazole, thiophene, quinoline, benzoimidazole, benzothiazole, benzopyrazole, naphthalene and benzothiophene; X and Y are simultaneously single bonds; Z denotes a hydrogen atom or a substitute selected from a group A; m equals 1 or 2; n equals 0-3; in group A and group B, R, R' and R" can, respectively and independently, be identical or different and denote a hydrogen atom or -C1-6-alkyl; said -C1-6-alkyl can be substituted with a group selected from -OH, -O(C1-6-alkyl),-CONH2, -CONH(C1-6-alkyl), -CON(C1-6-alkyl)2, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2); Sus denotes a C3-C7 saturated or a C5-C10 unsaturated hydrocarbon ring or a nitrogen-containing C3-C7 heterocyclic ring containing 1-4 nitrogen atoms or containing an additional O, S atom; said C1-6 alkylene in groups A and B can be substituted in positions 1-3 with a -N(C1-6- alkyl)2 group, values of radicals R1, A1, T, B and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, a PI3K inhibitor and a medicinal agent having PI3K inhibitor properties against a proliferative diseases such as a malignant tumour.

EFFECT: high efficiency of using the compounds.

21 cl, 645 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pharmaceuticals and medicine and pharmaceutically acceptable derivatives of 2-aminobenzothiazole of general formula 1.

EFFECT: high anti-hypoxic activity and high effectiveness of treatment.

7 cl, 3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

EFFECT: obtaining compounds and a composition which can inhibit phosphatase cdc25, particularly phosphatase cdc25-C and can be particularly used for treating cancer.

12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to method of obtaining organic salts, which contain anions of bis(perfluoroalkyl)phosphinate and can be applied in organic synthesis. Difference of claimed method lies in the fact that it includes carrying out reaction of tris(perfluoroalkyl)phosphinoxide with alcohol and organic base, stronger than alcohol.

EFFECT: elaboration of new method of obtaining organic salts with properties of ionic liquids.

11 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: present invention concerns the salts containing bis(trifluoromethyl)imide anions and saturated, partially or completely unsaturated heterocyclic cations, method of production and application thereof as ionic liquids.

EFFECT: production of new salts to be used as ionic liquids.

19 cl, 5 ex

FIELD: pharmacology.

SUBSTANCE: refers to application of compounds of common formula 1 for production of medicinal agent for inhibition of cdc25-phosphatases and/or CD45- phosphatase, medicinal agent for inhibition of cdc25-phosphatases or CD45- phosphatase, pharmaceutical formulations for inhibition of cdc25-phosphatases or CD45-phosphatase; invention also refers to compounds of formula 1 and provides high-degree inhibition of cdc25-phosphatases and/or CD45- phosphatase.

EFFECT: high degree of inhibition.

22 cl, 1 dwg, 3 tbl, 131 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of cyclohexan-1,4-diamine of the general formula (I): possessing binding property with ORLI receptors and showing homology to opioid μ-, κ- and δ-receptors. Compounds can be used for preparing drugs possessing analgesic effect. In the formula (I) R1 and R2 mean independently of one another (C1-C8)-alkyl, or residues R1 and R2 form in common a ring and mean -CH2-CH2NR6CH2CH2 or -(CH2)3-6 wherein R means (C1-C8)-alkyl; R3 means phenyl, naphthyl or 5-membered sulfur-containing heteroaryl wherein each of them is unsubstituted or monosubstituted with halogen atom, or unsubstituted phenyl added through saturated unsubstituted (C1-C4)-alkyl group; R4 means hydrogen atom (H), saturated (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen (O) or sulfur (S) atom; R means H or (C1-C8)-alkyl either unsubstituted phenyl or phenyl substituted with halogen atom; R5 means (C3-C8)-cycloalkyl, adamantyl, aryl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur and condensed with one or two benzene rings and wherein each of them is unsubstituted or monosubstituted with a substitute chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy or benzyloxy; or -CHR11R12, -CHR11-CH2R12, -CHR11-CH2-CH2R12, -CHR11-CH2-CH2-CH2R12, -C(Y)R12 wherein Y means O or H2; R11 means H, saturated, linear or branched (C1-C7)-alkyl, saturated or unsaturated, linear or branched, mono- or multisubstituted either unsubstituted -C(O)O-(C1-C6)-alkyl; R12 means phenyl or 5-membered heteroaryl comprising 1-3 heteroatoms chosen from nitrogen, oxygen or sulfur condensed with one or two benzene rings each of them is unsubstituted or mono- or multisubstituted and wherein in values R11 and R12 substituted of alkyl, phenyl or heteroaryl are chosen from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl or benzyloxy; or R4 and R5 form in common 5-membered nitrogen-containing heterocycle that represents unsaturated, monosubstituted lower alkoxycarbonyl-lower alkyl, halogen atom, or it is unsubstituted and condensed with benzene ring under condition that if R means substituted or unsubstituted phenyl and at least one R1 or R2 means (C1-C8)-alkyl then R4 can't mean alkyl, and R3 and R5 can't form in common heterocycle, or if R3 means unsubstituted phenyl and R1 and R2 mean in common -(CH2)5 then R4 means H or (C1-C8)-alkyl; Y means O, and R5 doesn't mean (C1-C6)-alkyl. Also, invention relates to a method for synthesis of compounds of the formula (I) and a drug.

EFFECT: valuable medicinal properties of compounds.

40 cl, 1 tbl, 94 ex

FIELD: medicine.

SUBSTANCE: with the underlying conventional drug therapy, the patient is exposed to millimetre-wave electromagnetic emission at the molecular spectrum frequencies of oxygen emission and absorption spectra with the exposure localised within the xiphoid appendix. The exposure time is 3 minutes continuously within one session. The output emissive power is 500 mcW at the power density on the skin surface of 17.4 mcW/cm2. A distance of the exposure point and an object is specified to be equal to 4 cm. The therapeutic course makes 7-10 sessions, one session a day.

EFFECT: higher therapeutic effectiveness in patients with angina or arterial hypertension ensured by the antihypertensive and antianginal effect resulted from the specified mode of the terahertz exposure.

2 ex

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