5-heterocycle-1,5-benzodiazepines and their pharmaceutically acceptable salts

 

(57) Abstract:

Describes new connections - 5-heterocycle-1,5-benzodiazepines General formula (I) and their pharmaceutically acceptable salts, where X is hydrogen or halogen; R1is a group NR4R5where R4stands WITH3-6alkyl, a R5represents phenyl substituted in the para-position by metaxylem; R2is indole, phenyl or a group with other11where R11is phenyl or phenyl substituted by carboxypropyl; R3is a heterocyclic group attached to the nitrogen through a carbon atom cyclic ring selected from pyridyl, pyrimidinyl or pyrazolyl, the latter in turn replaced three times WITH1-4by alkyl; z is 1. The compounds possess agonistic activity against CCK-A receptor, which gives them the ability to modulate the hormones gastrin and cholecystokinin (CCK) in mammals. Some of these compounds also possess agonistic activity against CCK-B receptors. 5 C.p. f-crystals, 1 PL.

The present invention relates to derivatives of 5-heterocycle-1,5-benzodiazepine and their pharmaceutically acceptable salts which exhibit agonistic activity of the melting.

Cholecystokinin (CCK) and gastrin are peptides with similar structures, which exist in gastrointestinal tissue and in the Central nervous system. Cholecystokinin include CCK-33, neuropeptide, which was originally allocated in the form of a peptide consisting of thirty-three amino acids, its carboxy-terminal oktapeptid, CCK-8 (also a naturally occurring neuropeptide), and 39 - and 12-amino acid forms. Gastrin is in the form of peptides of 34, 17 or 14 amino acids (34-, 17 - and 14-amino acid forms, with the minimum active sequence representing the C-terminal tetrapeptide, TRP-Met-ASP-Hairdryer-NH2(CCK-4), which is a common structural element, available as of CCK and gastrin.

CCK and gastrin are gastrointestinal hormones and neurotransmitters in neural and peripheral systems and perform their respective biological functions by binding to specific receptors localized in different parts of the body. There are at least two subtypes cholecystokinin receptors, referred to as CCK-a and CCK-B, found in both the peripheral and Central nervous system.

CCK-A receptor is lodochnoy gland, gall bladder, ileum, the pyloric sphincter and vagusnye afferent nerve fibers. CCK receptors And type is also detected in the brain in discrete areas where they are used to provide many of the functions of the CNS. Due to the ability of CCK-8 and CCK-selective agonists And type to suppress food intake in several species of animals had a significant interest in the creation of new substances that function as CCK agonists selective with respect to the receptor-type, which could serve as a means for reducing the appetite.

CCK-B or Gastronomie receptors found in peripheral neurons, smooth intestinal muscles and mucous membrane of the gastrointestinal tract, especially in the parietal cells, ECL cells, D cells and chief cells. CCK-B receptors predominate in the brain and they are involved in the regulation of anxiety, excitement and action of neuroleptic agents.

Known [U.S. patent N 4988692] derivatives of 3-acylamino-1-alkyl-5-phenyl-1,5-benzodiazepine, which act as antagonists of cholecystokinin, altering or blocking the action of endogenous hormone to its receptor.

Known [U.S. patent N 4490304; PCT application N W090/06937; application R the organisations suitable for the regulation of appetite, and for the treatment and/or prevention of gastrointestinal disorders or disorders of the Central nervous system in animals, and in particular in humans.

It is known [U.S. patent N 5187154] the application of the neuropeptide cholecystokinin (CCK) for control of gastric emptying in patients in the early ainsliezubaida diabetes and suffering from rapid gastric emptying. It is known [U.S. patent N 5187154] that compounds that inhibit gastric emptying, can be used to relieve or eliminate symptoms associated with early or pre-diabetes. Specific symptoms include elevated levels of glucose and insulin in the blood, insulin resistance, increased susceptibility to infection or glicerio while maintaining bowel emptying in normal limits.

Currently we have opened a new group of derivatives of 5-heterocycle-1,5-benzodiazepine, which have agonistic activity against CCK-A receptor, which gives them the ability to modulate the hormones gastrin and cholecystokinin (CCK) in mammals. Some of these compounds also possess antagonistic activity against CCK-B receptors.

Thus, according to the automatic acceptable salt,

where

X is hydrogen or halogen;

R1is a group-NR4R5,

where R4represents C3-6-alkyl, and

R5represents phenyl substituted in the para-position by metaxylem,

R2is indole, phenyl or a group-other11,

R3is a heterocyclic group attached to the nitrogen through a carbon atom cyclic ring selected from pyridyl, pyrimidinyl or pyrazolyl, the latter in turn three times substituted C1-4-alkyl, z is 1.

If R1represents a group NR4R5, examples of eligible groups include groups in which R4is C3-6-alkyl, such as propyl or isopropyl, and R5represents phenyl substituted in the para-position by metaxylem.

If R2represents a group other11, R11usually is phenyl, possibly substituted by carboxypropyl. If R11is one-deputizing phenyl group, the Deputy usually located in the meta-position.

Examples of the most acceptable R2groups include indole or group other11. Typically R2selected from the group UP>11.

If R3represents pyridyl, examples of eligible groups include 2-pyridyl, 3-pyridyl and 4-pyridyl.

If R3is pyrimidinyl, examples of eligible groups include 2-pyrimidinyl or 5-pyrimidinyl.

If R3represents pyrazolyl, examples of eligible groups include 1,3,5-trimethyl-1H-pyrazole-4-yl.

Examples of the most acceptable R3groups include pyridyl, for example 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, in particular 2-pyrimidinyl or 5-pyrimidinyl, or 1,3,5-trimethyl-1H-pyrazole-4-yl.

The most promising group of compounds according to the invention includes those compounds in which R1represents a group NR4R5in which R4is propylene or isopropyl, a R5is phenyl, possibly substituted in the para-position by metaxylem; R2represents phenyl or a group with other11where R11represents phenyl or phenyl substituted by carboxypropyl, and the Deputy is preferably in the meta-position, or indole; R34represents pyridyl, for example 2, 3 or 4-pyridyl, pyrimidinyl, for example 2 - or 5-pyrimidine of the present invention, which has a very high and selective affinity for the CCK-A receptor, with exceptional efficiency is observed in those cases where R2is indole group. Within this group the most promising compounds are those in which R4represents isopropyl, R5represents p-methoxyphenyl, a R3represents pyridyl, pyrimidinyl or 1,3,5-trimethyl-1H-pyrazole-4-yl, or, more specifically, R3represents 3-pyridyl, and X represents hydrogen.

Preferred compounds according to the invention include:

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo - 5-pyridin-2-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl} - amide 1H-indole-2-carboxylic acid;

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] - 2,4-dioxo-5-pyrimidine-2-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl}-amide 1H-indole-2-carboxylic acid;

2-[2,4-dioxo-3-(3-phenyl-ureido)-5-pyridin-2 - yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N- (4-methoxy-phenyl)-ndimethylacetamide and their enantiomers.

The most preferred compound of the invention is

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5-pyridin - 3-yl-2,3,4,5-is the description of the term alkyl, usually used to refer to aliphatic isomers of the corresponding alkyl with straight chain and branched chain. For example, it is assumed that C1-4-alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-phenyl, etc.

In this description, the term cycloalkyl represents all acyclic isomers of the corresponding alkyl. For example, the term C3-6-alkyl denotes, in particular, groups such as cyclopropyl, cyclopentyl and cyclohexyl.

It is implied that the term halogen means F, Cl, Br or I.

The term tetrazol as a group or part of a group refers to a (1H)-tetrazol-5-ilen group and its tautomers.

Professionals should be borne in mind that in compounds of formula (I) are stereocenter. Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers. If you want the connection formula (I) in the form of a single enantiomer, it can be obtained either by separation of the final product or by stereospecific synthesis from either and the aqueous product the intermediate or starting material can be carried out by any method known from the prior art [E. L. Eliel, Stereochemistry of Carbon Compounds (McGraw Hill, 1962); S. H. Wilen, Tables of Resoling Agents]. In addition, in situations where the possible tautomers of the compounds of formula (I), it is understood that the present invention includes all tautomeric forms of the compounds.

The specialist should also be borne in mind that the compounds of the present invention can also be used in the form of pharmaceutically acceptable salts. Physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic and organic acids, and Quaternary ammonium salts obtained by addition of acids. More specific examples of acceptable salts include hydrochloric, Hydrobromic, sulfuric, phosphoric, nitric, perchloro, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, Paveway, malonic, hydroxymaleimide, phenylacetic acid, glutaric, benzoic, salicylic, fumaric, toluensulfonate, methanesulfonate, naphthalene-2-sulfonic, benzosulfimide and the like acids. Other keys is Holocene salts, acceptable as intermediates in obtaining the compounds according to the invention and their pharmaceutically acceptable salts. Here is the link to the connection according to the invention include the compounds of formula (I) and their pharmaceutically acceptable salts.

Compounds of the present invention have a CCK-A agonist activity and can be considered as full or partial agonists, cholecystokinin, because they are associated with CCK-A receptors, fully or partially stimulating the contraction of the gallbladder and/or reducing food intake in animals.

As agonists of CCK-a receptors compounds of the present invention are acceptable as a means to reduce appetite in the treatment of obesity and related pathologies, such as diabetes or hypertension. Moreover, these compounds proposed for new methods for the induction of satiety, for the regulation of appetite and modification of food intake in mammals, especially humans, for the regulation of appetite, obesity and maintain weight loss. The compounds are also suitable for the treatment leisureservices diabetic state associated with rapid emptying nekotoruyu antagonistic activity on a particular site-specific CCK-B and gastronomic receptors, as demonstrated by their inhibition of CCK-4-stimulated contraction of isolated longitudinal muscle-muscular plexus of the ileum of the Guinea pig and stimulated pentagastrin acid secretion in isolated rat gastric mucosa in the well-known [M. Patel and C. F. Spraggs in Br.J.Pharmac., (1992), 106, 275-282; J. J. Reeves and R. Stables in Br.J.Pharmac., (1985), 86,677-684] tests.

The relative magnitude of the affinity of the compounds according to the invention to CCK-a and CCK-B receptors can be determined by traditional methods [Fomos et al. , J. Pharmacol.Exp.Ther., 1992, 261, 1056-1063].

The ability of compounds according to the invention to inhibit the secretion of gastric juice, for example-stimulated pentagastrin the secretion of gastric juice, can be determined from in consciousness rats with gastric fistula [Hedges and Parsons Journal of discrimination, 1977, 267, 191-194].

The compounds of formula (I) inhibit or delay gastric emptying, which can be determined using standard tests. For example, rats deprived of food for 18 hours, can be pre-processed test compound, introduced intraperitoneally for a certain period of time (20 minutes) prior to submission to the quality of the food methylcellulose, which is injected by means of the plant and the time intervals in rats kill, and determine the amount of food in the stomach by measuring the concentration present marker substances. Then this value is compared with a control animal that has not been pre-processed test the connection.

It was found that the compounds according to the invention have the most favorable activity profile due to their high bioavailability when administered orally in combination with a relatively good solubility in water.

In particular, the compound of formula (I) or its pharmaceutically acceptable salt suitable for use in therapy, in particular in the treatment of the person.

A specialist should be borne in mind that reference to treatment includes both prevention and treatment of established diseases or symptoms. In addition, it should be borne in mind that the number of compounds according to the invention required for treatment varies depending on the nature of the subject treated and the age and condition of the patient and must ultimately be at the discretion of the attending physician or veterinarian. In General, however, doses used for the treatment of an adult, usually lie in the range from 0.02-5000 mg per day, for example 1-1500 mg per day. The required dose for convenience may be presented in unit-dose or rasni.

Although it is possible therapeutic introducing the compound of the present invention in the form of the raw chemical compound, yet it is preferable to present the active ingredient as a pharmaceutical preparation containing the compound of formula (I) or its pharmaceutically acceptable salt together with one or more pharmaceutically acceptable carrier, and possibly other therapeutic and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense that it is compatible with other ingredients of the product and is not harmful to the recipient.

Drugs include drugs, specially prepared for oral, transbukkalno, parenteral, rectal injection or administration in the form of the implant, however, is preferred oral administration. For transbukkalno administration of the drug can be in the form of tablets or pellets made accordingly. Tablets and capsules for oral administration may contain conventional excipients such as binding agents (e.g. syrup, gum Arabic, gelatin, sorbitol, tragakant, starch paste or polyvinylpyrrolidone), fillers (e.g. lactose, is for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), leavening agents (e.g., potato starch or starch glycolate, sodium) or wetting agents such as sodium lauryl sulfate. Tablets can be coated using known from the prior art methods. Acceptable shell for tablets include basic intersolubility shell.

On the other hand, the compounds of the present invention, can be incorporated into liquid preparations for oral administration, such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. In addition, preparations containing these compounds, can be presented as a dry product intended for mixing before use with water or other acceptable media. Such liquid preparations may contain conventional additives such as suspendresume agents, for example sorbitol syrup, methylcellulose, syrup of glucose/sugar, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gel, aluminum stearate or hydrogenated edible fats; emulsifying agents such as lecithin, monooleate sorbitan or gum Arabic; non-aqueous vehicles (which may is, propylenglycol or ethyl alcohol; and preservatives, such as methyl - or propyl-p-hydroxybenzoate or sorbic acid. Such drugs may also be made in the form of suppositories containing, for example, conventional suppozitornoj bases such as cocoa butter or other glycerides.

When administered orally, the compounds according to the invention is usually administered in pill form in intersolubility shells or capsules made from intersolubility materials or coated intersolubility shell.

In addition, preparations containing compounds of the present invention can be manufactured for parenteral administration by injection or continuous infusion. Preparations for injection can have such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain preparative agents, such as suspendida, stabilizing and/or dispersing agents. On the other hand, the active ingredient may be in the form of a powder intended for mixing before use, with an acceptable carrier (e.g., sterile pyrogen-free water).

The preparation containing the compound according to the invention can be produced also draino or intramuscularly) or by intramuscular injection. Respectively, can be prepared preparations of the compounds according to the invention with an acceptable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil), with ion-exchange resin or in the form of slightly soluble derivatives, such as slightly soluble salt.

Preparations containing the compounds according to the invention may contain from 0.1 to 99% of active ingredient, for tablets and capsules is usually 30-95% 3-50% for liquid preparations. Compounds of General formula (I) and their salts can be obtained by the General methods described below. In the following description, the groups R1-R12and X are such as defined for compounds of formula (I), if it is not specifically mentioned, or may be groups that can be transformed.

For any of these processes may be necessary and/or desirable to protect sensitive or reactive groups. The protective groups used according to standard methods of organic synthesis [N. W. Green and P. G. M. Watts (1991) Protection Groups in Organic Synthesis, John Wiley & Sons] . These groups are removed at an appropriate stage of the synthesis, using the methods known from the prior art. So, for example, amino groups can be protected by a group selected from arelet the tion, then make subsequent removal of the protective groups by hydrolysis or hydrogenolysis, if appropriate, using standard conditions. Hydroxyl or carboxyl group can be protected using any standard hydroxyl - or carboxyl-protective group. Examples of acceptable hydroxyl - or carboxyl-protective groups are groups selected from alkyl, for example methyl, tert-butyl or methoxymethyl, arylmethyl, such as benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups, such as tetrahydropyranyl, acyl, for example acetyl or benzoyl, and silyl groups such as trialkylsilyl, for example tert-butyldimethylsilyl. The hydroxyl-protective group can be removed by appropriate means. So, for example, alkyl, similarily and heterocyclic groups can be removed by hydrolysis under acidic or alkaline conditions. Arylmethyl groups, such as triphenylmethyl, can be easily removed by hydrolysis in acidic conditions. Kalimatnya groups such as benzyl, can be split by hydrogenolysis in the presence of a catalyst of a noble metal, such as palladium on coal. Silyl groups can also be easily WaMu General way As the compounds of formula (I) can be obtained by a reaction between an amine of formula (III), where R1, R2, R3, X and z have the meanings defined in formula (I)

< / BR>
connection R11Y (IV) in which Y is a group-NCO, HNCOCl or NHCORawhere Rais fenoxaprop substituted by a nitro-group, or 1-imidazole group.

The reaction usually proceeds in the presence of a suitable solvent, such as halogenougljovodonika (e.g. dichloromethane), an ether (e.g. tetrahydrofuran) or a nitrile (e.g. acetonitrile), or a mixture thereof at a temperature in the range from 0 to 80oC.

The compounds of formula (IV) in which Y is-NCO, are commercially available or can be obtained by reaction of amines H2N-R11with phosgene or triphosgene in a suitable solvent, such as methylene chloride. The compounds of formula (IV) in which Y is NHCOCl, also formed as a result of reaction between amines H2NR11with phosgene or triphosgene in a suitable solvent, such as methylene chloride. The compounds of formula (IV) in which Y is NHCORaand Rais a 1-imidazole group, obtained by treatment of amines HN2-R11diimidazole in an acceptable solvent (dichloromethane, ether, tetrahydrofuran) Oh Y is HNCORaand Rais fenoxaprop substituted by a nitro-group, receive the result of the interaction of amines H2N-R11with the appropriate chloroformate RaCOCl in the presence of a base (pyridine, triethylamine) in a suitable solvent (dichloromethane) and at a temperature of from 0 to 50oC.

According to the following General method B, the compounds of formula (I) can be obtained by a reaction between the intermediate compounds of formula (V)

< / BR>
in which Y is a group-NCO, -NHCOCl or NHCORawhere Rais fenoxaprop substituted by a nitro-group, or 1-imidazole group, with an amine (VI)

H2N-R11(VI)

and possibly in the presence of a base such as tertiary amine (e.g. triethylamine).

The reaction usually proceeds in an appropriate solvent, such as halogenosilanes hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) or amide (e.g. N,N-dimethylformamide) at a temperature generally ranging from room temperature to the temperature of reflux distilled solvent.

As a rule, the compounds of formula (V) are obtained in situ from the amine (III).

In the particular case of method (B), when Y is g the beam amine of formula (VI) is mixed with the compound of the formula (III)

< / BR>
in the presence of carbonyldiimidazole under the above conditions.

In method B, when Y is a group NHCORaand Rais fenoxaprop substituted by a nitro-group, the reaction with the primary amine (VI) is preferably carried out in the presence of such grounds, as the tertiary amine, such as triethylamine.

In method B, when Y is an isocyanate group,- N=C=O, and the reaction with the primary amine (VI) is preferably carried out in an aprotic solvent, such as halogenougljovodonika, for example methylene chloride. Usually isocyanate receive in situ prior to addition of the primary amine (VI).

The compounds of formula (V) in which Rais a possibly substituted by phenoxypropane, can be derived from the primary amine (III) by reaction with an appropriate substituted by a nitro-group by phenylcarbamates in the presence of such bases as pyridine. The reaction can be carried out in a solvent such as halogenougljovodonika, for example dichloromethane, at a temperature from 0 to 50oC.

The compounds of formula (V) in which Rais a 1-imidazole group can be obtained by reaction of compounds of formula (III) with a carbonyl diimidazol in the presence of p is, tetrahydrofuran (THF) at a temperature in the range from 0 to 80oC (usually at room temperature).

The compounds of formula (V) in which Y is an isocyanate group-N=C=O or carbamoylation-NHCOCl, can be derived from the primary amine (III) by reaction with phosgene (COCl2or triphosgene in a suitable solvent, such as methylene chloride.

According to the following General method In the compounds of formula (I) can also be obtained through a reaction between the compounds of formula (VII)

< / BR>
with halogenated having the formula (VIII)

R1COCH2Hal (VIII)

where Hal = Cl or Br.

The reaction is usually carried out by treatment of compounds of formula (VII) with a strong base such as sodium hydride, in a polar aprotic solvent such as N,N-dimethylformamide, followed by interaction with azetilholinom (VIII).

Acetylgale (VIII) are obtained by reacting an amine R-1-H with the corresponding gloucestibraheem in dichloromethane at 0oC in the presence of a suitable base, such as triethylamine.

Amines R1-H, where R1is a group-NR4R5can be obtained by the restoration procedure G, compounds of General formula (I) can also be obtained by reaction between the intermediate compounds of formula (III) with acids of the formula (IX) below:

HOOC-R2(IX)

This reaction is the interaction of the intermediate compounds of formula (III) with an acid of formula (IX) can be carried out in the presence of a suitable dehydrating agent, such as, for example, dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (ejh) or 4-benzotriazol-1 - yloxytris-(dimethylamino)phosphodiesterase (BOP), in particular in the presence of a suitable alcohol (N-hydroxysuccinimide or N-hydroxybenzotriazole).

On the other hand, compounds of General formula (I) can be obtained by a reaction between the intermediate compounds of formula (III) with an activated derivative of the acid (IX), such as its acid chloride or anhydride, including mixed anhydrides.

Preferred solvents for General method D include N,N-dimethylformamide or dichloromethane. Preferred temperatures lie between 0 and 60oC. is Preferred for this reaction, the base include triethylamine, N-methylmorpholine or N,N-dimethylaminopyridine (DMAP).

3represents hydrogen, halide, R3Hal (where Hal is Cl or Br, a R3is a group defined in formula (I), more specifically heteroaryl group, for example, pyridium, pyrimidinium and so on). The reaction is usually carried out in the presence of metallic copper and potassium acetate in the presence of a solvent such as dimethylsulfoxide or N,N-dimethylformamide, and preferably the reaction is carried out at a temperature ranging from 25 to 100oC.

According to the following General method (S) of the compounds according to the invention can be converted into other compounds according to the invention. For example, the compounds of formula (I) in which R8is a group (CH2)bCO2H, can be obtained by reaction between the compounds of formula (I) in which R8is hydrogen, with a compound Br(CH2)bCOOR*where R*is C1-4-alkyl, in the presence of a strong base such as sodium hydride, followed by removal of carboxyl-protective group in the usual ways, for example by acid or alkaline hydrolysis.

The compounds of formula (I) in which R11absetzbar by acid hydrolysis with the formation of the compounds of formula (I), in which R11is phenyl, substituted by carboxyla.

The compounds of formula (III) can be obtained by the reduction of compounds of formula (X)

< / BR>
in which W is CH-N3or C=N-NHPh.

The compounds of formula (X), in which W is CH-N3can be restored to the compounds of formula (III) by hydrogenation in the presence of a suitable catalyst such as 5-10% palladium on a carrier such as carbon or calcium carbonate, or oxide of platinum (IV).

The reaction usually occurs in the presence of such a solvent as alkanol (e.g., ethanol), an ether (e.g. ethyl acetate or acetic acid.

The compounds of formula (X), in which W is C=N-NHPh, can be restored to the compounds of formula (III) in the reaction with zinc and acetic acid. This reaction can be carried out at a temperature in the range of 0-50oC.

The compounds of formula (X), where W is the CHN3can be obtained from compounds of formula (X), in which W is a group CH2by processing a strong base such as sodium hydride or hexamethyldisilazide potassium, or tert-butyl potassium, and then three-isopropylbenzenesulfonyl the R, tetrahydrofuran) at a temperature in the range from -78oWith up to 20oC.

The compounds of formula (III) can also be obtained by reaction between the compounds of formula (X), in which W is CH2, with a suitable base, such as bis(trimethylsilyl)amide and sodium O-(diphenyl-phosphinyl)hydroxylamine in a solvent such as dimethylformamide.

The compounds of formula (X), in which W is a group C=NNHPh or CH2can be obtained through a reaction between orthophenylphenol (XI) with dvukhchastotnym chloride (XII) in which Q is CH2or C=NNHPh, in a suitable solvent, such as ether, for example tetrahydrofuran,

< / BR>
< / BR>
The compound of formula (XII) in which Q is a group C=NNHPh can be obtained through a reaction between ketomalonate acid with phenylhydrazine with subsequent interaction with pentachloride phosphorus.

The compounds of formula (XI) are either known compounds or can be obtained in a similar way. For example, the compounds of formula (XI) can be obtained by alkylation of amine (XIII)

< / BR>
So-amine (XIII) may be subjected to a reaction between connection Rretele, as N,N-dimethylformamide, and such grounds as potassium carbonate.

Another way to obtain the intermediate compounds of formula (III), as listed below, includes processing the intermediate compounds of formula (XIV) with sodium hydride followed by the addition of halogenated (VIII) in an acceptable solvent such as N,N-dimethylformamide, at 0oC to receive the protected compounds of formula (XIV)

< / BR>
< / BR>
The intermediate compound (XVI) can be converted to the amine (III) by processing HBr in methylene chloride.

The intermediate compound (XIV) is obtained from the intermediate compounds of formula (XVI) in the reaction of interaction with benzyloxycarbonylation in dichloromethane using triethylamine as the base. This reaction usually proceeds at room temperature.

< / BR>
The intermediate compound (XVI) is obtained from phenylenediamine (XIII) in the next process.

In the reaction of diamine (XII) with p-methoxybenzylamine and subsequent reduction of the resulting amide with lithium-aluminiumhydride is formed of N-protected diamine (XVII)

< / BR>
In the reaction of compound (XVII) with two-acid chloride (XII; Q= C= NNHPh) posleduu) can be converted into the target compound (XVI) by reaction with Ce(NO2)6NH4(cerium-ammoniumnitrate).

The compounds of formula (VII) can be obtained from compounds of formula (XVI) by the General methods a, B and C described above.

Compounds corresponding to the compounds of formula (I), but in which R3represents hydrogen, can be obtained from the corresponding amine (III) in which R3represents hydrogen, using General procedures a, B and C. the compounds of formula (III) in which R3is hydrogen, can be obtained according to the General methods described above for preparing compounds of the formula (III) in which R3is a heterocyclic group, but using intermediate compounds in which R3is p-methoxybenzyloxy group, which can then be removed in an appropriate way.

Thus, in the reaction of diamine (XIX)

< / BR>
with halogenated (VIII) receive disubstituted diamine (XX)

< / BR>
As a result of reaction between the compound (XX) with two-acid chloride (XII) in which Q is a group C=NNHPh, followed by reduction with zinc and acetic acid have the benzodiazepine (XIX)

< / BR>
As a result of reaction between soybean is the Torah R3is hydrogen.

Diamine (XIX) can be obtained by the reaction nitrophthalonitrile (XXII)

< / BR>
with p-methoxybenzylamine and subsequent reduction of the nitro group.

The compounds of formula (X), in which W is a group CH2can be obtained by reaction of compounds of formula (XXIII), in which X, z and R1have the meanings defined in formula (I),

< / BR>
with bromide R3Br (R3shall have the meaning given above) in the presence of copper powder and potassium acetate. The reaction is preferably carried out in polar solvent such as dimethylformamide, and when heated.

The compound (XXIII) can be obtained by a reaction between the diamine (XXIV), in which X1, z and R1have the meanings given above,

< / BR>
with malonaldehyde similar to the method described for obtaining the compounds of formula (X), in which W is CH2.

The compounds of formula (I) contain at least one asymmetric carbon atom, namely the carbon atom diazepinone ring that is attached group substituted urea. Specific enantiomers of compounds of formula (I) can be obtained pore the m case, the desired enantiomer can be obtained from the corresponding enantiomeric amine of formula (III) by any means, described above to obtain compounds of formula (I) of the amine (III). Enantiomers amine (III) can be obtained from the racemic amine (II) with the use of appropriate procedures, such as salt formation with acceptable optically active acid or by preparative chiral GHUR.

Examples

The following examples are provided to illustrate the synthesis of certain specific compounds of the present invention and for illustration of private uses General methods a-D, Respectively, below the section Examples in no way serve to limit the scope of the invention described here.

Used here, the symbols and conventions used in these processes, schemes and examples, are identical used in the contemporary scientific literature, for example in Journal of American Chemical Society. If not otherwise noted, all starting materials were obtained from commercial sources and used without further purification. In particular, in the examples and the description of the invention can be used the following abbreviations: g (grams); mg (milligrams); l (liters); ml (milliliters); FCD (pounds per square inch); M (molar); mm (millimolar); B. C. (intravenous); Hz (Hertz); mol (moles) is I); MeOH (methanol); TFU (triperoxonane acid); THF (tetrahydrofuran); dimethyl sulfoxide (DMSO); Etoac (ethyl acetate); dichloromethane (DHM); dimethylformamide (DMF); 1,1-carbonyldiimidazole (CBI); isobutylparaben (ibuf); N-hydroxysuccinimide (Gouk); N-hydroxybenzotriazole (HOBT); 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (ejh); bis(2-oxo-3-oxazolidinyl)fatfingered (BOP); tert-butyloxycarbonyl (SIDE); dicyclohexylcarbodiimide (DCC); benzyloxycarbonyl (CBZ); 4-dimethylaminopyridine (DMAP). All references to ether are to diethyl ether. Unless otherwise noted, all temperatures are expressed inoC (degrees Celsius). All reactions take place at room temperature, unless otherwise noted.

1NMR spectra were taken either on a Varian VXR-300 or Varian Unity-300 spectrometer. Chemical shifts are expressed in parts per million (million-1d unit). The Association constants are expressed in units of Hertz (Hz). Options for splitting designated as s, singlet; d, doublet; t, triplet; q, Quartet; m, multiplet; b, broad.

Mass spectra of low-resolution (MS) filmed by JOEL JMX-AX505HA, JOEL 8X-102 and SCIEX API spectrophotometers. All mass spectra were obtained in the form of positive ions under the action of ionization by electron irradiation (EDP), the basic spectra (IR) were obtained on a Nicolet 510FT-IR spectrometer, using 1-mm NaCl item. Rotations were recorded on a Perkin-Elmer 241 the polarimeter. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck-silica gel plates (60F-254), visualized with UV light, 7% ethanol phosphomolybdenum acid or p-anisic aldehyde. Column chromatography quick separation was performed on silica gel (230-400 mesh mesh, Merck).

The products were purified by preparative liquid chromatography high-pressure reversed-phase (RP-ghvd) using Waters Model3000 Delta Prep, equipped with a Delta-pak radial compression element (C18, 300 a, 15 m, 47 mm x 300 mm). The solvent system consisted of A, water with 0.1% triperoxonane acid, B, 60% acetonitrile, 40% water with 0.1% triperoxonane acid and acetonitrile. All solvents contained 0.1% of TFU. In all cases we used linear gradients, the flow rate was 100 ml/minute (tabout= 5,0 min). Analytical purity was determined by means OF ghvd using Waters A system equipped with a Waters 990 diode array spectrometer (I interval 200-400 nm). The stationary phase was Vydac C18column (5 m, 4.6 mm x 250 mm). The flow rate ranged from 1.0 to 1.5 ml/min (tabout= a 2.8 or 3.0 min), and system rastvoritelyu through time).

Example 1

2-[2,4-Dioxo-3-(3-phenyl-ureido)-5-pyridin-2-yl-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide

To a solution of 2-(3-amino-2,4-dioxo-5-pyridin-2-yl-2,3,4,5 - tetrahydrobenzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide (100 mg) in methylene chloride (1 ml) solution was added phenylisocyanate (25.6 mg) in methylene chloride (1 ml), the mixture was mixed with K. so for 4 hours. The solvents were removed under vacuum, and the residue was recrystallized from ethyl acetate, to deliver a product that is specified in the header (44 mg) in the form of a whitish substance.1H NMR (300 MHz, CDCl3): 1,03 (2xd, J=7 Hz, 6N), 3,81 (s, 3H), 4,17 (d, J=16 Hz, 1H), 4,37 (d, J=16 Hz, 1H), 5,0 (sept, J=7,1 Hz, 1H), of 5.40 (d, J=6.3 Hz, 1H), 6,40 (d, J=5.3 Hz, 1H), 6,8 - of 7.3 (m,17H), 7,80 (br, 1H), 8,42 (d, J=3,9 Hz, 1H). TLC (10% MeOH, CH2Cl2Rf=0,53. m/z[MH]+= 593.

Example 2

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5-pyridin - 2-yl-2,3,4,5-tetrahydro-1H-benzo[1] [1,4] diazepin-yl}-amide 1H-indole-2-carboxylic acid

A solution of 2-(3-Amino-2,4-dioxo-5-pyridin-2-yl-2,3,4,5 - tetrahydrobenzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide (276 mg), BOP (244 mg), HOBT (78 mg), DMAP (69 mg) and indole-2-carboxylic acid (98 mg) in DMF (1 ml) was stirred at K. Yes sodium (g ml), water (20 ml), brine (20 ml), dried (K2CO3) and concentrated under vacuum, resulting in the crude product. After purification by jhud OF using a linear gradient (from 20% A, 80% B to 90% B, 10% B, 30 min) received the product specified in the header (26.6 mg), as a white lyophilisate; Tr=21,3 min 1H NMR (300 MHz, CDCl3): 0,98 (2xd, J= 7 Hz, 6N), 3,68 (s, 3H), 4,17 (d, J=16.6 Hz, 1H), 4,37 (d, J=16,8 Hz, 1H), 4,87 (sept, J=6.8 Hz, 1H), of 5.40 (d, J=6,8 Hz, 1H), 6,40 (d, J=5.3 Hz, 1H), 6.75 in-6,84 (m,5H), 6,92-of 6.99 (m,2H), 7,07 (t, J=7,3 Hz, 1H), 7,09 to 7.2 (m,4H), 7,24 (t, J=9,2 Hz, 1H), 7,40 (t, J=9.1 Hz, 2H), 7,52 (d, J=7.9 Hz, 1H), 7,72 (m,2H), scored 8.38 (d, J=4.4 Hz, 1H), 9,19 (s,1H), m/z[MH]+=617.

Examples 3 and 4

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5 - pyridin-2-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl} -amide (+) or (-) 1H-indole-2-carboxylic acid

A portion of a weight of 100 mg of the mixture of Example 2 was applied on prepreparation Pirkle D-Leucine column and using isocrates the solvent system consisting of hexane (77%), isopropyl alcohol (20%) and acetonitrile (3%) were suirable separate enantiomers. Each of the solvents contained 0.3% diethylamine.

The appropriate fractions were collected and combined. The solvent was removed under vacuum and the residue is washed with water. The precipitate was separated the ASS="ptx2">

Example 4: (Pirkle D-Leucine, 2 ml/min) tr=22,797 min (98,4%); m/z [MH]+= 617.

Example 5

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-pyrimidine - 2-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-yl}-amide 1H-indole-2-carboxylic acid

To a solution of 2-(3-amino-2,4-dioxo-5-pyrimidine-2-yl-2,3,4,5 - tetrahydro-benzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy - phenyl)-ndimethylacetamide (933 mg, 1.97 mmol) in DMF (20 ml) successively under stirring at ambient temperature was added indole-2-carboxylic acid (333 mg, 2,07 mmol), N-hydroxybenzotriazole (266 mg, 1.97 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (415 mg, of 2.16 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The solvent is evaporated under reduced pressure, obtaining the resulting yellow oil, which was dissolved in ethyl acetate (100 ml), washed with water (I ml), dried over MgSO4, filtered and concentrated under reduced pressure, resulting in the foam. The crude product was purified by chromatography rapid separation on silica gel (30 g), elwira with ethyl acetate (600 ml). The appropriate fractions were combined and concentrated under vacuum, resulting in the connection specified in the zag is, =6,8 Hz), to 5.03 (m, 1H), 4,45 (d, 1H, J=16.6 Hz), 3,99 (d, 1H, J= 16.6 Hz), 3,81 (s, 3H), of 1.07 (m,1H); TCX (CH2Cl2/CH3OH (19:1)): Rf=0,63; MC (the Belarusian library Association) m/z 618,2 (MH+).

Example 6

[1-[isopropyl-(4-methoxy-phenyl)- carbamoylmethyl] -2,4-dioxo-5-(1,3,5-trimethyl-1-pyrazole-4-yl)- 2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl] -amide of 1H-indole-2-carboxylic acid

To a solution of 2-(3-amino-2,4-dioxo-5-(1,3,5-trimethyl-1H-pyrazole - 4-yl)-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N- (4-methoxy-phenyl)-ndimethylacetamide (385 mg, from 0.76 mmol) in DHM (5 ml) was added indole-2-carboxylic acid (148 mg, of 0.92 mmol), HOBT (125 mg, of 0.92 mmol), Ejh (176 mg, of 0.92 mmol) and TEA (2 d). The solution was stirred at RT for 48 hours, then was poured into DHM (100 ml). The mixture was extracted with saturated sodium bicarbonate (x2), brine, dried over MgSO4and concentrated under vacuum. The resulting material was treated with ethanol, resulting in the connection specified in the header (159 mg): Tr=18,3 min (30-55% after 30 minutes);1H NMR (d6-DMSO, 300 MHz) d to 11.8 (s, 1H), 8,45 (s, 1H), 7,7-6,9 (m, 12H), are 5.36 (m, 1H), 4,78 (m, 1H), 4,23 (m, 2H), 3,79 (s, 3H), of 3.64 (d, 3, J=26,6 Hz), 2,11 (d, 3, J=31 Hz) and 1.5 (d, 3H, J=72 Hz); MC low resolution (of the Belarusian library Association) m/e 648 (MN+).

Example 7

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]- 2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H - oilmeal]-2,4 - dioxo-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl} -amide 1H-indole-2-carboxylic acid (0.14 g, 0.26 mmol) and 3-bromopyridine (40 μl, 0.42 mmol) in DMF (1 ml) was added copper powder (46 mg, 0.73 mmol) and potassium salt of acetic acid (38 mg, 0.73 mmol). The heterogeneous solution was stirred at 100oC for 15 h, and then was subjected to hot filtration through celite and washed with methanol. The precipitate was filtered and purified by jhud OF (40-60% WITH in 30 min), receiving the result of the connection specified in the header (19 mg) as a white lyophilisate: Tr=8,7 min (40-60% With in 30 min);1H NMR (d6-Acetone, 300 MHz) d 10,98 (s, 1H), of 9.02 (s, 1H), 8,76 (s, 1H), a 7.85 (d, 1H, J=8,8 Hz), and 7.5 (m, 15H), of 5.68 (d, 1H, J=7,6 Hz), 5,02 (m, 1H) and 4.65 (ABq, 2H, J=16,8, 135 Hz), was 4.02 (s, 3H), 2,19 (d, 3H, J=2.0 Hz), to 2.18 (d, 3H, J=2.0 Hz); MC low resolution (of the Belarusian library Association) m/e 617 (MN+).

Example 8

2-[2,4-dioxo-3-(3-phenyl-ureido)-5-pyridin-3-yl-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-(methoxy-phenyl)ndimethylacetamide

To a solution of 2-(3-amino-2,4-dioxo-5-pyridin-3-yl-2,3,4,5 - tetrahydrobenzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy - phenyl)-ndimethylacetamide (140 mg, 0,295 mmol) in methylene chloride (1 ml) solution was added phenylisocyanate (36,6 mg, 0,295 mmol) in methylene chloride (1 ml), the resulting solution was stirred at RT for 16 h the Solvent was removed under vacuum, and the residue was recrystallized from 5% methanol in ethyl acetate,3
): s 8,72 (s,1H), 8,56 (d, 1H, J=8.0 Hz), 7,92 (d, 1H, J=8.0 Hz), 6,91-the 7.43 (m, 16H), to 6.43 (d, 1H, J=8,3 Hz), 5,43 (d, 1H, J=8,3 Hz), of 4.95 (sept, 1H, J=6,8 Hz), 4,60 (d, 1H, J=6,8 Hz), 4,60 (d, 1H, J=11.8 Hz), 4,18 (d, 1H, J=11.8 Hz), 3,88 (s, 3H), 1.06 a (m, 6H). MC low resolution (of the Belarusian library Association) m/e 593 (m+).

Example 9

Tert-butyl ether 3-(3-{1-[isopropyl-(4-methoxy-phenyl)- carbamoylmethyl] -2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H - benzo[b] [1,4] diazepin-3-yl}-ureido)-benzoic acid

To a solution of tert-butyl methyl ether m-aminobenzoate a 43.3 mg, 0,224 mmol) in THF (5 ml) and triethylamine (0,068 ml) at 0oC was added triphosgene (22,1 mg), the mixture was stirred at 0oC for 1 h before addition of 2-(3-amino-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (106 mg, 0,224 mmol), the mixture was stirred at RT over night. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (50 ml) and washed with 0.5 N hydrochloric acid (g ml), water (30 ml), brine (30 ml), dried (MgSO4) and concentrated under vacuum, resulting in the received connection specified in the header (115 mg) as a white solid.1H NMR (300 MHz, CDCl3): s to 8.62 (s,1H), 8,59 (d,1H, J=8.0 Hz), 7,92 (d,1H, J=8.0 Hz), 6,91-7,83 (m, 15H), to 6.43 (d, 1H, J=8.1 Hz), 5,43 (d,1H, J=8.1 Hz), 4,91 (sept, 1H, J= 6,8 Hz), 4,60 (d] -2,4-dioxo-5 - pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1? 4]diazepin-3-yl}- ureido)-benzoic acid

A mixture of tert-butyl ester 3-(3-[1 - isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5-pyridin - 3-yl-2,3,4,5-tetrahydro-1H-benzo[b][1,4] diazepin-3-yl} -ureido)- benzoic acid (115 mg, 0,224 mmol) and 4N HCl in dioxane (1 ml) was stirred at RT for 1.75 h, after which was added 1 ml of 4N HCl in dioxane and stirred the reaction mixture at RT overnight. Added ether (20 ml), the precipitate was ground into powder with ether (CH ml), receiving the result of the connection specified in the header, in the form of a white powder.1H NMR (300 MHz, CDCl3): s1H NMR (300 MHz, CDCl3): s 8,61 (s, 1H), 8,56 (d, 1H, J=8,2 Hz), to $ 7.91 (d, 1H, J=8,2 Hz), 6,91-7,83 (m, 16H), 6,41 (d, 1H, J=7.9 Hz), 5,43 (d, 1H, J=7.9 Hz), 4,91 (sept, 1H, J=6,8 Hz), 4,60 (d, 1H, J=11.8 Hz), 4,18 (d, 1H, J=11.8 Hz), 3,86 (s, 3H), 1.06 a (m, 6H).

MC low resolution (of the Belarusian library Association) m/e 637 (m+).

Example 11

{1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-indologica-5 - pyridin-4-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl}-amide 1H-indole-2-carboxylic acid

To a solution of the 23.3 mg (0,049 mmol) of 2-(3-amino-2,4-dioxo-5-pyridin - 4-yl-2,3,4,5,5 and 9a-hexahydro-benzo[b][1,4]diazepin-1-yl)-N - isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide in 0.5 ml DMF was added 8.5 mg (0,052 mmol; 1.05 equiv) indole-2-carboxylic acid, 6,7 mg (0,049 mmol; 1 equiv) of N-hydroxybenzotriazole aminopropyl)-3-ethylcarbodiimide. The resulting mixture was stirred at ambient temperature for 18 hours. The solvent is evaporated under reduced pressure, after which he received a yellow oil, which was transferred in DHM (30 ml), washed with a feast upon. NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure with the formation of yellow-brown foam. The crude product was purified flash chromatography on silica gel (4 g), elwira successively with a mixture of ethyl acetate/hexane (4:1; 100 ml), ethyl acetate (100 ml). The appropriate fractions were combined and concentrated under vacuum, obtaining the result of 10.2 mg (0,017 mmol) of the compound indicated in the title, in the form of a white foam:1H NMR (d6-Acetone, 300 MHz) d 10,83 (s, 1H), 8,63 (s, 1H), 7,69 (m, 2H), to 7.61 (d, 1H, J=8,2 Hz), 7,53 (m, 3H), 7,45 (m, 1H), 7,38-7,28 (m, 4H), of 7.23 (t, 1H), to 7.09 (m, 4H), of 5.50 (d, 1H, J=7,6 Hz), is 4.85 (m, 1H) and 4.65 (d, 1H, J=16.6 Hz), 4,28 (d, 1H, J=16,7 Hz), 3,86 (s, 3H), 3,86 (s, 3H), 1,01 (m, 6H); TCX Rf= 0,36 (Eton); MC (the Belarusian library Association) m/z 617,3.

Example 12

Tert-butyl ether 3-(3-{ 7-fluoro-1-[isopropyl-(4 - methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5-pyridin-3-yl-2,3,4,5 - tetrahydro-1H-benzo[b][1,4] diazepin-3-yl}-ureido)-benzoic acid

A solution of 84 mg of 2-(3-amino-7-fluoro-2,4-dioxo-5-pyridin-3-yl - 2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4 - methoxy-phenyl)-ndimethylacetamide (0,165 th acid (0,165 mmol, 1 EQ) and heated at reflux distilled in a nitrogen atmosphere for 3 hours. The obtained suspension was cooled to 5oC, kept at this temperature for 30 minutes, filtered and dried under high vacuum, resulting in the 93 mg of the compound indicated in the title, in the form of a crystalline substance.1H NMR (300 MHz, d6-DMSO) d 9,41 (s, 1H), total of 8.74 (d, 1H, J=2.3 Hz), 8,61 (dd, 1H, J=1,5, a 4.9 Hz), to 7.99 (m, 1H), 7,95 (m, 1H), to 7.67 (dd, 1H, J= 5,6, and 9.3 Hz), EUR 7.57 (m, 2H), of 7.48 (m, 1H), 7,31 (m, 4H), 7,10 (d, 2H, J=8,9 Hz), 6,97 (d, 1H, J=7,7 Hz), 6.87 in (dd, 1H, J=8,9 Hz), 5,16 (d, 1H, J=7,6 Hz), 4,78 (m, 1H), 4,56 (d, 1H, J=16.5 Hz), 4,19 (d, 1H, J=16.5 Hz), of 3.84 (s, 3H), and 1.54 (s, 9H), and 0.98 (m, 6H); MC low resolution (of the Belarusian library Association) m/e 710 (MN+).

Example 13

3-(3-{ 7-fluoro-1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5 - pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}- ureido)-benzoic acid

A mixture of 84 mg of tert-butyl ester 3-(3- {7-fluoro-1-[1-isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4 - dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H - benzo[b][1,4]diazepin-3-yl}-ureido)-benzoic acid (amount of 0.118 mmol) and 4 ml triperoxonane acid was stirred in nitrogen atmosphere for 1.5 hours. Triperoxonane acid was removed under vacuum and the residue was ground into powder with diethyl ether. The suspension was filtered, washed with diethyl ether and sushi is eskay salt triperoxonane acid.1H NMR (300 MHz, d6-DMSO) d was 9.33 (s, 1H), 8,70 (b, 1H), to 8.57 (d, 1H, J= 4,7 Hz), 8,00 (m, 1H), of 7.97 (d, 1H, J=8.6 Hz), to 7.61 (dd, 1H, J=5,5, and 9.1 Hz), 7,55 (dd, 1H, J=4,88, 8,2 Hz), 7,47 (m, 2H), 7,26 (m, 4H), 7,05 (d, 2H, J=9.0 Hz), 6,92 (d,1H, J=7.8 Hz), PC 6.82 (dd, 1H, J=2,8, 9.6 Hz), 5,10 (d, 1H, J= 7,6 Hz), 4.72 in (m, 1H), 4,51 (d, 1H, J=16,8 Hz), 4,14 (d, 1H, J=16,8 Hz), of 3.78 (s, 3H), of 0.92 (m, 6H); MC low resolution (of the Belarusian library Association) m/e 655 (MN+).

Examples 14 and 15

[1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-5 - pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4] diazepin-3-yl] -amide (+) or (-) 1H-indole-2-carboxylic acid

By preparative liquid chromatography high pressure (ghvd) using a waters Model 4000 Delta Prep, equipped with a Daicel Chemical Industries Chiralpak AD preparative column (20 μm, 5 cm x 50 cm) as stationary phases were separated (> 99.9 percent) enantiomers in Example 7. As the mobile phase was applied a mixture of 72% hexane, 21% isopropyl alcohol and 7% of chloroform. Used isocratic conditions at a speed of flow of 50 ml/min (max = 16 min). The appropriate fractions were combined, concentrated under vacuum and liofilizirovanny of water and acetonitrile, receiving targeted counterparts. Analytical purity was determined by Ehud using a Hewlett Packard 1050 system equipped with a diode spectrometer type (lambda interval 200-400). As is described above, and the flow rate was 1.0 ml/min (max = 3 min). Retention time, WU, expressed in minutes, had for two isomers of the following values.

Enantiomer 1, Example 14: WU = 25,06 minutes

Enantiomer 2, Example 15: VU = an 81.39 minutes

The intermediate connection 1

Isopropyl-(4-methoxyphenyl)amine

To peremalyvavshaya to a solution of 4-methoxybenzylamine (1.24 g, from 6.22 mmol) in methanol (15 ml) at ambient temperature was sequentially added glacial acetic acid (415 mg, 6691 mmol), acetone (669 mg, 11.5 mmol) and 1M of cyanoborohydride sodium in THF (12,7 ml, 12.6 mmol). The reaction mixture was stirred over night at room temperature. Brought the pH to 2 with 6N HCl and stirred for 30 minutes to remove excess cyanoborohydride sodium. Then the pH was brought to 8.5 with 1N NaOH and the resulting solution was extracted with diethyl ether (2 x 50 ml) and ethyl acetate (50 ml). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure, to deliver the connection specified in the header (1.42 g, 5,91 mmol), as a yellow oil.1H NMR (300 MHz, CDCl3): d is 6.78 (d, J=8,8 Hz, 2H), to 6.57 (d, J=9.1 Hz, 2H), of 3.75 (s, 3H), 3,55 (m, 1H), 2,92 (br s,1H), 1,18 (d, J=6,1 Hz, 6H); TLC (Etoac/Gex (2:3K a solution of isopropyl-(4-methoxyphenyl)-amine (25,11 g, 152 mmol) in dichloromethane (250 ml) under stirring at ambient temperature was added triethylamine (15,38 g, 152 mmol). The solution was cooled in an ice bath (< 3oC) and after 45 minutes was added dropwise bromoacetamide (30,68 g, 152 mmol) dissolved in dichloromethane (100 ml). The reaction mixture was stirred over night at ambient temperature, washed with 0.3 N HCl (300 ml) and brine (300 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure, obtaining the resulting dark brown oil. The oil was filtered through a layer of silica gel (150 g), which was suirable a mixture of ethyl acetate/hexane (1:1, 90 ml) and the filtrate was evaporated under reduced pressure, to deliver the connection specified in the header (41,05 g, 143 mmol), in the form of a brown oil, which crystallized upon storage.

1H NMR (300 MHz, CDCl3): d, was 1.04 (d, J=6,8 Hz, 6N), 3,53 (s, 2H), of 3.84 (s, 3H), is 4.93 (m, 1H), 6,93 (d, J=9.1 Hz, 2H), 7,10 (d, J=9.1 Hz, 3H);

TLC (Etoac/Hexane (3:17)): Rf= 0,18.

Intermediate compound 3

2-(phenylhydrazone)-malonic acid

To intensively mix the solution of the monohydrate ketomalonate acid (29,33 g) in ethanol (140 ml) and water (300 ml) at ambient temperature for 40 minocha environment. The solid phase was separated by filtration, washed successively with cold water (100 ml) and ethanol (25 ml) and dried in the air. Then were dried at 75oC over night in a vacuum, resulting in the received connection specified in the header, in the form of a yellow solid (42,38 g).1H NMR (300 MHz, DMSO-d6): d for 7.12 (t,1H), 7,35-of 7.48 (m,4H); so pl.: 155-157oC (decomp.).

Intermediate compound 4

Duplissy 2-(phenylhydrazone)-propandiol

To peremalyvavshaya suspension of 2-(phenylhydrazone)-malonic acid (14,73 g) in chloroform (90 ml) and 5oC parts added pentachloride phosphorus (36,84 g) for 20-minute period of time. After the addition the solution was heated to room temperature and was stirred for 1 hour, then heated at reflux distilled for three hours. The solution was cooled in an ice bath and the precipitate was separated by filtration, washed with cold hexane (50 ml) and dried over night under vacuum, resulting in the connection specified in the header region (13.4 g) as a pale yellow solid.1H (300 MHz, DMSO-d6): d for 7.12 (t, 1H), 7,20-7,56 (m, 4H); so pl.: 135-138oC (decomp).

The intermediate compound 5

2-(2-Aminovaleric sodium (60% in oil, 1.26 g). Was added dropwise a solution of 2-peritrabecular (2,21 ml) in THF (8 ml), charged the mixture was stirred at room temperature overnight. Was added a saturated aqueous sodium carbonate (10 ml) and the separated aqueous phase was extracted into dichloromethane (3 x 10 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and concentrated under vacuum. After column flash chromatography (cyclohexane:ethyl acetate; 3:1 as eluent) received the connection specified in the header (of 2.23 g) as a red-orange solid.1H NMR (300 MHz, CDCl3): 6,83 (m, 3H), 7,42 (dt, J=1.7 Hz, 1H), 7,40 (dt, J=1.7 Hz, 1H), 8,08 (dd, J=1.7 Hz, 1H), 8,21 (d, J=1,15 Hz, 1H), 8,61 (dt, J=1.7 Hz, 1H), 10.0 g (s, 1H). So pl. = 71oC.

The intermediate compound 6

N-(2-pyridyl)phenylenediamine

2-(2-Aminopyridin)nitrobenzene (2.14 g) was dissolved in glacial acetic acid (45 ml), was added iron filings (5,57 g), the mixture was stirred at RT for 72 hours, then the solid phase was removed by filtration through celite, and the solvent was removed by concentration under vacuum. Was added aqueous sodium carbonate (2M), bringing the pH to 8, this mixture then was extracted into dichloromethane (3 X 30 ml). The combined organic phases prom the data in the header (1.68 g), in the form of a beige solid.1H NMR (300 MHz, CDCl3): 6,12 (br, 2H), 6.42 per (d, J=6 Hz, 1H), of 6.68 (m, 1H), 6,78 (m, 3H), 7,008 (dt, J=1.60 Hz, 1H), 7,15 (dd, 1,58 Hz, 1H), 7,42 (m, 1H), 8,15 (br, 1H). TCX (cyclohexane:ethyl acetate; 1:1) Rf= 0,2.

Intermediate compound 7

N-isopropyl-N-(4-methoxy-phenyl)-2-[2-(pyridine-2-illinoisillinois]- ndimethylacetamide

A mixture of N-(2-pyridyl)phenylenediamine (2.00 g), isopropyl-(4-methoxyphenyl)amine (is 3.08 g) and potassium carbonate (1.50 g) in DMF (30 ml) was stirred at RT for 22 h, the Solvents were removed under vacuum and the residue was fractionally between ethyl acetate (50 ml) and water (I ml). The organic phase was washed with brine (30 ml), dried (MgSO4) and concentrated under vacuum, resulting in the crude product is specified in the header, in the form of a brown substance. After two precrystallization of a mixture of ethylacetate (1:1) received the connection specified in the header, in the form of a yellowish-brown substance. 1H NMR (300 MHz, CDCl3): a 1.01 (d, J=7 Hz, 6N), and 3.4 (s,2H), 3,83 (s, 3H), 4,89 (sept, J=7 Hz), between 6.08 (s,1H), of 6.31 (d, J=8.5 Hz, 1H), 6.42 per (d, J= 8.0 Hz, 1H), 6,66 (m,2H), 6,9-7,1 (m,6H), 7,22 (d, J=8.0 Hz, 1H), 7,40 (t, J=6,5 Hz, 1H), 8,18 (d, J=3.5 Hz, 1H). TLC (10% MeOH, CH2Cl2Rf=0,42.

Intermediate compound 8

2-[2,4-dioxo-3-(3-phenyl-hydrazono)-5-pyridin-2-yl-2,3,4,5 - Tetra-(pyridine-2 - illinoisillinois] ] -ndimethylacetamide (500 mg) in THF (20 ml) and douglasthe 2-(phenylhydrazone)-propane diol (317 mg) in THF (20 ml) were added simultaneously to the volume of THF (20 ml) with the temperature at 0oC, the mixture was left to warm to CT during the night. The solvents were removed under vacuum, and the residue was dissolved in ethyl acetate (50 ml) and washed with 2N aqueous sodium bicarbonate (CH ml), water (30 ml), brine (30 ml), dried (MgSO4) and concentrated under vacuum, resulting in the crude product. After column flash chromatography on silica gel, elwira 10% mixture of methanol/methylene chloride, received the connection specified in the header, in the form of a 3:2 mixture of hydrazones (460 mg). Due to the fact that the product was a mixture of diastereoisomers,1H NMR data are not diagnosed. TLC (10% MeOH, CH2Cl2Rf= 0,62.

Intermediate compound 9

2-(3-Amino-2,4-dioxo-5-pyridin-2-yl-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N-(methoxy-phenyl)ndimethylacetamide

A mixture of 2-[2,4-dioxo-3-(phenylhydrazone)-5 - pyridin-2-yl-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl)-N - isopropyl-N-(4-methoxyphenyl)ndimethylacetamide (460 mg), zinc dust (430 mg) and acetic acid (5.6 ml) was stirred for 3 hours the Solids were removed by filtration through celite, the filtrate was concentrated under vacuum, and the residue was prepared by azeotropic mixture with hexane. The residue was dissolved in ethyl acetate (50 ml) and washed with 2N aqueous is the best in the crude product (270 mg), which was used without further purification.1H NMR (300 MHz, CDCl3): of 1.03 (d, J=7 Hz, 6N), 3,79 (s, 3H), was 4.02 (d, J=10 Hz, 1H), and 4.40 (s, 1H), 4,42 (d, J= 10 Hz, 1H), 5,0 (sept, J=7,1 Hz, 1H), 6,8-of 7.3 (m,10H), 7,44 (d, J=8.0 Hz, 1H), 7,68 (d, J= 8.0 Hz, 1H), 7,80 (m,1H), 8,42 (d, J=3,9 Hz, 1H). TLC (10% MeOH, CH2Cl2Rf=0,23.

Intermediate compound 10

(2-Nitro-phenyl)-pyrimidine-2-yl-amine

To a solution of 2-aminopyrimidine (10 g, 105 mmol) in DMF (100 ml), cooled to 5oC, was added 60% sodium hydride in mineral oil (vs. 5.47 g, 137 mmol), the mixture was stirred for one hour while cooling. Then within 20 minutes to peremalyvavshaya cooled solution was added dropwise 1-fluoro-2-nitrobenzene (14,83 g, 105 mmol) in DMF (30 ml). The solution was left for slow heating to ambient temperature under stirring for 3 hours. The product was besieged by adding water (300 ml), was separated by filtration and dried, resulting in the connection specified in the header (13,39 g of 61.9 mmol), as an orange solid:1H NMR (Acetone-d6, 400 MHz): 10,34 (br s, 1H), 9,00 (d, 1H, J=8.6 Hz), at 8.60 (d, 2H, J= 4,8 Hz), 8,23 (d,1H, J=8,4 Hz), 7,74 (t, 1H), 7,17 (t, 1H), 7,06 (t, 1H); TCX (Etoac/Hexane (3:17)): Rf= 0,27.

Intermediate compound 11

N-Pyrimidine-2-yl-benzene-1,2-diamine
3OH (250 ml) was awarded the connection specified in the header (8,21 g, 44.1kHz mol) as a gray solid:1H NMR (CDCl3, 400 MHz): scored 8.38 (d, 2H, J= 4,9 Hz), 7,37 (d, 1H, J=7.9 Hz), was 7.08 (t, 1H), 7,00 (br s, 1H), 6,83 (m, 2H), to 6.67 (t, 1H), 3,60 (br s, 2H); TLC (Etoac/Hexane (2:1)): Rf= 0,33.

Intermediate compound 12

N-Isopropyl-N-(4-methoxy-phenyl)-2[2-(pyrimidine-2-ylamino)- phenylamino] -ndimethylacetamide

To a solution of N-pyrimidine-2-yl-benzene-1,2-diamine (82 mg, 0,441 mmol) in DMF (2 ml) was added potassium carbonate (61 mg, 0,441 mmol), potassium iodide (7 mg, 0,044 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (126 mg, 0,441 mmol). The resulting reaction mixture was stirred over night at 60oC. the Solvent was removed under vacuum, and the crude material was fractionally between CH2Cl2(35 ml) and water (15 ml). The organic phase was separated, dried over MgSO4, filtered and concentrated to obtain a yellow oil, after pounded the IDA yellow crystals: 1H NMR (CDCl3, 300 MHz): at 8.36 (d, 2H, J=4,9 Hz), 7,38 (dd, 1H, J=1,2, 7,8 Hz), 7,06-of 7.90 (m, 6H), 6.75 in (t, 1H), 6,66 (t, 1H), 6,36 (dd, 1H, J=1,2, 7,8 Hz), equal to 4.97 (m, 1H), a 3.87 (s, 3H), 3.43 points (s, 2H), was 1.04 (d, 6H, J=6.8 Hz), TCX (Etoac): Rf= 0,62; MS (the Belarusian library Association) m/z 392,0 (MH+).

Intermediate compound 13

2-[2,4-dioxo-3-(phenyl-hydrazono)-5-pyrimidine-2-yl-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide

To a suspension of N-isopropyl-N-(4-methoxy-phenyl)-2-[2-(pyrimidine-2-ylamino)- phenylamino] -ndimethylacetamide (500 mg, 1.28 mmol) in THF (12 ml), cooled in an ice bath, is added dropwise within 5 minutes was added duplissy 2-(phenylhydrazone)propandiol (344 mg, 0,141 mmol) in THF (6 ml). After completion of the addition the solution was left to warm to room temperature overnight with stirring. The solvent was evaporated under reduced pressure and the resulting oil was dissolved in ethyl acetate (80 ml), washed with saturated sodium bicarbonate solution, dried over MgSO4, filtered and concentrated under reduced pressure, obtaining the resulting yellow oil. The crude product was purified by flash chromatography on silica gel (15 g), elwira mixture of EtOH/Hexane (2:1, 250 ml). The appropriate fractions were combined and concentrated, resulting in the connection of the criminal code is 14H), of 5.05 (m, 1H), 4,46 (m, 1H), 3,82 (m, 4H), of 1.12 (m, 6H); TCX (EtOH/Hexane (2:1)): Rf= 0,21; MC (the Belarusian library Association) m/z 564,1 (MH+).

Intermediate compound 14

2-(3-Amino-2,4-dioxo-5-pyrimidine-2-yl-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

To mix the solution 2-12,4 - dioxo-3-(phenyl-hydrazono)-5-pyrimidine-2-yl-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (500 mg, 0,886 mmol) in acetic acid (12 ml) at ambient temperature was added zinc dust (530 mg), the mixture was stirred for 1 hour. Zinc was separated by filtration, the filtrate was concentrated under vacuum and the resulting oil was fractionally between water (30 ml) and ethyl acetate (80 ml). Using 6N sodium hydroxide brought the pH to 8 and the phases were separated. The aqueous phase was extracted with ethyl acetate (CH ml), the organic extracts were combined, dried over magnesium sulfate, filtered and concentrated under vacuum, obtaining the resulting yellow foam. The crude product was purified by flash chromatography on silica gel (15 g), elwira a mixture of methylene chloride/methanol (19:1, 250 ml). The appropriate fractions were combined and concentrated, obtaining the connection specified in the header (255 mg, 0,537 mmol), in the form of white is dd, 1H, J=2.7, and 8.7 Hz), 6.89 in (dd, 1H, J= 2.7, and an 8.5 Hz), 6,86 (dd, 1H, J=1,2, 8,2 Hz), is 5.06 (m, 1H), to 4.52 (d, 1H, J=16.6 Hz), 4,43 (s,1H), 3,85 (d, 1H, J=16.6 Hz), 3,82 (s, 3H), 2,60 (br s, 2H), 1,11 (d, 6H, J=1.0 Hz); TCX (CH2Cl2/CH3OH (9:1)): Rf= 0,48; MC (the Belarusian library Association) m/z 475,3 (MH+).

Intermediate compound 15

(2-Nitrophenyl)-(1,3,5-trimethyl-1H-pyrazole-4-yl)-amine

To a solution of 1-fluoro-2-nitrobenzene (7,47 ml, to 70.9 mmol) in ethanol (35 ml) and H2O (105 ml) was added 4-amino-1,3,5-trimethylpyrazole (8.8 g, to 70.9 mmol). The solution was heated at reflux distilled for 15 hours, then cooled to room temperature. The precipitate was separated by filtration and washed with 25% aqueous ethanol, to deliver the connection specified in the header (8.6 g):1H NMR (CDCl3, 300 MHz) d 8,81 (s, 1H), 8,18 (dd, 2H, J=1,6, and 8.7 Hz), 6,69 (m, 1H), is 6.61 (dd, 1H, J=1,2, and 8.7 Hz), of 3.77 (s, 3H), 2,10 (s, 3H), of 2.06 (s, 3H); MC low resolution (of the Belarusian library Association) m/z 247 (MH+).

The intermediate connection 16

N-(1,3,5-Trimethyl-1H-pyrazole-4-yl)-benzene-1,2-diamine

To a solution of (2-nitro-phenyl)-(1,3,5-trimethyl-1H-pyrazole-4-yl)-amine (8.6 g, 35 mmol) in ethyl acetate (175 ml) was added 10% palladium on coal (1 g). The solution was stirred in nitrogen atmosphere (50 FCD) for 15 h, and then filtered through a layer of celite, washed with ethyl acetate and concentrated under vacuum, resulting in the s, 2H), 2.05 is (m, 6H); MC low resolution (of the Belarusian library Association) m/z 217 (MH+).

Intermediate compound 17

N-Isopropyl-N-(4-methoxy-phenyl)-2-[2-(1,3,5-trimethyl-1H-pyrazolidinone)-phenylamino]-ndimethylacetamide

To a solution of N-(1,3,5-trimethyl - 1H-pyrazole-4-yl)-benzene-1,2-diamine (7,56 g of 38.5 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (7,18 g of 38.5 mmol) in DMF (70 ml) was added potassium carbonate (14.5 g, 105 mmol) and potassium iodide (581 mg, 3.5 mmol). The solution was heated at 80oC for 15 hours and then was poured into DHM (100 ml). The mixture was extracted with H2O (X4), 1 N Hcl (x2) and brine, dried over MgSO4and concentrated under vacuum. The resulting foam was purified by grinding into powder with Et2O, receiving the result of the connection specified in the header (11.9 g);1H NMR (CDCl3, 300 MHz) d 8,08 (s, 1H), 7,07 (dd, 4H, J=2,2, 6,6 Hz), 6,63 (m, 2H), of 6.31 (m, 2H), to 5.03 (m, 1H), amounts to 4.76 (s, 1H), a 3.87 (s, 3H), 3,74 (s, 3H), 3.46 in (s, 2H), 2,02 (m, 6H), of 1.07 (d, 6H, J=6.8 Hz); MC low resolution (of the Belarusian library Association) m/z 422 (MH+).

Intermediate compound 18

2-[2,4-Dioxo-3-(phenyl-hydrazono)-5-(1,3,5-trimethyl-1H-pyrazole - 4-yl)-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N- (4-methoxy-phenyl)-ndimethylacetamide

A solution of N-isopropyl-N-(4-methoxy-phenyl)-2-[2-(1,3,5-trimethyl-1H - pyrazole-ylamino)-phenylamino] ndimethylacetamide (30 g, 7.1 mmol) in THF (70 ml) and Heidenau to 0oC. the Solution was stirred at RT for 15 hours, and then concentrated under vacuum, resulting in the connection specified in the header (8.1 g) which was used without further purification.

Intermediate compound 19

2-[3-Amino-2,4-Dioxo-5-(1,3,5-trimethyl-1H-pyrazole-4-yl)-2,3,4,5 - tetrahydro-benzo[b] [1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide

To a solution of 2-[2,4-dioxo-3-(phenyl-hydrazono)-5-(1,3,5 - trimethyl-1H-pyrazole-4-yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl]- N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (4.6 g, 7,74 mmol) in glacial acetic acid (45 ml) was added zinc dust (4.6 g). The heterogeneous solution was stirred at RT for 15 hours, and then filtered through a layer of celite, washed with ethyl acetate and concentrated until dry. The resulting oil was dissolved in ethyl acetate (200 ml) and was extracted with saturated sodium bicarbonate (X3), brine, dried with MgSO4and concentrated under vacuum. The resulting oil was purified by flash chromatography on silica gel (5% methanol/DHM), receiving the result of the connection specified in the header (385 mg):1H NMR (CDCl3, 300 MHz) d 7,60-7,80 (m, 10H), of 5.05 (m, 1H), 4,4 (m, 1H), 3,82 (s, 3H), 3,74 (s, 3H), 3,62 (s, 2H), 2,24 (s, 3H), of 1.20 (s, 3H), of 1.09 (m, 6H); MC low resolution/BR> 2-ftorirovannogo (80,65 ml, 0.77 mmol) dissolved in ethanol (200 ml) and water (600 ml), was added 4-methoxybenzylamine (100 ml, 0.77 mmol). The reaction mixture was heated at 92oC for 15 h, cooled to room temperature and was separated by filtration orange precipitate. The residue was recrystallized from a mixture of ethanol:water 1/3, then dissolved in ethyl acetate, dried over MgSO4and concentrated under vacuum, resulting in the connection specified in the header (117,88 g):1H NMR (300 MHz, CDCl3): d 8,35 (bs, 1H), 8,18 (d, J=8.5 Hz, 1H), 7,38 (dd, J=7,3, 7,8 Hz, 1), 7,27 (d, J=8.5 Hz, 2H), 6,85 (3H), of 6.66 (dd, J=7,3, and 7.8 Hz,1H), 4,47 (collapsibly ABq, J= 4,9 Hz, 2H), 3,81 (s,3H); MC low resolution (of the Belarusian library Association) m/z 258,99 (MN+).

The intermediate connection 21

N-(4-methoxy-benzyl)-benzene-1,2-diamine

To (4-methoxybenzyl)-(2-nitrophenyl)-amine (50 g, mmol) in glacial acetic acid (500 ml), cooled to 15oC in a three-neck round bottom flask equipped with a stirrer, fixed in the upper part, was added zinc powder (50 g). The reaction mixture was heated to room temperature and was stirred for 15 hours, the Reaction mixture was filtered through a layer of celite, and the filtrate was concentrated until dry. The oil obtained was transferred into a mixture utilize over MgSO4and concentrated under vacuum.

The crude product was purified by flash chromatography on silica gel (50% hexane/DHM), receiving the result of the connection specified in the header (33,34 g):1H NMR (300 MHz, CDCl3): d to 7.32 (d, J=8.5 Hz, 2H), to 6.88 (d, J=8.5 Hz, 2H), 6,97 (m, 4H), 4,25 (s, 2H), 3,81 (s, 3H); MC low resolution (of the Belarusian library Association) m/z 476 (MH+).

Intermediate compound 22

N-Isopropyl-2[2-(4-methoxy-benzylamino)-phenylamino]-N-(4-methoxy-phenyl)- ndimethylacetamide

To a solution of N-(4-methoxybenzyl)-benzene-1,2-diamine (2,42 g, 10.6 mmol) in DMF (40 ml) was added potassium carbonate (1.47 g, 10.6 mmol), potassium iodide (176 mg, 1.06 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide (3.03 g, 10.6 mmol). The resulting reaction mixture was stirred over night at 60oC. the Solvent was removed under vacuum, and the crude material was dissolved in Etoac (150 ml), washed with water (I ml) and brine (50 ml), dried with MgSO4, filtered and concentrated to a brown oil. The precipitate, which was formed by adding ether (70 ml), was filtered, receiving the result of the connection specified in the header (1.39 g, is 3.21 mmol), in the form of a yellow substance. The remaining filtrate was concentrated under reduced pressure to a brown oil, which was purified through heinali and concentrated under reduced pressure, receiving the second portion of the connection specified in the header (1.86 g, the 4.29 mmol), as a brown oil;1H NMR (300 MHz, CDCl3); d 7,30 (m, 2H), 7,05 (m, 2H), 6,95 (m, 2H), to 6.88 (m, 2H), 6.73 x-is 6.61 (m, 3H), 6,28 (m, 1H), free 5.01 (m, 1H), 4,23 (s, 2H), a 3.87 (s, 3H), of 3.80 (s, 3H), 3,40 (s, 2H), with 1.07 (m, 6H), TLC (Etoac/hexane (1:4)): Rf= 0,14.

Intermediate compound 23

N-Isopropyl-2-[5-(4-methoxy-benzyl)-2,4-dioxo-3-(phenyl-hydrazono)- 2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-(4-methoxy-phenyl)- ndimethylacetamide

To a solution of N-isopropyl-2-[2-(4-methoxybenzylamine)-phenylamino]-N-(4-methoxy-phenyl)- ndimethylacetamide (3.25 g, 7,51 mmol) in THF (50 ml), cooled in an ice bath (< 5oC), dropwise over 20 minutes was added duplissy 2-(phenyl-hydrazono)propandiol (1.84 g, 7,51 mmol) in THF (50 ml). After complete addition, the solution was left to warm to room temperature and was stirred overnight. The solvent was evaporated under reduced pressure and the resulting oil was dissolved in ethyl acetate (300 ml), washed with saturated sodium bicarbonate solution (100 ml) and brine (50 ml), dried over MgSO4, filtered and concentrated under reduced pressure, to deliver the connection specified in the header (4,55 g, 7,51 mmol), as a yellow oil:1s, 3H), and 3.72 (s, 3H), 1,11 (m, 6H); TCX (Etoac/hexane (2:3)): Rf= 0,30.

Intermediate compound 24

2-[3-Amino-5-(4-methoxy-benzyl)-2,4-dioxo-2,3,4,5-tetrahydro-benzo [b] [1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide

To a stirred solution of N-isopropyl-2-[5-(4-methoxy - benzyl)-2,4-dioxo-3-(phenyl-hydrazono)-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-(4-methoxy-phenyl)-ndimethylacetamide (4,55 g, 7,51 mmol) in acetic acid (50 ml) was added zinc dust (4,50 g), the mixture was stirred for 4 hours at ambient temperature. Zinc was separated by filtration, the filtrate was concentrated under vacuum, the resulting oil was fractionally between water (150 ml) and ethyl acetate (250 ml). Brought the pH to 8 with 6N sodium hydroxide and the separated phase. The aqueous phase was extracted with ethyl acetate (CH ml), the organic phases were combined, dried over magnesium sulfate, filtered and concentrated under vacuum to a brown oil. The crude product was purified by flash chromatography on silica gel (70 g), elwira consistently mixtures Etoac/hexane (2:1, 500 ml) and methylene chloride/methanol (19: 1, 500 ml). The appropriate fractions were combined and concentrated, resulting in the connection specified in the header (2.85 g, 5,52 mmol), VI= 15.1 Hz, 1H), 5,00 (m, 1H), a 4.86 (d, J=15.1 Hz, 1H), 4,25 (s, 1H), 4,21 (d, J= 16.6 Hz, 1H), 3,85 (s, 3H), of 3.69 (s, 3H), 3,48 (d, J=16.6 Hz, 1H), 1,09 (m, 6H); TLC (CH2Cl2/CH3OH (29:1): Rf= 0,11.

Intermediate compound 25

2-(3-Amino-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl] - N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

To a stirred solution of 2-[3-amino-5-(4-methoxy-benzyl)-2,4 - dioxo-2,3,4,5-tetrahydrobenzo[b] [1,4] diazepin-1-yl]-N-(4-methoxy-phenyl)- ndimethylacetamide (2,63 g 5,09 mmol) in a mixture of acetonitrile/H2O (9:1, 70 ml) at ambient temperature portions over one hour was added cerium ammonium nitrate (of 10.05 g, and 18.3 mmol). The solution was stirred over night at room temperature. The solution was concentrated under vacuum, was extracted with toluene (g ml) and the residue was extracted with CH2Cl2(G ml), filtered and concentrated to an orange glassy substance. The crude product was purified by flash chromatography on silica gel (100 g), elwira successively with a mixture of CH2Cl2/CH3OH (15:1, 1.5 l) and CH2Cl2/CH3OH (10:1, 1.3 l). The appropriate fractions were combined and concentrated under reduced pressure, to deliver the connection specified in the header (1.97 g, equal to 4.97 mmol), as a brown PE>CL2/CH3OH (13:1): Rf= 0,21.

The intermediate connection 26

{ 1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl] -2,4-dioxo-2,3,4,5 - tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-amide 1H-indole-2-carboxylic acid

To a solution of 2-(3-amino-2,4-dioxo-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy - phenyl)-ndimethylacetamide (350 mg, 0,883 mmol) in DMF (10 ml) successively under stirring was added indole-2-carboxylic acid (142 mg, 0,883 mmol), N-hydroxybenzotriazole (119 mg, 0,883 mmol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,169 mg, 0,883 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The solvent is evaporated under reduced pressure, obtaining a yellow oil, which was dissolved in ethyl acetate (60 ml), washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered and concentrated under reduced pressure to a yellow oil which hardened on standing. The crude product was ground into powder with boiling ethanol (20 ml), cooled, filtered and dried, obtaining the result of the connection specified in the header (169 mg, 0,313 mmol), as a yellow solid:1H NMR (300 MHz, Acetone-d6): d 10,85 (br s,1H), 9,83 (br s,1H), to 7.67 (m, 2H), 7,53 (m, 2H), 7,37-7,20 (m, 7H),? 7.04 baby mortality (>= 0,24; MC (the Belarusian library Association): m/z = 540 (MN+).

Intermediate compound 27

N-Isopropyl-N-(4-methoxy-phenyl)-2-phenylimidazole

A mixture of N-isopropyl-N-(4 - methoxy-phenyl)bromoacetamide (257,6 g, 924 mmol), 1,2 - phenylenediamine (100 g, 924 mmol) and potassium carbonate (128 g, 924 mmol) in DMF (1200 ml) was stirred at 0oC for 2 h and then left to warm up to CT for 20 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under vacuum. The obtained residue was dissolved in Etoac (1200 ml), washed with water (I ml), brine (200 ml), dried (MgSO4) and concentrated under vacuum. After removing about 70% of the solvent to precipitate formed, which was separated by filtration and washed with cold Etoac, dried and got the connection specified in the header (67,1 g), in the form of a beige substance. The combined filtrates were concentrated under vacuum, obtaining a dark oil (88 g). After two precrystallization from ethanol received second portion of the connection specified in the header, in the form of a beige substance (29,6 g).1H NMR (300 MHz, DMSO-d6): s 7,22 (m, 2H), 7,05 (m, 2H), 6,47 (m, 1H), 6,34 (m, 2H), 5,95 (m, 1H), 4,81 (sept, 1H, J=6,8 Hz), 4,59 (dt, 1H, J=27,2, 6,1 Hz), 4,4 (s, 2H), of 3.77 (s, 3H), 3,30 (s, 2H), of 0.96 (d, 6H, J=6.8 Hz).

The intermediate connection 28

2-(pyl-N-(4-methoxy-phenyl)-2-phenylimidazoline (20 g, to 63.8 mmol) in THF (500 ml) and the solution malonaldehyde (6.2 ml, to 63.8 mmol) in THF (500 ml) were added simultaneously over 40 minutes to a THF (100 ml), the resulting solution was stirred at RT for 72 hours, after which was added 3.0 ml of malonaldehyde. After 5 h the solvent was removed under vacuum, and the residue was dissolved in methylene chloride (300 ml) and washed with 2N aqueous sodium bicarbonate (g ml). The combined organic phases were washed with water (I ml), brine (200 ml), dried (MgSO4) and concentrated under vacuum, resulting in the crude product (23,8 g). Then it intensively rubbed into powder with ether, and the resulting brown substance was then purified by column flash chromatography, elwira 5% methanol in methylene chloride, receiving the result of the connection specified in the header (cent to 8.85 g) as a beige substance. 1H NMR (300 MHz, CDCl3): s to 7.7 (s, 1H), and 7.4 (m, 1H), 6.90 to-to 7.3 (m, 7H), equal to 4.97 (sept., 1H, J=6,8 Hz), 4,4 (m, 1H), 3,81 (s, 3H), of 3.78 (m, 1H), 3,40 (s, 2H), 1.06 a (d, 6H, J=6.8 Hz).

Intermediate compound 29

2-(2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

A mixture of 2-(2,4-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)- N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (3.5 g, 9,48 mmol), copper is ri 100oWith over 7 hours was Added 0.4 ml of 3-bromopyridine and the resulting mixture was stirred at 100oC for another 14 hours. Was added copper powder (1,09 g, 17,06 mmol), 3-bromopyridine (of 0.91 ml, 9,48 mmol) and potassium acetate (1,11 g, 11,37 mmol) and was heated to 110oWith over 6 hours the Solids were removed by filtration, the filtrate was concentrated under vacuum and the residue was fractionally between ethyl acetate (150 ml) and 10% aqueous solution of ammonium hydroxide (150 ml). The combined organic phases were washed with water (I ml), brine (50 ml), dried (MgSO4) and concentrated under vacuum, resulting in the connection specified in the header (2,56 g), in the form of krivodanova substances.1H NMR (300 MHz, CDCl3): s 7,86 (d, 1H, J=8.1 Hz), 7,01-the 7.43 (m, 10H), 6,92 (d, 1H, J= 8,3 Hz), of 5.05 (sept, 1H, J=6,8 Hz), 4,22 (m, 2H), 3,88 (s, 3H), to 3.58 (dd, 2H, J=32,2, 12.0 Hz), of 1.06 (m, 6H).

The intermediate connection 30

2-(3-Azido-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

To a solution of 2-(2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (750 mg, of 1.64 mmol) in THF (15 ml), cooled to -78oWith over seven minutes was added dropwise hexamethyldisilazide potassium (0.5 M in toluene, solargenerated (632 mg, 2.05 mmol) and stirred the reaction mixture at -78oC for 4 min before the addition of acetic acid (0,235 ml), after which he left the reaction mixture is heated to CT. The solvents were removed under vacuum, resulting in the crude product. It was purified by column flash chromatography, elwira 5% methanol in methylene chloride, receiving the result of the connection specified in the header (530 mg) as a colourless foam.1H NMR (300 MHz, CDCl3): s of 7.96 (d,1H, J=8.0 Hz), 6,91-the 7.43 (m, 11H), of 5.05 (sept, 1H, J=6,8 Hz), 4,42 (d, 1H, J=12.1 Hz), to 4.38 (m, 1H), 4,22 (d, 1H, J=12.1 Hz), 3,88 (s, 3H), 1.06 a (m, 6H).

The intermediate connection 31

2-(3-Amino-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

A mixture of 2-(3-azido-2,4-dioxo-5-pyridin-3-yl - 2,3,4,5-tetrahydrobenzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4 - methoxy-phenyl)-ndimethylacetamide (530 mg, 1.06 mmol) and 10% palladium on coal (53 mg) was stirred in ethanol (50 ml) in a nitrogen atmosphere for 9 hours was Added following a portion of palladium on coal (53 mg) and stirred the mixture for 16 hours the Solids were removed by filtration through celite, the filtrate was concentrated under vacuum, resulting in the connection specified in the header (520 mg), which is H, J=6.8 Hz), 4,42-4,22 (m, 3H), 3,88 (s, 3H), 1.06 a (m, 6H).

The intermediate connection 32

2-(2,4-Dioxo-5-pyridin-4-yl-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

To peremalyvavshaya solution of 400 mg of 1 -[isopropyl-(4-methoxy-phenyl)-amino]-1,5-dihydro-benzo[b][1,4] diazepin-2,4-dione in 20 ml of DMF was added 212 mg (2,16 mmol, 2.0 equiv) of potassium acetate, 206 mg (3.25 mmol, 3.0 equiv) of copper powder and 245 mg (2,62 mmol, 2 equiv) 4-bromopyridine. The resulting solution was warmed up at 122oC for 7 h, the Reaction mixture was subjected to hot filtration through a layer of celite layer was washed with 10 ml of methanol, and the filtrate was concentrated under vacuum. The residue was diluted Etoac (100 ml) and washed with 5% ammonium hydroxide (CH ml). The organic layer was separated, dried (MgSO4), and the solvents were removed under vacuum. After purification by chromatography rapid separation on silica gel using as eluent a mixture of Etoac/Hexane/NH4OH (80:20:1) followed by recrystallization from Eton received 80 mg (16%) of the compound indicated in the title: 1H NMR (Acetone-d6, 300 MHz) d to 8.57 (d, 1H, J=4,6 Hz), 7,46 (m, 3H), 7,31 (m, 4H), 6,97 (m, 3H), 4,86 (sept., 1H), 4,48 (d, 1H, J=16,8 Hz), is 4.21 (d, 1H, J=16,8 Hz), 3,86 (s, 3H), to 3.67 (d, 1H, J=and 12.2 Hz), up 3.22 (d, 1H, J= 12,2 Hz is Ino-2,4-Dioxo-5-pyridin-4-yl-2,3,4,5,5 and, 9a-hexahydrobenzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)ndimethylacetamide

To a mixed solution of 80 mg (0,175 mmol) of 2-(2,4-dioxo-5-pyridin-4-yl-2,3,4,5 - tetrahydrobenzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)- ndimethylacetamide in 3 ml of DMF at 0oC was added 0,210 ml (0,209 mmol, 1.2 equiv) 1N bis(trimethylsilyl)amide sodium in THF. After stirring for 0.5 h was added 63 mg (0,262 mmol; 1.5 equiv) O-(diphenyl-phosphinyl)hydroxylamine [Hager. J. C. S. Perkin I, 3284-3288] and stirred the reaction mixture for 16 hours at ambient temperature. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography on 5 g of silica gel, elwira consistently Etoac (100 ml), the mixture DHM/CH3OH (19:1, 100 ml). The appropriate fractions were combined and concentrated under vacuum, resulting in the connection specified in the header, in the form of a transparent glass: MS low resolution (of the Belarusian library Association) m/z 474,2 (MN+); TLC Rf= 0,31 (DHM/CH3OH, 19:1)).

The intermediate connection 34

2-Amino-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

A solution of 2.86 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)ndimethylacetamide (10 mmol) in 100 ml of methanol saturated with ammonia at 0oC and left the, and the residue was dissolved in 100 ml of chloroform and washed with water (I ml). The organic layer was dried over anhydrous MgSO4was filtered, concentrated under vacuum and dried under high vacuum, resulting in 2.7 g of compound indicated in the title, in the form of butter.1H NMR (300 MHz, CDCl3d of 6.96 (m, 4H), 4,99 (m, 1H), 3,84 (s, 3H), of 2.97 (s, 2H), 1,58 (s, 2H), of 1.05 (d,6H, J=6.6 Hz); MS low resolution (EDP) m/e 223 (MN+).

The intermediate connection 35

2-(4-fluoro-2-nitro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl) ndimethylacetamide

The mixture 9,06 g 2,5-debtor-nitrobenzene (60 mmol) and 12,64 g 2-amino-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (60 mmol, 1.0 equiv) was subjected to interaction in 225 ml of a mixture of 2:1 ethanol/water and heated with delegacia in nitrogen atmosphere with vigorous stirring over night (approx. 16 hours). The resulting slurry was cooled to ambient temperature, filtered and washed with a mixture of 2:1 water/ethanol. Wet substance was dissolved in methylenechloride, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was ground into powder with hexane, filtered and washed with hexane. The product was dried in high vacuum, while receiving to 9.32 g of compound indicated in the title, in the form of an orange substance.is 16.8 Hz); MS low resolution (EDP) m/e 362 (MN+).

Intermediate compound 36

2-(2-Amino-4-fluoro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl) ndimethylacetamide

A solution of 30 ml of ethyl acetate, 175 ml of ethanol and 2.50 g of 2-(4-fluoro - 2-nitro-phenylamino)-N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (6,92 mmol) was mixed with 0.25 g of palladium on coal (10% by weight) and hydrogenosomal under a hydrogen balloon for 16 hours. The reaction mixture was filtered and evaporated under vacuum, resulting in the 1,91 g of compound indicated in the title, in the form of a solid substance.1H NMR (300 MHz, CDCl3): d 7,03 (m, 2H), 6,94 (m, 2H), 6,36 (m, 3H), 4,99 (m, 1H), 4,37 (b, 3H), 3,86 (s, 3H), 3,39 (s, 2H), with 1.07 (d, 6H, J=6.8 Hz); MC low resolution (of the Belarusian library Association) m/e 332 (MN+).

The intermediate connection 37

2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)- N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide

The solution 1,724 g 2-(2-amino-4-fluoro-phenylamino)-N - isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (5,20 mmol) in 15 ml of tetrahydrofuran was transferred into a funnel for feeding substances. The solution 0,506 ml malonaldehyde (5,20 mmol, 1.0 equiv) in 15 ml of tetrahydrofuran was transferred into a separate funnel for feeding substances. The solutions of all reagents simultaneously dropwise within 30 minutes was added to 100 ml of tetrahydro what I'm in for 20 minutes at ambient temperature in a separate portion was added an additional amount of malonaldehyde (5,20 mmol, 0.1 equiv). The reaction mixture was stirred additionally for 2.5 hours and then was evaporated under vacuum to obtain a residue. The residue was purified on silica gel for rapid separation elution first with a mixture of 1:3 ethyl acetate/hexane, and then 3: 1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated under vacuum to obtain the residue was ground into powder with hexane. Hexane was removed under vacuum, and the remaining substance was dried in high vacuum, resulting in the 1,061 g of compound indicated in the title, in the form of tannins.1H NMR (300 MHz, CDCl3): d 8,14 (b, 1H), 7,45 (dd, 1H, J=5,5, 9,2 Hz), 7,29 (m, 1H), 7,05 (m, 1H), 6,94 (m, 3H), 6,78 (m, 1H), 4,99 (m, 1H), 4,37 (d, 1H, J= 16.4 Hz), 3,82 (s, 3H), of 3.69 (d, 1H, J=16.0 Hz), 3,40 (m, 2H), of 1.09 (d, 6H, J=6.8 Hz); MC low resolution (of the Belarusian library Association) m/e 400 (MN+).

Intermediate compound 38

2-(7-Fluoro-2,4-dioxo-5-pyridin-3-yl - 2,3,4,5-tetrahydro-benzo[b] [1,4] diazepin-1-yl)-N-isopropyl-N-(4 - methoxy-phenyl)-ndimethylacetamide

The mixture 0,880 g of 2-(7-fluoro-2,4-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)- N-isopropyl-N-(4-methoxy-phenyl)-ndimethylacetamide (2,20 mmol), 420 g of copper (bronze, is 6.61 mmol, 3 equiv), 476 mg of potassium acetate (4,85 mmol, 2.2 equiv) and 0,290 ml 3-bromopyridine (4,85 mmol, 2.2 equiv) in 10 ml of dimethylformamide was warming at 100oC in nitrogen atmosphere in the buy 2 hours. The reaction mixture was cooled to ambient temperature, filtered through a funnel fused glass, and then was evaporated to residue under vacuum. The residue was fractionally between ethyl acetate and aqueous ammonium hydroxide (5 ml conc., diluted to 100 ml). After separation of the layers the organic layer is washed with aqueous ammonium hydroxide (5 ml conc., diluted to 100 ml) and then saturated aqueous brine. The organic phase is then thrice was extracted with aqueous HCl (1N). The acidic layers were combined and neutralized aqueous sodium hydroxide (1N). The neutralized mixture was extracted twice with methylene chloride. Layers of methylene chloride were combined, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to a residue. The residue was ground into powder with hexane and then concentrated under vacuum, resulting in the 0,705 g of compound indicated in the title, in the form of a yellow-brown solid.1H NMR (300 MHz, CDCl3d at 8.60 (m, 2H), 8,08 (b, 1H), 7,54 (b, 1H), 7,39 (m, 1H), 7,15 (m, 2H), 7,00 (m, 3H), to 6.57 (dd,1H, J=2.7, and a 9.2 Hz), of 4.95 (m, 1H), 4,32 (d, 1H, J=17,9 Hz), 3,85 (s, 3H), 3,61 (d, 1H, J=12.1 Hz), 3,52 (d, 1H, J=12.1 Hz), of 1.06 (d, 6H, J=6.8 Hz); MC low resolution (of the Belarusian library Association) m/e 477 (MH+).

The intermediate connection 39

Tert-butyl ether 3-nitro-benzol the 6,94 mmol) in dry tetrahydrofuran (70 ml) and was stirred for 2 hours in nitrogen atmosphere. The reaction mixture was concentrated under vacuum and was fractionally between dichloromethane and water. After phase separation the aqueous layer was again extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated under vacuum. The crude product was purified on silica gel for fast separation, using a 0-5% gradient of ethyl acetate in n-hexane. Fractions containing the product were combined, concentrated under vacuum, and then dried in high vacuum, resulting in the 3,82 g of compound indicated in the title, in the form of butter.1H NMR (300 MHz, CDCl3d 8,79 (m, 1H), 8,35 (m, 2H), 7.62mm (m, 1H), and 1.63 (s, 9H); MC low resolution (HEE) m/e 224 (MN+).

The intermediate connection 40

Tert-butyl ester 3-amino-benzoic acid

A solution of tert-butyl methyl ether 3-nitro-benzoic acid (3.77 g, to 16.9 mmol) in absolute ethanol (50 ml) was mixed with palladium on coal (10% by weight, of 0.30 g) and hydrogenosomal under a balloon of hydrogen gas for approximately 3 hours. The reaction mixture was filtered through a layer of diatomaceous earth, and then concentrated under vacuum to an oil, which crystallized upon drying in high vacuum obtaining in the 3,26 g with the d 7,38 (d, 1H, J=8.0 Hz), 7,29 (m, 1H), 7,19 (m, 1H), 6,83 (m, 1H), 1,58 (s, 9H); MC low resolution (HEE) m/e 194 (MN+).

The intermediate connection 41

Tert-butyl ester 3-[(4-nitrophenyl)oxycarbonyl] -amino-benzoic acid

To a solution of tert-butyl ester 3-amino-benzoic acid (3.15 g, 16,24 mmol) under nitrogen atmosphere at 0-5oC for 20 minutes was added dropwise a solution of 4-nitro-phenylcarbamate in dry dichloromethane (25 ml) and anhydrous pyridine (1,379 ml, 17,05 mmol) in anhydrous dichloromethane (25 ml). The reaction mixture was left under stirring to warm to ambient temperature overnight. After washing the aqueous HCl (1N) reaction solution was dried over anhydrous magnesium sulfate and concentrated under vacuum to a solid state. The crude product was stirred in n-hexane for 30 min, filtered and dried in high vacuum, resulting in the 4,460 g of compound indicated in the title, in the form of a white crystalline substance. 1H NMR (300 MHz, CDCl3d 8,30 (m, 2H), 7,92 (m, 1H), 7,78 (d, 2H, J=7.5 Hz), the 7.43 (m, 3H), 7,11 (bs, 1H), 1.69 in (s, 9H); MC low resolution (L-SIMS) m/e 358 (MH+).

The intermediate connection 42

2-(3-Azido-7-fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5 - tetrahydro-benzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-meth is propyl-N-(4-methoxyphenyl)- ndimethylacetamide (0,550 mmol) in 5 ml of anhydrous tetrahydrofuran at -78oC in an atmosphere of nitrogen was treated dropwise and 1.54 ml of bis(trimethylsilyl)amidon potassium (0.5 M in toluene, 0,770 mmol, 1.4 EQ.). After stirring for 15 min was added 212 mg of 2,4,6-triisopropylbenzenesulfonyl (0,687 mmol, 1.25 equiv. [J.Org. Chem. 1984, 49, 1430-1434]). After stirring for 4 min, the reaction mixture was cooled by adding 78,6 ml of glacial acetic acid (1.38 mmol, 2.5 EQ.) and left to warm to ambient temperature. The reaction mixture was evaporated under vacuum to a residue and purified it on flash silica using a mixture of 1:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated under vacuum and dried in a high vacuum, resulting in the 170 mg of the compound indicated in the title, in the form of an amorphous solid.

MC low resolution (of the Belarusian library Association) m/e 518 (MN+); TLC (silica) 3:1 ethyl acetate:hexane Rf= 0,68.

The intermediate connection 43

2-(3-Amino-7-Fluoro-2,4-dioxo-5-pyridin-3-yl-2,3,4,5 - tetrahydro-benzo[b] [1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) ndimethylacetamide

A solution of 152 mg of 2-(3-azido-7-fluoro-2,4-dioxo-5-pyridine-2,3,4,5 - tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl)- ndimethylacetamide in 10 ml of ethyl acetate was mixed with 60 mg of palladium on coal (10 wt.%) and hydro is m and was purified on flash silica gel, using a mixture of 3:7 methanol/ethyl acetate. The appropriate fractions were combined, evaporated under vacuum and dried in a high vacuum, resulting in the 82 mg of the compound indicated in the title, in the form of foam. MS low resolution (of the Belarusian library Association) m/e 492 (MN+); TLC (silica) 95:5 dichloromethane/methanol Rf= 0,30.

Pharmaceutical example

Tablet

Active ingredient: 50 mg

Anhydrous lactose USP: - 163 mg

Microcrystalline cellulose NF: - 69 mg

Pre gelatinizing starch Ph.Eur. 15 mg

Magnesium stearate USP 3 mg

Total weight: 300 mg

The active ingredient, microcrystalline cellulose, lactose and pre gelatinizing starch is sifted through a sieve with a mesh size of 500 μm and mixed in an appropriate mixer. Magnesium stearate is sifted through a sieve with a mesh size of 250 μm and mixed with the active mixture. The mixture is pressed into tablets using appropriate presses, and then cover with acetamitaphen pulp.

TEST THE BINDING OF CCK-A RECEPTOR

Preparation of tissue:

Prepared solutions of 0.3 M and 0.2 M sucrose and cooled them overnight at 4oC. the next day was added inhibitors so that their healthamerica (8.5 mg/500 ml sucrose).

Rats were killed by decapitation using a guillotine. Rat exterior of the abdominal wall was wet with methanol and removed the fur and skin. The abdominal cavity was opened, carefully carved pancreas and put them in a beaker with a capacity of 50 ml, containing 0.3 M sucrose. After collecting all the pancreas was removed excess fat and lymph nodes. The tissue of the pancreas was divided into aliquots weighing approximately 4.0 g and placed them in a beaker with a capacity of 30 ml, each of which contained 1.0 ml of 0.3 M sucrose.

Indoors, cooled to 4oC, the pancreas were crushed with the help of scissors and was diluted 1:10 weight:volume of 0.3 M sucrose. Aliquots homogenized in chilled Wheaton bottle by 4 strokes up and down with the pestle "B", and then 4 strokes up and down with the pestle "And". The homogenates were filtered through 2 layers of filter cloth in chilled beaker with a capacity of 500 ml, then diluted with stirring 2.0 M sucrose, receiving the result of the homogenate to a final concentration of sucrose, equal to 1.3 M Obtained 1.3 M homogenate were distributed on the ice in 18 thin polyallomer tubes (approximately 30 ml of homogenate per tube) and in each tube was sequentially layered is ovale in Sorvall RC70 an ultracentrifuge at speeds 27500 rpm (100000 xg) for 3 hours at 4oC. chilled graduated cylinder gathered boundary layer, diluted and mixed with cold distilled water to a total volume of 312 ml and was centrifuged at 100000 xg for 50 min at 4oC. Precipitation resuspendable in KRH buffer, was transferred to a Wheaton tube and homogenized by 4 strokes up and down fit (tight) pestle "And". This homogenate was transferred into a 2-ml polycarbonate tubes and centrifuged at 100000 xg for 30 min at 4oC. the Precipitate resuspendable (1 ml KRH buffer/GM weight of the original fabric), was transferred to a container of the appropriate size and homogenized by 4 strokes up and down fitted pestle "And". Aliquots of 1 ml were stored at -70oC in microcentrifuge tubes.

The results are presented in the table.

Test:

Test compounds were diluted in buffer to test the binding in the baseline concentrations 10 times larger than the desired final concentration for the test.

50 ml of connection + 400 ml buffer + 25 ml of [125I] sulfated CCK-8, labeled by Bolton and Hunter reagent (Amersham, 2000 Cl/mmol), + 25 ml of the prepared membranes from rat pancreas were incubated for specificheskogo binding was applied 1 mm L-364718 (final concentration).

The reaction was stopped using a Brandell Cell Harvester, washed with 3 x 3 ml chilled on ice (4oC) buffer for testing binding washing.

Tissue was collected on Whatman GF/B filter paper pre-soaked in buffer for testing, and analyzed it using counter gamma radiation.

TEST THE BINDING OF CCK-A RECEPTOR

Preparation of tissue:

Male Hartley Guinea pigs (250-300 g, Charles River) were killed by cutting off their heads. Removed the brain and put it in the 4oC buffer (buffer 50 mm Tris/HCl, pH=7,4).

The cortex was cut off and placed in 4oC buffer. Determined the total wet weight of all the tissues of the bark and diluted 1:10 (weight:volume) buffer.

The cerebral cortex was broken up using a Tekmar Tissuemizer, and then homogenized in a buffer through 5 moves the piston up and down using a motor attached to the homogenizer glass/Teflon. The preparation was stored at 4oC (on ice).

The membrane was besieged by centrifugation in a Sorvall RC5C at 4oC using a SA 600 rotor, rotating with a speed of 16000 rpm (47800 X g Maximum). The precipitate was collected, and the supernatant was discarded. Sediments were combined and resuspendable in buffer at 4oC, and up and down in the homogenizer glass/Teflon with a mechanical drive, using the same volume as before. The resulting homogenates were centrifuged at 16000 rpm (47800 X g Maximum, 36592 X g in average) for 15 minutes at 4oC. Precipitates were collected, and supernatant cast. Precipitation was then combined with buffer to a final volume of 300 ml and was preparing a mixture by using a Tekmar Tissuemizer. By Biorad protein test was determined by the original protein content. The volume of suspension was brought buffer so that the result of bringing the volume final concentration was 4 mg/ml, which was confirmed by Biorad protein test. The final suspension was transferred in the form of aliquot volume of 4.0 ml plastic tubes and frozen at -70oC.

Analysis:

Buffer = 20 mm HEPES, 1 mm EGTA, 118 mm NaCl, 5 mm KCl, 5 mm MgCl2, 0.05% BSA at pH 7,4.

Skatermovie filters soaked with buffer with 0.1% bovine serum albumin (BSA) for one hour prior to collection.

Prepared fresh 100 mm bestain and 3 mm phosphoramidon. (Final experimental concentration had to be exactly 10 mm).

Test compounds were diluted in buffer to test the binding in the baseline concentrations 10 times more concentrated compared to the required final concentrations for analysis. R is Estina + 25 ml of phosphoramidon + 25 ml of the test compound + 50 ml radioligand + 25 ml buffer + 100 ml membranes of the cerebral cortex of Guinea pigs were incubated for 150 minutes at room temperature.

To determine the INaboutbuffer for testing binding was replaced with the test compound.

To determine the binding filter buffer for analysis was replaced with the test compound and the membranes of the cerebral cortex of Guinea pigs.

To determine nonspecific binding of 1 mm sulfated CCK-8 (Sigma) was replaced with the test compound.

The reaction was stopped by filtration through automatic Skatron Cell Harvester. Filters were washed with 4oC buffer. Then the filters were performable, were placed in test tubes and analyzed by the count of gamma radiation.

ANALYSIS OF THE GALL BLADDER OF THE GUINEA PIG

Preparation of tissue:

In Guinea pigs, dead by their necks were removed gall bladders. Extracted gall bladders were purified from adhering connective tissue and cut into two rings from each animal (2-4 mm long). The rings are then suspended in containers for bodies containing physiological salt solution of the following composition (mm): NaCl (4,7), MgSO4H2O (1,2); CaCl22H2O (2,5); KH2PO3(1,2); NaHCO3(25) and dextrose (11,1). Washing solution was kept at a temperature of 37o

Analysis:

Rings gradually stretched (within 120 minutes) prior to the base residual voltage, comprising 1 GM, which was maintained during the experiment. In the process of creating the base voltage of the ring four times immersed in acetylcholine (ACH, 10-M) to control contractility. Then the fabric was treated with a submaximal dose of sulfated CCK-8 (Sigma, 3 x 10-M). After obtaining a stable response of the tissue was rapidly washed 3 times for 5-10 minutes each hour to restore a stable base line.

Compounds were dissolved in dimethyl sulfoxide (DMSO), then diluted with water and tested by the cumulative curve of the response of the concentration for the tested compounds (10-11up to 3 x 10-6M), and then curve response from concentrations for sulfated CCK-8 (10-11up to 10-6M) in the presence of the highest dose of the test compound. As a final analysis was added ACH (10 mm) for the induction of maximum concentration the results, obtained in this test with a typical compounds according to the invention. Compounds were tested at a concentration of 1 μm, and the results were expressed as % of maximum response sulfated CCK-8.

Example N - Reduction

1

2

3 - 91

4 - 64

5 - 83

6 - 67

7 - 51

8 - 32

9 - 77

10 - 81

11 - 83

12 - 67

13 - 96

14 - 84

15 - 93

EXAMPLE 18-HOUR DEPRIVATION-INDUCED FOOD

Male Long-Evans rats (Carles River Co. , Raleighhh, NC) weighing 300-375 g, individually adapted for at least one week in suspended cells from stainless steel mesh (17.8 x 25.4 x 17.8 cm high) with free access to water (administered through automatic drinking tube in the back of the camera) and food (Lab Blox, Purina Laboratory Rodent Chow # 5001) when the 12-hour cycle of light/dark (light from 0600-1800 hours or hours) at approximately 22,8oC. Before testing at 16.00 h remove all food, but not water. At 09.00 h the next morning, rats were weighed. At 09.45 h rats were injected intraperitoneally (C. B.), oral (p. O.), or through the introduction of a cannula into the duodenum tested the connection, or the filler (2 ml/kg) and returned them to their cells. Food was given at 10.00 o'clock To 10.30 hours, the remaining food is controlled doses. Why not observed any side effects with the introduction of compounds to rats in therapeutically used doses.

1. 5-Heterocycle-1,5-benzodiazepines General formula I

< / BR>
and their pharmaceutically acceptable salts,

where X is hydrogen or halogen;

R1is a group NR4R5where R4represents C3-6alkyl;

R5represents phenyl substituted in the para-position by metaxylem;

R2is indole, phenyl or a group-other11where R11denotes phenyl or phenyl substituted by carboxypropyl;

R3is a heterocyclic group attached to the nitrogen through a carbon atom cyclic ring selected from pyridyl, pyrimidinyl or pyrazolyl, the latter in turn three times substituted C1-4the alkyl,

z is 1.

2. Connection on p. 1, where R3is-3-peredelnoj group.

3. Connection under item 1 or 2, where R4is isopropyl, and R5is 4-methoxyphenyl.

4. The compound according to any one of paragraphs.1 to 3, where R2is indole or a group with other11in which R11is phenyl or 3-carboxyphenyl.

5. The compound according to any one of paragraphs.1 - 4, g-phenyl)-carbamoylmethyl] -2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-1H-benzo[b] [1,4]diazepin-3-yl}-amide H-indole-2-carboxylic acid and its enantiomers.

 

Same patents:
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to a derivative of asola used as antifungal therapeutic agents and their use

The invention relates to 4-pyrimidine - or pyridinoline production of indole-3-yl-alkylpiperazine formula 1, where X Is = N - or-CH=; R1is hydrogen, halogen, lower alkoxygroup, amino, cyano, hydroxy, nitro-group, a group of the formula: -OCH2CN, -OCH2CONH2, -SO2NH2, -O2CR9, NR7SO2R9where R7is hydrogen, lower alkyl; R9is lower alkyl; or a group of the formula:R2is hydrogen, lower alkoxygroup; a group of the formula: CO2R9where R9lower alkyl, halogen; R3is hydrogen, lower alkyl; R4is lower alkyl; R5is hydrogen; R6is hydrogen, lower alkyl; provided that the portion of the molecule R1- (CH2cannot be hydrogen, lower alkyl, lower alkoxygroup, -N - R7SO2R9if X == N-

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert
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