Condensed derived thiazole or its pharmaceutically acceptable salt, pharmaceutical composition active agonist 5-ht*003 - receptor based on it

 

(57) Abstract:

The proposed condensed derived thiazole, useful as 5-HT3receptor agonist represented by the following General formula (I)

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or its pharmaceutically acceptable salt, and a pharmaceutical composition, where R: hydrogen atom, halogen atom, hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, nitro group, amino group, cyano group or a protected hydroxyl group, A phenyl ring or a naphthalene ring, L1and L2one is a direct bond and the other a linear or branched lower alkalinous group, which may include terminating an oxygen atom or a sulfur, an oxygen atom or a sulfur atom or a lower alkynylamino group, L: a direct bond or linear or branched lower Allenova group. Im: a group represented by the formula:

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where R1, R2and R3: the same or different from one another, each represent a hydrogen atom or a lower alkyl group; R4, R5and R6: the same or different from one another, each represent a hydrogen atom or a lower Alky is from thiazole, useful as a pharmaceutical agent, particularly as an agonist of 5-HT3receptors its pharmaceutically acceptable salt, method thereof and pharmaceutical compositions comprising this compound as an active ingredient.

The compound of the invention acts as a potent and selective agonist of neuronal serotonin receptor (5-HT), located in the primary afferent nerve nervous system abdominal or Central nervous system. This type of receptor is considered at present as 5-HT3the receptor. Connection performs its function through the release of acetylcholine from efferent nerve endings in the digestive tract. It is known that stimulation of the acetylcholine receptor in the digestive tracts accelerates contractility of the gastrointestinal tract and improves functional recovery. [Goonman and Gilman's, the Pharmacological Basis of Therapentics 8th edition, p.125, (1990), Pergamon Press]

It is also known that 5-HT3the receptor is present in presinapticheskoy area of the Central nervous system and suppresses neural activity during his irritation [J. Neurosoi. 11, 1881 (1991)

As a result, it is believed that 5-HT3receptor ageusia selective agonistic activity to the 5-HT3receptor, applicants invention said that thiazole derivatives disclosed in WO 92/07849 have a selective 5-HT3receptor agonistic activity.

The inventors have continued further studies on agonistic activities relative to 5-HT3receptors, which resulted in the implementation of the present invention and found that 2-(imidazolyl)alkylen-condensed diazopropane shows excellent 5-HT3receptor agonistic activity, which was the result of the synthesis of compounds with 5-HT3receptor agonistic activity with regard to the contractile effect of 5-HT mediated through 5-HT3the receptor on the isolated colon of the Guinea pig as a marker, independent of reflex Bezold-Jarisch [A. S. Paintal et al. Physiol. Rev. 53, 159(1973)] which is commonly used as a marker of 5-HT3receptor agonistic activity.

Although 2-aminobenzothiazole derivative having anti-ulcer activity, disclosed in JP-A-62-252780 (the term "JP-A" used here means "non-examination of the patent application of Japan"), and 2-amino condensed derived thiazole having muscarin prescriptions is La, the compound of this invention is a new compound and its structure and activity is completely different from the structure and activity of the above compounds.

Condensed derived thiazole represented by the General formula (I) or its pharmaceutically acceptable salt is characterized by the fact that it has a high affinity for 5-HT3the receptor causes the contractile effects in the isolated colon of the Guinea pig, used as a marker of 5-HT3receptor agonistic activity.

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The symbols in the formula above mean

R: hydrogen atom, halogen atom, hydroxyl group, lower alkoxy group, carboxy group, lower alkoxy-carbonyl group, nitro group, amino group, cyano group or a protected hydroxyl group;

A: phenyl ring or a naphthalene ring;

L1and L2one is a direct bond and the other is

a) linear or branched lower alkylene group which may contain a terminating atom of oxygen or sulfur,

b) an oxygen atom or a sulfur atom, or

c) lower alkalinous group;

L: a direct bond or linear or razvetvlenno> and R3the same or different from one another, each represent a hydrogen atom or a lower alkyl group;

R4, R5and R6the same or different from one another, each represent a hydrogen atom or a lower alkyl group.

The purpose of the invention, the receiving condensed derived thiazole represented by the above General formula (I) or its pharmaceutically acceptable salt.

Another objective of the invention to provide a pharmaceutical composition, which comprises the condensed derived thiazole (I) above, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

Another aim of the invention is to provide a method of producing the above derivative (I) or its pharmaceutically acceptable salt.

The compounds of this invention are described below.

Unless otherwise indicated, the term "lower" in the definition of the General formula of this specification means a linear or branched carbon chain having 1 to 6 carbon atoms.

In the illustrative examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-b is isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl etc.

Of these groups, preferred C1-C4alkyl group, especially a C1-C3the alkyl group.

Illustrative examples of "lower alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), isopentylamine, tert-pentyloxy, neopentylene, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1 ethylpropoxy, hexyloxy and the like, of which the preferred C1-C4alkoxy group, especially a C1-C2alkoxy group.

Illustrative examples of "lower alkoxycarbonyl group" include (C1-C6alkoxy) carbonyl group, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, isopentylamine, neopentylglycol, tert-pentyloxybenzoyl, hexyloxymethyl, etc. of which predmosti">

Illustrative examples of the "linear or branched lower akilagpa", denoted by L include methylene, ethylene, METROTILE, trimethylene, 1-methylation, 2-mutilation, tetramethylene, 1-metallisation, 2-metallisation, 3-metallisation, 1-ethylethylene, 2-ethylethylene, 1,2-dimethylethylene, propylethylene, pentamethylene, 1-methyltyramine, 2-methyltyramine, 3-methyltyramine, 4-methyltyramine, 1-ethyltryptamine, 2-ethyltryptamine, 3-ethyltryptamine, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene, 1-methylpentylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 5-methylpentanediol, 1,1-dimethyltrimethylene, 4,4-dimethyltrimethylene, etc., of which preferred are linear or branched C1-C4alkylene group, especially, linear or branched C1-C3alkylen group.

"Linear or branched lower alkylene group which may contain a terminating atom of oxygen or sulfur represented by any one of the L1and L2includes "lower alkylene group, which contains a terminating atom of oxygen or sulfur and low alkylen group", and examples of the lower alkylene groups include pre-Christ. 3 alkylene groups that contain a terminating atom of oxygen or sulfur. Also illustrative examples of lower alkylene group, which contains a terminating atom of oxygen or sulfur, include all groups represented by the formula-L3-Y-L4in which each of the L3and L4is a direct bond or linear or branched C1-C6alkylene group, L3and L4contain from 1 to 6 carbon atoms in total, and Y is oxygen atom or sulfur), particularly preferred examples include oxymethylene group (-O-CH2and metalinox group (-CH2-O-), dimetilan group (-S-CH2-), mutilatio group (-CH2S), 1-extremeties group (-O-CH2-CH2- the item substitution here and hereinafter), 2-extremeties group (-CH2-O-CH2), 3-extremeties group (-CH2CH2-O-0, 2-methyl-1-oxyethylene group, 1-methyl-2-oxyethylene group 1-tetramethylene group (-S-CH2CH2-), 2-tetramethylene group (-CH-S-CH0, 3-tetramethylene group 9-CH2CH2-S-), 2-methyl-1-tietjen group and 1-methyl-2-tietjen group

Illustrative examples of "lower albaniles group" represented by any one of the L1and L2, including the 1-methylvinyl, 2-methylvinyl, 1-butylen, 2-butylen, 3-butylen, 1,3-butadienyl, 1-methylpropenyl, 2-methylpropene, 3-methylpropenyl, 1-methyl-2-propanole, 2-methyl-2-propanole, 3-methyl-2-propanole, 1-ethylvinyl, 2-ethylvinyl, 1-propylaniline, 2-propylaniline, 1-isopropylaniline, 2-isopropylaniline, etc. of these preferred groups having C2-C4albaniles group as alkanolamines chain that contains a loop, especially with C2albaniles group as alkanolamines chain that contains a loop.

Illustrative examples of halogen atoms include fluorine atom, chlorine atom, bromine atom and iodine atom.

Illustrative examples of the protective group for the hydroxyl group" include benzyl, tert-butyl, acetyl, triptorelin, benzoyl, benzyloxycarbonyl etc.

The compound (I) of the invention forms a salt accession acid. It forms a salt with a base, in some cases, depending on the type of its structure.

Pharmaceutically acceptable salts of compounds (I) are also included in this invention, and illustrative examples of these salts include acid additive salt accession with inorganic acids such as hydrochloric acid, sulphuric acid is IP, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, coal, methansulfonate, econsultancy, aspartic and glutamic etc., salts with inorganic bases, such as salts of potassium, sodium, magnesium, calcium and the like, or with organic bases such as trimethylamine, triethylamine, cyclohexylamine, monoethanolamine, diethanolamine, triethanolamine, arginine, lysine, etc., and ammonium salt.

Due to the presence of imidazole rings for compounds of the invention are 1H and 3H, the tautomers. Also, depending on the type of group connection in some cases may contain asymmetric carbon atom. Each individual isomer, isolated from a mixture of different isomers or their mixtures are also included in the present invention.

In addition, the compound of the invention is isolated in some cases in the form of its hydrate, solvated substance or polymorphic form, and these substances are also included in the invention.

Particularly preferred examples of compounds of the invention are those examples in which the cycle is phenyl cycle, L1represents a direct link, and L2is a linear or branched LASS="ptx2">

(1) 2-(4-Imidazolidinyl)-8H-indeno[1,2-d]thiazole or its pharmaceutically acceptable salt.

(2) 2-(4-Imidazolidinyl)-4,5-dihydronaphtho[1,2-d]thiazole or its pharmaceutically acceptable salt.

Way to obtain is the following.

The compound (I) of the invention and its pharmaceutically acceptable salts can be obtained by application of various methods of synthesis using characteristics of their basic chemical structure or Deputy. From the point of view of manufacturing technology in some cases is effective protection of the amino group (including the nitrogen of the imidazole), carboxy groups and hydroxy groups of the compounds of the invention suitable protective groups, namely functional groups, which can easily be re-converted into amino group (including the nitrogen of the imidazole), carboxy group and hydroxyl group, respectively. Examples of such protective groups include groups reported by Greene and Wuts in Protective Groups in Organic Synthesis 2nd edition, and these groups may not be used depending on the reaction conditions. In addition to these protective groups, other functional groups, which can easily be converted into amino group, carboxy group and a hydroxyl group, Sposoby obtain the compound (I) of the invention and its salts.

The method of obtaining I (cyclization reaction)

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In reaction scheme A, L1, L2L and Imsuch as defined above, R7is the same group as R, which may have a protective group. Lais a linear or branched lower alkylene group which may contain a terminating atom of oxygen or sulfur; b) an oxygen atom or a sulfur atom, or (c) the lowest alkylene group and X is a halogen atom.

The compound (I) of the invention can be obtained by the reaction of a derivative of halogenation represented by the General formula (IIa) or (IIb) with thioamides derivative represented by the General formula (III) or its salt to implement cyclization, and then, if necessary, the protective group can be removed.

Examples of the halogen atom denoted by X include an iodine atom, a bromine atom, a chlorine atom, etc.

It is advisable to perform the reaction in an inert organic solvent such as alcohol solvents such as isopropanol, methanol, ethanol or etc.) or an aqueous alcohol solvent at room temperature or with heating, preferably by heating to the boiling point, using equimolar quantities of (IIa) or (IIb) and (II the spine from the type of protective group; for example, the catalytic reaction can accordingly be used when the protective group for amino group is substituted or unsubstituted, benzyloxycarbonyl group or so on, or in some cases can be treated with acid treatment, for example, Hydrobromic acid /acetic acid, Hydrobromic /triperoxonane, hydrofluoric acid, or, etc., In the case of other protective groups of the urethane type, such as tert-butoxycarbonyl group, etc. to unprotect acid treatment Hydrobromic acid/acetic acid, triperoxonane, hydrochloric, muriatic/acetic, hydrochloric acid/dioxane or etc.

As for removing the protective group for the carboxy group, methylgroup and telgraph can be easily removed by saponification, and benzerga and various kinds of substituted bosilgrad can be removed by catalytic regeneration or saponification, tert-butyl group can be removed by the above-mentioned acid treatment and trimethylsilyl group can be removed by contact with water.

As for the protective group for hydroxy group, most of them can be removed by treatment with sodium/liquid of Madalena catalytic recovery and acyl protective groups such as a benzoyl group, acetyl group, etc., can be removed by hydrolysis in the presence of acid or alkali.

This processing can be performed in the usual way.

The method of obtaining 2 (C-alkylation or N-alkylation of imidazole ring)

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(In the reaction formula, R, R7, A, L1, L2, L, X and Imsuch as previously defined, R1bis a hydrogen atom, a lower alkyl group or a protective group for the imidazole nitrogen, and R2b, R3band R4bthe same or different from each other and each represents a hydrogen atom or a lower alkyl group, provided that at least one of R1b, R2b, R3bor R4bis a hydrogen atom).

The compound (I) of the invention and its salt can be obtained by the interaction between halogenoalkane-substituted condensed thiazole derivative represented by the General formula (IV), which may have a protective group to the imidazole derivative represented by the General formula (V), which may have a protective group for the imidazole nitrogen atom, and then removing the protective groups, when necessary.

It is advisable to perform the reaction using equimolar is from low to high or when heated to the boiling temperature in inert solvents, such as dimethylformamide, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, methanolate, methylene chloride, dichloroethane, chloroform or the like, optionally in the presence of a base such as pyridine, picoline, dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, sodium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or the like.

Especially in the case of the reaction of C-alkylation is possible to conduct the reaction of the compound (IV) with an alkali metal salt of compound (V) at temperatures in the range from a low temperature, for example -100oC to room temperature in an inert aprotic solvent such as diethyl ether, tetrahydrofuran, dioxane or the like, if necessary with the addition of hexamethylphosphoramide, hexamethylphosphoric triamide, tetramethylethylenediamine or the like and using the correct amount of base, such as n-utility, second-utility, t-utility, lithium diisopropylamide, t-piperonyl potassium, sodium hydride or the like.

Removing the protective groups can be easily produced in the same way as in the case of a JV is benzhydryl group is used as a protective group for the imidazole nitrogen. Hydrochloric acid, acetic acid, triperoxonane acid or their mixture can be used as the acid, and the catalytic reduction can be carried out in the presence of a catalyst such as palladium on carbon, palladium oxide, palladium hydroxide, platinum, platinum oxide, Nickel, Rhenium, or etc.

The method of obtaining 3 (mutual transformation of target compounds)

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(In the reaction formula, L1, L2L and Imsuch as defined above).

The compound of the invention in which R represents an amino group, i.e. the compound (I) can be obtained by reduction of the nitro compound (Ia).

This reaction can be performed with conventional methods for recovering aromatic nitro compounds, in particular the way in which the catalytic hydrogenation is carried out in an inert solvent such as an alcoholic solvent (e.g. methanol, ethanol, isopropanol or similar) or an aqueous alcohol in the presence of a catalyst, such as Raney Nickel, palladium on charcoal, platinum, platinum black or the like.

The compound (I) prepared in this way is isolated and purified in the form of free connection of the appropriate salt of compound (I) can also be obtained, if you expose the connection customary salt formation reaction.

Isolation and purification of the compounds is performed by conventional chemical methods such as extraction, fractional crystallization, recrystallization, various chromatography fractionated etc.

The tautomers can be separated using differences in physicochemical properties between the isomers.

Racemic compound can be converted to pure stereochemical isomer by using the appropriate starting material or in accordance with the usual method of separation (for example, the way in which the connection becomes diastereomer salt using conventional optically active acid (tartaric acid, etc.,) and then subjected to optical separation). In addition, diastereomers the mixture can be separated in the usual way, for example fractionated crystallization, chromatography or the like.

Industrial applicability.

The compound of the invention exhibits excellent 5-HT3receptor agonistic activity, especially in terms of its influence on the contractile activity highlighted colon of the Guinea pig. Below Elno 5-HT3receptors.

For cooking strips of about 20 mm was cut out of the distal large intestine in male Hartley Guinea pigs (500 to 800 g).

Each strip longitudinally hung in the tube Magnus and the response reduction effect was measured isometrically.

5-HT (5-oxitriptan) causes a dose-dependent reduction in the range of concentrations from 0.1 to 30 μm and showed a maximal response at a concentration of from 10 to 30 μm, the effect of 5-HT mediated through 5-HT3receptor; J. Pharmacol, Exp. Ther. 259, 15-21, 1991).

The activity of each compound is expressed by a relative value in comparison with the activity of 5-HT in each sample.

The maximum response is presented in percent of the maximum response for each connection, the maximum contraction to 5-HT is taken for 100%

The relative performance is shown relative EU50the value for each connection, based on the standard value of (I) the corresponding values for 5-HT (see table.1).

1) Compound of the invention exhibits contractile actions in selected colon of the Guinea pig in a concentration-dependent form at a concentration of 300 μm.

2) Contractile activity and>receptor antagonist described in example 44 JP-A-3-223278.

2) Experiment on receptor binding

The compound of example 1 showed a high affinity for 5-HT3receptor in the experiment on receptor binding. On the basis of obtained results it was concluded that the compound of the present invention is a strong 5-HT3receptor agonist.

A preferred example of the compound is a compound which exhibits the above steps, but barely shows the 5-HT3receptor agonistic activity, when measured using reflex Bezold-Jarisch (S. Paintal et al. Physiol.Rev. 53, 159 (1973)), which is the usual index of 5-HT3receptor agonistic activity.

In this regard, the invention also includes some compounds which are 5-HT3receptor antagonistic activity, and these compounds should be considered as a variant of the embodiment of the invention. These compounds apparently suitable for medical applications disclosed by the present applicants in respect of derivative tetrahydroimidazo, for example, in JP-A-3-223278, such as suppression of vomiting caused cancerstricken means A pain, neuralgia of the trigeminal nerve, the symptoms of anxiety disorders gastrointestinal contractility, peptic ulcers, irritable bowel syndrome (mucous colitis), etc., Compound (I) of the invention or its salt, MES or hydrate show a specific effect on neuronal 5-HT3the receptor is located in the nerve plexus of the muscular layer of the intestine, and are therefore useful in the treatment of gastrointestinal disorders, such as senile, atonic or protagonisti constipation, acute or chronic gastritis, gastric or duodenal ulcer, gastrointestinal neurosis, bathygastry, reflux esophagitis, impaired gastrointestinal contractility caused by diseases such as diabetes and the like, the failure of gastrointestinal function after surgery using usual means, the stagnation in the stomach, dyspepsia, flatulence, etc. It can also be used to treat pancreatic insufficiency, caused by such diseases as the fat absorption failure, etc.

The compound of the invention is also useful in the treatment of some symptoms, such as mental disorder is d, the connection is suitable for use as a medical device. For example, none of the compounds of examples 1 and 3 does not cause serious side effects when it is administered at the dosage of 100 mg/kg intravenous ICR male mice (age 7-8 weeks, 30-40 g, n=5-6).

The compound (I) of the invention and its pharmaceutically acceptable salts and similar substances can be produced in the form of tablets, powders, fine granules, capsules, pills, solutions, injections, suppositories, ointments, plasters, etc. use in the manufacture of commonly used pharmaceutically acceptable carriers, excipients and other additives and are entered pills (including sublingual administration) or parenteral.

Carriers and excipients used for the preparation of drugs, are solid or liquid non-toxic substances for medical use. Their illustrative examples include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, juice, acacia, olive oil, sesame oil, cacao butter, ethylene glycol and other commonly used substances.

Clinical dose of the compound is usually determined by the symptoms body weight, age, sex, etc. for dnevna dose may be divided into 1 or more doses per day.

The best variant embodiment of the invention

The following is an example of the preparation of a pharmaceutical product using the compound of the present invention.

Example composition (tablets).

The composition of the Tablet 20 mg

The compound of the invention 20 mg

Lactose 75

Corn starch 16

Hydroxypropylcellulose 4,5

Calcium carboxymethylcellulose 8,7

Magnesium stearate 0,7

Just 120 mg

Tablet 20 mg

a 100 g portion of the compound is uniformly mixed with 375 g of lactose and 80 g of corn starch, using the apparatus for manufacturing granules coated in the fluidized layer. To this mixture was added 225 g of 10% aqueous spray solution hydroxypropylcellulose order to obtain granules. After drying the granules pass through a 20 mesh. (0.84 mm), mixed with 19 g of calcium carboxymethyl cellulose and 3.5 g of magnesium stearate and then processed into tablets, each weighing 120 mg using a rotary tablet machine with punch 7 mm x 8.4 R.

In the following examples, NMR spectra:

m, multiplet; d, doublet; t, triplet; s, singlet; br broadened signal; dt, double triplet; dd, double doublet.

The following examples are given to further the deposits. The method of obtaining the source materials are listed in the following reference examples.

Reference example 1.

a) 373 mg of sodium hydride (60%) was added to 5 ml of dimethylformamide and the resulting suspension was added dropwise a solution of 1.0 g of 4-cyanopyrimidine in 10 ml of dimethylformamide. After 1 h stirring at room temperature, to the solution was added 1.9 ml (2-Chloromycetin)trimethylsilane and stirred at room temperature for 2 hours the Reaction solution was mixed with water and chloroform and the resulting organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to column chromatography on silica gel, elwira a mixture of hexane-ethyl acetate (1: 1) with 1,128 g of 4-cyanomethyl-1-trimethylsilylimidazole and 0,362 g 5-cyanomethyl-1-trimethylsilylimidazole.

4-Cyanomethyl-1-trimethylsilylamodimethicone

NMR(CDCl3, TMS internal standard) 0,29(2H,t), a 3.50(2H,t), and 3.72(2H, s), a 5.25(2H,s), was 7.08(1H,s), 7,56(1H,s).

5-Cyanomethyl-1-trimethylsilylamodimethicone

The NMR spectrum (CDCl3, TMS internal standard) d 0,93 (2H, t), 3,49(2H, t), 3,81(2H,s), 5,33(2H, s), 7,10(1H, s) 7,58 (1H, s).

b) 0.16 ml methyl IO is (a), the mixture was heated in a sealed ampoule at 60oC within 24 hours After adding to the reaction solution of diethyl ether and removal of the formed above the liquid residue was dried under reduced pressure, obtaining 82 mg of 4-cyanomethyl-3-methyl-1-trimethylsilylimidazole iodide.

NMR spectrum (DMSO-d6, TMS internal standard) d and 0.90(2H, t), 3,62(2H, t), 3,83(2H, s), 4,35(3H,s), to 5.56(2H,s), of 7.90(1H,s), 9,42 (1H,s).

c) 157 mg of 4-cyanomethyl-3-methyl-1-trimethylsilylamodimethicone iodide obtained in the above stage (b), was dissolved in 5 ml of ethanol, mixed with 5 ml of 1N. hydrochloric acid and then heated at 60oC for 6 hours the Reaction solution was mixed with 1H. aqueous solution of sodium hydroxide and diethyl ether and the resulting organic layer was collected, washed with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to chromatography on a column of alumina elwira a mixture of dichloromethane-methanol (30:1) with 15 mg of 5-cyanomethyl-1-methylimidazole.

The result of mass spectrometric analysis (m/z): 112 (M+)

The NMR spectrum (CDCl3, TMS internal standard) d 3,70(5H,s), 6,9 evidenoe above stage (a), received 75 mg of 4-cyanomethyl-1-methyl-3-trimethylsilylimidazole iodide by the same method described in the above stage (b).

NMR spectrum (DMSO-d6, TMS internal standard) d of 0.90(2H, t), 3,62(2H, t), 3,83(2H, s), 3,51(3H, s), to 5.56(2H, s), 7,92(1H, s), 9,40(1H, s).

e) 200 mg 4-cyanomethyl-1-methyl-3-trimethylsilylimidazole iodide obtained in the above stage (d), processed so as stated in the methodology stage c) with 20 mg of 4-cyanomethyl-1-methylimidazole.

The result of mass spectrometric analysis (m/z): 112 (+)

The NMR spectrum (CDCl3, TMS internal standard) d to 3.67(3H, s), and 3.72(2H, s), 7,00(1H, s), 7,47(1H, s).

Reference example 2. 1.3 g of sodium hydride (60%) was added to 10 ml of tetrahydrofuran and the resulting suspension was added dropwise a solution of 2.0 g of imidazole in 10 ml of tetrahydrofuran. After 2 h stirring at 0oC the solution was mixed with 1.86 ml chloroacetonitrile and stirred at room temperature for 3 hours To the reaction solution were added water and chloroform, and the organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to chromatography on a column of alumina elwira a mixture of dichloromethane-IU (M++1)

The NMR spectrum (CDCl3, TMS internal standard) d of 4.95(2H, s), 7,06(1H, d), to 7.09(1H, d), EUR 7.57(1H, s).

Reference example 3. Using 2.35 ml 3-chloropropionitrile, 2.0 g of imidazole and 1.3 g of sodium hydride (60%) was obtained 3.2 g of 1-(2-cyanoethyl)imidazole, using the same technique as described in reference example 2.

The result of mass spectrometric analysis (m/z): 121(M+)

The NMR spectrum (CDCl3, TMS internal standard) d

Reference example 4.

Using a 1.75 g of 4-chlorobutyronitrile, 805 mg of imidazole and 566 mg of sodium hydride (60%), got to 1.15 g of 1-(3-cyanopropyl)imidazole by the same method as in reference example 2.

The NMR spectrum (CDCl3TMS internal standard) d 2,05-to 2.42 (4H, m), of 4.12(2H, t), of 6.96(1H, s), was 7.08(1H, s), 7,51(1H, s).

Reference example 5.

a) 1.5 g of 2-imidazole of carboxaldehyde dissolved in 2,18 ml of triethylamine and added 4.3 g of triphenylmethyl chloride to the above solution, and then the resulting mixture was stirred at room temperature for 24 hours To the reaction solution was added saturated aqueous sodium bicarbonate solution and chloroform, the resulting organic layer was collected, washed with a saturated aqueous solution of sodium chloride and then dried over Kagel, elwira a mixture of dichloromethane-methanol (50:1), having 4,717 g 1-triphenylmethyl-2-imidazole of carboxaldehyde.

The result of mass spectrometric analysis (m/z)% 339 (M++ 1)

The NMR spectrum (CDCl3, TMS internal standard) d: 7,02-7,51 (17H, m), 9,23 (1H, s)

b) 4,717 g 1-triphenylmethyl-2-imidazole of carboxaldehyde obtained in the above stage (a) was dissolved in 50 ml of methanol-tetrahydrofuran (1: 1), to the solution was added at -78oC 526 mg of sodium borohydride. After stirring at -78oC for 1 h, saturated aqueous ammonium chloride solution and dichloromethane were added to the resulting solution. The resulting organic layer was collected, washed with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was washed with diethyl ether, having 1,691 g of 2-hydroxymethyl-1-triphenylimidazole.

The result of mass spectrometric analysis (m/z): 341 (M++ 1)

The NMR spectrum (CDCl3, TMS internal standard) d 3,66(2H, s), 6,79(1H, d), 7,00-7.41 (M, m).

(C) While cooling in an ice bath to 6.2 ml of thionyl chloride are added to 7,728 g of 2-hydroxymethyl-1-triphenylimidazole obtained in the enter the 3,466 g 2-chloromethylthiazole hydrochloride.

NMR spectrum (DMSO-d6, TMS internal standard) d: of 5.05(2H, s), of 7.70(2H, s).

d) Under cooling in an ice bath, 7.5 g of potassium cyanide dissolved in 26 ml of water, to the solution were sequentially added dropwise a solution of 3,446 g 2-chloromethylthiazole hydrochloride obtained in the above stage (C) in 130 ml of ethanol for 1.5 h and then was stirred 2.5 h at room temperature. The reaction solution was filtered, the resulting filtrate was added a saturated aqueous solution of sodium carbonate and then the solvent was removed by evaporation. The residue was extracted with ethyl acetate, the extract was filtered and then the solvent was removed by evaporation. The residue was chromatographically on a column of alumina elwira a mixture of dichloromethane-methanol (50:1); received 1,218 g of 2-cyanopyrimidine.

The result of mass spectrometric analysis (m/z): 108(M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d: 4,07(2H, s), 7,33 (2H, s).

Reference example 6. 450 mg of sodium hydride (60%) was added to 5 ml of dimethylformamide and the resulting suspension was added dropwise a solution of 1.0 g of 4-cyanopyrimidine in 10 ml of dimethylformamide. After stirring for 1 h at room temperature to the resulting solution is added water and chloroform, and the resulting organic layer was collected and dried over anhydrous sodium sulfate, followed by evaporation of the solvent. The residue was subjected to column chromatography on silica gel, elwira a mixture of chloroform-methanol (30:1) with 500 mg of 4-cyanomethyl-1-(2-propyl)imidazole.

The NMR spectrum (CDCl3, TMS internal standard) d: 1,32 (6N, (d), of 3.54(2H, s), 4,20(1H, m), 6,83 (1H, s), 7,82 (1H, s).

Reference example 7. 660 mg of 5-cyanomethyl-1-methylimidazole obtained in reference example 1C)b added 10 ml of 4 n solution of hydrochloric acid in ethyl acetate, and then to 0.92 ml of 0,0-diethyl dithiophosphate, and the mixture was stirred at room temperature for 18 hours the Formed solid product was collected by filtration, washed ethyl acetate and then diethyl ether and dried under reduced pressure, getting 966 mg (1-methyl-5-imidazole)thioacetamide hydrochloride.

The result of mass spectrometric analysis (m/z): 156 (M++ 1)

Reference example 8. Using 185 mg of 4-cyanomethyl-1-methylimidazole obtained in reference example 1E), received 282 mg (1-methyl-4-imidazolyl)thioacetamide hydrochloride by the same method described in reference example 7.

The result of mass spectrometric analysis (m/z): 156 (M+

The result of mass spectrometric analysis (m/z): 142 (M++1)

NMR spectrum (DMSO-d6, TMS internal standard) d: 5,23(2H, s), to 7.64(1H, d), to 7.68(1H, d), with 9.14(1H, s), 9,98(2H, br).

Reference example 10. Using 3.2 g of 1-(2-cyanoethyl)imidazole obtained in reference example 3, received 3,219 g of 3-(1-imidazole)propanedione hydrochloride by the same method described in reference example 7.

The result of mass spectrometric analysis (m/z): 155 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d: 3,19(2H, t), 4,58(2H, t), 7,06(2H, d), 7,55(1H, s), 9,98(2H, br).

Reference example 11. The use of 1.15 g of 1-(3-cyanopropyl)imidazole obtained in reference example 4, was prepared to 1.96 g of 4-(1-imidazole)butandione hydrochloride by the same method described in reference example 7.

The result of mass spectrometric analysis (m/z): 169(M+)

Reference example 12. Use 1,0208 g of 2-cyanopyrimidine obtained in reference example 5) was prepared 1,005 g 2-imidazolidinone hydrochloride SIP/z): 142 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d: or 4.31(2H, s), 7,56(2H, s), 9,95(2H, br).

Reference example 13. Using 850 mg of 4-cyanomethyl-1-(2-propyl)imidazole obtained in reference example 6, was prepared 905 g (1-(2-propyl)-4-imidazolyl)thioacetamide hydrochloride by the same method described in reference example 7.

The result of mass spectrometric analysis (m/z): 184 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d: 1,47(6N, d) to 3.99(2H, s), 4,63(1H, m), 7,74(1H, s), 9,18(1H,s), 9,95(2H, br).

Reference example 14. Using 1.9 g of 4(5)-(1-cyanoethyl)-1-triphenylimidazole, prepared 2.0 g of 2-(4-imidazolyl)proportioned hydrochloride by the same method described in reference example 7.

The result of mass spectrometric analysis (m/z): 156 (M++ 1)

Example 1. B g 2-bromo-1-indanone and b g of 4-imidazolyl thioacetamide hydrochloride was dissolved in 7 ml of 2-propanol by heating, and the solution was heated for 30 minutes under reflux to the boiling point.

After cooling, the reaction solution is dropped crystals, which were collected by filtration and washed ethyl acetate. The collected crystals were distributed between chloroform and saturated aqueous washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. By evaporation of solvent received b g (32%) of 2-(4-imidazolidinyl)-8H-indeno[1,2-d]thiazole. This free base was dissolved in methanol and mixed with b g of fumaric acid to induce crystallization. The resulting crude crystals were recrystallize from methanol-diethyl ether, having b g fumarata.

Melting point: 202-203oC methanol-diethyl ether.

The data of elementary analysis (for C14H11N3S C4H4O4)

Calculated C 58,53; H 4.09 To; N 11,38; S 8,68.

Found, C 58,37; H 4,21; N 11,25; S 8,69.

The result of mass spectrometric analysis (m/z): 253 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d: a 3.87(2H, s), 4,34(2H, s), 6,63(2H, s), 7,07(1H, s), from 7.24(1H, t), of 7.36(1H, t), 7,54(1H, d), 7,63(1H, d), of 7.69(1H, s).

Examples 2 through 27A. The following compounds are obtained by the same method described in example 1.

Example 2. 2-(4-Imidazolidinyl)-4H-indeno[2,1-d]thiazole hemifumarate

Starting compound: 1-bromo-2-indanone, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 170-172oC ethanol-diethyl ether

The data of elementary analysis (for C14H11N3S0,5 C4H4O40.1 H2O dramaticheskogo analysis (m/z): 253 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,81(2H,s), 4,32(2H,s), 6,63(1H,s), 7,1-7,8(6N, m).

Example 3. 2-(4-Imidazolidinyl)-4,5-dihydronaphtho[1,2-d]thiazole fumarate.

Starting compound: 2-bromo-1-tetralone, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 180-182oC methanol-diethyl ether.

The data of elementary analysis (for C15H13N3SC4H4O40.1 H2O)

Calculated C 59,24; H 4,50; N 10,91; S8,32.

Found, C 58,99; H 4,50; N10,86; S8,36.

The result of mass spectrometric analysis (m/z): 267 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 2,95(4H,s), 4,20(2H,s), of 6.71(2H,s), 7,1-7,9(6N,m).

Example 4. 2-(4-Imidazolidinyl)-5,6-dihydro-4H-benzo[6,7] -cyclohepta [1,2-d]thiazole fumarate.

Starting compound: 2-bromo-1-benzocoumarin, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 149-150oC methanol-ethyl acetate

The data of elementary analysis (for C16H15N3SC4H4O40.25 H2O)

Calculated C 59,76; H 4,89; N 10,45; S 7,98.

Found, C 59,71; H 4,84; N Accounted For 10.39; S 7,70.

The result of mass spectrometric analysis (m/z: 201 (M+)

NMR spectrum (DMSO-d6x2">

Example 5. 2-(4-Imidazolidinyl)-5-methyl-4,5-dihydronaphtho[1,2-d]-thiazole

Starting compound: 2-bromo-4-methyl-1-tetralone, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 184-186oC (decomp.) ethyl acetate

The data of elementary analysis (for C16H15N3S0,1H2O)

Calculated C 67,86; H 5,46; N 14,84; S 11,32.

Found, C 67,90; H 5,43; N 14,80; S 11,37.

The result of mass spectrometric analysis (m/z): 282 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d of 1.20(3H,d), 2,77(1H, dd), 3,05-3,18(2H, m) to 4.23(2H,s), 7,03(14,m), 7,21-7,29(3H,s), to 7.61(1H,d), 7,78(1H, dd), 11,99(1H, brs)

Example 6. 2-(4-Imidazolidinyl)-4H-[1]benzopyrano[4,3-d]-thiazole fumarate

Starting compound: 3-bromo-4-chromanone, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 180-184oC (decomp.) methanol

The data of elementary analysis (for C14H11N3OSC4H4O40.1 H2O)

Calculated C 55,84; H 3,96; N 10,85; S 8,28.

Found, C 55,77; H To 3.92; N A 10.74; S 8,12.

The result of mass spectrometric analysis (m/z): 269 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d to 4.28(2H, s), the 5.45(2H, s), 6,63(2H,s), 6,93(1H, d), 7,03(1H, t) 7,07(1H, s), 7,20(1H, t), 7,63-to 7.68 (2H, m)

Example 7. 2-(4-Imidazolidinyl)-4-[1]Ben

Melting point: 199-202oC (decomp.) methanol

The data of elementary analysis (for C14H11N3S20.2 H2O)

Calculated C 58,19; H 3,98; N 14,54; S 22,19.

Found, C 58,29; H Of 3.97; N 14,47; S 21,93.

The result of mass spectrometric analysis (m/z): 285 (M+)

The NMR spectrum (CDCl3, TMS internal standard) d 4,10(2H,s), 4,35(2H,s), 6,97(2H,s),7,17(1H,dt), of 7.23(1H,dt), 7,32(1H,dd), to 7.64(1H,s), 8,00 (1H, dd).

Example 8. 2-(4-Imidazolidinyl)benzofuro[3,2-d]thiazole

Starting compound: 2-bromo-3-coumaranone, 4-imidazolyl the thioacetamide hydrochloride

Melting point: 184-186oC (decomp.) methanol

The data of elementary analysis (for C13H9N3OS0,1 H2O)

Calculated C 60,73; H 3,61; N 16,34; S 12,47.

Found, C 60,82; H 3,59; N 16,24; S 12,47.

The result of mass spectrometric analysis (m/z: 225 (M+)

The NMR spectrum (CDCl3, TMS internal standard) d of 4.45(2H,s), 7,02(1H,s), 7,30-7,37(2H,m), 7,55(1H,dd), 7,66(1H,s), 7,89(1H,dd).

Example 9. 2-(4-Imidazolyl)-8H-indeno[1,2-d]thiazole

Starting compound: 2-bromo-1-indanone, 4-imidazole carbothioamide

Melting point: 228-230oC (decomp.) chloroform diethyl ether.

The data of elementary analysis (for C13H9N+
)

NMR spectrum (DMSO-d6, TMS internal standard) d of 3.95(3H,s), 7,26(1H,t), 7,38(1H,t), EUR 7.57(1H,d), the 7.65(1H,d), 7,79(1H,s), to 7.61(1H,s).

Example 10. 2-(1-Imidazolidinyl)-8H-indeno[1,2-d]thiazole fumarate

Starting compound: 2-bromo-1-indanone, 1-imidazolyl the thioacetamide hydrochloride

Melting point: 155-159oC methanol-diethyl ether

The data of elementary analysis (for C14H11N3SC4H4O40,1 H2O)

Calculated C 58,24; H 4,13; N 11,32; S 8,64.

Found, C 58,21; H 4.09 To; N 11,05; S A Total Of 8.74.

The result of mass spectrometric analysis (m/z): 253 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,93(2H,s), 5,69(2H,s), 6,63(2H, s), 6,98(1H, s), 7,28(1H, t), 7,33(1H,s), 7,38(1H,t), EUR 7.57(1H,d), 7,66(1H,d), 7,89(1H,s).

Example 11. 2-(2-Imidazolidinyl)-8H-indeno[1,2-d]thiazole fumarate

Starting compound: 2-bromo-1-indanone, 2-imidazolyl the thioacetamide hydrochloride

Melting point: 201-204oC methanol

The data of elementary analysis (for C14H11N3SC4H4O40,3 H2O)

Calculated C 57,60; H 4,20; N 11,21; S 8,56.

Found, C 57,56; H 4,10; N 11,27; S 8,42.

The result of mass spectrometric analysis (m/z): 254 (M++ 1)

NMR spectrum (DMSO-d6T is detail)methyl]-8H-indeno[1,2-d]-thiazole fumarate

Starting compound: 2-bromo-1-indanol, (5-methyl-4-imidazolyl)thioacetamide hydrochloride

Melting point: 169-172oC methanol-diethyl ether

The data of elementary analysis (for C15H13N3SC4H4O40,45 H2O)

Calculated C 57,80; H 4,58; N 10,42; S 7,95.

Found, C 58,07; H 4,66, N 10,47; S 7,66.

The result of mass spectroscopy (m/z): 267 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d a 2.71(2H,s), 3,85(3H,s), 4.26 deaths(2H, s), 6,62(2H, s), 7.23 percent(1H, t), 7,34(1H,t), 7,53(1H,t), 7,54(1H,d), a 7.62(1H,d).

Example 13. 2-[(2-Methyl-4-imidazolyl)methyl]-8H-indeno[1,2-d]-thiazole.

Starting compound: 2-bromo-1-indanol, (2-methyl-4-imidazolyl)thioacetamide hydrochloride

Melting point: 187-190oC methanol-diethyl ether

The data of elementary analysis (for C15H13N3S0,45H2O)

Calculated C 65,40; H 5,09; N 15,25; S 11,64.

Found, C 65,35; H A 4.83; N 15,53; S 11,59.

The result of mass spectrometric analysis (m/z): 267 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 2,31(3H,s), a 3.87(2H,s), to 4.23(2H,s), from 7.24(1H,t), of 7.36(1H,t), of 7.55(1H,d), a 7.62(1H,d).

Example 14. 2-[(1-Methyl-4-imidazolyl)methyl]-8H-indeno[1,2-d]thiazole

Starting compound: 2-bromo-1-indanol, (1-m is R

The data of elementary analysis (for C15H13N3S)

Calculated C 67,39; H 4,90; N 15,72; S 11,99.

Found, C 67,17; H 4,94; N 15,49; S 12,09.

The result of mass spectrometric analysis (m/z): 268 (M++ 1)

The NMR spectrum (CDCl3, TMS internal standard) d of 3.65(3H,s), with 3.79(2H,s), and 4.40(2H, s), PC 6.82(1H, s), 7,22(1H, t), of 7.36(1H,t), 7,40(1H,s), of 7.48(1H,d), of 7.70(1H,d).

Example 15. 2-[(1-Methyl-5-imidazolyl)methyl]-8H-indeno[1,2-d]-thiazole

Starting compound: 2-bromo-1-indanol, (1-methyl-5-imidazolyl)thioacetamide hydrochloride

Melting point: 148-151oC chloroform-diethyl ether

The data of elementary analysis (for C15H13N3S)

Calculated C 67,39; H 4,90; N 15,72; S 11,99.

Found, C 67,33; H 4,96; N 15,89; S 11,88.

The result of mass spectrometric analysis (m/z): 268 (M+) + 1).

The NMR spectrum (CDCl3, TMS internal standard) d to 3.58(3H,s), 3,80(2H,s), of 4.44(2H, s), of 7.70(1H, s), 7,26(1H, t), 7,34(1H,t), 7,46(1H,s), to 7.50(1H,d), 7,76(1H,d).

Example 16. 2-[[1-(2-Propyl)-4-imidazolyl]methyl]-8H-indeno[1,2-d]-thiazole

Starting compound: 2-bromo-1-indanone, [1-(2-propyl)-4-imidazolyl] thioacetamide hydrochloride

Melting point: 90:93oC methanol diethyl ether.

The data of elementary analysis (for C17H< the mass-spectrometric analysis (m/z): 295 V+)

The NMR spectrum (CDCl3, TMS internal standard) d 1,46(6N, (d), of 3.78(2H,s), the 4.29(1H, m) to 4.41(2H, s), 6.89 in(1H, s), 7,22(1H,t), of 7.36(1H,t), 7,47(1H,d), to 7.77(1H,d).

Example 17. 2-[1-(4-Imidazolyl)ethyl]-8H-indeno[1,2-d]-thiazole fumarate

Starting compound: 2-bromo-1-indanone, 2-(4-imidazolyl)proportioned hydrochloride

Melting point: 177-180oC methanol.

The data of elementary analysis (for C15H13N3SC4H4O40.1 H2O)

Calculated C 59,24; H 4,50; N 10,91; S 8,32.

Found, C 59,19; H 4,49; N 10,75; S 8,18.

The result of mass spectrometric analysis (m/z): 267 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 1,71(3H,d), a-3.84(2H,s), 4,56(1H, m), 6,63(2H, s), 7,06(1H, s), from 7.24(1H,t), of 7.36(1H,t), 7,54(1H,d), 7,66(1H,d), of 7.69(1H,s).

Example 18. 2-[2-(4-Imidazolyl)ethyl]-8H-indeno[1,2-d]thiazol sesquifumarate

Starting compound: 2-bromo-1-indanone, 3-(4-imidazolyl)proportioned hydrochloride

Melting point: 143-147oC methanol

The result of mass spectrometric analysis (m/z):267(M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,03(2H,t), 3,39(2H,t), with 3.89(2H, s), 6,62(3H, s), to 6.88(1H, s), 7,25(1H,t), of 7.36(1H,t), of 7.55(1H,d), 7,63(1H,d), of 7.70(1H,s).

Example 19. 2-[2-(1-Imidazolyl)ethyl]-8H-indeno[1,2-d]thiazole

IP the 21oC methanol-diethyl ether

The data of elementary analysis (for C15H13N3S0,4H2O)

Calculated C 65,62; H 5,07; N 15,30; S 11,68.

Found, C 65,74; H 4,90; N 15,13; S 11,60.

The result of mass spectrometric analysis (m/z): 267 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d of 3.57(2H,t), with 3.89(2H,s), of 4.49(2H, t), 7,26(1H, d), 7,27(1H, t), 7,37(1H,t), 7,56(1H,d), to 7.64(1H,d), 7,71(1H,s).

Example 20. 2-[2-(2-Imidazolyl)ethyl]-8H-indeno[1,2-d]thiazole fumarate

Starting compound: 2-bromo-1-indanone, 3-(2-imidazolyl)propotioned hydrochloride

Melting point: 177-180oC methanol

The result of mass spectrometric analysis (m/z): (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d a 3.15(2H,t), of 3.48(2H,t), with 3.89(2H, s), 6,62(2H, s), 6,94(2H, s), 7,25(1H,t), of 7.36(1H,t), 7,54(1H,d), 7,63(1H,d).

Example 21. 2-[3-(1-Imidazolyl)propyl]-8H-indeno[1,2-d]thiazol the dihydrochloride

Starting compound: 2-bromo-1-indanone, 4-(1-imidazolyl)butandione hydrochloride

Melting point: 175-177oC methanol

The data of elementary analysis (for C16H15N3S2 HCl0,3 H2O)

Calculated C 53,43; H Is 4.93; N 11,68; S 8,91; Cl 19,71.

Found, C 53,08; H 4,75; N 11,65; S 9,07; Cl 20,02.

The result of mass spectrometries), 4,36(2H, t), 7,27(1H,t), 7,37(1H,t), EUR 7.57(1H,d), to 7.64(1H,d), 7,71(1H,s), 7,87(1H,s), a 9.25(1H,s).

Example 22. 2-(4-Imidazolidinyl)-5-methoxy-8H-indeno[1,2-d]-thiazole

Starting compound: 2-bromo-6-methoxy-1-indanone, 4-imidazolidinone hydrochloride

Melting point: 190-191oC ethyl acetate.

The data of elementary analysis (for C15H13N3OS0.1H2O)

Calculated C 63,18; H Of 4.67; N 14,74; S 11,25.

Found, C 63,06; H With 4.64; N 14,64; S 11,29.

The result of mass spectrometric analysis (m/z): 270 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d of 3.78(2H,s), 3,81(3H,s), or 4.31(2H, s), to 6.80(1H, dd),? 7.04 baby mortality(1H,s), 7,18(1H,s), 7,42(1H,d), to 7.64(1H,s), 12,10(1H, br).

Example 23. 2-(4-Imidazolidinyl)-8-nitro-4,5-dihydronaphtho-[1,2-d]-thiazole

Starting compound: 2-bromo-7-nitro-1-tetralone, 4-imidazolidinone hydrochloride

Melting point: 230-233oC (decomp.) the ethyl acetate

The data of elementary analysis (for C15H12N4O2S0.2H2O)

Calculated C 57,02; H 3,96; N 17,73; S 10,15.

Found, C 57,15; H 3,90; N 17,45; S 10,06.

The result of mass spectrometric analysis (m/z): 313 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d totaling 3.04(2H,t), 3,14(2H,t), 4,27(2H, s), 7,06(1H, s), 7,56(1H, d), 7,63(1H,s), 8 the derivative compounds: 2-bromo-5-methoxy-1-tetralone, 4-imidazolidinone hydrochloride

Melting point: 187-190oC (decomp.) ethyl acetate

The result of mass spectrometric analysis (m/z): 298 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d of 2.92(4H,s), 3,81(3H,s), 4,22(2H, s), 6,92(1H, d), 7,03(1H, s), 7,25(1H,t), 7,42(1H,d), to 7.61(1H,s), 12,00(1H,br).

Example 25. 2-(4-Imidazolidinyl)-10,11-dihydropyrano[1,2-d]-thiazole

Starting compound: 2-bromo-1,2,3,4-tetrahydrofurane-1-he, 4-imidazolidinone hydrochloride

Melting point: 225-230oC (decomp.) methanol

The data of elementary analysis (for C19H15N3S0.4H2O)

Calculated C 70,30; H 4,91; N 12,94; S 9,88.

Found, C 70,30; H Equal To 4.97; N 12,78; S 9,67.

The result of mass spectrometric analysis (m/z): 317 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,11(2H,t), of 3.43(2H,t), 4.26 deaths(2H, s), 7,05(1H, s), of 7.48(1H, t), 7,56(1H,dt), a 7.62(1H,s), 7,86(1H,d), to $ 7.91(1H,d), with 8.05(1H,d), of 8.15(1H,d), 12,01(1H, br).

Example 26. 5-Fluorescent-2-(4-imidazolidinyl)-8H-indeno[1,2-d] thiazole

Starting compound: 2-bromo-6-fluorescent-1-indanone, 4-imidazolidinone hydrochloride

Melting point: 175-178oC ethyl acetate

The result of mass spectroscopy (m/z): 271 (M+)

NMR spectrum (DMSO-d6, TMS vnutrenniy)-8H-indeno[1,2-d]-thiazole 0.8 hydrochloride 1.2 hydrobromide

Starting compound: 4-benzoyloxy-2-bromo-1-indanone, 4-imidazolidinone hydrochloride

Melting point: 220-225oC (decomp.) 2-propanol

The data of elementary analysis (for C21H15N3O2S0.8HCl1,2HBr)

Calculated C 50,48; H 3,43; N To 8.41; S 6.42 Per; Cl 5,68; Br 19,19.

Found, C 50,12; H 3,43; N 8,31; S 6,55; Cl 5,24; Br 18,95.

The result of mass spectrometric analysis (m/z): 374 (M++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,91(2H,s), to 4.62(2H,s), 7,25(1H, d), 7,51(1H,t), to 7.61-to 7.67(4H,m), 7,80(1H,t), 8,21(1H,d), 9,11(1H, s).

Example 27b. 1 ml of 5 n aqueous solution of sodium hydroxide was added to the solution 0,358 g 7-benzoyloxy-2-(4-imidazolidinyl)-8H-indeno[1,2-d] thiazole hydrochloride, hydrobromide obtained in example 27A, in methanol (10 ml) and the mixture was stirred at room temperature for 30 minutes After evaporation was dissolved, the residue was acidified using 1 N. hydrochloric acid, neutralized with sodium bicarbonate and then extracted with a mixture of chloroform-methanol. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting crude crystals (0.20 g) was recrystallize from ethanol, having 77 mg of 7-hydroxy-2-(4-imidazolidinyl)-8H-indeno[1,2-d] thiazole.

OS)

Calculated C 62,43; H 4,12; N 15,60; S 11,91.

Found, C 62,33; H 4,10; N 15,47; S 11,94.

The result of mass spectroscopy (m/z): 270 (V++ 1)

NMR spectrum (DMSO-d6, TMS internal standard) d 3,71(2H,s), 4,30(2H,s), 6,72(1H, d), 7,03(1H, s), 7,12(1H, d), 7,19(1H,t), to 7.61(1H,s), 9,62(1H,s), 11,99(1H, br).

Example 28. 0.1 ml of bromine was added dropwise to a solution of 0.47 7-benzoyloxy-1-indanone in tetrahydrofuran (10 ml) at room temperature, and the mixture was stirred for 30 minutes To 7-benzoyloxy-2-bromo-1-indanone obtained by evaporation of the solvent, was added 15 ml of 2-propanol and 0.33 g of 4-imidazolidinone hydrochloride, followed by heating for 2.5 h under reflux to boiling point. After cooling and evaporation of the solvent, the residue was mixed with ethyl acetate and was extracted with 1 N. hydrochloric acid. The aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The remaining 4-benzoyloxy-2-(4-imidazolidinyl)-8H-indeno[1,2-d] thiazole was dissolved in 10 ml of methanol, to the solution was added 1 ml of 5 N. aqueous solution of sodium hydroxide and then stirred at room temperature for 15 minutes After podkashlivanija using 1H. sotalol, and then the extract was dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting crude crystals were recrystallize from ethanol, having received 55 mg of 4-hydroxy-2-(4-imidazolidinyl)-8H-indeno[1,2-d] thiazole.

Melting point: 267-269oC (decomp.) ethanol

The data of elementary analysis (for C14H11N3OS0,3H2O)

Calculated C 61,21; H 4.26 Deaths; N 15,30; S 11,67.

Found, C 61,23; H 4,15; N 15,01; S 11,96.

The result of mass spectrometric analysis (m/z): 269 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d of 3.80(2H,s), 4,30(2H,s), for 6.81(1H,d), 6,98-7.06(3H,m),7,60(1H,s),9,51(1H,s), 11,98(1H,br).

Example 29. 5.0 g of Raney Nickel (wet) was added to a solution of 0.52 g of 2-(4-imidazolidinyl)-8-nitro-4,5-dihydronaphtho[1,2-d] thiazole obtained in example 23, in 1,4-dioxane (40 ml), methanol (20 ml) and the mixture was stirred for 2 h in hydrogen atmosphere (1 ATM).

After filtration of nerastvorimogo substances solvent was evaporated from the filtrate, and the residue was mixed with ethyl acetate to induce crystallization. The resulting crude crystals were washed with hot ethyl acetate, receiving 0.27 g (57%) of 3-amino-2-(4-imidazolidinyl)-4,5-dihydronaphtho[1,2-d]thiazole.

The temperature of the melt

Calculated C 62,22; H 5,15; N 19,35; S 11,07.

Found, C 62,17; H 4,90; N 19,15; S 11,03.

The result of mass spectrometric analysis (m/z): 282 (M+)

NMR spectrum (DMSO-d6, TMS internal standard) d: 2,78(2H,t), 2,85(2H, t), 4,18(2H,s), to 4.98(2H,s), of 6.49)1H,dd), to 6.88(1H,d),? 7.04 baby mortality(1H, brs), to 7.09(1H, d), 7,60(1H,s), 11,96(1H,br).

Reference example 15. To 3,98 g 2-methylnaphtho[1,2-d] thiazole dissolved in carbon tetrachloride (40 ml), was added to 3.56 g of N-bromosuccinimide and 0.20 g of benzoyl peroxide, followed by heating to boiling under reflux for 6 hours After cooling the reaction solution, the insoluble material was removed by filtration, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel, elwira a mixture of hexane-chloroform (5:1) with 3.50 g (63%), 2-bromomalonate [1,2-d]thiazole.

The result of mass spectrometric analysis (m/z): 277, 279 (M+)

The NMR spectrum (CDCl3, TMS internal standard) d 4,94(2H,s), of 7.5 to 7.7 (2H, m), 7,8-8,0(3H,m), 8,77(1H,dd).

Example 30. 0.06 g of sodium hydride (60%) was added to a solution of 0.1 g of imidazole in tetrahydrofuran (30 ml). After 30 min stirring at room temperature, to the solution was added a solution of 2-bromomalonate[1,2-d] thiazole in tetrahydrofuran (10 ml). After peremeshivaya acid and ethyl acetate. The organic layer was extracted with 1 n hydrochloric acid. The combined aqueous layer was neutralized with sodium bicarbonate and then extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was evaporated, receiving 0.27 g (100% ) 2-(1-imidazolidinyl)oil[1,2-d] thiazole. This free base was dissolved in methanol and mixed with 0.10 g of fumaric acid to induce crystallization, which gave 0.32 g fumarata.

Melting point: 163-165oC methanol

The data of elementary analysis (for C15H11N3SC4H4O4)

Calculated Cl 59,83; H 3,96; N 11,02; S To 8.41.

Found, Cl 59,83; H 3,91; N Of 10.93; S Scored 8.38.

The result of mass spectrometric analysis (m/z): 265 (V+)

NMR spectrum (DMSO-d6, TMS internal standard) beta: 5,88(2H,s), only 6.64(2H, s),? 7.04 baby mortality(1H,s), the 7.43(1H,s), the 7.65(1H,t), 7,63(1H,t), of 7.95(1H,d), of 7.97(1H,s), of 8.09(1H,d), 8,13(1H,d), 8,65(1H,d).

The following compound was obtained in the same manner as described in example 1.

Example 31. 8-Cyano-2-(4-imidazolidinyl)-4,5-dihydronaphtho[1,2-d]thiazole

Starting compound: 2-bromo-7-cyano-1-tetralone, 4-imidazolidinone hydrochloride

Melting point: 201-205oC methanol-ethyl acetate

Data elementary Academy is 0; H 4.26 DEATHS; N 18,64; S 10,81.

The result of mass spectroscopy (m/z): 292 (M+)

IR spectrum (KBr) cm-1: 2228 (C N)

NMR spectrum DMSO-d6, TMS internal standard) : 3,00(2H,t), is 3.08(2H, t) to 4.23(2H,s), 7,07(1H,s), 7,49(1H,d), to 7.61(1H,s), 7,66(1H,dd), 8,01(1H,s), 11,96(1H,br).

The structure of the compounds of examples 1-31 shown in the table.1.

In addition to the compounds described above, other compounds In-1 In-14 shown in the following table.3. These connections do not need any special experiments because they can be synthesized according to synthetic routes and methods described in the above schemes and the examples, as well as in accordance with their modifications known to anyone ordinary skilled in the relevant technology.

1. Condensed derived thiazole of General formula I

< / BR>
where R is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxygroup, carboxypropyl, lower alkoxycarbonyl group, a nitrogroup, amino, cyano or protected hydroxyl group;

A is A phenyl or naphthalene ring;

L1and L2are: one of the groups is a direct link, and the other LINEST, what volume of oxygen, sulfur atom or lower alkynylamino group;

L is a direct bond or linear or branched lower alkalinous group;

Imis a group of General formula

< / BR>
or the General formula II

< / BR>
where R1R3are the same or different and each represents a hydrogen atom or a lower alkyl group;

R4R6are the same or different and each represents a hydrogen atom or a lower alkyl group,

or its pharmaceutically acceptable salt.

2. Connection on p. 1, in which A is A phenyl ring, L1- direct connection and L2straight or branched lower alkalinous group or lower alkynylamino group.

3. 2-(4-Imidazolidinyl)-8H-indeno[1,2-d]thiazole or its pharmaceutically acceptable salt.

4. 2-(4-Imidazolidinyl)-4,5-dihydronaphtho[1,2-d]thiazole or its pharmaceutically acceptable salt.

5. The pharmaceutical composition active agonist 5-HT3receptor comprising an active ingredient and a pharmaceutically acceptable carrier, wherein the active substance contains an effective amount of the compound forms the th, carboxypropyl, lower alkoxycarbonyl group, a nitrogroup, amino, cyano or protected hydroxyl group;

A is A phenyl or naphthalene ring;

L1and L2are: one of the groups is a direct connection and the other a linear or branched lower alkalinous group which may contain a terminating atom of oxygen or sulfur, an oxygen atom, a sulfur atom or niche alkenylamine group;

L is a direct bond or linear or branched lower alkalinous group;

Imis a group of General formula

< / BR>
or the General formula II

< / BR>
where R1R3are the same or different and each represents a hydrogen atom or a lower alkyl group;

R4R6are the same or different and each represents a hydrogen atom or a lower alkyl group.

 

Same patents:

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new cephalosporins, namely to derive 1-zetia-diazaphosphorines General formula 1:

(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to benzothiazole derivative that is highly effective as a medicinal product, namely, benzothiazole derivative, useful as a preventive and therapeutic agent for diseases in which the function of suppressing the production of leukotrienes and thromboxanes are effective

The invention relates to new derivatives of 2-aminobenzothiazole, and to their use in pharmaceutical compositions having activity against convulsions induced by glutamate

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to the field of organic chemistry, in particular to the synthesis of medicinal substances
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