Piperazine derivatives

 

(57) Abstract:

Derivatives of piperazine of the formula I, where Q is phenyl, naphthyl, pyridyl, pyrimidyl, ethenolysis, furyl, benzofuranyl, dihydrobenzofuranyl, benzyl, diphenylmethyl, possibly substituted by 1 or more substituents selected from alkyl, alkoxyl, trifloromethyl, dialkylamino, halogen, cyano and Ethylenedioxy; R - groups (a) and (b), where R1and R2- C1-C6-alkoxyl or methylendioxy; G - C3-C6-cycloalkyl, phenyl, benzoyl, benzylcarbamoyl, alpha hydroxybenzyl, pyrrolyl, where the nitrogen atom is a hydrogen atom or an alkyl or participate in binding with R, an alkyl group, a substituted heterocyclic group (thienyl, imidazolyl); alkanolamines, morpholinoethyl, 1-alcheringa-2-ilen group, phenylalkyl. The compounds of formula I can be used as a therapeutic agent for various diseases of the circulatory system or cerebral region, especially those diseases that are caused by excessive activation of calmoduline. 12 C.p. f-crystals, 6 tab.,

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory system and rvnoy system, such as anti-anxiety activity and protivogololednoy activity, as described in U.S. patent 3362956. It is also known that some of piperazine derivatives have inhibitory calmodulin activity, as described in Azzneim-Forsch. Vol. 37(4), pp. 498 - 502 (1987).

Derivatives of piperazine represented by the formula I, according to the present invention are new compounds on physiological activity have not yet been reported.

In recent years, diseases of the circulatory system or cerebral areas, such as hypertension, heart failure, chest angina, apoplexy, cerebral infarction, Alzheimer's disease or Parkinson's disease, has increased, and a variety of drugs for the prevention and treatment of these diseases. On the other hand, compounds with inhibiting calmodulin activity have been described and some of them discovered that they possess antihypertensive activity and vasodilating activity.

The object of the present invention is a compound used as a therapeutic agent for various diseases of the circulatory system or cerebral region, especially those diseases that are caused izbas to obtain new derivatives of piperazine, represented by formula I, shown below, and their salts and to establish that these compounds possess inhibitory calmodulin activity, antihypoxic activity, inhibitory activity against delayed death of neurons in the mediated (Meriones shawi) and improves the activity of cerebral oedema. Thus, the compounds of formula I possess not only inhibiting calmodulin activity, but strong defending cerebral activity.

The present invention relates to a piperazine derivative of General formula I:

< / BR>
where

Q represents phenyl, naftalina, pyridyloxy, pyramidalnou, izohinolinove, follow, benzofuranyl, dihydrobenzofuranyl, benzyl, diphenylmethyl group, these groups may be substituted by one or more substituents selected from alkyl groups having from 1 to 6 carbon atoms, CNS group having from 1 to 6 carbon atoms, triptorelin group, dialkylamino having from 1 to 6 carbon atoms in each alkyl part, a halogen atom, ceanography and Ethylenedioxy, and these substituents on diphenylmethylene group are phenyl nucleus, or cycloalkyl GRUR> and R2independently represent CNS group having from 1 to 6 carbon atoms, or methylenedioxy;

G represents cycloalkyl group containing 3 to 6 carbon atoms, a substituted or unsubstituted phenyl group, a benzoyl where the phenyl fragment substituted or not substituted, benzylcarbamoyl, where the phenyl fragment substituted or not substituted, alpha hydroxybenzyl group in which the phenyl part is substituted or not substituted, substituted or unsubstituted pyrrolidinyl group, where the nitrogen atom is a hydrogen atom, or alkyl group having from 1 to 6 carbon atoms, or participate in binding with R, alkyl group, substituted heterocyclic group consisting of substituted or unsubstituted thienyl group, substituted or unsubstituted imidazolidine group, substituted or unsubstituted peredelnoj group and C1-C3alkalinous group, alkanolamines having from 2 to 7 carbon atoms, morpholinoethyl the group consisting of morpholino group and C1-C3alkalinous group, 1-alcheringa-2-ilen group having from 1 to 6 carbon atoms in the alkyl part, where the indole part may optionally be substituted, phenylalkyl the group consisting of h is then Deputy G has substituents, the latter are members selected from alkyl groups having from 1 to 6 carbon atoms, CNS group having from 1 to 6 carbon atoms, ancilliary having from 1 to 6 carbon atoms, alkylsulfonyl group having from 1 to 6 carbon atoms, halogen atom and methylendioxy;

Z represents C1-C3alkylenes group, C2-C4alkylenes group, C1-C3alkylenes group having one hydroxyl group, or alkilinity group containing a carbonyl group at one end or in the middle of the carbon chain, or a salt of the compound.

Preferred compounds according to the invention are the compounds of formula I, where the substituent R has the structure represented by the following formula:

< / BR>
Preferred compounds are also compounds of formula I, where the substituent R has the structure represented by the following formula:

< / BR>
Preferred compounds of formula I, where Deputy Q is a phenyl group having at least one substituent in a meta-position in relation to the place of attachment of the phenyl group to piperazinone part.

For the preferred compounds of formula I are niederdorfelden the compounds of formula I, where Q is 2-methyl-3-chloraniline group.

To further preferred is a compound of formula I, where Z is alkalinous group having 2 to 3 carbon atoms.

More preferably the compound of formula I, where Z is alkalinous group having 2 carbon atoms.

The preferred compound is a compound of formula I, where the substituent R represents a 5,6-dimethoxy-1H-indazol part, and the connection of the formula I, where the substituent R represents a 5,6-methylenedioxy-1H-indazol part.

More preferred is a compound of formula I, where Deputy G R is selected from the group comprising 3,4-dimethoxybenzyl group, 4-imidazolylalkyl group, 2-pyridylmethyl group, 3-pyridylmethyl group and 4-pyridylmethylene group.

Preferred are the compounds of formula I, where the substituent R represents a 2-substituted 4,5-dimethoxyaniline part, and the compounds of formula I, where the substituent R represents a 2-substituted 4,5-methylenedioxyaniline part.

Salts of the compounds of formula I typically include salt accession acid. Acid to produce salts of the acids of accession connection fo the oil acids (for example, acetic, propionic, lactic and fumaric acid) and sulphonic acids (for example, methanesulfonate, benzolsulfonat and toluensulfonate acid). For treatment a compound of formula I may be administered to man in the form of salt accession acid when the acid forming salt, harmless to humans.

In the case where the compound of the invention of formula I is an acid, the Deputy, the connection can be converted into a salt with organic or inorganic bases.

The connection according to the invention or salts thereof may form a hydrate(s).

Examples of preferred compounds are:

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6-dimethoxy - 1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - methylenedioxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - methylenedioxy-1-(4-imidazolidinyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(2-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chlorine is fenil)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(3-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - methylenedioxy-1-(3-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(4-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] ethyl-5,6 - methylenedioxy-1-(4-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-6-methoxyphenyl)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-6-methoxyphenyl)-1-piperazinil] ethyl-5,6 - methylenedioxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-triptoreline)-1-piperazinil] ethyl-5,6 - dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-triptoreline)-1-piperazinil] ethyl] -5,6 - methylenedioxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

5,6-dimethoxy-2-[[4,5-dimethoxy-2-[4-(2-methoxyphenyl)-1 - piperazinil]ethyl]phenyl]-1-methylindol or its salt;

5,6-dimethoxy-2-[[4,5-methylenedioxy-2-[4-(2-methoxyphenyl)-1 - piperazinil]ethyl]phenyl]-1-methylindol or its salt;

1-(3-chloro-2-were)-4-[2-[[4,5-dimethoxy-2-(3,4 - acid)]phenyl]ethyl]piperazine or its salt;

1-(3-chloro-2-were)-4-[2-[[4,5-methylenedioxy-2-(3,4 - acid)]phenyl]ethyl]piperazine or its salt;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] prop is] -5,6 - methylenedioxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(4-imidazolidinyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - methylenedioxy-1-(4-imidazolidinyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(2-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - methylenedioxy-1-(2-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(3-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - methylenedioxy-1-(3-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(4-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-2-were)-1-piperazinil] propyl] -5,6 - methylenedioxy-1-(4-pyridylmethyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-6-methoxyphenyl)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-chloro-6-methoxyphenyl)-1-piperazinil] propyl]-5,6 - methylenedioxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-triptoreline)-1-piperazinil] propyl] -5,6 - dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol and its salts;

3-[2-[4-(3-triform and-2-[[4,5-dimethoxy-2-[4-(2-methoxyphenyl)-1 - piperazinil] propyl]phenyl]-1-methylindol or its salt;

5,6-dimethoxy-2-[[4,5-methylenedioxy-2-[4-(2-methoxyphenyl)-1 - piperazinil]propyl]phenyl]-1-methylindol or its salt;

1-(3-chloro-2-were)-4-[2-[[4,5-dimethoxy-2-(3,4 - acid)]phenyl]propyl]piperazine or its salt and

1-(3-chloro-2-were)-4-[2-[[4,5-methylenedioxy-2-(3,4 - acid)]phenyl]propyl]piperazine or its salt.

The compounds of formula I according to the invention can be obtained, for example, processes A - E, presented at the end of the description.

Process A. carboxylic acid Derivative II, which is obtained according to a known method, as described here further, a derivative of piperazine III condense getting connection amide IV. The condensation reaction is carried out in the presence of a condensing agent, such as dichlorochlordene, carbodiimides, a pyridyl disculfidlifederfpan etc. Amide compounds IV then restore with obtaining compounds I. the reduction is usually carried out using a metal hydride, such as sociallyengaged, sodium bis(2-methoxyethoxy)aluminum hydride, sodium borohydride chloride, borane or borane-tertrahydrofuran ring complex, in an inert solvent such as ether (e.g. diethyl ether, tetrahydrofuran, dioxane or demo, at a temperature of from -20oC to the boiling point of the used solvent.

The process B. Carboxylic acid II is converted into the acid chloride of the acid V and the acid chloride of the acid V is subjected to interaction with piperazine derivatives III with getting amide IV, which then restores the connection I.

The reaction of obtaining the carboxylic acid V is performed with the use of thionyl chloride or oxalicacid in the presence of an inert solvent, such as halogenated (for example, dichloromethane or dichloroethane) or an aromatic hydrocarbon, or a temperature from -20oC to the boiling point of the used solvent.

The reaction between the acid chloride of the acid V and piperazine derivatives III is carried out in an inert solvent, such as halogenated (for example, dichloromethane or dichloroethane), an ether (e.g. diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane), amide (e.g., ndimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone, acetonitrile, or an aromatic hydrocarbon, at a temperature of from -20oC to the boiling temperature under reflux solvent used. Recovery amide IV conducted according to the technique of process A.

The process C. the Compound VI, where ylsulphonyl group (for example, methyloxirane) or arylsulfonyl group (for example, tailorshop), the alkyl or aryl portion of which may be substituted by halogen atom, alkyl group, etc. which is obtained according to a known method as described herein further subjected to interaction with piperazine derivatives III.

The reaction is preferably carried out in the presence of organic or inorganic bases. Suitable inorganic bases include carbonate, bicarbonate, etc. of an alkali metal such as potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate or bicarbonate of lithium. Suitable organic bases include tertiary amines, such as trialkylamine (for example, triethylamine, tributylamine and diethylethanolamine), aromatic amines, such as dialkylanilines (for example, N, N-dimethylaniline and N,N-diethylaniline), and heterocyclic compounds such as saturated or aromatic heterocyclic compounds (for example, N-alkylpiperazine, N-alkylboronic, pyridine and 4-dimethylaminopyridine).

Instead the Foundation of the reaction may be conducted using an excess of piperazine derivative III, for example, 2 or more molar equivalence carried out in an inert solvent, such as halogenated (for example, dichloromethane or dichloroethane), amide (e.g., ndimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone), dealkylation (for example, acetone or methyl ethyl ketone, acetonitrile or an aromatic hydrocarbon, at a temperature of from -20oC to the boiling point of the used solvent.

Process D. Amino VII, which is obtained in a known manner, as described hereafter, is subjected to the interaction with bis(2-chloroethyl)amino derivatives.

The interaction is carried out in a basic medium, for example, in the presence of organic or inorganic bases, as described in the process C, or using an excess of compound VII.

The interaction is carried out in an inert solvent, preferably in the presence of NaI, etc. at a temperature of from -20oC to the boiling point of the used solvent. Suitable solvents include halogenoalkane, such as dichloromethane and dichloroethane, amides, for example, ndimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone, dealkylation, for example acetone or methyl ethyl ketone, acetonitrile, aromatic hydrocarbons, and halogenases, such as chlorobenzene.

Process E. the Compound of the formula I can also be sintezirovat presented to G.

Compound VIII is subjected to interaction with G-L, where L is the deleted group selected from a halogen atom or a substituted sulfonyloxy groups, such as alkylsulfonyl group (for example, methyloxirane) or arylsulfonyl group (for example, tailorshop), the alkyl or aryl portion of which may be substituted by halogen atom, alkyl group, etc. in the presence of a suitable base such as sodium hydride, sodium methoxide, potassium carbonate, sodium hydroxide, lithium methylate, utility or potassium hydroxide, to obtain the compound IX.

The reaction can be carried out in the presence of an inert solvent such as an amide (for example, ndimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone), dealkylation (for example, acetone or methyl ethyl ketone), an ether (e.g. diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane), acetonitrile or dimethyl sulfoxide. The reaction temperature is from -20oC to the boiling temperature under reflux solvent used.

When G is a residue substituted derivative of benzene, compound IX can be obtained by the method of M. A. Khan et al., described in Chemical and Pharmaceutical Bullettin, Vol.25, No. 11, pp.3110-3114 (1977). Thus, compound VIII of podverg the presence of a suitable copper compounds, such as a salt of copper (e.g. copper bromide or chloride of copper or copper oxide. The reaction is carried out in the presence or in the absence of potassium carbonate, in a solvent or without it, such as an amide (for example, ndimethylacetamide, dimethylformamide or N-methyl-2-pyrrolidone), dimethyl sulfoxide, hexamethylphosphoramide, pyridine or quinoline at temperatures from room temperature to the boiling point of the used solvent.

When you start with compound X, which is removed by the group L is a halogen atom (e.g. bromine or iodine), a substituted phenyl group and substituted phenolic group can be introduced as G reaction Ullman, using powder of copper or a suitable copper compounds, such as salt of copper.

The introduction of acetylene part of the circuit can be implemented using acetylene copper, synthesized according to the method of J. R. Carson et al., described in J. Med. Chem., Vol. 31, pp. 630-636 (1988). The reaction is carried out in a solvent or without it, such as pyridine, quinoline, dimethylformamide, dimethylsulfoxide or hexamethylphosphoramide, at a temperature from room temperature up to the boiling temperature under reflux solvent used.

When removed by the group L is a halogen atom (for example, brogo lithium such as utility or LDA in a suitable solvent, such as tetrahydrofuran or diethyl ether, at a temperature of from -100oC to the boiling temperature under reflux of the used solvent, and then subjected to the interaction of the reaction product derived from aldehyde G-CHO and subsequent processing, combining basic syntheses.

When L in the compound X is a proton, the introduction of a substituent acyl type is carried out in a suitable solvent, such as dichloromethane, dichloroethane or nitrobenzene, in the presence of a Lewis acid such as aluminum chloride, zinc chloride, tin chloride or boron TRIFLUORIDE, or a proton acid such as sulfuric acid or polyphosphoric acid, at a temperature of from -20oC to the boiling temperature under reflux solvent used.

Although for illustration compounds VIII - XI, above, regarding the process E have two substituent (R1and R2) imidazole, or phenyl ring, it does not limit the number of alternates two.

The structural part R in the compounds of formula I can be obtained in various ways. Typical methods are described below.

The process 1. The compounds I, keyslot synthesized according to method G. Corsi et al., described in Journal of Medicinal Chemistry, Vol. 19, pp. 778-783, 1976. This compound is obtained after adding one or two carbon atoms to the remainder of the carboxylic acid of known chemical methods, may lead to a connection with I any process from A to E or a combination thereof.

3-Chloromethyl-1H-imidazole obtained by the method described in Synthetic Communication, Vol. 18, pp. 259-264 (1988), may also lead to a connection with I any of the processes A to E or a combination of both.

A derivative of piperazine, having an imidazole skeleton, can also be obtained by the method described in published examined application Japan, JP-B-41-9779. In addition, the desired Deputy G can be introduced according to the process E.

Process 2. Compounds with indole skeleton in R, can be synthesized using method M. E. Speeter et al., described in Journal of American Chemical Society, Vol. 76, pp. 6208-6210 (1954), indole derivatives, synthesized in a known manner, the interaction derived indole with oxalylamino and piperazine derivatives III in a solvent such as diethyl ether or tetrahydrofuran, at a temperature of from -100oC to the boiling point of the solvent under reflux, used in the synthesis of diketone is varicela, such as diethyl ether or tetrahydrofuran, at temperatures from -20oC to the boiling point of the used solvent under reflux.

Derived indole may be then subjected to the process E to obtain compound I.

Process 3. Compounds having the skeleton indolene in R, can be synthesized by applying a method described in examined published application Japan JP-A-2-73062. Compounds with CNS group, a 5 - or 6-position of the skeleton indolene can be obtained, for example, the interaction of 3,4-dimethoxyphenylacetone with ethylene oxide in the presence of sodium amide for the formation of 1-hydroxy - 3-(3,4-dimethoxy)butyronitrile, transfer 1-hydroxy-3-(3,4-dimethoxy)butyronitrile in acid hydrolysis and lactonization, the introduction of nitro group in the lactone with subsequent catalytic hydrogenation (in the presence of platinum oxide, and so on) and cyclization to obtain 5,6-dimethoxy-3-hydroxy-2-oxoindole and the conversion of 5,6-dimethoxy-3-hydroxy-2-oxoindole in connection with I any of the processes A to E or a combination of both.

Process 4. Compounds having binarily skeleton in R, can be synthesized by applying the method described in Tet is the notes, using a palladium catalyst.

Then aromaticspecialities derivative described in Journal of Organic Chemistry, Vol. 34, pp. 1372-1379 (1978), is subjected to the interaction with the aryl Grignard reagent for the synthesis of becerileri derivative, which is further treated with a combination of known chemical techniques.

Process 5. Of compounds having the structure of the part of R, shown for compound X, those that have deoxybenzoin the type of the substituent in the form of Z, can be synthesized by the introduction deoxybenzoin type of the substituent in ethylvinylacetate derived in the presence of a Lewis acid such as aluminum chloride, in the presence or in the absence of a solvent, such as dichloromethane or dichloroethane, the reaction Friedel-and, if necessary, protected carboxyl group, converting the compound obtained in connection I with the combination of known chemical methods and any of the processes A and E.

Upon receipt of the compounds of formula I, where the original compound contains a carboxyl group, an amino group, NH group, hydroxyl group, Tilney group or similar functional substitute, it is recommended in some cases to pre-protect functional groups of the f functional groups do not need protection until while they are inactive in the reaction.

Derivatives of piperazine of formula I synthesized this way, and their salts and/or hydrates possess a remarkable inhibiting calmodulin activity. Derivatives of piperazine I manifest their effect upon oral or not oral use, so they can be assigned to oral or not oral ways.

The dose of a compound determined as appropriate in accordance with the symptoms, age and body weight of the patient. Oral dose ranges from 1 to 1000 mg, preferably from 10 to 500 mg, per day per adult in single or divided into several doses dose. Oral dosage forms include tablets, capsules, powders and granules. These dosage forms are obtained from the use of conventional additives, such as solvents, lubricant and binder, conventional techniques. For not oral assignments are used subcutaneous injection, intravenous injection or intravenous infusion for a total dose ranging from 1 to 2000 mg, preferably from 10 to 500 mg per day for an adult.

In combination with other drugs derived from piperazine of the formula I are expected to exercise additional effect or synergistic EDINENIE according to the present invention can be combined include medications to improve cerebral blood circulation (for example, Cinepazide maleate), agents for improving cerebral metabolism (for example, Idebenone, Indeloxazine), psychotropic drugs (e.g., Timiperone, Imipramine and Diazepam), intracranial antihypertensive agents (e.g. Glycerol), antihypertensive agents, vasodilators (e.g., Trapidil), antipyretics, analgesics, anti-inflammatory agents, protivotromboznoe drugs (eg, Ticlopidine), anticoagulants (eg, Heparin), drugs to stimulate fibrinolysis (for example, the activator is tissue plasminogen), diuretics, antihyperlipidemia agents (for example, Probucol), therapeutic agents for ulcers of the digestive system, blood substitutes and agents against malignant tumors.

Compounds of the invention and their pharmacologically acceptable salts have a significant inhibiting calmodulin activity and also wonderful antihypoxic activity. Additionally, the compounds show a remarkable effect on the models of different diseases at dose levels causing minor Central inhibitory action through oral or not oral assignment (action).

Thus, the compounds according to the invention and their pharmacologically acceptable salts vysokopolsky as drugs for the inhibition of intracellular calcium physiological activities, with the participation of calmodulin. Thus, they are used as a prophylactic and therapeutic agent for various diseases caused by excessive activation of calmoduline, especially hypertension, ischemic diseases of the brain, heart, kidneys and so on (for example, cerebral infarction, cerebral embolism, transient cerebral ischemic attack, cerebral thrombosis, cardiac infarction, pulmonary angina, heart failure, acute renal failure and nephritis), the disease in areas of the brain (e.g., Alzheimer's disease, Parkinson's disease and dementia on Binswanger), chemical poisoning, gas poisoning, traumatic cerebral diseases and symptoms, based on these diseases (for example, decreased spontaneity, depression and memory disorders).

The invention will be illustrated in more detail with reference to reference examples, examples, examples, tests, but the invention cannot be regarded as Alenia in chromatography given are by volume, unless stated otherwise.

Test example 1. Inhibiting calmodulin (CaM) activity.

Inhibitory calmodulin activity of the compounds evaluated, using its effect by inhibition calmoduline cyclic nucleotide phosphodiesterase (PDE) as an indicator. Test PDE inhibitory activity carried out by the method described by Thompson (Advances in Cyclic Nucleotide Research, 10, 69, 1979) with modifications. The first stage of incubation is carried out at 30oC for 10 min with the following reaction mixture: 50 mm Tris-HCl buffer (pH 7.5), 5 mm MgCl21 mg/ml bovine serum albumin, CaM from bovine brain [3H] -cGMP, 1 mm CaCl2or 1 mm EGTA, PDE from bovine brain and the test compound in a total volume of 0.5 ml After incubation, the mixture is heated on a boiling water bath for 1 minute, Then to the reaction mixture add 50 ál of snake venom (1 mg/ml) and the whole mixture was incubated at 30oC for 10 min After incubation to this mixture 0.5 ml resin AGI-X2 (suspension in water 1:1) and centrifuged at 3000 revolutions/minute for 20 minutes, the Radioactivity of the surface of the solution is measured liquid acquired scintillation counter. The value of the IC50define as the concentration showing 50% inhibi example 2. Activity on the model of the nitrogen-induced hypoxia in mice.

Each mouse in a group of nine or ten mice given oral 30 mg of the test compound. After 60 min after injection, each mouse was placed in a 500 ml volume of a transparent container having an outlet hole, and introduce nitrogen gas into a container with a speed of 5000 ml/min to Measure the time from the start of the input of nitrogen to stop breathing and get the speed increase time compared with the control group (100%). The results obtained are shown in table.2.

Example 1. 5,6-Dimethoxy-1-(3,4-acid)-3-[2-[4-[2- methoxyphenyl] -1-piperazinil]ethyl]indole.

A solution of 1.0 g of 5,6-dimethoxyindole in 120 ml of anhydrous ethyl ether is added dropwise to 0,49 ml oxalicacid at 0oC, followed by stirring 20 minutes To the mixture of 1.08 g of 2-methoxyphenylpiperazine and the mixture is then stirred at this temperature for 30 minutes After completion of the reaction, water is added and the mixture extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent evaporated to obtain 1.5 g of crude crystalline lidocaine.

The crystals are dried and then added to a suspension of 260 mg sociallyengaged in 50 ml tetrahedr is but the type of 0.26 ml of water, of 0.26 ml of 10% aqueous sodium hydroxide solution and 0.78 ml of water. Insoluble material removed by filtration using Celite, and dried over anhydrous sodium sulfate. The solvent is evaporated and the residue purified column chromatography on silica gel. From elyuirovaniya the ethyl acetate fraction allocate 820 mg of the derivative of piperazine.

Derived piperazine (820 mg) are added to a suspension of 124 mg of 60% sodium hydride in dimethylformamide. After stirring at room temperature for 30 minutes add 960 mg of 3,4-dimethoxybenzaldehyde, followed by stirring at room temperature for 1 h After the reaction to the reaction mixture, water is added, followed by extraction with ethyl acetate. The extract is washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel. From elyuirovaniya the ethyl acetate fraction receive 600 mg specified in the title compound as a yellow oily substance.

IR (KBr)max(cm-1): 1503, 1464, 1242, 1137, 1026.

1H-NMR (CDCl3) memorial plaques: of 2.7-3.0 (6H, m), 3,9-3,3 (4H, m), of 3.78 (3H, s), of 3.84 (3H, s), 3,86 (3H, ASS="ptx2">

In 40 ml of 1,1,2,2-tetrachlorethane dissolve 4.0 g of 3,4-dimethoxyaniline and to the solution was added 28 mmol of trichloride boron in an argon atmosphere under ice cooling. To the reaction mixture and then 2.3 g of chloroacetonitrile followed by heating under reflux for 1.5 hours

After cooling, to the reaction mixture are added 20 ml of 2 N. hydrochloric acid. After stirring at 80oC for 30 min emerged syrup is removed by decantation. The residue is extracted with dichloromethane. The residue is collected, neutralized with an aqueous solution of sodium hydroxide, filtered using Celite and again extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel (hexane:ethyl acetate 3:1) to obtain 809 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: is 3.82 (3H, s), a 3.87 (3H, s), 4,70 (2H, s), 6,12 (1H, s), 7,03 (1H, s).

Example 2. 5,6-Dimethoxy-3-[[4-[2-methoxyphenyl]-1-piperazinil]methyl]-1H-indazol.

In 20 ml of concentrated hydrochloric acid dissolved 800 mg of 4,5-dimethoxy-2-amino-chloracetophenone and there is added a solution of 264 mg (3.8 mmol) of sodium nitrate 4.0 ml of water at -10oC authorized hydrochloric acid, followed by stirring for 1 h The resulting precipitate is collected by filtration, washed once with water and dried in air. The solid product is dissolved in dimethyl sulfoxide and to the solution was added 700 mg of N-(2-methoxyphenyl)piperazine and 3.0 g of potassium carbonate. After 3 minutes add the ethyl acetate and the solution washed three times with water and once with saturated aqueous sodium chloride. The organic layer is dried and the solvent evaporated. Purification of the residue column chromatography (ethyl acetate:ethanol 6:1) on silica gel gives 594 mg specified in the connection header.

Melting point: 192oC.

IR (KBr)max(cm-1): 3376, 1503, 1488, 1317, 1242, 1209.

1H-NMR (CDCl3) memorial plaques: 2,6-2,8 (4H, m), 2,9-3,2 (5H, m), of 3.84 (3H, m), 3,93 (6H, Shir.C.), 6,8-7,0 (5H, m), 7,26 (1H, s).

Example 3. 5,6-Dimethoxy-1-(3,4-acid)methyl-3-[[4-[2- methoxyphenyl]-1-piperazinil]methyl]-1H-indazol.

In dimethylformamide are suspended for 61.6 mg of sodium hydride at 0oC and there is added 590 mg of 5,6-dimethoxy-3-[[4-[2-methoxyphenyl]-1-piperazinil]-methyl] -1H - indazole, followed by stirring for 30 minutes To the mixture of 290 mg of 3,4-dimethoxyphenethylamine. After 1.5 h to the reaction mixture add 2.0 ml of water followed by evaporation of solvent.

C ethanol with getting 654 mg specified in the connection header.

Melting point: 149 - 150oC.

IR (cm-1): 1506, 1473, 1257, 1158, 1140, 1029.

1H-NMR (CDCl3) memorial plaques: 7,26 (s, 1H), 7.0 and 6.5 in (m, 8H), of 5.45 (s, 2H), 3,95 (s, 2H), 3,92 (s, 3H), 3,86 (s, 3H), of 3.84 (s, 6H), 3,76 (s, 3H), 3,2-3,0 (m, 4H), of 2.8 to 2.6 (m, 4H).

Referential example 2. N-(3,4-Dimethoxyphenethyl)-2-(4,5 - dimethoxyphenyl)ndimethylacetamide.

Dry dichloromethane solution (1000 ml) of 3,4-dimethoxyphenylethylamine made with 325 g of 3,4-dimethoxyphenylacetic acid and 300 ml of thionyl chloride are slowly added to a biphasic solution containing 300 g of 3,4-dimethoxyphenethylamine, 850 ml of 2 n sodium hydroxide and 2000 ml of dichloromethane with stirring under ice cooling. To the mixture add chloroform to dissolve the precipitated sludge. The aqueous layer was removed and the organic layer was washed with saturated aqueous sodium bicarbonate, dried and the solvent evaporated. To the residue is added methanol and allow to cool, and the so formed precipitate collected by filtration to obtain 570 g specified in the connection header.

Reference example 3. 1-(3,4-Dimethoxybenzyl)-3,4-dihydro-6,7-dimethoxyisoquinoline hydrochloride.

A solution of 570 g of N-(3,4-dimethoxyphenethyl)-2-(4,5-acid)ndimethylacetamide and 500 ml of phosphorus oxychloride in 3500 ml azet the following which allow to stand. Selected crystals thus collected by filtration to obtain 590 g specified in the connection header.

1H-NMR (d6-DMSO) : 7,63 (s, 1H), 7,26 (s, 1H), 7,11 (s, 1H), 7,0 to 6.8 (m, 2H), 4,58 (s, 2H), 3,88 (s, 3H), 3,83 (s, 3H), 3,74 (s, 3H), 3,70 (s, 3H), of 4.0 to 3.8 (m, 2H), 3,1-2,9 wide. So, J = 7 Hz, 2H).

Reference example 4. TRANS-2-acetyl-7,7-dimethoxy-1-(4,5-dimethoxybenzamide)- 1,2,3,4-tetrahydroisoquinoline.

To 600 g of 1-(4,5-dimethoxybenzyl)-3,4-dihydro-6,7 - dimethoxyisoquinoline hydrochloride add 2000 ml of acetic anhydride and the mixture is refluxed for 6 h, and then allow to cool over night. Released thus crystalline precipitate is collected by filtration and recrystallized from ethanol to obtain 500 g specified in the connection header.

IR (cm-1): 1632, 1518, 1263, 1245.

1H-NMR (CDCl3) memorial plaques: 7,13 (s, 1H), 7,05 (s, 1H), 6.90 to (s, 1H), of 6.71 (s, 1H), 6,62 (s, 1H), of 5.05 (d, J=9 Hz, 1H), of 3.97 (s, 3H), with 3.89 (s, 9H), 3,8-2,5 (m, 4H), of 1.81 (s, 3H).

Reference example 5. 2-(2-Acetamidomethyl)-4,4',5,5'- tetramethoxybenzene.

To 500 g of TRANS-2-acetyl-7,7-dimethoxy-1-(4,5-dimethoxybenzamide) -1,2,3,4-tetrahydroisoquinoline add 1000 ml of 10% hydrochloric acid and 500 ml of methanol and the mixture refluxed. The reaction cracka under reduced pressure. Recrystallization of the precipitate from ethanol gives 270 g specified in the connection header.

IR (cm-1): 1680, 1638, 1515, 1128.

1H-NMR (CDCl3) memorial plaques: 7,26 (s, 1H), 6,9-of 6.75 (m, 4H), 6,7-6,5 (width, 1H), 4,15 (s, 2H), 3,91 (s, 3H), with 3.89 (s, 3H), 3,86 (s, 3H), 3,85 (s, 3H), 3,6-3,4 (m, 2H), 2,92 (t, J = 7.2 Hz, 2H), 1,89 (s, 3H).

Reference example 6. 2-(2-Acetamidomethyl)-2'-nitro-4,4',5,5'- tetramethoxybenzene.

To a solution of 200 g of 2-(2-acetamidomethyl)-4,4',5,5'- tetramethoxybenzene in 2000 ml of acetic acid is added slowly 60 ml of 70% nitric acid at 0oC. Immediately after the addition, the mixture was poured into water and extracted with methylene chloride. The extract is neutralized with an aqueous solution of sodium bicarbonate and washed with saturated aqueous sodium chloride. The solvent is removed under reduced pressure and the residue is recrystallized from ethanol to obtain 196 g specified in the connection header.

Melting point: 142-144oC.

IR (cm-1): 1524, 1272, 1128.

1H-NMR (CDCl3) memorial plaques: 7,79 (s, 1H), was 7.36 (s, 1H), 6,80 (s, 1H), 6,76 (s, 1H), 6,4 (width, 1H), 4,60 (s, 2H), 4,0 (width, 12H), 3.45 points (K, J = 7.2 Hz, 2H), equal to 2.94 (t, J = 7.2 Hz, 2H), of 1.85 (s, 3H).

Reference example 7. 2-[2-(2-Acetamidomethyl)-4,5-acid]-5,6-dimethoxyindole.

To a solution of the t 4.7 g of zinc at 85oC. the Reaction mixture was filtered, washed with ethanol and the solvent evaporated. To the residue add an aqueous solution of ammonium hydroxide and the mixture extracted with ethyl acetate. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate) to give 1.84 g specified in the procurement of the connection.

1H-NMR (CDCl3) memorial plaques: 8,10 (s, 2H), 8,08 (s, 1H), of 8.06 (s, 1H), 7,72 (s, 1H), 7,44 (s, 1H), 6,80 (width, 1H), 3,92 (s, 6H), 3,88 (s, 6H), 3,5-3,3 (m, 2H), from 3.0 to 2.8 (m, 2H), 1,92 (s, 3H).

Reference example 8. 2-[2-(2-Acetamidomethyl)-4,5-acid]-5,6-dimethoxy-1-methylindole) are studied.

In dimethyl sulfoxide slowly suspended 480 mg 35% potassium hydride and the suspension added to 1.37 g of 2-[2-(2-acetamidomethyl)-4,5-acid]-5,6-dimethoxyindole, followed by stirring for 10 minutes then add To the mixture of 700 mg of dimethylsulfate, followed by stirring for 30 minutes the Reaction mixture was poured into water and extracted with methylene chloride. The extract is successively washed with water and saturated aqueous sodium chloride and the solvent is removed under reduced pressure. Recrystallization of the precipitate from ethanol gives 1.20 g specified in the connection header.

IR (cm-1): 3376, 1168, 1486, 1222.

1, ,65 (t, J = 7.2 Hz, 2H), of 1.84 (s, 3H).

Reference example 9. 2-[2-(2-Aminoethyl)-4,5-acid]-5,6-dimethoxy-1-methylindole hydrochloride.

A solution of 53 g of 2-[2-(2-acetamidomethyl)-4,5 acid]-5,6-dimethoxy-1-methylindole 2 N. hydrochloric acid is refluxed for 17 hours, the Reaction mixture is subjected to the azeotropic distillation under reduced pressure with ethanol and benzene and the residue is recrystallized from ethanol to obtain 48 g specified in the connection header.

IR (cm-1): 3272, 2832, 1504, 1454, 1244, 1010.

1H-NMR (CDCl3) memorial plaques : 6,98 (width, 3H), 7,06 (s, 1H), 7,00 (s, 1H), 6,9-6,7 (m, 2H), 6.35mm (s, 1H), 3,94 (s, 3H), 3,90 (s, 3H), a 3.87 (s, 3H), of 3.80 (s, 3H), of 3.45 (s, 3H), 3,0-2,7 (width, 4H).

Example 4. 5,6-Dimethoxy-2-[[4,5-dimethoxy-2-[4-(2-methoxyphenyl)-1-piperazinil]ethyl]phenyl]-1-methylindole) are studied.

A solution of 47 g of the hydrochloride of 2-[2-(2-amino-ethyl)-4,5-acid]-5,6-dimethoxy-1-methylindole, a 30.7 g of bis(2-chloroethyl)aminoanisole, with 37.2 g of sodium iodide and 34,0 g of potassium carbonate in 200 ml of dimethylformamide is heated at 80oC 1 h the solution was added 17 g of potassium carbonate, 3 hours later, add 17 g of potassium carbonate followed by heating for 15 hours the Solvent is removed under reduced pressure and the residue is dissolved in water and extracted with have from ethanol to obtain 32 g (51%) specified in the connection header.

Melting point: 171 - 173oC.

IR (cm-1): 1500, 1486, 1236, 1212.

1H-NMR (CDCl3) memorial plaques: 7,10 (s, 1H), 7,0 to 6.8 (m, 7H), 3,98 (s, 3H), of 3.94 (s, 3H), of 3.84 (s, 3H), 3,82 (s, 3H), equal to 2.94 (s, 3H), of 3.1 and 2.9 (m, 4H), 2,8-2,4 (m, 8H).

Reference example 10. 4,5-Dimethoxy-2-(1-pyrrolyl)benzoimidazol.

In 100 ml of tetrahydrofuran is dissolved 14.5 g of methyl 4,5-dimethoxy-2-(1-pyrrolyl)benzoylperoxide and there are added dropwise to 24.5 ml (3.4 M) of sodium bis(2 - methoxyethoxy)aluminum hydride under stirring with ice cooling. Once added, the mixture warmed up to room temperature and heated for 6 hours After completion of the reaction 0.63 ml of a saturated aqueous solution of sodium bicarbonate and 1.55 ml of water is added in order and the precipitate removed by filtration. The filtrate is evaporated and the residue is subjected to chromatography on a column of silica gel. From the faction, elyuirovaniya chloroform, allocate 10.3 g of a brown oily substance. Recrystallization from ethyl ether gives specified in the title compound as colorless crystals.

Melting point: 92 - 93oC.

IR (cm-1): 3530, 2960, 2930, 1610, 1520 (KBr).

1H-NMR (CDCl3) memorial plaques: 3,86 (3H, s), of 3.95 (3H, s), of 4.45 (2H, d, J = 5.3 Hz), 6,30 (2H, t, J = 2.1 Hz), at 6.84 (2H, t, J = 2.1 G the 15 ml of ethyl ether was dissolved 3.0 g of 4,5-dimethoxy-2-(1-pyrrolyl)benzoimidazole and there is added 15 ml of concentrated hydrochloric acid, followed by stirring at room temperature for 1 h To the reaction mixture 50 ml of water and the mixture is neutralized with a saturated aqueous solution of sodium carbonate and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to obtain a brown oily substance. Separately dissolve 460 mg of metallic sodium in 25 ml of ethanol there is added 6,18 g ethylmalonate for solution preparation. To this solution add a solution in tetrahydrofuran (25 ml) vysheperechislennogo brown oily substance. After stirring at room temperature for 3 h the solvent is removed under reduced pressure. To the residue water is added and the mixture is acidified with concentrated hydrochloric acid and then extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. Purification of residue by chromatography on a column of silica gel (chloroform) gives 3,10 g specified in the title compound as a brown oily product.

1H-NMR (CDCl3) memorial plaques : to 1.16 (6H, t, J = 7.0 Hz), 3,00-3,25 (2H, m), 3,70-are 3.90 (1H, m), 3,83, 3,88 (3H, s) 4,08 (4H, K, J = 7,0 Hz), 6,30 (2H, t, J = 2.0 Hz), 6,77 (2H, s).

Referential example 12. Ethyl-3-(4,5-dimethoxy-2-(1-saws] malonate and to the solution add 5.0 ml of 35% aqueous sodium hydroxide followed by heating under reflux for 3 hours The solvent is removed under reduced pressure and to the residue water is added. The residue is acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure to obtain a pale brown powder. The powder is heated at 150oC for 10 min, allowed to cool and purified column chromatography on silica gel (chloroform-methanol) to obtain 2.1 g of a pale brown powder. Recrystallization from a mixture of chloroform-ethyl ether gives specified in the title compound as colorless crystals.

Melting point: 170 - 173oC.

1H-NMR (CDCl3) memorial plaques: for 2.83 (2H, t, J = 7.8 Hz), 2,77 (2H, t, J = 7.8 Hz), 3,84, are 3.90 (3H, s), 6,30, 6,74 (2H, t, J = 2.0 Hz), 6,78 (2H, s).

Example 5. 1-(3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)-1-oxopropyl)- 4-(2-methoxyphenyl)piperazine.

In 20 ml of tetrahydrofuran is dissolved 1.20 g of N,N-carbonyldiimidazole and a solution of 2.0 g of ethyl 3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)propionate in 40 ml of tetrahydrofuran are added to a solution at room temperature under stirring. The stirring is continued for an additional 1 h and add 2,98 g of 1-(2-methoxyphenyl)piperazine, followed by stirring at 40-60 what s on silica gel (chloroform-methanol) to obtain 1.9 g of a colorless oily substance. Recrystallization from ethanol gives specified in the title compound in the form of crystals.

Melting point: 141 - 142oC.

IR (KBr, cm-1): 2940, 2840, 1630, 1590, 1520.

1H-NMR (CDCl3) memorial plaques: 1,15-to 1.45 (2H, m), 2,70 is 3.15 (6H, m), 3,15-are 3.90 (4H, m), 3,83, 3,84, 3,91 (acwc. 3H, s), 6,27 (2H, t, J = 2.2 Hz), 6,60-7,05 (8H, m).

Elemental analysis for C26H31N3O4:

Calculated, %: C 69,47; H 6,95; N 9,35;

Found, %: C 69,37; H 6,88; N 9,14.

Example 6. 1-(3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)propyl)- 4-(2-methoxyphenyl)piperazine the dihydrochloride hemihydrate.

To 100 ml of tetrahydrofuran, add 18 ml of 1.0 M complex, borane-tetrahydrofuran and 1.14 g of 1-(3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl - 1-oxopropyl)-4-(2-methoxyphenyl)piperazine at room temperature and the mixture is heated under reflux for 27 hours since discovered that the reaction is not completely next, add 10 ml of borane-tertrahydrofuran ring complex and boiling under reflux continued an additional 9 hours After cooling to room temperature, to the reaction mixture add 10 ml of water and the solvent is removed under reduced pressure. To the residue add 35 ml of 5% hydrochloric acid followed by heating from 50 to 60o

Melting point: 210 - 212oC.

IR (KBr, cm-1): 2950, 2750-2000, 1600, 1510.

1H-NMR (CDCl3) memorial plaques: 1,65-2,10 (2H, m), 2,50-3,15 (4H, m), 3,15 to 3.8 (4H, m), 3,86, 3,94, 4,08 (3H, s), 4,00-4,60 (2H, m), 4,90-of 5.40 (2H, m), 6,28 (2H, t, J = 2.0 Hz), 6,78 (4H, s), 7,00-7,80 (3H, m), of 8.25 (1H, d, J = 7,8 Hz).

Elemental analysis for C26H33N3O32HCl1/2H2O:

Calculated, %: C 60,35; H 7,01; N 8,12;

Found, %: C 60,61; H 6,95; N 8,02.

Reference example 13. m-Meconin.

A mixture of 250 g veratrole acid, 275 ml of formaldehyde (40%) and 1000 ml of concentrated hydrochloric acid is heated at 60 - 70oC for 12 h under stirring. To the reaction mixture add an equal volume of ice water and the mixture is vigorously stirred in an ice bath. Insoluble material is removed by filtration and the filtrate allowed to stand at 5oC to room temperature for 24 h, during which time the precipitate crude crystals, which are collected by filtration, washed with water the ka melting point: 155oC.

1H-NMR (CDCl3) memorial plaques: 3,98, 3,94 (each 3H, s), 6.90 to, 7,31 (each 1H), 5,23 (2H).

Reference example 14. m-Semipinnata acid.

A mixture of 7.8 g m-meconine, 80 ml of water and 1 n sodium hydroxide was stirred at 50-70oC for about 1 h on a water bath for hydrolysis. After cooling in a water bath add to 3.36 g of sodium bicarbonate and then after 5 min add 160 ml 1/3 M potassium permanganate. After 10 min the ice bath put aside. After 30 min heat subsides, and the reaction is finished. The reaction mixture is filtered, the filtrate acidified with concentrated hydrochloric acid and after concentration under reduced pressure gain of 5.3 g m-hemipenial acid, having a melting point of 180oC.

Reference example 15. m-Hemipenial anhydride.

Two grams of m-hemipenial acid dehydration and sublimate at 180-200oC in freeze-purifying installation with obtaining 1.6 g m-gemeentewapen anhydride having a melting point of 174 - 176oC.

IR (KBr, cm-1): 1764.

Example 7. 5,6-Dimethoxy-1,3-dioxo-N-2-(4-(2-methoxyphenyl)-1-piperazinyl)utilizando.

A mixture of 1-(2-amino)ethyl-4-(2-methoxyphenyl)piperazine (640 mg) and 723 mg what Hladilnika for 5 h, during which the deposited crystals are collected by filtration. The mother liquor is purified column chromatography on silica gel and recrystallized from toluene to obtain colorless crystals. The total output of 700 mg.

Melting point: 206oC.

1H-NMR (CDCl3) memorial plaques: 4,00 (6H, s), 3,85 (3H, s), 7,31 (2H, s), 6,8-7,0 (4H, m).

Receive hydrochloride connection.

Melting point: 237 - 242oC.

Elemental analysis for C23H27N3O52HCl1/2H2O:

Calculated, %: C 54,44; H 5,98; N 8,28;

Found, %: C 54,83; H 5,94; N 8,64.

Example 8. 5,6-Dimethoxy-1-oxo-N-2-(4-(2-methoxyphenyl)- 1-piperazinyl)utilizando.

5,6-Dimethoxy-1,3-dioxy-N-2-(4-(2-methoxyphenyl)- 1-piperazinyl)utilizando (900 kg) is refluxed in 34 ml of acetic acid in the presence of 1.8 g of zinc for 200 minutes, the Reaction mixture was filtered, concentrated under reduced pressure and purified column chromatography on silica gel (dichloromethane : methanol 30:1) to obtain 600 mg of the amorphous compound. The compound obtained is dissolved in a small amount of ethanol and add an excess of 3% hydrogen chloride in ethanol to obtain hydrochloride specified in zag is 9N3O42HClH2O:

Calculated, %: C 54,98; H 6,62; N AT 8.36;

Found, %: C 54,48; H Is 6.78; N 8,18.

Reference example 16. 5,6-Dimethoxy-3-benzylidene.

25 ml-type flask was placed 4.0 g m-gemeentewapen anhydride, of 4.54 g of homoveratric acid and sodium acetate and the flask is heated on a sand bath at 235-240oC, leave the mixture to interact within 6 hours, the Reaction mixture was purified column chromatography on silica gel (dichloromethane) to obtain the specified title compound as a colorless amorphous compound.

1H-NMR (CDCl3) memorial plaques: 3,9 - 4,0 (each 3H x 4), 6,24 (h, C), 6,89 (1H, d, J = 9.0 Hz), 7,09, 7,29 (1H x 2, c x 2), 7,32 (1H, DD, J = 1,8, 9.0 Hz), to 7.50 (1H, d, J = 1,8 Hz).

Reference example 17. 4,5-Dimethoxy-2-(3,4-acid)acetyl - N-2-(4-(2-methoxyphenyl)-1-piperazinyl)ethylbenzamide.

A mixture of 5,6-dimethoxy-3-benzylideneamino (3.0 g) and 3.0 g of 1-(2-amino)ethyl-4-(2-methoxyphenyl)piperazine in ethanolsoluble (1:1) is refluxed 5 hours After completion of the reaction the solvent is concentrated and the residue purified column chromatography on silica gel (dichloromethane : methanol 40:1) to obtain 5.2 g in the form of a colorless amorphous compound.

Example 9. 5,6-Dimethoxy-1-(3,4-dimethoxy)b g of 4,5-dimethoxy-2-(3,4-acid)acetyl-N-2- (4-(2-methoxyphenyl)-1-piperazinyl)ethylbenzamide in acetic anhydride is refluxed for 1 h Acetic anhydride is removed under reduced pressure and the residue purified column chromatography on silica gel (dichloromethane:methanol 40:1). Recrystallization from methanol gives 850 mg of colorless crystals with getting 5,2 g in the form of a colorless amorphous compound.

Melting point: 127 - 128oC.

1H-NMR (CDCl3) memorial plaques: 6,55 (1H, Shir. C) of 4.05 (2H, m), 2,8 (2H, Sch.C.), of 2.9 (4H, Sch.C.), the 3.2 (4H, Shir.C).

The resulting crystals are dissolved in a small amount of ethanol and add an excess of 3% hydrogen chloride in ethanol. Recrystallization from ethanol gives specified in the title compound as colorless crystals.

Melting point: 240 - 241oC.

Elemental analysis for C32H37N3O62HCl3/2H2O:

Calculated, %: C 58,27: H 6.42 per: N 6,37;

Found, %: C 58,47; H 6,45; N 6,25.

Example 10. 5,6-Dimethoxy-1-(3,4-dimethoxy)benzyl-3-oxo-2-(4-(2 - methoxyphenyl)-1-piperazinyl)utilizando the dihydrochloride sesquihydrate.

5,6-Dimethoxy-1-(3,4-dimethoxy)benzylidene-3-oxo-2-(4-(2 - methoxyphenyl)-1-piperazinyl)utilizando catalytically restore in ethanol in the presence of 5% palladium on carbon. The catalyst was removed by filtration, to the filtrate add 3% chlorine is reed collected by filtration.

Melting point: 159 - 165oC (decomposition).

Elemental analysis for C32H39N3O62HCl1/2H2O:

Calculated, %: C 59,72; H to 6.58; N 6,53;

Found, %: C 59,67; H 6,67; N 6,62.

Reference example 18. Acetylene 3,4-dimethoxyaniline.

In 15 ml of aqueous ammonia dissolving 0.39 g of copper iodide and the solution added to a solution of 0.33 g of 3,4-dimethoxyphenylacetone in 20 ml of ethanol at room temperature. The mixture is stirred for 1 h, filtered, washed five times with water, once with ethanol and once with ethyl ether, and dried under reduced pressure at 40oC to obtain 110 mg specified in the connection header.

Example 11. 1-(2-(2-(3,4-Acid)ethinyl)-4,5-acid)ethyl-4-(2-methoxyphenyl)piperazine the dihydrochloride monohydrate.

In 50 ml of pyridine is dissolved 1,58 g (1-(2-iodine-4,5 - acid)ethyl-4-(2-methoxyphenyl)piperazine and add 0,80 g acetylenic 3,4-dimethoxyaniline. The mixture is heated at 120oC in nitrogen atmosphere for 24 hours the Reaction mixture was poured into water and extracted with ethyl acetate. Two-phase (organic and aqueous) liquid is filtered using Celite, and then again divided into two phases. The organic layer was washed with saturated aqueous Ho sediment. Cleaning the sediment column chromatography on silica gel gives 0.75 g of amorphous 1-(2-(2-(3,4-acid)ethinyl)-4,5-acid)ethyl-4-(2-methoxyphenyl) piperazine, which is then converted into the hydrochloride and recrystallized from ethanol to obtain 0,70 g specified in the title compounds as colorless crystals.

Melting point: 164 - 167oC.

IR (cm-1): 2210.

Mass spectrum (EI): 516 (M+, 5,28).

1H-NMR (CDCl3) memorial plaques: 2,96 (4H, m) to 3.36 (6H, m), 3,80 - of 3.96 (2H, m), of 3.84 (3H, s) to 3.89 (3H, s), 3,91 (6H, s) to 3.92 (6H, s), 6,86 - 7,20 (4H, m), 7,35 (3H, m), 7,53 (2H, m).

Elemental analysis for C31H36N2O52HClH2O:

Calculated, %: C 61,28; H 6,64: N BR4.61;

Found, %: C 61,37; H Is 6.78; N 4,55.

Example 12. 1-[2-[4,5-Dimethoxy-2-[(3,4-acid) hydroxymethyl]] phenyl]ethyl-4-(2-methoxyphenyl)piperazine.

To tertrahydrofuran ring to a solution of 1.80 g of 1-[2-[2-bromo-4,5 - acid] ethyl] -4-(2-methoxyphenyl)piperazine add a 15% hexane solution of 5.0 mmol of utility at -78oC. After stirring for some time add 830 mg paratroopa aldehyde and the mixture is heated to 0oC. To the reaction mixture are added water and then extracted with ethyl acetate. Solution the receiving of 1.62 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: 7,05 to 6.8 (m, 7H), 6,70 (s, 1H), 6,60 (s, 1H), 5,93 (W, 1H), with 3.89 (s, 6H), 3,85 (s, 6H), 3,71 (s, 3H), 3,4 - 2,4 (m, 13H).

Example 13. 1-[2-[4,5-Dimethoxy-2-[(3,4-acid)methyl]] phenyl]ethyl-4-(2-methoxyphenyl)piperazine.

Acetic acid a solution of 1-[2-[4,5-dimethoxy-2-[(3,4 - acid)hydroxymethyl]]phenyl]ethyl-4-(2-methoxyphenyl) piperazine is subjected to hydrogenation in the presence of a catalyst of palladium on coal. After the reaction, the catalyst was removed by filtration and the solvent is subjected to the azeotropic distillation with benzene to obtain 1.60 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: of 7.1 and 6.6 (m, 9H), 3,93 (s, 2H), with 3.89 (s, 3H), 3,86 (s, 3H), 3,85 (s, 3H), 3,82 (s, 3H), 3,81 (s, 3H), 3,3 - 2,7 (m, 14H).

Example 14. 1-[2-[4,5-Dimethoxy-2-[(3,4-acid)acetyl]] phenyl]ethyl-4-(2-methoxyphenyl)piperazine.

To tertrahydrofuran ring solution 5,80 g of 1-[2-[2-bromo-4,5 - acid] ethyl] -4-(2-methoxyphenyl)piperazine add 9,44 ml of a 15% hexane solution of utility at -78oC. After stirring for some time raise the temperature under reduced pressure to remove gases. To the solution was added 1.92 g of pualeilani at -78oC.

Separately of 10.2 ml of a 15% hexane solution bucilla the 8oC, followed by stirring for 30 minutes the resulting solution is added dropwise to vysheperechislennogo solution. The temperature was raised to 0oC and the mixture is stirred for 2 hours and Then water is added and the mixture extracted with ethyl acetate, the extract washed with saturated aqueous sodium chloride, dried over sodium sulfate and the solvent evaporated. The precipitate is first purified column chromatography on silica gel. Then add 4 N. hydrochloric acid and heated at 100oC for 15 min to obtain a transparent solution. The solution is cooled, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract is purified column chromatography on silica gel (hexane, ethyl acetate) to give 490 mg specified in the title compound as amorphous powder.

1H-NMR (CDCl3) / memorial plaques: 7,1 - 6,7 (m, 9H), of 4.13 (s, 2H), 3,92 (s, 3H), a 3.87 (s, 6H), 3,86 (s, 3H), 3,85 (s, 3H), 3,3 - 2,6 (m, 12H).

Reference example 19. 1-[(2-Amino-4,5-dimethoxy)phenyl]acetyl-4-(2-methoxyphenyl)piperazine.

Methylenechloride solution containing 15 g (4,5-dimethoxy-2-nitro)phenylacetic acid, 12 g of 2-methoxyphenylpiperazine and 13 g of dichlorophenylisocyanate stirred at room is etousa filtering to obtain 19.7 g of solid product. To the solid product add 400 ml of ethyl acetate and 1.0 g of platinum oxide and carry out the hydrogenation in the night. The reaction mixture is filtered, the solvent evaporated and the residue crystallized from ethyl acetate to obtain 7.5 g specified in the connection header.

Melting point: 113 - 116oC.

IR (cm-1): 3348, 1606, 1520, 1500, 1462, 1240, 1212, 1038.

1H-NMR (CDCl3) memorial plaques: a 7.1 to 6.8 (m, 4H), of 6.96 (s, 1H), 6,91 (s, 1H), a 3.87 (s, 3H), 3,82 (s, 3H), 3,79 (s, 3H), 3,62 (s, 2H), 3,3-to 2.7 (m, 8H).

Reference example 20. 1-[[2-(4-Chloroethylamino)-5,6-dimethoxy]phenyl]ethyl-4-(2-methoxyphenyl)piperazine.

To tetrahydropyranol suspension of 300 mg of sociallyengaged boiling under reflux add 1.5 g of 1-[(2-amino-4,5-dimethoxy)phenyl] acetyl-4-(2 - medociprin)piperazine. Add saturated aqueous solution of sodium sulfate and the mixture is extracted with ethyl acetate. The solvent is subjected to the azeotropic distillation with benzene and the residue immediately add 50 ml of methylene chloride, 1.0 ml of triethylamine and 5.50 g of 4-chlorobutyronitrile. Add an aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate) to obtain 700 mg of UCU(s, 9H), 3,66 (t, 2H, J = 7 Hz), 3,2-3,0 (m, 4H), 2.8 to 2.0 (m, 10H), 2,0-1,5 (m, 2H).

Example 15. N-[2-[2-[4-(2-Methoxyphenyl)piperazinil]ethyl]-4,5 - dimethoxy] phenyl]pyrrolidone.

To dimethylformamide solution of 110 mg of sodium hydride added 660 mg of 1-[[2-(4-chloroethylamino)-5,6-dimethoxy] phenyl] ethyl-4-(2 - methoxyphenyl)piperazine and the mixture is heated at 80oC. After completion of the reaction, the reaction mixture is extracted with methylene chloride and the solvent is subjected to the azeotropic distillation of water and the benzene under reduced pressure. Purification of column chromatography on silica gel (3% ethanol/chloroform) gives 463 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: 7,24 (s, 1H), 7,0 to 6.8 (m, 4H), of 6.61 (s, 1H), 3,88 (s, 3H), a 3.87 (s, 3H), of 3.84 (s, 3H), 3,8-3,6 (m, 2H), 3,2-3,0 (m, 4H), 2,8-2,5 (m, 10H), 2,3-2,2 (m, 2H), 1,3-1,1 (m, 2H).

Reference example 21. Ethyl 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)- 1H-indazol-3-carboxylate.

In 5000 ml of dimethyl sulfoxide, dried over molecular sieve 4A Molecular Sieve 4A), suspended 250,2 g ethyl-5,6-dimethoxy-1H-indazol-3-carboxylate and added 38.0 g of lithium methylate. After stirring at room temperature for 1 hour and added dropwise to 185,6 g of 3,4-dimethoxybenzaldehyde (obtained from 336,4 g of 3,4-dimethoxybenzyl alcohol, 300 ml of the Oia at room temperature for 1 h type of 55.6 g of 3,4-dimethoxybenzaldehyde, followed by stirring at room temperature for 1 h To the mixture then of 55.6 g of 3,4-dimethoxybenzaldehyde, followed by stirring at room temperature for 1 h, the Reaction mixture was poured into 30000 ml of ice water with stirring. Emerges at the surface of the liquid discharged by decantation and the residue add 15000 ml of water, followed by stirring at room temperature over night. Emerges at the surface liquid is removed by decantation and the residue is dissolved in 10,000 ml of chloroform. The solution is dried over sodium sulfate and filtered, and the solvent is removed under reduced pressure. The residue, weighing 497,0 g, purified column chromatography on silica gel (2 kg 9) using a mixture of chloroform : carbon tetrachloride : ethyl acetate 5:5:1, and then on silica gel (2 kg 4) using a mixture of ethyl acetate : hexane 2:1. The resulting eluate is recrystallized from ethyl acetate to obtain 205,0 g specified in the title compounds as colorless prismatic crystals.

Melting point: 138 - 141oC.

IR (KBr) cm-1: 1728, 1496, 1266, 1216, 1204, 1138, 1022.

1H-NMR (CDCl3) memorial plaques: for 1.49 (3H, t, J = 6.8 Hz), of 3.78 (3H, s), 3,85 (6H, s), of 3.95 (3H, s), a 4.53 (2H, K, J = 6,8 Hz), to 5.58 (2H, s), 6,63 (1H, s) 6,76 (1H, s), to 6.80 (2H, s), 7,56 (1H, s).

Elemental analysis for C21

In 1500 ml of tetrahydrofuran suspended 205,0 g of ethyl 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-carboxylate, ground in a mortar to a powder at room temperature and add to 96.8 g of sodium borohydride, followed by stirring at room temperature. To the mixture is added dropwise to 300 ml of methanol for more than 30 minutes After the addition, the reaction mixture was heated to 50oC and stirred for 5 hours then add To the mixture of 19.4 g of sodium borohydride and 60 ml of methanol. The reaction mixture is slowly poured into a mixture of 200 ml of concentrated hydrochloric acid, 5000 ml of water and 1 kg of ice with stirring. To the aqueous layer add a saturated aqueous solution of sodium bicarbonate at room temperature under stirring to establish a pH of about 8, when this starts to land a colorless solid product. The solid product is collected by filtration, washed with water two portions of 500 ml, dissolved in 10,000 ml of chloroform, dried over sodium sulfate, filtered and evaporated the solvent to obtain 185,2 g colorless solid product. The solid product is used in subsequent reactions without further purification.

Separately neenie colorless crystal prisms, having a melting point of 187 - 188oC.

IR (KBr) cm-1: 3272, 1520, 1470, 1438, 1418, 1318, 1284, 1256, 1210, 1166, 1140, 1062, 1026, 870, 834.

1H-NMR (CDCl3) memorial plaques: of 3.77 (3H, s), 3,82 (3H, s), a 3.87 (3H, s) to 3.92 (3H, s), equal to 4.97 (2H, s), of 5.40 (2H, s), 6,62 (1H, s), 6,69 (1H, m), 6.75 in (2H, m), 7,13 (1H, s).

Reference example 23. 3-Chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol.

In 1500 ml of dichloromethane is dissolved 184,0 g of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol at room temperature, followed by stirring under ice cooling. To the solution is added dropwise 75,4 ml of thionyl chloride for more than 20 minutes a Minute later, the stain of the original material for thin-layer chromatography (ethyl acetate : hexane 2:1) disappears. The reaction mixture was warmed up to room temperature and add 3500 ml of dichloromethane. The mixture was washed with 1000 ml of saturated aqueous sodium bicarbonate, filtered and evaporated the solvent to obtain 189,7 g colorless solid product. This product is used in subsequent reactions without further purification.

1H-NMR (CDCl3) memorial plaques: of 3.78 (3H, s), of 3.84 (3H, s), 3,88 (3H, s), of 3.95 (3H, s), of 4.95 (2H, s), 5,44 (2H, s), of 6.65 (1H, s) of 6.71 (3H, m), 7,10 (1H, s).

Reference example 24. 5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H - indazol-3-acetonitrile, followed by stirring at room temperature. To the solution add 134,0 g of potassium cyanide, ground in a mortar to a powder, followed by stirring at 50oC for 2 h, the Reaction mixture was cooled to room temperature, poured into 15000 ml of water and stirred for 1 h the residue is collected, washed with water three servings of 1000 ml, dissolved in 5000 ml of chloroform, dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography using 2 kg of silica gel and a mixture of chloroform : ethanol 50:1 and then 2 kg of silica gel and a mixture of ethyl acetate : hexane 36:1, obtaining 111,0 g of a pale-brown solid product. This product is used in subsequent reactions without further purification.

1H-NMR (CDCl3) memorial plaques: 3,80, (3H, s), of 3.84 (3H, s) to 3.89 (3H, s), of 3.94 (3H, s), was 4.02 (2H, s), 5,43 (2H, s), of 6.66 (1H, c), 6,72 (2H, m), 6,69 (1H, m), 7,06 (1H, m).

Reference example 25. 5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H - indazol-3-ukususa acid.

In 1000 ml of ethanol is suspended 111,0 g of 5,6-dimethoxy-1-(3,4 - dimethoxybenzyl)-1H-indazol-3-acetonitrile at room temperature and stirring. To the suspension, add 10 N. aqueous sodium hydroxide solution and then heated under reflux for 2 hours, the Reaction mixture was cooled to room at room temperature over night. Any insoluble material is removed by filtration and to the filtrate is added 500 ml of ethyl ether. Organic solvent - soluble material is removed and the aqueous layer was adjusted to pH 4 to 5 with concentrated hydrochloric acid. The precipitate is collected by filtration and fractional crystallization from ethanol gives 41,0 g specified in the connection header. This connection is used in subsequent reactions without further recrystallization.

1H-NMR (CDCl3) memorial plaques: of 3.77 (3H, s), of 3.84 (3H, s), 3,88 (3H, s), 3,91 (3H, s), a 4.03 (2H, s), 5,44 (2H, s), only 6.64 (1H, s), 6,72 (2H, m), 6,77 (1H, m), of 6.96 (1H, s).

Example 16. 1-((5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol - 3-yl)acetyl)-4-(3-chloro-2-were)piperazine.

In 500 ml of dichloromethane suspended 41,0 g of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-acetic acid and added to the mixture of 24.5 g of the disulfide 2,2-dipyridyl and 30.0 g of triphenylphosphine, followed by stirring at room temperature. To the mixture is added dropwise a solution of 23.5 g (3-chloro-2-were)piperazine in 200 ml of dichloromethane for more than 5 min, followed by stirring at room temperature for 30 minutes After confirmed the disappearance of the spot of the original material for the thin chromatogram (ethyl acetate the th layer is dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography on silica gel (ethyl acetate : hexane 2:1; silica gel: 2 kg) with the receipt of 61.5 g of colorless solid product, which is used in subsequent reactions without further recrystallization.

A small amount of solid product is recrystallized from ethanol to obtain colorless crystal prisms, having a melting point of 165 - 169oC.

IR (KBr) cm-1: 1652, 1516, 1264, 1236.

1H-NMR (CDCl3) memorial plaques: 1,24 (1,5 H, so J = 7,3 Hz, Me of EtOH), of 1.65 (4H, s) to 2.55 (2H, m) of 2.75 (2H, m), and 3.72 (1H, m, CH2from EtOH), 3,76 (3H, s), of 3.78 (3H, s) to 3.89 (3H, s), of 3.94 (3H, s), 4.09 to (2H, s) 5,41 (2H, s), of 6.65 (1H, s), 6,69 (2H, m), of 6.73 (1H, s), 7,03 (1H, t, J = 7.8 Hz), to 7.09 (1H, d, J = 6.8 Hz), 7,19 (1H, s).

Example 17. 3-(2-(4-(3-Chloro-2-were)-1-piperazinil)ethyl)-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol.

In 1000 ml of tetrahydrofuran is suspended of 60.5 g of 1-((5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-yl)acetyl)-4- (3-chloro-2-were)piperazine and add 500 ml of tertrahydrofuran ring solution containing 1.0 mol of the complex, borane-tetrahydrofuran, followed by heating under reflux for 2 hours, the Reaction mixture was cooled to room temperature and add 30 ml of water for antiromance hydrochloric acid, followed by stirring at 50oC for 1 h Aqueous layer was cooled down to room temperature, alkalinized with potassium carbonate and extracted with 3000 ml of chloroform. The organic layer is dried over sodium sulfate, filtered and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (chloroform : ethanol 40: 1) to obtain 50.0 g of colorless solid product. Recrystallization from ethanol gives 48,3 g in the form of colorless crystal prisms.

Melting point: 148 - 150oC.

IR (KBr) cm-1: 1518, 1466, 1454, 1260, 1236, 1140, 1022, 1004.

1H-NMR (CDCl3) memorial plaques: 2,35 (3H, c), 2,85 (2H, m), to 3.02 (4H, m), 3,26 (2H, m), of 3.78 (3H, s), 3,83 (3H, s), a 3.87 (3H, s), of 3.94 (3H, s), 5,43 (2H, s), 6,62 (1H, s), 6,72 (2H, s), 6,78 (1H, m), of 6.96 (1H, m), 7,11 (3H, m).

Elemental analysis for C31H37N4O4Cl:

Calculated, %: C 65,89; H 6,60; N To 9.91; Cl 6,27;

Found, %: C 65,65; H 6,59; N 9,58; Cl 6,36.

Example 18. 5,6-Dimethoxy-1-(3,4-dimethoxyphenethyl)-3-(2-(4-(2- methoxyphenyl)-1-piperazinil)ethyl)-1H-indazol the dihydrochloride monohydrate.

In 100 ml of dichloromethane was dissolved 2.2 g of 5,6-dimethoxy-1-(3,4-dimethoxymethyl)-1H-indazol-3-acetic acid and to the solution was added 1.5 g of triphenylphosphine, 1.26 g of the disulfide 2,2-dipyridyl and 1.1 g of 2-methoxyphenylpiperazine extracted with dichloromethane. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (ethyl acetate : hexane 2:1) to obtain 2.6 g of colorless oil. Oil (2.6 g) is dissolved in 40 ml of tetrahydrofuran and added dropwise 40 ml of a 1.0 n solution of complex, borane-tetrahydrofuran, followed by stirring at room temperature for 8 hours To the solution add 5.0 ml of water under ice cooling and the mixture is stirred, and the solvent evaporated. To the residue is added 20 ml of concentrated hydrochloric acid, followed by stirring at 60oC for 30 minutes the Solution is poured into a saturated aqueous solution of sodium carbonate to give it basicity and extracted with chloroform. The organic layer is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified column chromatography on silica gel (dichloromethane : ethanol 20:1) to obtain 2.4 g of colorless oil. The oil is dissolved in ethanol and to the solution add 10 ml of 1 N. hydrochloric acid, followed by stirring. Recrystallization of the precipitate from a mixture of ethyl acetate-ethanol gives 2.7 g specified in the title compounds as colorless crystals.

T1
H-NMR (CDCl3) memorial plaques: with 8.05 (1H, m), 7,42 (1H, t), 7,25 (1H, s),? 7.04 baby mortality (2H, m), at 6.84 (2H, m), 6,76 (1H, m), of 6.65 (1H, s), the 5.45 (2H, m), is 4.85 (2H, m), 4,27 (2H, m,), 4,06, 3,98, 3,90, 3,84, 3,83 ( each 3H, s), 3,70 (2H, s), 3,88 of 3.56 (4H, m).

Elemental analysis for C31H38N4O5Cl2:

Calculated, %: C 58,40; H 6,64; N 8,79; Cl 11,12;

Found,%: C 58,55; H 6,50; N 8,64; Cl 11,40.

Reference example 26. 1-Hydroxy-3-(3,4-acid)butyronitrile.

To the dry benzene solution containing 45 g of sodium amide, slowly add 177 g of 3,4-dimethoxyphenylacetone while cooling in an ice bath. The mixture is heated under reflux for 30 min and then cooled to room temperature. In the reaction mixture is slowly blown into 50 ml of ethylene oxide, followed by stirring overnight. Water is added and the mixture is acidified with 10% hydrochloric acid. Extracted benzene layer is purified column chromatography on silica gel (hexane : acetone 2:1 to 1:1) to give 48 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: a 7.0 to 6.8 (m, 3H), of 4.05 (t, 1H, J = 7,3 Hz), 3,90 (s, 3H), with 3.89 (s, 3H), from 3.9 to 3.7 (m, 2H), 2,3 - 2,0 (m, 2H).

Reference example 27. - 47(3,4-Acid)butyrolactone.

The solution (100 ml), 35 g of 1-hydroxy-3-(3,4 - acid)butirosin during the night. The reaction mixture is extracted three times with methylene chloride. The organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel (hexane : acetone 2:1 to 1:1) to obtain the 28,3 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: the 6.9 to 6.8 (m, 3H), 4,5 - 4,4 (m, 1H), 4,4 - 4,3 (m, 1H), with 3.89 (s, 3H), a 3.87 (s, 3H), of 3.77 (DD, 1H, J = 8,8, 10,2 Hz), of 2.8 to 2.6 (m, 1H), 2,5 - 2,3 (s, 1H).

Reference example 28. -(2-Nitro-4,5-acid)butyrolactone.

Concentrated hydrochloric acid (3.0 mol) is added to a solution of -(3,4-acid)of butyrolactone in 30 ml of a mixture of acetic acid/acetic anhydride 2: 1. The reaction mixture was poured into aqueous sodium hydrogen carbonate solution and extracted three times with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is evaporated and the residue crystallized from ethanol to obtain 3,36 g specified in the connection header.

Melting point: 144 - 147oC.

1H-NMR (CDCl3) memorial plaques: of 7.70 (s, 1H), 6,76 (s, 1H), 4,6 - 4,4 (m, 2H is -2(2H)-indole.

An ethyl acetate solution containing 2.0 g -(2-nitro-4,5 - acid)of butyrolactone and 500 mg of platinum oxide is stirred at 2.0 ATM hydrogen atmosphere. To the reaction mixture add ethanol followed by filtration. The solvent is evaporated to obtain 1,76 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: from 9.1 to 9.0 (broad, 1H), 6,83 (s, 1H), is 6.54 (s, 1H), 4.75 V - 4,4 (m, 1H), a 3.87 (s, 3H), 3,86 (s, 3H), 3.9 to 3.5mm (m, 2H), 2,3 - 2,0 (m, 2H).

Reference example 30. 5,6-Dimethoxy-3-methylthio-3-hydroxyethyl-1,3-dihydro-2(2H)-indole.

To 50 ml of dimethylformamide added 360 mg of sodium hydride and there add to 1.76 g of 5,6-dimethoxy-3-hydroxyethyl-1,3-dihydro-2(2H)- indolene and 706 mg of dimethyl disulfide. To the reaction mixture an aqueous solution of sodium bicarbonate and the solvent evaporated. The residue is extracted three times with methylene chloride and the organic layer dried over sodium sulfate. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate) to obtain 1,21 g specified in the connection header.

1H-NMR (CDCl3) memorial plaques: from 9.1 to 9.0 (broad, 1H), 6,85 (s, 1H), 6,55 (s, 1H), 3,88 (s, 6H), 3,8 - 3,5 (m, 2H), 2,5 - 2,0 (m, 2H), of 1.85 (s, 3H).

Reference example 31. 5,6-Dimethoxy-3-[2-[4-(2-methoxyphenyl)-1-P3-methylthio-3 - hydroxyethyl-1,3-dihydro-1(2H)-indolene and 0.5 ml of triethylamine added 2.2 equivalents of methylchloride while cooling with ice. To the reaction mixture an aqueous solution of sodium bicarbonate and the mixture extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate). The product is dissolved in dimethylformamide and to the solution was added 300 mg (2-methoxyphenyl)piperazine, 200 mg of potassium carbonate and 200 mg of sodium iodide, followed by stirring overnight. Add an aqueous solution of sodium bicarbonate and the reaction mixture is extracted three times with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel (ethyl acetate) to obtain 140 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: a 9.5 and 9.4 (broad, 1H), 7,0 - 6,7 (m, 5H), to 6.58 (s, 1H), with 3.89 (s, 3H), 3,88 (s, 3H), 3,79 (s, 3H), of 3.8 to 1.9 (m, 12H), of 1.80 (s, 3H).

Example 19. 5,6-Dimethoxy-1-[(3,4-acid)methyl]-3-[2-[4-(2-methoxyphenyl)piperazinil]ethyl]-2-oxoindole.

In dimethylformamide are suspended 38 mg of sodium hydride. To the suspension is added 285 mg of 5,6-dimethoxy the reaction mixture is added an aqueous solution of sodium bicarbonate and the mixture extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is evaporated and the residue is dissolved in ethanol. Separately acetone solution containing 2.0 g of Raney Nickel, heated under reflux and the solvent is removed by decantation. The remainder is added to prepared as described above ethanol solution followed by heating under reflux for 15 minutes the Precipitate is removed by filtration, the solvent evaporated and the residue purified column chromatography on silica gel (hexane : ethyl acetate 1:2 to 0:1) to give 201 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: a 7.0 and 6.7 (m, 8H), 6,38 (s, 1H), 4,13 (d, 1H, J = 6.9 Hz), 4,10 (d, 1H, J = 7,3 Hz), 3,85 (s, 3H), 3,85 (s, 6H), 3,83 (s, 3H), of 3.78 (s, 3H), 3,7 - 3,5 (m, 1H), 3,2 - 2,2 (m, 12H).

Reference example 32. 1-[7-(2,3-dihydrobenzofuranyl)]piperazine.

In 10 ml of acetic acid are dissolved 884,0 mg of 1-(7-benzofuranyl)piperazine and type of 56.7 mg of the catalyst of Permana (Pearman). The mixture was stirred at 65oC in a stream of hydrogen for 4 hours After the reaction, the catalyst was removed by filtration using Celite. The solvent is evaporated and the residue is subjected to column chromatography on syliv connection, which is used in subsequent reactions without further purification.

Example 20. 3-[2-[4-[7-(2,3-Dihydrobenzofuranyl)]-1 - piperazinil]ethyl]-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol.

In 15 ml of anhydrous dichloromethane was dissolved 1.28 g of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazolinone acid. To the solution was added sequentially 868,6 mg of triphenylphosphine, 729,4 mg disulfide 2,2-dipyridyl and 729,4 mg 1-[7-(2,3 - dihydrobenzofuranyl)]piperazine, followed by stirring at room temperature for 10 minutes After completion of the reaction, water is added and the mixture extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, the solvent evaporated and the residue is subjected to column chromatography on silica gel (ethyl acetate) to obtain 1,16 g of amide compound as colorless oily substance. The oily product is dissolved in 20 ml of anhydrous tetrahydrofuran and added to 8.1 ml of a 1.0 M solution of the complex, borane-tetrahydrofuran, followed by heating under reflux for 1 h After completion of the reaction, add 10 ml of 10% hydrochloric acid, followed by further heating under reflux for 1 h, After cooling, add the powder m sodium sulfate and the solvent is evaporated and the residue purified column chromatography on silica gel (ethyl acetate) to obtain the 729,3 g specified in the title compounds as a colorless oily substance.

IR (KBr) cm-1: 1514, 1486, 1260, 1028.

1H-NMR (CDCl3) memorial plaques: 3,70-of 3.77 (4H, m), 3,79, 3,83, 3,88, 3,94 (each 3H, s) 5,43 (2H, s), 6,62-to 7.61 (8H, m).

Elemental analysis for C32H38N4O51/2 H2O:

Calculated, %: C 67,70; H 6,92; N 9,86;

Found, %: C 67,62; H 6,59; N 9,24.

Reference example 33. 1-[(2-Methoxycarbonyl-4,5-dimethoxy)phenyl]ethyl-4-(2-methoxyphenyl)piperazine.

To tertrahydrofuran ring to a solution of 3.8 g of 1-[(2-bromo-4,5-dimethoxy) phenyl] ethyl-4-(2-methoxyphenyl)piperazine type of 6.4 ml of a 15% hexane solution of n-utility at -78oC. After stirring for some time, add 0.5 g of solid carbon dioxide. The solvent is removed by evaporation. To the residue is added methanol and then about 1 ml of concentrated hydrochloric acid followed by heating under reflux over night. The reaction mixture was carefully neutralized with an aqueous solution of sodium bicarbonate and add ethyl acetate. The organic layer is separated. The aqueous layer was acidified, extracted with methylene chloride and again subjected to esterification. The obtained organic layer is evaporated and the residue crystallized from ethanol to obtain 530 mg specified in the connection header.

That is 3,88 (s, 3H), 3,4-2,6 (m, 12H).

Example 21. 1-[2-[4,5-Dimethoxy-2-(2-pyridyl)acetyl]phenyl]ethyl-4-(2-methoxyphenyl)piperazine the dihydrochloride dehydrate.

To tertrahydrofuran ring to a solution of 158 g of Diisopropylamine successively added 1.0 ml of a 15% hexane solution of n-utility and 145 mg of 2-picoline at -78oC, followed by stirring for some time. To the solution was added 650 mg of 1-[(2-methoxycarbonyl-4,5-dimethoxy)phenyl] ethyl-4- (2-methoxyphenyl)piperazine. The temperature is gradually raised to room temperature at which the mixture is stirred for 20 minutes To the reaction mixture is added saturated aqueous solution of ammonium chloride and the reaction mixture is extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and the solvent evaporated. The residue is purified column chromatography on silica gel (ethyl acetate : ethanol 10:1) to obtain 360 mg specified in the connection header.

Melting point: 179-181oC (melts and then solidifies).

IR (cm-1): 2500, 1682, 1520, 1504, 1344, 1272, 1246, 1124.

1H-NMR (equivalent mixture of ketoform : enol form 2:1) M. D.: 8,56 (d, J = 4,9 Hz, 2/3H), of 8.28 (d, J = 4.5 Hz, 1/3H), 7,7-to 7.15 (m, 3H Reference example 34. Ethyl 5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3-carboxylate.

In 5000 ml of dimethyl sulfoxide suspended 250,2 g of ethyl 5,6-dimethoxyindole-3-carboxylate and suspension type with 40.2 g of lithium methoxide, followed by stirring at room temperature for 1 hour is Added dropwise a solution of 447,8 g of 4-chloromethyl-1-tritylimidazole in 2000 ml of dimethyl sulfoxide at room temperature for more than 10 minutes After stirring at room temperature for 2 h, then added to 4.2 g of lithium methoxide and 44.8 g of 4-chloromethyl-1-tritylimidazole, followed by stirring at room temperature for 1 h, the Reaction mixture was poured into 30000 ml of ice water with stirring. The precipitated crystals are collected, washed three times with water portions to 2000 ml and dried. The solid product is dissolved in 10,000 ml of chloroform and the solvent is dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography on silica gel (chloroform : ethanol 50:1) and recrystallized from a mixture of chloroform/isopropyl alcohol with getting 222,0 g specified in the title compounds as colorless crystal prisms.

Melting point: 184 - 186oC.

IR ( t, J = 7,3 Hz), 3,93 (3H, s), of 3.97 (3H, s) to 4.01 (1H, m, CH of I-D), of 4.49 (2H, K, J = 7,3 Hz), 5,61 (2H, s), 6,79 (1H, s), 7,03 (5H, m), 7,13 (1H, s), 7,28 (10H, m), 7,47 (1H, s), 7,51 (1H, s).

Elemental analysis for C35H32N4O4C3H8O:

Calculated, %: C 72,13; H 6,37; N cent to 8.85;

Found %: C 71,53; H 6,37; N 8,70.

Reference example 35. 5,6-Dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3-methanol.

In 1300 ml of tetrahydrofuran suspended 222,0 g of ethyl 5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3 - carboxylate, ground in a mortar to a powder at room temperature and the suspension is cooled with ice water. To the suspension is added about of 250.0 ml of 3.4 M toluene solution of biotoxicological for more than 15 min, followed by stirring under ice cooling for 30 minutes. To the reaction mixture is added saturated aqueous solution of sodium sulfate. After stirring for 1 hour, add the sodium sulfate followed by filtration. The sodium sulfate on the filter is washed with five portions of 500 ml of hot chloroform. The filtrate and washing liquid are combined and the solvent evaporated to obtain to 220.1 g of colorless solid product. Recrystallization of the product from chloroform gives 181,0 g ukazannoj the decomposition).

IR (KBr) cm-1: 3216, 3172, 3008, 2936, 1510, 1488, 1472, 1444, 1302, 1260, 1172, 1156, 1128, 1102, 1036, 1014, 836, 764, 702, 678, 666, 636.

1-H-NMR (CDCl3) memorial plaques: 3,91 (3H, s) to 3.92 (3H, s) to 4.92 (2H, s), 5,44 (2H, s) 6,76 (1H, s), to 6.95 (1H, s), 7,05 (5H, m), 7,26 (1H, s, CHCl3), 7,28 (1H, s), 7,31 (10H, m), 7,46 (1H, s).

Elemental analysis for C33H30N4O3CHCl3:

Calculated, %: C 62,83; H to 4.81; N 8,62;

Found, %: C 62,50; H 4,63; N 8,42.

Reference example 36. 3-Chloromethyl-5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol.

In 1700 ml of dichloromethane suspended of 180.0 g of 5,6-dimethoxy-1- (1-trityl-4-imidazolyl)methyl-1H-indazol-3-methanol, ground in a mortar to a powder at room temperature, followed by stirring under ice cooling. To the reaction mixture is added dropwise to 48.6 ml of thionyl chloride for more than 5 minutes a Minute later, the stain of the original material for the thin chromatogram (chloroform : ethanol 30:1) disappears. The reaction mixture is poured into 2000 ml of a saturated aqueous solution of sodium bicarbonate and extracted with 5000 ml of chloroform. The extract was dried over sodium sulfate, filtered and the solvent evaporated to obtain 165,1 g colorless solid product. This product is used in subsequent reactions without further clean the CLASS="ptx2">

Reference example 37. 5,6-Dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3-acetonitrile.

In 1200 ml of dimethyl sulfoxide suspended 165.0 g of 3-chloromethyl-5,6-dimethoxy-1- (1-trityl-4-imidazolyl)-methyl-1H-indazole, followed by stirring at room temperature. To the suspension is added by 43.6 g of potassium cyanide, ground in a mortar to powder, and the mixture was stirred at 70oC for 1 h, the Reaction mixture was cooled to room temperature and poured into 15000 ml of water with vigorous stirring, followed by stirring for 1 h the Precipitated product is collected, washed three times with water portions 1000 ml and dissolved in 5000 ml of chloroform. The solution is dried over sodium sulfate, filtered and the solvent is evaporated. Column chromatography on silica gel (ethyl acetate) sediment yields to 108.7 g of a pale-brown solid product, which is used in the subsequent reaction as such.

1H-NMR (CDCl3) memorial plaques: to 3.92 (3H, s), of 3.94 (3H, c), of 3.97 (2H, s), 5,42 (2H, s), 6,79 (1H, s), 7,00 (1H, s), 7,02 (1H, s), 7,06 (5H, m), 7,30 (10H, m), 7,46 (1H, s).

Reference example 38. 5,6-Dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3-acetic acid.

In 1000 ml of ethanol is suspended 107,0 g of 5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indaz of 40.0 g of sodium hydroxide and 100 ml of water, followed by heating under reflux for 6 hours, the Reaction mixture was cooled to room temperature and poured into 5000 ml of water. Adjusted to pH 3 to 4 with 10% hydrochloric acid and the colorless solid product, which is collected by filtration, washed with three portions of water 500 ml and dissolved in 5000 ml of chloroform. The solution is dried over sodium sulfate, filtered and the solvent is evaporated to obtain 134,0 g specified in the connection header, which is used in the subsequent reaction as such.

1H-NMR (CDCl3) memorial plaques: a-3.84 (3H, s), a 3.87 (3H, s) to 3.89 (2H, s), 5,43 (2H, s) 6,76 (1H, s), to 6.88 (1H, s), 6,93 (1H, s), 7,03 (5H, m), 7,28 (10H, m), of 7.48 (1H, s).

Example 22. 4-(3-Chloro-2-were)-1-(5,6-dimethoxy-1-(1-trityl-4-imidazolyl) methyl-1H-indazol-3-yl)acetyl)piperazine.

In 1000 ml of dichloromethane suspended 134,0 g of 5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H-indazol-3-acetic acid. To a suspension type of 63.5 g of the disulfide 2,2-dipyridyl and 75.6 g of triphenylphosphine, followed by stirring at room temperature, during which the suspension becomes homogeneous transparent solution. Add a solution of 60.7 g of 4-(3-chloro-2-were)piperazine in 200 ml of dichloromethane over 5 min and the mixture was stirred at komnata, followed by stirring. Precipitated solid product is collected by filtration, washed with two portions of 500 ml of ethyl acetate and dried to obtain 140,4 g colorless solid product. The solid product was then purified column chromatography on silica gel (chloroform : ethanol 30:1) to obtain 134.9 g of colorless solid product. Recrystallization from ethanol gives to 120.0 g of colorless crystal prisms.

Melting point: 103 - 105oC.

IR (KBr) cm-1: 1646, 1628, 1508, 1466, 1450, 1430, 1260, 750, 702.

1H-NMR (CDCl3) memorial plaques: 1,23 (1,2 H, t, J = 6.8 Hz, Me of EtOH), of 2.28 (3H, s) to 2.55 (2H, m), 2,73 (2H, m) to 3.67 (4H, m), 3,71 (0,8 H, K, J = 6,8 Hz, CH2from EtOH), 3,90 (3H, s), 3,93 (3H, s), a 4.03 (2H, s), 5,43 (2H, s), of 6.68 (1H, s), 6,72 (1H,, J = 8,3 Hz), make 6.90 (1H, s), 7,03 (7H, m), 7,14 (1H, s), 7,27 (10H, m), 7,41 (1H, s).

Elemental analysis for C45H43N6O3Cl 4EtOH H2O:

Calculated, %: C 70,10; H 5,70; N 10,70; Cl 4,72;

Found, %: C 70,02; H 5,78; Or 10.60 N; Cl 5,11.

Example 23. 3-(2-(4-(3-Chloro-2-were)-1-piperazinil)ethyl)-5,6-dimethoxy-1-(4-imidazolidinyl)-1H-indazol.

In 1000 ml of tetrahydrofuran is suspended to 120.0 g of 4-(3-chloro-2-were)-1-(5,6-dimethoxy-1-(1-trityl-4-imidazolyl)methyl-1H - indazol-3-yl)acetyl)piperazine. To the suspension is added 800 ml of 1.0 M complex, borane-tetrahydrofuran, followed agrianians decompose excess reagent. The tetrahydrofuran is removed under reduced pressure and to the residue is added 150 ml of concentrated hydrochloric acid, 200 ml of water and 40 ml of ethanol, followed by stirring at 50oC for 1 h Aqueous layer was cooled down to room temperature, alkalinized with potassium carbonate and extracted with 3000 ml of chloroform. The organic layer is dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography on silica gel (chloroform : ethanol 40:1) to give colorless solid product which is then recrystallized from isopropyl alcohol/isopropyl ether to obtain 71,0 g specified in the title compounds as colorless crystal prisms.

Melting point: 143 - 144,5oC.

IR (KBr) cm-1: 1510, 1464, 1432, 1272, 1238, 1206, 1006.

1H-NMR (CDCl3) memorial plaques: of 2.34 (3H, s), 2,78 (4H, m), 2,90 (2H, m), of 2.97 (4H, m), 3,17 (2H, m), 3,90 (3H, s), 3,91 (3H, s), the 5.45 (2H, s), 6,83 (1H, s), at 6.84 (1H, s), 6,92 (1H, m), 7,00 (1H, s), to 7.09 (2H, m), 7,52 (1H, C).

Elemental analysis for C26H31N6O2Cl:

Calculated, %: C 63,09; H of 6.31; N 16,98; Cl 7,16;

Found, %: C 62,93; H 6,30; N 16.88 In; Cl 7,16.

Reference example 39. 1-Benzyloxycarbonyl-4-(3-(2-etoxycarbonyl)ethyl)carbylamine-2-methylpheni the Razin and is 3.08 g ethylsuccinate and type of 5.17 g of potassium carbonate followed by heating under reflux for 2 hours The reaction mixture is cooled to room temperature and add methylene chloride. The mixture is washed with water, dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography on silica gel (ethyl acetate : hexane 1:2) to give 5.32 g specified in the connection header.

1H-NMR (CDCL3) memorial plaques: of 1.27 (3H, t, J = 6.8 Hz), of 2.23 (3H, s), a 2.71 (2H, m) of 2.75 (2H, m), and 2.83 (4H, m), 3,66 (4H, m), 4,14 (2H, K, J = 6,8 Hz) to 5.17 (2H, s), at 6.84 (1H,, J = 7.8 Hz), 7,16 (1H, t, J = 8,3 Hz), 7,37 (5H, m), 7,53 (1H,, J = 7,8 Hz).

Example 24. 5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-3-(2-(4-(2-ethyl-3-(1-Succinimidyl) phenyl)-1-piperazinil)ethyl)-1H-indazol.

In 50 ml of methanol was dissolved 1.50 g of 1-benzyloxycarbonyl-4-(3-(2-ethoxycarbonylethyl)carbylamine-2-were) piperazine and add 1.0 g of 10% palladium on coal, followed by stirring at room temperature in a hydrogen atmosphere for 2 hours, the Reaction mixture is filtered and the solvent evaporated to obtain 0,99 g of 3-(2-ethoxycarbonylethyl)carbylamine-2-methylphenylhydrazine, which is used in subsequent reactions without further purification.

In 30 ml of methylene chloride was dissolved 800 mg of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-ethanol and 270 mg of methylchloride. To a solution of da methylene chloride and the reaction mixture is washed with water, dried over sodium sulfate, filtered and the solvent is evaporated. The residue is dissolved in 30 ml of dimethylformamide and to the solution add 990 mg, prepared as described above, 3-(2-ethoxycarbonylethyl)carbylamine-2-methylphenylhydrazine and 3.0 g of potassium carbonate. The mixture was stirred at 60oC for 2 hours, the Dimethylformamide is removed under reduced pressure and the residue extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, filtered and the solvent evaporated. The residue is purified column chromatography on silica gel (ethyl acetate) and the resulting solid product is recrystallized from isopropyl alcohol to obtain 520 mg of 5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-3-(2-(4-(2-ethyl-3-(1-Succinimidyl) phenyl)-1-piperazinil)ethyl)-1H-indazole of hemihydrate.

Melting point: 99,5 - 103,5oC.

Mass spectrum (FAB): M++1: 628.

IR (KBr) cm-1: 1780.

1H-NMR (CDCl3) memorial plaques: of 2.08 (3H, s), was 2.76 (4H, m), with 2.93 (6H, m) of 3.00 (4H, m), 3,19 (2H, m), with 3.79 (3H, s), 3,83 (3H, s), a 3.87 (3H, s), 3,93 (3H, s), 5,43 (2H, s), 6,62 (1H, s), 6,77 (4H, m), 7,03 (1H, s), 7,14 (1H, m), 7,27 (1H, m).

Elemental analysis for C35H41N5O61/2H2O:

Calculated, %: C 66,02; H of 6.65; N TO 10.09;

Found, %: C 65,98; H 6,95; N 10,08.

Melting point: 84 - 86oC.

1H-NMR (CDCl3) memorial plaques: 7,30 (s, 1H), 7,26 (s, 1H), 6,53 (s, 1H), 4,11 (s, 2H), 3,92 (s, 3H), 3,90 (s, 3H), a 3.87 (s, 3H), of 1.42 (s, 6H).

Reference example 41. 2-[4,5-Dimethoxy-2-(3,4-acid]-4,4-dimethyl-2-oxazoline.

Dimethoxyaniline bromide, obtained from bromoveratrole, is slowly added to tertrahydrofuran ring to a solution of 2.65 g of 4,4-dimethyl-2-(2,4,5-trimethoxyphenyl-2-oxazoline, followed by stirring over night, add an aqueous solution of ammonium chloride and smast 2:1 - the ethyl acetate). Recrystallization from hexane gives 1.9 grams specified in the connection header.

Melting point: 109 - 110oC.

1H-NMR (CDCl3): M. D.: 7,27 (s, 1H), 6,9-6,8 (m, 4H), of 3.97 (s, 3H), 3,92 (s, 6H), to 3.89 (s, 3H), 3,80 (s, 2H), 1,31 (s, 6H).

Reference example 42. 4,5-Dimethoxy-2-(3,4-acid)benzoic acid.

A solution of 2.6 g of 2-[4,5-dimethoxy-2-(3,4-acid)]-4,4 - dimethyl-2-oxazoline in methylene chloride is stirred overnight to obtain 3.0 g of sediment. To the precipitate add 20% aqueous sodium hydroxide solution followed by heating under reflux over night. The reaction mixture is neutralized 5 N. hydrochloric acid and extracted with methylene chloride. The solvent is evaporated and the resulting crystals are washed with ethanol to obtain 1.51 g specified in the connection header.

IR (KBr) cm-1: 1692, 1508, 1256, 1176, 1026.

1H-NMR (CDCl3) memorial plaques: a 9.7 (broad, 1H), 7,52 (s, 1H), 6,9-6,8 (m, 4H), of 3.94 (s, 3H), 3,91 (s, 6H), 3,85 (s, 3H).

Reference example 43. 4-Chloromethyl-1,2-dimethoxy-5-(3,4-acid)benzene.

Heated under reflux tertrahydrofuran ring suspension of 1.5 g of sociallyengaged and to it was added 2,43 g of 4,5-dimethoxy-2-(3,4-acid)benzoic sweet is she. The solvent is evaporated and the residue is dissolved in methylene chloride. To the solution was added concentrated hydrochloric acid and the mixture is stirred for 2 h, followed by extraction. Purification of the extract column chromatography on silica gel (hexane : ethyl acetate 5:1 to 1:1) to give 820 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: 7,1-6,9 (m, 4H), 6,78 (s, 1H), to 4.52 (s, 2H), 3,95 (s, 3H), 3,93 (s, 3H), 3,92 (s, 3H), with 3.89 (s, 3H).

Reference example 44. [[4,5-Dimethoxy-2-(3,4-acid]phenyl]acetic acid.

Dimethylformamide solution containing 1.4 g of 4-chloromethyl-1,2 - dimethoxy-5-(3,4-acid)benzene and 565 mg of potassium cyanide, stirred for one day at 50oC. the Solvent is removed under reduced pressure and to the residue is added ethyl acetate. The solution is successively washed with water and saturated aqueous sodium chloride. The solvent is evaporated and to the residue is added 40 ml of 20% aqueous sodium hydroxide solution and 15 ml of ethanol followed by heating under reflux over night. After cooling, water is added and the reaction mixture is washed with ethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with methylene chloride. The solvent is removed under reduced giving the Mrs (CDCl3) memorial plaques: the 6.9 to 6.8 (m, 4H), 6,8 (s, 1H), 3,91 (s, 6H), a 3.87 (s, 3H), 3,85 (s, 3H), of 3.57 (s, 2H).

Example 25. 1-[2-[[4,5-Dimethoxy-2-(3,4-acid)]phenyl]acetyl]-4-(2-methoxyphenyl)piperazine.

One drop of dimethylformamide is added to thionylchloride solution 517 mg [[4,5-dimethoxy-2-(3,4-acid)] phenyl]acetic acid. Thionyl chloride is removed by azeotropic distillation with benzene. To methylenechloride solution of the residue add 2-methoxyphenylpiperazine. After stirring for some time the organic layer is extracted and purified column chromatography on silica gel (hexane : ethyl acetate 1:1 - ethyl acetate) to give the 599 mg specified in the connection header.

1H-NMR (CDCl3) memorial plaques: 7,0-6,7 (m, 9H), 3,91 (s, 6H), a 3.87 (s, 6H), 3,85 (s, 3H), 3,9-3,6 (m, 2H), 3,4-3,2 (m, 2H), from 3.0 to 2.8 (m, 2H), 2,8-2,6 (m, 2H).

Example 26. 1-[2-[[4,5-Dimethoxy-2-(3,4-acid)]phenyl]ethyl]-4-(2-methoxyphenyl)piperazine.

To tetrahydropyranol suspension of 150 mg of sociallyengaged boiling under reflux add 593 mg of 1-[2-[[4,5-dimethoxy-2-(3,4-acid]phenyl]acetyl]-4-[2 - methoxyphenyl]piperazine. Allow to cool and the reaction mixture is added saturated aqueous solution of sodium sulfate with subsequent extraction of etelaat the title compound.

Melting point: 111 - 113oC.

IR (KBr) cm-1: 1504, 1464, 1252, 1174, 1340, 1026.

1H-NMR (CDCl3) memorial plaques: an 8.0 to 7.7 (m, 9H), to 3.92 (broad s, 9H), of 3.84 (s, 6H), of 3.2 and 2.9 (broad, 4H), 2,9-2,4 (m, 8H).

Example 27. 1-(3-Chloro-2-were)-4-[2-[[4,5-dimethoxy-2-(3,4-acid)]phenyl]acetyl]piperazine.

Specified in the title compound is synthesized with the output 748 mg the same way as described above, except that use 645 mg [[4,5-dimethoxy-2-(3,4-acid)] phenyl] acetic acid, 2.0 ml of thionyl chloride and 500 mg (3-chloro-2-were)piperazine.

1H-NMR (CDCl3) memorial plaques: a 7.1 to 7.0 (m, 2H), 6,9-6,7 (m, 6H), to 3.92 (s, 6H), a 3.87 (s, 6H), 3,63 (s, 2H), 3,8-3,6 (m, 2H), 3,4-3,2 (m, 2H), 2,8-2,6 (s, 2H), 2,6-2,4 (m, 2H), 2,32 (s, 3H).

Example 28. 1-(3-Chloro-2-were)-4-[2-[[4,5-dimethoxy-2-(3,4 - acid)]phenyl]ethyl]piperazine.

Specified in the title compound is synthesized with the output of 540 g in the same way as described above, except that use 740 mg of 1-(3-chloro-2-were)-4-[2-[[4,5-dimethoxy-2-(3,4 - acid)] phenyl] acetyl]piperazine and 170 mg of sociallyengaged.

Melting point: 137 - 139oC.

IR (cm-1): 1504, 1464, 1250, 1136, 1008.

1H-NMR (CDCl3) memorial plaques : an 8.2 to 7.7 (m, 8H), 3,93 (s, 9H), a 3.87 (s, 3H), 3,2-2,5 (P>, R2, K, G, Z and Q are defined in table. 3 (see the end of the description), are synthesized by the same methods as in the previous examples. Connection, where K is "C", are indole compounds, and where K is the "N" are indazol connections. In these compounds G is 3,4-dimethoxybenzyl group, if the table does not specify otherwise. In those compounds where R1and R2both represent a methoxy group, a methoxy group is in the 5 - and 6-positions, except otherwise specified.

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Examples of 100 - 118. Compounds having the formula shown below, in which the symbols R1, R2, G, Z and Q are defined in table. 4 (see the end of the description), are synthesized by the same methods as in the previous examples. In those compounds where R1and R2both represent a methoxy group, a methoxy group is in the 5 - and 6-positions, except otherwise specified.

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Example 119. 5,6-Dimethoxy-1-(4-imidazolidinyl)-3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1H-indazol,5H2O.

A mixture of 4.95 g of 5,6-dimethoxy-1-(4-imidazolidinyl)-3-[2-[1-[4-(3-chloro - 2-were)piperazinil] ] ethyl] -1H-indazole and 20 ml of 1 N. hydrochloric acid are mixed and to the mixture water is added to achieve the total alyemeni to room temperature, the solution was stirred at this temperature overnight. The precipitated crystals are collected by filtration. The crystals are dried at atmospheric pressure for 2 days to obtain 5.5 g specified in the title compounds as colorless prisms.

Melting point: 166 - 167oC.

IR (KBr) cm-1: 3400, 2850, 1625, 1505, 1460, 1425, 1245, 1150, 1010, 840.

1H-NMR (d6-DMSO) / memorial plaques: 2,39 (3H, s), 3,30-3,80 (20H, m), 5,74 (2H, s), to 7.15 (1H, DD), 7,28 (1H, s), 7,30 (1H, DD), 7,43 (1H, s), 7,52 (1H, s), of 7.69 (1H, s), 9,13 (1H, s), RS 11.80 (1H, Shir), 14,80 (1H, Shir).

Elemental analysis for C26H31N6O2Cl3,5H2O:

Calculated, %: C 49,41; H is 6.54; N 13,30; Cl equal to 16.83;

Found, %: C 49,15; H 6,44; N To 13.29; Cl 16,99.

Reference example 45. 5,6-Dimethoxy-1-[4-(1-tritylimidazole)methyl]indazol-3-propionic acid.

To a cooled with ice to a solution of diethylmalonate (2.25 g) in tetrahydrofuran (50 ml) is added sodium hydride (0.56 g) and the mixture is stirred for 15 minutes To the mixture is added dropwise a solution of 3-chloromethyl-5,6-dimethoxy-1-[4-(1-tritylimidazole)methyl] indazole (of 7.70 g) in tetrahydrofuran (50 ml). After stirring the mixture for 1 h the mixture is diluted with ethyl acetate. The mixture is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated and the residue (5.5 g define derived),1H-NMR (400 MHz, M. D., CDCl31
H-NMR (400 MHz, M. D., CDCl3) : of 3.54 (2H, t, J = 5,9 Hz), the 3.65 (1H, t, J = 5.4 Hz), 3,68 (3H, s), 3,90 (3H, s), 5,09 (2H, s), 6,30 (1H, s), to 6.43 (1H, s), 6,98 (7H, m), 7,30 (9H, m), 7,74 (1H, s), then heated at 120oC for 30 min with the receipt of 4.00 g specified in the connection header.

1H-NMR (CDCl3, 400 MHz) M. D.: of 2.81 (2H, t, J = 7,3 Hz), 3,17 (2H, t, J = 7,3 Hz), 3,85 (3H, s) to 3.89 (3H, s), 5,32 (2H, s), to 6.67 (1H, s), of 6.75 (1H, s), 6,93 (1H, s), 7,05 (6H, m), 7,29 (9H, m), 7,74 (1H, s).

Reference example 46. 4-(3-Chloro-2-were)-1-[[5,6-dimethoxy-1-[4-(1-tritylimidazole)methyl]-1H-indazol-3-yl]propyl]piperazine.

To a mixture of 5,6-dimethoxy-1-[4-(1-tritylimidazole)methyl]indazol - 3-propionic acid (3.6 g) in dichloromethane (30 ml) add disulfide 2,2'-dipyridyl (1.66 g) and triphenylphosphine (1.98 g). Then for 1 min to the mixture add a solution of 4-(3-chloro-2-were)piperazine (1.60 g) in dichloromethane (30 ml). The mixture is stirred for an additional 1 h and tel removed under reduced pressure. The remainder chromatographic on silica gel using ethyl acetate as eluent to obtain 4.3 g specified in the connection header.

1H-NMR (CDCl3, 400 MHz) ppm: 2,32 (3H, s), to 2.57 (2H, m), of 2.72 (2H, m), and 2.83 (2H, t, J = 7,8 Hz) at 3.25 (2H, t, J = 7.8 Hz), 3,49 (2H, m), 3,74 (2H, m), a 3.87 (3H, s) to 3.92 (3H, s), of 5.40 (2H, s), 6,69 (1H, s), 6,77 (1H, d, J = 7.8 Hz), at 6.84 (1H, s), 7,01 (1H, s), 7,05 (6H, m), 7,12 (2H, m), 7,29 (9H, m), 7,35 (1H, m).

Example 120. 5,6-Dimethoxy-1-(4-imidazolidinyl)-3-[2-[1-[4-(3-chloro-2-were)piperazinil]]propyl]-1H-indazol.

To a solution of 4-(3-chloro-2-were)-1-[[5,6-dimethoxy - 1-[4-(1-tritylimidazole)methyl]-1H-indazol-3-yl]propyl]piperazine (4.3 g) in tetrahydrofuran (100 ml) is added 1.0 M solution of the complex of borane-tetrahydrofuran (56 ml) and the mixture heated under reflux in an atmosphere of argon gas for 90 minutes the Mixture is cooled to room temperature and add water to the mixture. The tetrahydrofuran is removed under reduced pressure and to the mixture is added concentrated hydrochloric acid (10 ml), water (10 ml) and ethanol (20 ml). The mixture was stirred at 50oC for 1 h, then cooled to room temperature. The mixture is alkalinized, then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, filtered and the solvent is evaporated. The remainder of x is S="ptx2">

The crude product is collected and recrystallized from a mixture of isopropanol/isopropyl ether to obtain 2.8 g specified in the title compounds as colorless prisms.

Melting point: 85 - 89oC.

1H-NMR (CDCl3, 400 MHz) M. D.: 2,03 (2H, m), 2,32 (3H, s), of 2.53 (2H, t, J = 7.8 Hz), 2.63 in (4H, m), 2.91 in (6H, m), 3,91 (3H, s) to 3.92 (3H, s), the 5.45 (2H, s), 6,85 (1H, s), 6,92 (1H, m), of 6.96 (1H, s), was 7.08 (2H, m), 7,54 (1H, d, J = 1.0 Hz).

Elemental analysis for C27H33N6O2Cl:

Calculated, %: C 61,53; H 6,69; N 15,94; Cl 6.73 x;

Found, %: C 61,44; H 6,98; N 15,66; Cl 6,59.

Example 121. 5,6-Dimethoxy-1-(4-morpholinylcarbonyl)-3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1H-indazol.

To the mixture 3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1H-indazole (700 mg) in dimethyl sulfoxide (10 ml) was added lithium methylate (140 mg) and the mixture stirred at room temperature for 15 minutes Then the solution for 1 min add a solution of 4-morpholinepropanesulfonic (1570 mg, 68% purity, containing 32% 4-morpholinobenzenediazonium alcohol) in dimethyl sulfoxide (10 ml). The mixture was stirred at 50oC for 1 h the Mixture was poured into water and the precipitated solid product is collected and washed with water, then dried. The product is dissolved in chloroform silicagel using a mixture of chloroform : ethanol (100:1 by volume) to give 0.84 g specified in the title compound as a white solid product.

IR (KBr) cm-1: 2952, 2824, 1590, 1512, 1466, 1434, 1352, 1262, 1166, 1114, 1094, 1004, 944, 730.

1H-NMR (CDCl3, 400 MHz) M. D.: 2,35 (3H, s), 2,77 (4H, m), 2,97 (10H, m), 3,21 (2H, m), of 3.73 (4H, m), 3,90 (3H, s), of 3.95 (3H, s), to 5.58 (2H, s), 6,60 (1H, s), to 6.95 (1H, m), to 7.09 (3H, m), 7,24 (2H, m), to 7.67 (2H, m).

Example 122. 5,6-Dimethoxy-1-(4-pyridylmethyl)-3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1H-indazol.

To the mixture 3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1H-indazole (1 g) in dimethyl sulfoxide (10 ml) was added lithium methylate (200 mg) and the mixture was stirred at 50oC for 15 minutes Then to the solution was added a solution of the hydrochloride of 4-chloromethylpyridine (433 mg) and the mixture was stirred at 50oC for 1 h the Mixture was poured into water and the precipitated solid product is collected, washed with water and dried. The product is dissolved in chloroform and the solution is dried over anhydrous sodium sulfate.

The solvent is evaporated and the residue chromatographic on silica gel with a mixture of chloroform : ethanol (15:1 by volume) to obtain 235 g specified in the title compounds as colorless needles.

Melting point: 117 - 118,5oC.

IR (KBr) cm-1: 2820, 1512, 1464, 1432, 1416, 1270, 1238, 1212, 1162, 1132, 1038, 1006.

1H-NMR (CDCl3, 400 MHz) M. D.: 2,35 (3H, s), was 2.76-2.91 in (4H, m), 2,93-of 2.97 (6H, m), 3,17-is 3.21 (2H, m)>8H32N5O2Cl:

Calculated, %: C 66,46; H 6,37; N At 13.84; Cl 7,01;

Found, %: C 66,43; H 6.42 Per; N 13,74; Cl 7,26.

Example 123. 3-[2-[1-[4-(3-chloro-2-were)piperazinil]]ethyl]-1-(4-imidazolidinyl)-5,6-methylenedioxy-1H-indazol.

1.0 M solution of the complex of borane-tetrahydrofuran (10 ml) are added to 4-(3-chloro-2-were)-1-[[5,6-dimethoxy-1-[4-(1-tritylimidazole)methyl] -1H-indazol-3-yl] ethyl] piperazine (1,91 g) in tetrahydrofuran (10 ml) and heated under reflux in an argon atmosphere for 90 minutes the Reaction mixture is cooled to room temperature and then water is added to decompose excess reagent. After evaporation of the tetrahydrofuran to this mixture is added concentrated hydrochloric acid (1.0 ml), water (1.0 ml) and ethanol (2.0 ml) followed by stirring at 50oC for 1 h, the Reaction mixture was cooled to room temperature and alkalinized, then extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and filtered, and the solvent evaporated. The remainder chromatographic on silica gel with a mixture of chloroform : ethanol (25:1) and recrystallized from isopropyl alcohol/isopropyl ether to obtain 3-[2-[1-[4-(3-chloro-2-were)piperazinil] ] ethyl]-1-(4-what - 177oC.

IR (KBr) cm-1: 2944, 2900, 2832, 1462, 1374, 1274, 1244, 1004, 938, 838.

1H-NMR (CDCl3, 400 MHz) M. D.: of 2.34 (3H, s), 2,73 (4H, m), 2,82-of 2.86 (2H, m), 2,93-2,95 (4H, m), is 3.08-of 3.12 (2H, m), of 5.40 (2H, s), 5,97 (2H, s), 6,79-of 6.96 (2H, m) 6,94 (1H, s), 7,06-7,10 (1H, m), to 7.09 (1H, s), 7,54 (1H, s), 9,62 (1H, s).

Materials and methods experiment

1. The compounds.

The compound of example 18.

Structure

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The compound of example 101

Structure

< / BR>
2. Animal testing.

Used eighty male mice Slc:ddY age 4-5 weeks (22,5-27,4 g by weight). These mice were subjected to preliminary experiments for 6 days, after which one of them was selected healthy mice. In each group of tests used five individuals of equal weight, after which they were hungry exposure during the night before the introduction of the samples.

3. Introduction.

3.1. Dose.

Tested three different doses (200 mg/kg 400 mg/kg and 800 mg/kg).

3.2. Method.

All samples were forcibly injected at the dose of 10 mg/kg using a probe after their suspension in 0.5% aqueous solution of methylcellulose.

5. Monitoring.

Observations on the subjects of mice was carried out for 10 days, including Hughes of life and death (of the tested individuals).

Test in mice the toxicity of a single dose (PO) are presented in table. 5 (see the end of the description).

The effect of inhibition of PDE-dependent CaM

I. test Method.

(1) In a glass tube (in ice water) were placed the following reaction mixture:

50 mm TRIS-HCl (pH 7.5) 175 ál,

50 mm MgCl250 µl,

1 mm CaCl2(used to measure Ca2+-specific activity) or 10 mm etc (used for measuring the activity of which is not dependent on the Ca2+) of 0.2 u/ml PDE 50 ál,

The CaM solution 10 units/ml or in different concentrations (containing mg/ml BSA) and 50 ál,

Solution samples/DMSO/50 mm TRIS 25 µl.

(2) a Solution of [3H]-cGMP was added to 250 μm solution of cGMP in the amount of from 2000 to 3000 num.u.min/ml with the receiving substrate solution (1 ál hot. /1 ml solution).

(3) received 100 μl of substrate solution was introduced into the glass tube was mixed and then incubated at 30oC for 10 minutes

(4) After heating for 1 min in boiling water the reaction was stopped.

(5) After adding 50 μl of an aqueous solution of snake venom in a glass tube, and the mixture was mixed and then incubated at 30oC for 10 minutes

(6) To the system is mixing.

(7) the resulting solution was centrifuged at 1600 rpm at 4oC for 20 minutes

(8) After sampling 500 μl of the supernatant thus obtained supernatant was mixed with 10 ml of scintillation mixture ASC-11 and using a liquid scintillation counter read its radioactivity.

II. Calculation of inhibitory activity against PDE, %.

(1) the calculation of the dependent CaM PDE activity.

Dependent Ca2+/CaM activity was calculated by the following equation for each concentration of the sample:

(dependent Ca2+/CaM activity) = (radioactivity tube for measurement of Ca2+-specific activity (radioactivity tube for measurement is not dependent on the Ca2+-activity).

(2) Activity in the presence of each sample was calculated as a percentage based on the activity (100%) diluent.

III. Calculation of inhibitory activity against PDE (index of inhibition).

(1) calculation of the concentration of 50% activation to CaM against PDE.

Concentration 50% activation CaM (EC50) was calculated in the presence of sample and diluent (5% DNSO).

(2) the Calculation of the index of inhibition.

Index of ioby)/(EC50for CaM in the presence of a diluent).

IV. Reagent:

(1) a solution of [3H]-cGMP: NEM,

Cyclic guanosin-3'5'-phosphate[3H]

(2) 50 mm TRIS-HCl (pH 7.5).

The following reagents (except for snake venom and resin) were prepared with 50 mm TRIS-HCl:

(3) 50 mm MgCl2,

(4) 1 mm CaCl2,

(5) 10 mm EGTA,

(6) 1 mg/ml BSA,

(7) 10 u/ml of calmoduline (CaM):Sigma

3'5'-cyclic nucleotide activator phosphodieterase from the brain of a bull

2500 IU/vial/2.5 ml 1 mg/ml BSA in TRIS

50 ál of 1000 units/ml + 4,95 ml BSA 1 mg/ml = 10 IU/ml,

(8) and 0.2 u/ml PDE: (Sigma, Lot 71H9520)

3'5'-cyclic nucleotide phosphodiesterase from the brain of a bull

1 IU/vial/5 ml 50 mm TRIS = 0,2 u/ml,

(9) 250 μm cGMP: 3', 5'-cyclic guanosine monophosphate (Sigma, Lot 121H0549)

9,5 ml of 50 mm TRIS-HCl was added to 0.5 ml of 5 mm cGMP,

(10) 1 mg/ml aqueous solution of snake venom

phosphodiesterase 1, Type V from Bothrops atrox (Sigma, Lot 100H0074),

(11) Suspension anion-exchange resin in methanol (1:5 V/o).

After activation of the chloride form AG1-X8 (200-400 mesh) (Sigma, Lot 35492) with the help of 0.01 N. NaOH final solution was washed with pure water until neutral, and then dried.

(12) Scintillation mixture ACS-11.

V. The Results.

the mi on specific examples, the specialist may use different variations and modifications of the invention within the scope of his claims.

1. Derivatives of piperazine of General formula I

< / BR>
where Q represents phenyl, naftalina, pyridyloxy, pyramidalnou, izohinolinove, follow, benzofuranyl, dihydrobenzofuranyl, benzyl, diphenylmethyl group, these groups may be substituted by one or more substituents selected from the group: alkyl groups having from 1 to 6 carbon atoms, CNS group having from 1 to 6 carbon atoms, triptorelin group, dialkylamino having from 1 to 6 carbon atoms in each alkyl part, a halogen atom, ceanography and Ethylenedioxy, and these substituents on diphenylmethylene group are on the phenyl nucleus, or cycloalkyl group having from 3 to 8 carbon atoms;

R represents a group

< / BR>
< / BR>
where R1and R2independently represent CNS group having from 1 to 6 carbon atoms, or methylenedioxy;

G represents cycloalkyl group containing 3-6 carbon atoms; substituted or unsubstituted phenyl group, a benzoyl where the phenyl fragment Sames the PPU, in which the phenyl part is substituted or unsubstituted; substituted or unsubstituted pyrrolidinyl group, where the nitrogen atom is a hydrogen atom or alkyl group having from 1 to 6 carbon atoms, or participate in binding with R, alkyl group, substituted heterocyclic group consisting of substituted or unsubstituted thienyl group, substituted or unsubstituted imidazolidine group, substituted or unsubstituted peredelnoj group and C1-C3alkalinous group; alkanolamines having from 2 to 7 carbon atoms; morpholinoethyl the group consisting of morpholino group and C1-C3alkalinous group; 1-alcheringa-2-ilen group having from 1 to 6 carbon atoms in the alkyl part, where the indole portion may be optionally substituted; phenylalkyl the group consisting of substituted or unsubstituted phenyl group, and C1-C6alkalinous group; and a hydrogen atom, and when the Deputy G has substituents, the latter are members selected from alkyl groups having from 1 to 6 carbon atoms, CNS group having from 1 to 6 carbon atoms, ancilliary having from 1 to 6 carbon atoms, alkylsulfonyl group having from 1 to 6 atom of the C2-C4alkynylamino group, C1-C3alkylenes group having one hydroxyl group, or alkilinity group containing a carbonyl group at one end or in the middle of the carbon chain,

or salt compounds.

2. Connection on p. 1, where the substituent R has the structure represented by the following formula:

< / BR>
3. Connection on p. 1, where the substituent R has the structure represented by the following formula:

< / BR>
4. Connection PP. 1,2 or 3, where the Deputy Q is a phenyl group having at least one substituent in a meta-position in relation to the place of attachment of the phenyl group to piperazinone part.

5. Connection on p. 4, where meta-Deputy phenyl group is a halogen atom.

6. Connection on p. 5, where Q is 2-methyl-3-chloraniline group.

7. Connection PP.1 - 5 or 6, where Z is alkalinous group having 2 to 3 carbon atoms.

8. Connection on p. 7, where Z is alkalinous group having 2 carbon atoms.

9. Connection PP.1 - 7 or 8, where the substituent R represents a 5,6-dimethoxy-1H-indazolinone part.

10. Connection PP.1 - 7 or 8, where the substituent R is the R value is a member, selected from 3,4-dimethoxybenzyl group, 4-imidazolylidene group, 2-pyridylmethyl group, 3-pyridylmethyl group and 4-pyridylmethylene group.

12. Connection PP.1,2,4 - 7 or 8, where the substituent R is 2-substituted-4,5-dimethoxyaniline part.

13. Connection PP.1,2,4 - 7 or 8, where the substituent R is 2-substituted-4,5-methylenedioxyaniline part.

 

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< / BR>
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< / BR>
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