Derivatives of 5h-thiazole[3,2-a]pyrimidine, intermediate products and drug

 

(57) Abstract:

The invention relates to new derivatives of 5H-thiazole[3,2-a]pyrimidine of the General formula I, where R1means (ness.)alkyl or benzyl; R2means (ness.) alkyl, (ness.)alkoxygroup, -O(CH2)nN(R13)(R14or-N(R15)(CH2)nN(R13)(R14); R3-R14each denotes hydrogen, halogen, (NISS. )alkyl, (ness.)alkoxygroup or benzyloxy or R6and R7together form a benzene ring; R13-R15each denotes hydrogen or (ness.)alkyl, n = 1-3, as well as pharmaceutically acceptable salts. Derivatives dioxopyrimidine General formula II as intermediate products, where the values of R1-R7above. The drug with the effect of the antagonist of metabotropic glutamate receptors containing the compound of formula I and a therapeutically inert carrier. The technical result is to provide new compounds having the action of an antagonist of metabotropic glutamate receptors. 3 s and 5 C.p. f-crystals.

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The invention relates to derivatives of 5H-thiazole[3,2-a]pyrimidine of the General formula

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where R1denotes hydrogen,>(R13)(R14), -(CH2)nN(R13)(R14or-N(R15)(CH2)nN(R13)(R14);

R3-R12each denotes hydrogen, halogen, trifluoromethyl, (ness.)alkyl, cycloalkyl, (NISS. )alkoxygroup, hydroxyl, nitro-group, cyano, -N(R13)2, phenyl, fenoxaprop, benzyl or benzyloxy or

R6and R7together denote a benzene ring;

R13- R15each denotes hydrogen, (ness.)alkyl or cycloalkyl and

n denotes the number of 1-5,

and their pharmaceutically acceptable salts.

These compounds and their salts are new products, which are characterized by valuable therapeutic properties.

It was found that compounds of General formula I are antagonists of metabotropic glutamate receptor and/or its agonists.

In the Central nervous system (CNS), the transmission of impulses occurs due to the interaction of the neurotransmitter, which is sent by a neuron, with neuroreceptors.

L-Glutamic acid, the most widely found in the Central nervous system neurotransmitter, plays a crucial role in a large number of physiological processes. Glutamatergicakie receptors the traditional channels. Metabotropic glutamate receptors (mglur) belong to the second major group, and, therefore, belong to the family of receptors coupled with G-protein.

Currently, there are eight different representatives of these mglur and some of them even are divided into subtypes. Based on the structural parameters, the difference in the effect on the synthesis of secondary metabolites and the difference of affinity to low molecular weight chemical compounds, these eight receptors can be divided into three subgroups.

mglur and mglur belong to subgroup I, mglur and mglur belong to subgroup II, and mglur, mglur, mglur and mglur belong to subgroup III.

Metabotropic glutamate receptors belonging to the second group, can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as restricted brain function caused by the operations overlay anastomoses or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, heart block and hypoglycemia.

Other diseases that can be treated by these means, are disease Alia, disorders of cognitive abilities, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate deficiency, such as, for example, muscle cramps, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, chronic pain, dyskinesia, depression and pain.

Objects of the present invention are the compounds of formula I and their pharmaceutically acceptable salts, as such and as pharmaceutically active substances, their receipt of the medicinal product on the basis of the compounds in accordance with the invention and their receipt and use of these compounds in accordance with the invention in the treatment or prevention of diseases of the aforementioned type and, thus, in the preparation of the drugs.

Objects of the present invention are, in addition, the compounds of formula

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where the values of R1-R7above, which are intermediates in obtaining the compounds of formula I.

The invention includes, in addition to the racemate, all stereoisomeric forms.

Used in this is key with 1-7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.

The term "cycloalkyl" denotes cyclic saturated hydrocarbon residues with 3-7 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "(NISS. )alkoxygroup" means (ness.)the alkyl residue is as defined above connected through an oxygen atom.

The term "halogen" includes fluorine atoms, chlorine, bromine and iodine.

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained by the coupling of compounds of formula

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with bromoacetaldehyde formula

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and, if necessary, conversion of the functional group in the compound of formula I into another functional group, and optionally converting the compounds of formula I in a pharmaceutically acceptable salt.

Thus, in particular, nitro compounds of formula I can be gidrirovanii to amino groups, and amino groups can be alkilirovanii to (ness.)alkylamino - or di(ness.)alkylamino or you can alkilirovanii hydroxyl group.

In accordance with the invention spend interaction accordingly sameshima formula II, for example, (R, S)-1-[4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl] atenonol. The reaction proceeds at room temperature for 60-70 h in an inert solvent, such as tetrahydrofuran (THF) or acetonitrile. After cooling the reaction mixture to about 0oWith the separated solid product is maintained at an elevated temperature with concentrated acetic acid for several hours and purified by known methods.

In accordance with methods that are known to the nitro group can be gidrirovanii to amino groups. In a preferred embodiment, the hydrogenation is carried out in the presence of Raney Nickel at room temperature under normal pressure in the absence of chlorine in the molecule.

Alkylation of the amino groups of appropriate conduct in the following way. For example, the compound of General formula I, which contains an amino group, dissolved in acetonitrile and treated with formaldehyde and NaBH3CN. After adjusting the pH to 6, for example, hydrochloric acid, this process is repeated, getting on the end of the reaction period of approximately 2 hours methylamino compound of formula I. Another method involves treating compound f is aStore NR3in THF.

Alkylation of the hydroxyl group can be carried out in accordance with known methods. As the alkylating agent for methylation is convenient to use dimethylsulfate. This can be done by dissolving alkilirutego connection in an acceptable solvent, such as toluene, processing dimethylsulfate, acid tetrabutylammonium sulfate and sodium hydroxide solution with vigorous stirring. The reaction conditions can be varied depending on the particular alkylating agent and accordingly alkilirutego connection.

Pharmaceutically acceptable salts can be easily obtained in accordance with known methods and taking into account the nature of the turn in the Sol connection. To obtain pharmaceutically acceptable salts of basic compounds of formula I are suitable mineral and organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, p-toluensulfonate, etc. To obtain pharmaceutically priemlemye, for example, sodium, potassium, calcium, magnesium, etc., basic amines and basic amino acids.

In General, the process of producing compounds of formula I using as raw material compounds of formulas IV, V and VI are given in the end of the description scheme . Intermediates of formula II are new. -Bromoacetaldehyde can be obtained in accordance with U.S. patent 3660418. Obtaining typical compounds of the formula I described in examples 1-27.

Values of the substituents in the circuit shown above.

The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, the antagonists of metabotropic glutamate receptors, so they can be used for treatment or prevention of acute and/or chronic neurological disorders, such as restricted brain function caused by the operations overlay anastomoses or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, heart block, and hypoglycemia. Other diseases that can be treated by these means, are Alzheimer's disease, Huntington's chorea, BASS, AIDS-dementia, phonism, caused by medications, conditions which lead to glutamate deficiency, such as, for example, muscle cramps, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, chronic pain, dyskinesia, depression and pain.

The binding of compounds of formula I in accordance with the invention with a metabotropic glutamate receptor group II were determined in vitro. The drugs investigated in accordance with the following test method.

To determine the affinity of the compounds to mglur group II used the test GTP35S. Receptors stimulated by 10 μm 1S. 3R-ACPD.

For test compounds are calculated TOi. These values FORiwas determined by the following formula:

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where is the IR50represent the concentration of test compounds in μm, at which achieved 50% antagonistic effect on the effect of stimulus 1S,3R-ACPD. [L] represents the concentration of 1S, 3R-ACPD and the value of EC50is the concentration of 1S,3R-ACPD in microns, which provides approximately 50% stimulation.

Activity TOicompounds described in primarilythe as medicines, for example, in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the introduction can also be rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection.

When the pharmaceutical preparation of the compounds of formula I and their pharmaceutically acceptable salts can be combined with pharmaceutically inert, inorganic or organic carriers. As such carriers in the manufacture of tablets, coated tablets, dragées and hard gelatin capsules can be used, for example, lactose, corn starch and its derivatives, talc, stearic acid and its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, solid fats, semi-solid and liquid polyols etc., However in the case of soft gelatin capsules, depending on the nature of the active substance is usually no media required. Preparation of solutions and syrups acceptable carriers are, naprimerova salts of compounds of formula I can be applied adjuvants, such as alcohols, polyols, glycerol, vegetable oils, etc., but, as a rule, they are optional. Suitable for the manufacture of suppositories carriers are, for example, natural or hardened oils, waxes, solid fats, semisolid and liquid polyols, etc.

Moreover, the pharmaceutical preparations can include preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts for varying the osmotic pressure, buffers, masking additives and antioxidants. However, they can also include other therapeutically valuable substances.

As indicated above, the medicaments containing the compounds of formula I or their pharmaceutically acceptable salt and a therapeutically inert fillers, are also the object of the present invention, as the method of preparation of such medicines, which includes the transfer of one or more compounds of the formula I or their pharmaceutically acceptable salts and optionally one or more other therapeutically valuable substances in herbal dosage form together with one or more therapeutically inert carriers.

painted individual needs. Typically, the effective dose for oral or parenteral administration is in the range from 0.01 to 20 mg/kg / day, and for all the above indications, the preferred dose is 0.1-10 mg/kg / day. Therefore, the daily dose for an adult weighing 70 kg is in the range from 0.7 to 1400 mg, preferably within 7-700 mg.

Further, as mentioned above, the object of the invention is the use of compounds of the formula I and their pharmaceutically acceptable salts for the preparation of drugs primarily for the treatment or prevention of acute and/or chronic neurological disorders of the above type.

Example 1

(R,S)-1-[2-(2,6-Dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-yl]alanon

a) a Solution of 12.1 ml of 0.1 mol) of 4-methoxybenzaldehyde, 10.3 ml of 0.1 mol) of acetylacetone and 9,13 g (0.12 moles) of thiourea in 30 ml of ethanol was treated with 10 drops of concentrated hydrochloric acid and boiled under reflux with simultaneous stirring for 4 h the Reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (dichloromethane/methanol in the ratio 98:2). In the subsequent crystallization from ethanol was obtained 6.2 g of the CSOs substances with tPL175oC.

b) a Mixture of 1.9 grams (to 7.09 mmol) of a-bromo-2,6-dichlorobenzaldehyde with 1.78 g (6.45 mmol) of (R,S)-1-[4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl] ethanone in 50 ml of tetrahydrofuran at room temperature was stirred for 65 hours, the mixture was cooled to 0oWith and loose precipitated solid was filtered, dissolved in 75 ml of concentrated acetic acid and boiled under reflux with simultaneous stirring for 8 hours, the Reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (dichloromethane/methanol in the ratio 95:5). The result was 1,95 g (68%) of (R, S)-1-[2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-yl]ethanone in the form of a yellow foam.

in) 1,95 g (of 4.38 mmole) of (R,S)-1-[2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-yl] ethanone with simultaneous stirring was dissolved in 20 ml of 2,6 N. methanolic solution of hydrochloric acid and was treated with 100 ml of diethyl ether. After 1 h the crystals were filtered off. In this way received 1.54 g (73%) of the hydrochloride of (R,S)-1-[2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-yl] ethanone in the form of a beige solid pyrimidine-6-yl]alanon

Analogously to example 1A and using as starting compounds 2-methoxybenzaldehyde, thiourea, acetylacetone and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization received hydrobromide (R, S)-1-[2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-yl]ethanone in the form of a white solid with tPL290oC.

Example 3

Ethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

a) a Mixture of 2.0 g (7.5 mmol) of a-bromo-2,6-dichlorobenzaldehyde with 2,08 g (6.8 mmol) of ethyl-(R,S)-4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate in 40 ml of tetrahydrofuran was stirred at room temperature for 17 hours later the mixture was cooled to 0oWith and fell precipitated solid was filtered, dissolved in 75 ml of concentrated acetic acid and boiled under reflux with simultaneous stirring for 24 h the Reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (ethyl acetate). The result was 1,82 g (51%) of ethyl-(R,S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate as a yellow foam.

PL233oC.

Example 4

(R,S)-2-(2,6-Dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 3A-b, using as starting substances ethyl-(R, S)-4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization got hydrochloride ethyl-(R,S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate as a white solid with tPL201oC.

Example 5

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

a) a Solution of 3.0 g (17.3 mmol) of 2-dimethylaminoethyl-3-oxobutanoate, and 2.1 ml (17.3 mmol) of 4-methoxybenzaldehyde and 1.58 g (20.8 mmol) of thiourea in 15 ml of concentrated acetic acid was boiled under reflux for 4 hours, the Reaction mixture was the end of the ammonia in the ratio of 8:1:0,1). The result was 2.76 g (46%) 2-dimethylaminoethyl-(R, S)-4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate as a pale yellow solid with tPL80oC.

b) 0.9 g (2.6 mmole) 2-dimethylaminoethyl-(R,S)-4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-carboxylate was dissolved in 10 ml of methanolic solution of hydrochloric acid and concentrated. The obtained hydrochloride and 0.77 g (2.86 mmole) -bromo-2,6-dichlorobenzaldehyde dissolved in 50 ml of acetonitrile was heated under reflux with simultaneous stirring for 16 hours the Reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (solution of dichloromethane/methanol/ammonium hydroxide in a ratio of 8:1:0,1). The result was 0,83 g (61%) of 2-dimethylaminoethyl-(R,S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate in the form of a greenish foam.

in) 0,83 g (1.6 mmole) 2-dimethylaminoethyl-(R,S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with simultaneous stirring was dissolved in 10 ml of 2,6 N. methanolic solution of hydrochloric acid and was treated with 50 ml of diethyl ether. After 3 h the crystals hoteltravel-5H-thiazole[3,2 a] pyrimidine-6-carboxylate in the form of a beige solid with tPL> 240oC.

Example 6

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization received dihydrobromide 2-dimethylaminoethyl-(R,S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate as a pale yellow solid with tPL237oC.

Example 7

3-Dimethylaminopropyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2 - methoxybenzaldehyde, 3-dimethylaminopropyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 3-dimethylaminopropyl-(R, S)-2- (2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with tPL175oC (with decomposition).

Example 8

2-Dimethylaminoethyl-(R, S)-2-(4-chlorophenyl)-5-(2-methoxyphenyl)-7-x substances 2-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-4-chlorophenylalanine after salt formation and crystallization in the form of a pale green solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(4-chlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL178oC.

Example 9

2-Dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazol[3.2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,4-dichlorobenzaldehyde after salt formation and crystallization in the form of a pale yellow solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with tPL191oC.

Example 10

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(3-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting substances 3-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallizatio is phenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL155oC (with decomposition).

Example 11

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(4-chlorophenyl)-7-methyl-5H-thiazole [3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 4-chlorobenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(4-chlorophenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL190oC.

Example 12

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-chlorobenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL169oC.

Example 13

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-isopropyl-5H-thiazole[3,2-a]pyrimidine, 2-dimethylaminoethyl-4-methyl-3-oxopentanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-isopropyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL165oC (with decomposition).

Example 14

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxopentanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL167oC (with decomposition).

Example 15

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2 - methoxybenzaldehyde, 2-dimethylaminoethyl-4-phenyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorophenylisocyanate-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL170oC (with decomposition).

Example 16

N-(2-Dimethylaminoethyl)amide (R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylic acid

Analogously to example 5A-C, using as starting compounds 2-methoxybenzaldehyde, N-(2-dimethylaminoethyl)-3-oxobutanamide, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of N-(2-dimethylaminoethyl) amide (R,S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylic acid with tPL232oC.

Example 17

N-(2-Dimethylaminoethyl)-N-methylamide (R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylic acid

Analogously to example 5A-C, using as starting compounds 2 - methoxybenzaldehyde, N-(2-dimethylaminoethyl)-N-methyl-3-oxobutanamide, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of N-(2-dimethylaminoethyl)-N-methylamide (R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl 18

N-(2-Dimethylaminoethyl)amide (R, S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylic acid

Analogously to example 5A-C, using as starting compounds 4 - methoxybenzaldehyde, N-(2-dimethylaminoethyl)-3-oxobutanamide, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a light yellow solid substance was obtained the dihydrochloride of N-(2-dimethylaminoethyl)amide (R,S)-2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-benzyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylic acid with tPL180oC (with decomposition).

Example 19

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2,3-acid)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting substances 2,3-dimethoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a light brown solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2,3-acid)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL144oC.

Example 20

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2,6-dimetane starting compounds 2, 6-dimethoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a light green solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2,6-acid)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL171oC (with decomposition).

Example 21

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-forfinal)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-forventelige, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a beige solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-forfinal)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL169oC (with decomposition).

Example 22

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-were)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-methylbenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorophenylisocyanate-(R,S) -2- (2,6-dichlorophenyl)-5-(2-were)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL157oC (with decomposition).

Example 23

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-ethoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-ethoxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a white solid substance obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-ethoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with tPL188oC (with decomposition).

Example 24

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-isopropoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2 - isopropylbenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a pale brown solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-isopropoxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL172oC (with decomposition).

Example 25

2-Dimethylamine is a measure 5A-using as starting compounds 2-methoxynaphthalene, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde after salt formation and crystallization in the form of a brown solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyethyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with tPL174oC (with decomposition).

Example 26

2-Dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2-methoxybenzaldehyde, 2-dimethylaminoethyl-3-oxopentanoate, thiourea and-bromo-2,4-dichlorobenzaldehyde after salt formation and crystallization in the form of a yellow solid obtained the dihydrochloride of 2-dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate with tPL199oC (with decomposition).

Example 27

2-Dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-benzyloxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate

Analogously to example 5A-C, using as starting compounds 2 - benzyloxybenzaldehyde, 2-dimethylaminoethyl-3-oxobutanoate, thiourea and-bromo-2,6-dichlorobenzaldehyde politicamente-(R, S)-2-(2,6-dichlorophenyl)-5-(2-benzyloxyphenyl)-7-methyl-5H-thiazole[3,2-a]pyrimidine-6-carboxylate with tPL147oC (with decomposition).

An example of a

By the usual method of manufacture of tablets of the following composition (mg/tablet:

Active ingredient: 100

Powdered lactose - 95

White corn starch - 35

Polyvinylpyrrolidone - 8

Na-Carboximetilkrahmal - 10

Magnesium stearate - 2

Weight tablets - 250

Example B

By the usual method of manufacture of tablets of the following composition (mg/tablet:

Active substance - 200

Powdered lactose - 100

White corn starch - 64

Polyvinylpyrrolidone - 12

Na-Carboximetilkrahmal - 20

Magnesium stearate

Weight tablets - 400

The example IN

Make capsules with the contents of the following composition (mg/capsule:

Active substance - 50

Crystalline lactose - 60

Microcrystalline cellulose - 34

Talc - 5

Magnesium stearate - 1

The mass of the contents of a capsule - 150

The active substance with an acceptable particle size, crystalline lactose and microcrystalline cellulose are mixed among themselves until a homogeneous state, sift, and then primes is.

1. Derivatives of 5H-thiazole[3,2-a] pyrimidine of the General formula

< / BR>
where R1means (NISS. )alkyl or benzyl;

R2means (NISS. )alkyl, (NISS. )alkoxygroup,

-O(CH2)nN(R13)(R14or

-N(R15)(CH2)nN(R13)(R14);

R3-R12each denotes hydrogen, halogen, (NISS. )alkyl, (NISS. )alkoxygroup or benzyloxy or

R6and R7together denote a benzene ring;

R13-R15each denotes hydrogen or (NISS. )alkyl;

n = 1-5,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, where

R1means (NISS. )alkyl or benzyl;

R2means (NISS. )alkyl, (NISS. )alkoxygroup, -O(CH2)2N(CH3)2, -O(CH2)3N(CH3)2, -NH(CH2)2N(CH3)2or-N(CH3)(CH2)2N(CH3)2;

R3denotes hydrogen, (NISS. )alkoxygroup, halogen or benzyloxy;

R4denotes hydrogen or (NISS. )alkoxygroup;

R5denotes hydrogen, halogen or (NISS. )alkoxygroup;

R6denotes hydrogen;

R7denotes hydrogen or (NISS. each denotes a hydrogen or halogen.

3. Connection PP. 1 and 2, where

R1denotes methyl or ethyl;

R2- O(CH2)2N(CH3)2;

R3- methoxy group, chlorine or isopropoxy;

R4- R7each denotes hydrogen;

R8- R12each denotes a hydrogen or chlorine.

4. Connection on p. 3, selected from the group including:

2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate,

2-dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate,

2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate,

2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate,

2-dimethylaminoethyl-(R, S)-2-(2,6-dichlorophenyl)-5-(2-isopropoxyphenyl)-7-methyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate and

2-dimethylaminoethyl-(R, S)-2-(2,4-dichlorophenyl)-5-(2-methoxyphenyl)-7-ethyl-5H-thiazole[3,2-a] pyrimidine-6-carboxylate.

5. Connection PP. 1-4, obtained by the interaction of the compounds of formula II

< / BR>
where the values of R1-R7specified in paragraph 1,

with bromoacetaldehyde formula III

< / BR>

6. Connection PP. 1-4, with the action of an antagonist of metabotropic glutamate receptors.

7. Derivatives dioxopyrimidine General formula II

< / BR>
where the values of R1- R7specified in paragraph 1.

8. The drug with the effect of the antagonist of metabotropic glutamate receptors containing the compound according to any one of paragraphs. 1-4 and a therapeutically inert excipient.

 

Same patents:

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to the field of production of new heterocyclic O-dicarbonitriles, which can be used to achieve different hexatriene, useful as active media of liquid and solid lasers, scintillators, for the transformation of shortwave radiation in the long wavelength in the transmission of information through fiber-optic communication lines and so on

The invention relates to medicine and relates to a method of inhibiting tyrosine kinase receptor, epidermal growth factor, for example, Erb-b2, Erb-b3, or Erb-b4, by introducing to a mammal in need, an effective amount of nitrogen-containing heterocyclic compounds, which is that as the nitrogen-containing heterocyclic compounds used as a compound of formula I, where R1-R9are specified in the claims value, or its pharmaceutically acceptable salt, or hydrate, thereof the pharmaceutical composition and the contraceptive composition based on them

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, and method of production thereof

The invention relates to new compounds of the formula (I), where a represents the group CH2or atom That denotes H or halogen, D is CH2, OCH2, NHCH2CH2CH2, R denotes phenyl, benzothiazolyl, indolyl, indazoles, purinol, pyridyl, pyrimidyl, thiophenyl, each of these groups may be substituted or unsubstituted

The invention relates to substituted diaminocarbenes acids of the formula I

< / BR>
and/or a stereoisomeric form of the compounds of formula (I), and/or physiologically acceptable salts of the compounds of formula (I), where1- phenyl, phenyl, one - or twofold substituted linear or branched (C1-C7)-alkyl, hydroxyl, group (C1-C6)-alkyl-C(O)-O-group (C1-C6)-alkyl-O-, halogen, CN-group, methylenecyclopropane; group R4- (R5)N-, R2, R4and R5are the same or different and mean a hydrogen atom, (C1-C6)-alkyl; R3and G are the same or different and mean: 1

The invention relates to new compounds for combating pests, in particular derivatives carbanilide and fungicide-insecticidal tool based on them

The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen

The invention relates to a method for producing derivatives of 2-aminothiazoline formula I, in which R1represents C1-5alkyl straight or branched chain, R2is1-3alkyl, by reacting the compounds of formula II in which R3represents phenyl which may be optionally mono-pentamidine independently chlorine, methoxy, ethoxy, phenoxy or nitro, with the compound of the formula III in which Y represents a leaving group, in a solvent and in the presence of a base

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to a method for obtaining compounds of formula I in each case in free form and in salt form, where Q denotes CH or N, Y represents the NO2or CN, Z means СНR3OH , NR3or S, R1and R2each independently of one another denotes hydrogen, unsubstituted or R4-substituted C1-C8alkyl or together form Allenby bridge of two or three carbon atoms, and Allenby bridge may optionally contain a heteroatom selected from the group comprising NR5, O or S, R3means H, unsubstituted or R4-substituted C1-C12lcil, R4means unsubstituted or substituted aryl or heteroaryl, R5means N or C1-C12alkyl, by transformation of compounds of formula II in which R is cyclohexyl, phenyl, benzyl or a group of formula (a)1means a leaving group, using a halogenation agent in the compound of formula IV, where X is halogen, the conversion of the compounds of formula IV by reacting with the compound of the formula V to the compound of formula VI, which is then transformed using glorieuses agent in the compound of formula I

The invention relates to a method for obtaining compounds of formula I in each case in free form and in salt form, where Q denotes CH or N, Y represents the NO2or CN, Z means СНR3OH , NR3or S, R1and R2each independently of one another denotes hydrogen, unsubstituted or R4-substituted C1-C8alkyl or together form Allenby bridge of two or three carbon atoms, and Allenby bridge may optionally contain a heteroatom selected from the group comprising NR5, O or S, R3means H, unsubstituted or R4-substituted C1-C12lcil, R4means unsubstituted or substituted aryl or heteroaryl, R5means N or C1-C12alkyl, by transformation of compounds of formula II in which R is cyclohexyl, phenyl, benzyl or a group of formula (a)1means a leaving group, using a halogenation agent in the compound of formula IV, where X is halogen, the conversion of the compounds of formula IV by reacting with the compound of the formula V to the compound of formula VI, which is then transformed using glorieuses agent in the compound of formula I

The invention relates to a method for obtaining compounds of formula I in each case in free form and in salt form, where Q denotes CH or N, Y represents the NO2or CN, Z means СНR3OH , NR3or S, R1and R2each independently of one another denotes hydrogen, unsubstituted or R4-substituted C1-C8alkyl or together form Allenby bridge of two or three carbon atoms, and Allenby bridge may optionally contain a heteroatom selected from the group comprising NR5, O or S, R3means H, unsubstituted or R4-substituted C1-C12lcil, R4means unsubstituted or substituted aryl or heteroaryl, R5means N or C1-C12alkyl, by transformation of compounds of formula II in which R is cyclohexyl, phenyl, benzyl or a group of formula (a)1means a leaving group, using a halogenation agent in the compound of formula IV, where X is halogen, the conversion of the compounds of formula IV by reacting with the compound of the formula V to the compound of formula VI, which is then transformed using glorieuses agent in the compound of formula I

The invention relates to new derivatives of formula (I), where R1- R4- hydrogen atoms; X - alkylene with 1 to 6 carbon atoms; Y is lower alkyl; B is - NR5R11where R5is a hydrogen atom, R11selected from 5 - to 6-membered heterocyclic radical, in which one ring member is a carbon and 1 to 4 members of the heteroatoms nitrogen, or sulfur, or their pharmaceutically acceptable salts, are useful as inhibitors of the synthesis of nitric oxide
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