Condensed derived benzazepine, the intermediate compound to obtain the pharmaceutical composition

 

(57) Abstract:

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I. the Symbols in the formula have the following meanings: ring is a nitrogen - containing aromatic 5-membered cycle having at least 1 nitrogen atom and optionally 1 oxygen atom or sulfur, which may, but not necessarily, have a substituent(s), R1, R2the same and represent a hydrogen atom, And is a single bond, a group represented by the formula-NHCO-(CR3R4)n-, n is 0 or 1, R3, R4may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group (provided that R3and R4may together form a lower alkylenes group having from 2 to 7 carbon atoms), and the ring is a benzene ring which may, but not necessarily, have a substituent(s), and salts thereof, to the intermediate connection suitable for the synthesis of these compounds, and to pharmaceutical compositions that contain these compounds as active ingredient. Compounds of the present invention are useful as antagonists organisatorisches aromatic heterocyclic ring, used as antagonists Organisatorische, to their salts, to pharmaceutical preparations which contain these compounds as an active ingredient, and to intermediate compounds suitable for the synthesis of these compounds.

Background of the invention

Organisatorisches (AVP) is a peptide consisting of 9 amino acid residues, which is synthesized and secreted in the hypothalamus-neurohypophyseal system. As antagonists Organisatorische synthesized peptide compounds and ones type. For example, the compound described in JP-A-2-32098, known as the connection peptide type (used here the abbreviation "JP-A" means published unexamined patent application of Japan"). On the other hand, derivatives of 2,3,4,5-tetrahydro-1H-benzazepine represented by the following General formula described in EP-A-0514667 and JP-A-5-132466 as antagonists of vasopressin ones type.

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(In relation to formula symbols above see above patent publication).

In addition, in international patent publication N 91/05549 described compound represented by the following General formula, and derivatives of 2,3,4,5-tetrahydro-1H-benzodiazepine and derived the tins formula above see above patent publication).

Although they were, as described above, carried out various studies, the creation of new antagonists Organisatorische having more excellent characteristics, at present, still remains an important clinical task.

On the other hand, almost no known compounds having the skeletal structure benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, which is the main connection structure of the present invention, and were only reports of methods of synthesis of several compounds having such a cyclic structure in J. Chem, Soc., Petkin Trans. 1 (1978), N 8, 862-70 and Org. Prep. Proced. Int., 25 (5), 602-6 (1993), but their structure is clearly different from the structure of the compounds of the present invention. In addition, it is not known use of these compounds as pharmaceuticals.

Description of the invention

The authors of the present invention have conducted extensive studies of compounds exhibiting antagonism towards Organisatorische, and made the present invention based on the discovery that a new derived benzazepine with condensed aromatic heterocyclic ring represented by following General formula (I), provoide the invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered ring, represented by the following formula (I), and salts thereof.

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where ring B is a nitrogen-containing aromatic 5-membered ring having at least 1 nitrogen atom and one oxygen atom or sulfur represented by the formula

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where the symbols in the formula have the following meanings:

X1X3one of them is a group =N-, and the other is a group-NR5-, -O - or-S-,

X2: group = CR6-,

R5: a hydrogen atom, a lower alkyl group, and

R6:

(a) a hydrogen atom;

b) a lower alkyl group, unsubstituted or substituted by the following groups:

amino group; morpholinopropan; 1-piperazinilnom group, which optionally may be substituted by a lower alkyl group on the nitrogen atom of the ring; phenyl, imidazolidine, peredelnoj groups, which may optionally be substituted lower alkyl group;

c) cycloalkyl group having from 3 to 8 carbon atoms;

(d) amino group; amino group mono - or disubstituted by lower alkyl or lower alkanoyloxy group (these groups may optionally be substituted amino group; mono - or di-lower alkylaminocarbonyl; piperidino; morpholinopropan; endingup or

f) a hydroxyl group, a lower CNS group, lower allylthiourea, and

R1and R2the same and represent a hydrogen atom;

A: Single bond, a group represented by the formula

-NHCO-(CR3R4)n-,

n = 0 or 1;

R3, R4may be the same or different and each represents a hydrogen atom, a lower alkyl group (provided that R3and R4may together form a lower alkylenes group having 2 to 7 carbon atoms),

ring C is a benzene ring which may have optionally from 1 to 5 substituents selected from the group:

a) a lower alkyl group,

b) unsubstituted lower alkoxygroup,

c) halogen atom,

d) phenyl group, which optionally may be substituted by a lower alkyl group, and

e) imidazolidine group, which optionally may be substituted by a lower alkyl group.

Preferred are derivatives benzazepine with condensed nitrogen-containing aromatic 5-membered cycle or its salt, where the ring B represents a ring of formula:

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where R5and R6above.

Even more preferably, the production of the e ring C represents a benzene ring, unsubstituted or substituted lower alkyl substituted phenyl group.

The most preferred derivatives benzazepine are 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)-carbonyl]-2-phenylbenzene;

4'-[(2-ethyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene;

4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene; and

4'-[(2-propyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene or their salts.

In addition, the invention relates to a pharmaceutical composition having antagonistic activity against Organisatorische, which contains an effective amount of a derivative benzazepine with condensed nitrogen-containing 5-membered ring or its salt of the above, as an active ingredient and pharmaceutically acceptable carriers, diluents or excipients.

Further, the invention relates to 4-biphenyl-2-ylcarbonyl)benzoic acid, which is an intermediate product for the synthesis of the above compounds of General formula (I).

Salt of the compounds of the present invention is a Sol joined the Kim Foundation moreover, it is preferable pharmaceutically acceptable salt. Illustrative examples of such salts include a salt accession acid, formed with inorganic acid, such as hydrochloric, Hydrobromic, itestosterone, sulphuric, nitric, phosphoric acid or etc., organic acid, such as formic, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, metasolv, econsultation or similar, or acidic amino acid such as aspartic acid, glutamic acid or so on; and a salt with an inorganic base, such as sodium, potassium, magnesium, calcium, aluminum or etc., an organic base such as methylamine, ethylamine, ethanolamine, or so forth, or basic amino acid such as lysine, ornithine or etc., are also Useful Quaternary ammonium salt. Illustrative examples of Quaternary ammonium salts include lower alkylhalogenide lowest alkyldiphenyl lowest alkyllithium, benzylchloride etc., preferably methyliodide, benzylchloride etc.

The compound of General formula (I) can form optical isomers due to the asymmetric carbon atom, RMI different isomers, such geometric and optical isomers are also included in the scope of the present invention. In the scope of the present invention also includes hydrates, solvate, tautomers, etc., the compounds of General formula (I). Some of the compounds of the present invention exhibit polymorphism, and all types of polymorphism of the proposed compounds are also included within the scope of the present invention.

Ways to get

The compound of the present invention and salts thereof can be obtained by various synthesis methods based on the use of characteristics of the basic carbon skeleton or type of substituents. In this case, it may be efficient from the point of view of production technology to replace the amino group, carbonyl group, hydroxyl group and mercaptopropyl intermediate compound or compounds of the present invention suitable protective groups, namely functional groups that can be easily converted into the amino group, carbonyl group, hydroxyl group and mercaptopropyl. In accordance with the reaction conditions may, but need not, be used protective groups are described, for example, Greene and Wuts in "Protective Groups in Organic Synthesis, 2nd ed.". In addition to these groups GID carbonyl group, and such a functional group can also be used as protection for the carbonyl group.

Described below are typical examples of methods for obtaining compounds of the present invention.

The first method (amidation A)

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or its reactive derivative, or its salt

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(In the above formulas, R1, R2, A, ring B and ring C have the same respective meanings as described above).

The compound (I) of the present invention can be obtained by customary way amidation of substituted benzoic acids represented by the formula (III), which may optionally be protected, or its reactive derivative and derivative benzazepine with condensed 5-membered nitrogen-containing aromatic heterocyclic ring represented by formula (IV), which may not necessarily be protected, or its salt, and, if necessary, removing the protective group.

Examples of the reactive derivative of compound (III) include his usual esters such as methyl ester, ethyl ester, isobutyl ester, tert-butyl methyl ether and so on; its anhydrides, such as Chloroaniline derivative, such as p-NITROPHENOL or N-hydroxylamino derivative such as 1-hydroxysuccinimide, 1-hydroxybenzotriazole or similar ; symmetric acid anhydrides; and mixed acid anhydrides, including mixed anhydrides of organic acids, obtained by the interaction with alkylamine esters halogencarbonic acids, such as halides alkalicarbonate acid or pivaloyloxy, and mixed anhydrides of phosphoric acid obtained by the interaction with diphenylphosphinylchloride or N-methylmorpholine.

In addition, when providing the compound (III) opportunities to respond as the free acid, as the active complex ether without selection or etc., it is desirable to use a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl, diethylphosphoramidite, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or etc.

The reaction can be carried out usually in an inert organic solvent selected, for example, from halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., aromatic hydrocarbons such as benzene, toluene, xylene and so on, ethers such as IER the sulfoxide depending on the reactive derivative, condensing agent, etc., and when the cooling temperature or at a temperature ranging from the temperature of cooling to room temperature, or from room temperature to the heating temperature depending on the reactive derivative.

For a soft reaction can sometimes be convenient to use the compound (III) in excess, or to carry out the reaction in the presence of a base, such as N-methylmorpholine, trimethylamine, triethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, lutidine or so on the Pyridine can also be used as solvent.

The reaction can be carried out preferably in the absence of mercaptopropyl and reactive amino-, carboxy-, hydroxy -, etc. groups, but the target product can be obtained by implementation of the response after the introduction of the protective groups and the removal of the protective group after the reaction.

The method of removal of the protective groups change depending on the type of used protective group.

For example, when the protective group for the amino group is substituted or unsubstituted benzyloxycarbonyl group, or so on, then the hydrogen and acetic acid, a mixture of Hydrobromic and triperoxonane acid, hydrofluoric acid, etc. In the case of other protective groups of the urethane type, such as tert-butoxycarbonyl group and so on , it is convenient to use an acid treatment with a mixture of Hydrobromic and acetic acids, triperoxonane acid, hydrochloric acid, a mixture of hydrochloric and acetic acids, a mixture of hydrochloric acid and dioxane, etc.

When the protective group for amino group is a group which forms phthalimidopropyl with the nitrogen atom of an amino group, primary amino group can be formed by removing falorni group by treatment with hydrazine, such as hydrazine, methylhydrazine, acylhydrazone etc., ammonia or primary amines such as methylamine, ethylamine, Propylamine, etc.,

The protective group for the carboxyl group can be easily removed by saponification, when the protective group are methyl and ethyl groups by catalytic reduction or saponification, when the protective group is benzyl group and various substituted benzyl group, by the above acid treatment, when the protective group is tert-butylene the

When using protective groups for mercaptopropyl and hydroxyl groups, they can be removed in most cases by treatment with a mixture of sodium and liquid ammonia or treatment of hydrofluoric acid, some types of protective groups (for example, O-benzyl, O-benzyloxycarbonyl and S-para-nitroaniline) can be removed by catalytic regeneration and protective acyl group can be removed by hydrolysis in the presence of acid or alkali.

The above processing can be carried out in the usual way.

In this regard, we can say that the starting compound (III) and (IV) can be easily obtained by implementing the above amidation reaction or the reaction of cyclization, which will be described later.

The second method (amidation B)

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or its reactive derivative, or its salt

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(In the above formulas, R1, R2, R3, R4, n, ring B and ring C have the same respective meanings as mentioned previously).

The compound (Ia), as one of the compounds of the present invention, in which A represents A

-(CR3R4)n-CONH-,

can be obtained by implementing what about the not necessarily, to have a protective group, or its reactive derivative and the corresponding amine (VI), which optionally may have a protective group, or its salt and the removal of the protective group, if necessary.

The types of the reactive derivative, the reaction conditions, the removal of protective groups, etc. are the same as in the first method, the reaction can be carried out in the same way.

In this regard, we can say that the starting compound (VI) can be easily obtained by implementing the above amidation reaction or the reaction of cyclization, which will be described later.

The third way (amidation C)

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or its reactive derivative, or its salt

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(In the above formulas, R1, R2ring C and A have the same respective meanings as given above, and ring B' is the same as ring B, except that one hydrogen atom or Deputy removed, R8represents a lower alkyl group, which optionally can be substituted amino, or mono-or di-lower alkylaminocarbonyl, optional may have a protective group, and A1represents a single bond or lower alkylenes group).

The types of the reactive derivative, the reaction conditions, the removal of protective groups, etc. are the same as in the first method, the reaction can be carried out in the same way.

In addition, you can get the same as in the first method, the compound, which 5-membered cycle introduced substituted or unsubstituted aminocarbonyl group, or another compound, in which ring C is introduced a group-NHCO - or-CONH-.

The fourth way (cyclization)

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(In the above formulas, R1, R2, ring C, A, X1and X3have the same respective meanings as mentioned previously, some of the Y1and Y2and Y3and Y4form in combination oxoprop (=O), while others represent a halogen atom

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R9is a hydrogen atom or Deputy;

Z is a group represented = N, oxazolines or thiazole cycle, can be obtained by interaction of the corresponding halogenation (VIII), which may optionally have a protective group, with the appropriate amidine, guanidine, inorganic salts, urea, timidly or timeonline represented by the formula (IX), and the removal of the protective group, if necessary.

In this reaction, the corresponding thioamide and thiourea, amidon and guanidine or amide carboxylic acid and a derivative of urea may form a salt with the acid. To accelerate the reaction can be carried out in the presence of inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or etc., or salts of weak acid with strong base or organic base, such as pyridine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0] non-5-ene, or similar Reaction may preferably be carried out in an inert solvent, which includes alcohol solvents such as methanol, ethanol, isopropyl alcohol and so on, ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide and dimethylsulfoxide, and at a temperature within the tion can be carried out under pressure.

When used in the reaction amidino or guanidino in this case can sometimes be formed oksazolov. When carrying out the reaction in an atmosphere of gaseous ammonia in the presence of ammonium carbonate, ammonium acetate, formamide, or similar, as the main product can be obtained imidazoles.

Used in this reaction the original compound (VIII) can be obtained, as shown in the following reaction scheme, implementation as well as in the first method, the amidation reaction between para-substituted benzoic acid (X), which may, but not necessarily, have a protective group, or its reactive derivative and the derivative (XI) benzazepine, which may, but not necessarily, have a protective group, or its salt, and the interaction of the obtained product with a halogenation agent to remove at any stage protective group, if necessary. In this connection a connection in which the symbol A in para-substituted benzoic acid (X) is -(CR3R4)-CONH-, can be obtained by the implementation as well as in the first method, the amidation reaction between the corresponding carboxylic acid (XIII) or its reactive derivative and the corresponding para-aminobenzoic is mvol A have the same respective values, as mentioned above, and some of the Y5and Y6, Y7and Y8form in combination oxoprop, while others are both hydrogen atoms

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The types of the reactive derivative, the reaction conditions, methods of removal of the protective groups, etc. in the first stage, the amidation reaction are the same as in the first method.

As for the halogenation agent used at the stage of halogenation, it is possible to use any substance traditionally used for halogenation of saturated cyclic ketones, but is preferably a metal reagent, such as a halide of copper (II) (for example, bromide, copper (II) chloride copper (II) or similar), or perbromide pyridine, / -pyrrolidone, Quaternary ammonium compounds, dioxane or similar, such as deoxyribose, phenyltrimethylammonium, perbromic of pyridinesulfonamide, pyrrolidinylcarbonyl or etc., and the halogen, such as chlorine, bromine or etc., or halogen acid, such as hydrochloric, Hydrobromic or etc.

When using a metal reagent or perbromide the reaction of the compound (XII) with this halogenation agent is usually carried out in an inert solvent selected, for example, from halogenide diethyl ether, tetrahydrofuran, dioxane, etc., alcohols, such as methyl, ethyl, etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc., acetic acid, ethyl acetate, water or mixtures thereof, and at room temperature or with heating in the presence of, if necessary, a small amount of catalyst such as halogenation or etc.

The target compound can be also obtained by the interaction of the compound (XII) with the halogen as the halogenation agent in an inert solvent such as a halogenated hydrocarbon (e.g., dichloromethane, chloroform, carbon tetrachloride, etc.,) and ethylene glycol, acetic acid, etc. or interaction of the compound (XII) with a halogen acid as the halogenation agent in its acidic solution or basic solution such as aqueous solution of sodium hydroxide. In this case, the reaction can be carried out at a temperature in the range preferably from -30oC to the temperature of the return flow of the used solvent.

The above-described method of synthesis of compounds with condensed imidazole, oxazoline or thiazole cycle, but you can obtain a connection to the condensed oxadiazole, thiadiazole is maintained above formulas, R1, R2ring C and A have the same respective meanings as above and Y9represent a halogen atom).

That is, the compound (Ie) with condensed 1,2,5-oxadiazolyl cycle and the compound (If) with condensed 1,2,5-thiadiazolidin cycle can be obtained by the interaction derived benzazepine with hydroxylaminopurine in the presence of a base such as sodium acetate or similar, to get dioxime (XVI) and de-hydration of the obtained compound by heating in the presence of a dehydrating agent or treatment of this compound with hydrogen sulfide. Each stage can be done the traditional way.

On the other hand, the compound (Ig) with condensed 1,2,3-oxadiazolyl cycle can be obtained by treating compound (VIIIa) ammonia and processing of the obtained compound (XVIII) diastereomer agent such as sodium nitrite. That is, the compound (Ig) is in equilibrium with diazoketones (XIX). In addition, compound (Ih) with condensed 1,2,3-oxadiazolyl cycle and the compound (Ii) with condensed 1,2,3-triazole cycle can be obtained by the interaction of diazocompounds (XIX) or the compound (Ig) with ammoniagenesis.

The original compound (XV) can be easily obtained as in the above-described method of amidation to obtain compound (XII) from compound (XI), and the other starting compound (VIII-a) can be easily obtained by the method described previously.

When instead of the compound (VIII-a) as a starting compound used halogeton with other provisions for the carbonyl group and the halogen atom, there can be obtained compounds in which 1,2,3-oxadiazolyl and 1,2,3-thiadiazolyl cycles condensed in the other positions.

The fifth way (interconversion of substituents in the aromatic hydrocarbon ring)

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(In the above formulas, R1, R2, ring B and A have the same respective meanings as given above, and the ring C' equally with the ring C, except that one hydrogen atom or Deputy removed, R10and R11may be the same or different from each other and represent each a hydrogen atom, a lower alkyl group, a protective group or amidinopropane provided that R10and R11can be combined with the adjacent nitrogen atom to form heterocycle, which may, but need not, be substituted).

what can be obtained by selecting the corresponding parent compound and repetition of the method described above, but, when the substituent in the aromatic carbon ring contains a characteristic functional group, it can be obtained by mutual transformations such as the introduction or substitution of the substituent in the aromatic carbon ring.

For example, compound (Ik), which contains at least one Deputy type amine in the ring C may be obtained by interaction of persuadere (Ij) with-CO -, or-CN/ in adjacent positions, when A represents A single bond or-CONH-, with ammonia, an appropriate amine, the corresponding cyclic Eminem or guanidine.

This method can be applied to the traditional method of N-alkylation. That is, although the reaction proceeds in the absence of solvent, it is possible to carry out in an inert organic solvent selected, for example, dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons such as benzene, toluene, xylene and so on, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., and alcohols such as methyl, ethyl, isopropyl, etc. To ensure a smooth reaction may sometimes be expedient to carry out the reaction in the presence of inorganic base is based temperature when heated or when the temperature of the return flow.

This method of transformation with the formation of amine type of the substituent in the aromatic carbon ring can be also applied to the case of the implementation of the transformation in such amine type Deputy, as R2.

The sixth method (interconversion of substituents in the heterocycle)

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(In the above formulas, R1, R2, ring B', A, ring C, R10and R11have the same respective meanings as above, and A2represents a single bond or lower alkylenes group and Y11represents a halogen atom, a residue of an organic sulfonic acids or, when A is a single bond, alkoxy - or allylthiourea).

Interconversion of substituents in the 5-membered heterocycle can be achieved more easily than in the case of aromatic rings. For example, the compound (Im) containing at least one amine of the type of substituent in the heterocycle may be obtained by interaction of the corresponding halide or sulfonate or, when A is a single bond, a simple ester or tiefer (Il) with the amine (XX).

Examples of the residue of the organic sulfonic acids include the remains of alkanesulfonyl, is such as benzolsulfonate, toluensulfonate (in particular, para -), etc.

The reaction can be carried out almost the same as in the fifth method.

In this case, the mutual transformation in the Deputy type amine in the heterocycle can be used as a technique in which the N-substituted compound is produced by interaction of aminosidine condensed with the nitrogen-containing heterocycle, with the corresponding halide or sulfonate, such as lower alkylhalogenide or lower alkylsulfonyl.

Other ways

Although the above describes only the amidation, cyclization and the introduction of a Vice-amine type, but the connection according to the present invention can be synthesized by various conventional methods, because the proposed compound contains various characteristic functional groups.

For example, the compound having a carboxyl group can be obtained by hydrolysis of its corresponding complex ether, ester can be obtained by esterification of the corresponding carboxylic acid; alcohol, phenol, mercaptan and thiophenol can be obtained by simple hydrolysis of the ester and tiefer; and simple ether and thioether can be obtained by the interaction of the match is="ptx2">

Obtained in the ways described, the reaction products isolated and purified in the form of free compounds and their salts, hydrates or solvate. Salts can be obtained by carrying out the normal reactions of the salt formation.

Isolation and purification is carried out by performing common chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various types of chromatography.

As described above, exist separately or as a mixture of isomers of compounds of the present invention, such as racemates, optically active substances, diastereoisomer etc. Racemic compound can be converted into pure stereochemical isomer by using appropriate starting compound or traditional methods of separation of racemic mixtures (for example, a method in which a racemic compound transform then reduced to diastereoisomeric salt conventional optically active acid (wine or similar ) and then subjected to optical separation). A mixture of diastereoisomers can also be separated by conventional means such as fractional crystallization, chromatography, etc.

Promyshlennofinansovaya V1- and/or V2the receptor. That is, the compounds of the present invention include a compound that exhibits strong antagonism and V1- and V2receptors, a compound that selectively reveals a strong antagonism to the V1the receptor, and the compound which selectively exerts a strong antagonism to the V2the receptor.

Particularly preferred is a compound exhibiting a strong antagonism to the V1- and V2-receptors.

Compounds of the present invention exhibit high absorption when administered orally and proper long-term effect due to their resistance to metabolism in vivo.

As a result (on the basis of these functions), compounds of the present invention provide such acts as diuretic, increasing urine output, inhibition of secretion of factor VIII, the blood vessels to dilate, the acceleration of cardiac activity, inhibition of reduction mesangial cells, inhibition of proliferation mesangial cells, inhibition of gluconeogenesis in the liver, inhibition of platelet aggregation, inhibition of the secretion of aldosterone, the inhibition of the production of endothelin, regulation of blood pressure, regulation is in and so on, and useful as a characteristic diuretics, amplifiers urinary tract, vasodilator, hypotensive means, the means used for the treatment of cardiac and renal failure, and inhibitors of blood coagulation and effective in the prevention and treatment of heart failure, hyponatremia (low sodium in the blood), syndrome of abnormal secretion of vasopressin (SIADH), hypertension, kidney disease (nephrosis, nephritis, diabetic nephropathy, chronic or acute renal failure), hydrocephalus, cerebral edema, ascites, cirrhosis, hypokalemia (low potassium in the blood), disorders of water metabolism, diabetes, various ischemic diseases, diseases of the brain vessels, cyclothymic disorder, stomach ulcers, nausea, vomiting, fainting, disorders of the kidneys, etc., and mitigate the consequences of cerebral infarction, intracerebral hemorrhage, etc.

The usefulness of the compounds of the present invention was confirmed by the following tests.

(1) Test the binding of V1receptors

According to the method of Nakamura et al. (J. Biol. Chem., 258, 9283 (1983)) was used to sample membranes of rat liver, and [3H]-Arg-vasopressin (2 nm, specific-8 = 10-4M) were incubated at 30oC for 30 minutes in 250 μl of 100 mm Tris-HCl buffer (pH 8.0) containing 5 mm magnesium chloride, 1 mm ethylendiaminetetraacetic acid (EDTA) and 0.1% bovine serum albumin (BSA). After that he sucked out the incubation solution, using the device to collect the cells, grown in culture, and removed the free ligand and excess buffer by passing the reaction mixture through a glass filter (CF/B), resulting in the filter caught associated with the labeled receptor ligand. Removing the filter, carefully dried, after which the contents were mixed with liquid scintillation mixture, and measured by liquid scintillation counter number associated with the membrane [3H]-vasopressin to calculate the coefficient of inhibition by the following formula.

The ratio of inhibition (%)

where C1- the number of [3H]-vasopressin, is associated with the membrane in the presence of known amounts of each of the test drug substance, and [3H] -vasopressin,

C0- the number of [3H]-vasopressin, is associated with the membrane without addition of the test drug substance,

B1- the number of [3H]-vasopro the/SUB>the concentration of the test drug substance, which under the above calculation gives the ratio of inhibition equal to 50%, used it in the following formula to calculate the affinity of binding of the non-radioactive ligand, namely dissociation constants (Ki).

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where [L] is the concentration of radioactive ligand,

KD is the dissociation constant calculated from the graph of Scatchard.

The negative logarithm of the calculated values was used as the value of pKi. The results are shown in table 1.

(2) Test the binding of V2receptor

Method ampbell et al. (J. Biol. Chem., 247, 6167 (1972)) was prepared by the sample membranes of the brain substance of a kidney rabbit, and [3H]-Arg-vasopressin (2 nm, specific activity = 75.8 cubic inches/mmol), 100 µg sample of membranes and each test drug (10-8- 10-4M) was tested in the same way as in the above test the binding of V1receptor, and as there were calculated the values of the pKi. The results are shown in table. 1 (see the end of the description).

Compounds of the present invention exhibit a strong antagonism to Organisatorische. For example, the compounds of examples 17, 18(2), 20, enii connection with OPC-31260 - antagonist V2-receptor and compound OPC-21280 - antagonist V1receptors, which are developed as antagonists Organisatorische (compare table 1).

(3) V1the antagonism of conscious rats (oral administration)

V1the antagonism was tested on male animals Wister rats (body weight 300 - 320 g), each of which was entered (for 2 - 3 days before the test) cannula into the left carotid artery for measuring blood pressure in the left jugular vein for injection of Organisatorische (WUAs). Blood pressure was measured without anesthesia by means of the pressure sensor through a cannula in the carotid artery. Each test compound suspended in 0.5% aqueous solution of methylcellulose and administered orally with a dose of 1 or 10 mg/kg

The increase in diastolic blood pressure caused by intravenous administration of 30 mIU/kg WUA before the introduction of the test compound was taken as 100%, and measured the increase in pressure caused by intravenous administration of 30 mIU/kg WUAs, periodically during the period from 30 minutes after administration of the test compound to 8 hours after administration of the test compound to calculate the coefficient of inhibition increasing pressure test connection, i.e. below during the period from 30 minutes after injection of the sample for testing up to 6 hours after administration of the test compounds by introduction of 1 mg/kg of each of the compounds of examples 18(2), what shows on the prolonged effects of the proposed compounds. On the other hand, for the suppression caused by the WUA increase the pressure to 50% or lower oral introduced compound OPC-21268 at the dose of 10 mg/kg, ten times higher than the dose of these compounds of the present invention, but during the period of from 30 minutes to 1 hour after logging, and the pressure increase caused by the WUAs, and returned to 100% at 4 hours after injection, indicating that the disappearance of the V1-antagonism.

The above results confirmed that V1the antagonism of the compounds of the present invention when oral administration in conscious rats appeared to be more strong and sustainable compared to the connection of OPC-21268.

(4) V2-antagonism (water diuresis) in conscious rats (oral administration)

Each test compound suspended in 0.5% aqueous solution of methylcellulose and administered orally with a dose of 3 mg/kg male animals Wister rats (body weight 270 - 300 g) deprived of water before and during 16 - 20 hours. Using the camera for metabolism studies, collected urine sample immediately after the introduction of each test sample and up to what drove each of the compounds of examples 18(2), 20, 21 and 23, the amount of urine collected during the period from the time immediately after the introduction of up to 2 hours after administration, was 47 95 times greater than in the group that was administered the solvent, and the amount of urine collected over a period of 2 to 4 hours after injection, was 8 to 10 times higher than in the group that was injected solvent that shows for a long gain effect of water diuresis. On the other hand, in the group, which was introduced OPC-31260, the amount of urine collected during the period from the time immediately after the introduction of up to 2 hours after administration was 11 times higher than in the group that was administered the solvent, and the amount of urine collected over a period of 2 to 4 hours after injection, was almost the same as in the group that was administered the solvent, indicating that the disappearance of the enhancement effect of water diuresis.

The above results confirmed that enhance water diuresis action of the compounds according to the present invention when oral administration in conscious rats appeared to be more severe and prolonged compared with the connection of OPC-31260.

Pharmaceutical composition comprising as an active ingredient one or more compounds of General formula (I) and their pharmaceutically PR is, granules, capsules, pills, solutions, injections, suppositories, ointments, plasters, etc., using traditionally used pharmaceutical carriers, excipients and other additives and administered orally or parenterally.

Clinical dose of the compound of the present invention for a person can, though not necessarily, to be assigned with consideration of symptoms, body weight, age, sex, etc. of each individual patient, but usually it can be from 0.1 to 500 mg per adult person per day in the case of oral administration, and the daily dose can be used in one piece or separate portions. Because the dose varies depending on various conditions, sufficient effects can be obtained in some cases with less than the specified limits, the dose.

As solid compositions for oral administration according to the present invention can be used in tablets, powders, granules, etc. In such solid compositions one or more active ingredients can be mixed with at least one filler, such as lactose, mannitol, glucose, hydroxypropylcellulose, fine crystalline cellulose, starch, the aqueous filler, supplements that include a lubricating substance, such as magnesium stearate, loosening the substance, such as fibrinolitical, a stabilizing agent, such as lactose, and solubilizers substance or adjuvant solution, such as glutamic or aspartic acid. If necessary, tablets or pills may be coated with a film of dissolved in the stomach or in the intestine of a substance, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or etc.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elexir, etc. that contain traditionally used inert diluents, such as distilled water and ethanol. Besides inert diluents such compositions can contain auxiliary substances, such as solubilizers substance or adjuvant solution, wetting agent, suspendisse substance, etc., and sweetening, flavoring, fragrance and antiseptic substances.

Injectable solutions for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions and emulsions. Examples of the diluent for the COI is Zoologicheskii saline. Examples of the nonaqueous solvent for use in solutions and suspensions include vegetable oils such as propylene glycol, polyethylene glycol, olive oil, etc., alcohols, such as ethanol, etc., and Polysorbate 80 (trade name). Such compositions may also contain such additives as a tonic, antiseptic, moisturizing, emulsifying, dispersing, stabilizing (e.g., lactose), solubilizers (or adjuvant solution) substances, etc., These compositions are sterilized by bacterial filtration through retaining bacteria filter, germicidal mixing or exposure. In accordance with another option you can use made sterile solid composition, dissolved before use in sterile water or sterile injecting the solvent.

The best way of carrying out the invention.

Thus, the above-described compounds of the present invention and methods for their production, which will hereinafter be further illustrated in more detail with reference to the following examples. However, these examples do not limit the present invention. Because some of the source compounds of the present invention are new CLASS="ptx2">

In 33 ml of dichloromethane was dissolved of 3.32 g of 2,3,4,5-tetrahydro-1H-benzazepin-5-and she or 4.31 ml of triethylamine, and the resulting solution was added under stirring in an ice bath 4.59 g of p-nitrobenzaldehyde. The reaction solution was stirred at room temperature for another 60 minutes. Then the reaction solution was mixed with saturated aqueous sodium bicarbonate and subjected to phase separation. Separated layer dichloromethane and washed with 1 N. aqueous solution of hydrochloric acid and saturated aqueous sodium chloride (once each solution). Washed as specified layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallized from methyl alcohol, receiving a result of 5.68 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS):

2.17 (2H, m), 2.90 (total 3H), 4.1 (1H), 6.7 (1H, m), 7.2-7.55 (total 4H), 7.78-8.15 (total 3H).

MC (FAB): 3211 (M++ 1).

Reference example 2

In a mixed solvent consisting of 200 ml of dimethylformamide and 100 ml of methyl alcohol was dissolved 19.2 g of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1 be Inom pressure. After the absorption of hydrogen, the reaction solution was filtered and concentrated. The residue was dissolved in dichloromethane and then washed with saturated aqueous sodium bicarbonate. The obtained dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from methyl alcohol, resulting in 15.5 g of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-it.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3internal standard FCM):

2.15 (2H, m), 2.90 (2H, m), 4.05 (2H), 6.45 (2H, d), 6.77 (1H, m), 7.0-7.35 (total 4H), 7.88 (1H, m).

MC (FAB): 281 (M++ 1).

Reference example 3

To a solution obtained by dissolving 3.4 g of o-vinylbenzoic acid in 34 ml of dichloromethane, was added with stirring at -15oC 2.25 ml oxalicacid and a catalytically effective amount of N,N-dimethylformamide, and the resulting mixture was brought to room temperature for 2 hours and stirred for another 2 hours. The reaction solution was concentrated under reduced pressure and three times was subjected to azeotropic treatment with dichloromethane. The residue was dissolved WAGO solution, containing 4.0 g of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepin-5-she and 3.0 ml of triethylamine. The reaction solution was brought to room temperature and continued to stir for another 120 minutes. The resulting reaction solution was mixed with saturated aqueous sodium bicarbonate and subjected to phase separation. Separated dichloromethane layer, drying over magnesium sulfate, concentrated. The residue was recrystallized from toluene, giving the result 5.82 g of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS):

2.23 (2H, m), 2.87 (2H, m), 4.1 (2H), 6.75 (1H, m), 6.8-7.7 (total 15H), 7.85 (1H, m).

MC (FAB): 461 (M++ 1).

Reference example 4

Using o-(4-were)benzoic acid and 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-source materials, repeated the procedure of reference example 3, resulting in 2-(4-were)-4-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl]benzanilide.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS:

2.18 (2H, m), 2.35 (3H, s), 2.88 (2H, m), 4.1 (2H), 6.72 (1H, m,), 6.85-7.7 (�-2,3,4,5- tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent, consisting of 15 ml of chloroform and 1.5 ml of ethyl acetate, the resulting solution was mixed with 560 mg of copper bromide (II) and subjected to heating under reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, was filtered, the insoluble materials and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 12 ml of ethanol, and the resulting solution was mixed with 100 mg of thiourea and subjected to 3 hours of heating under reflux. During this heating to precipitate colorless crystals. After cooling the reaction solution in an ice bath, the crystals were filtered off and washed with small volumes of ethyl alcohol, resulting in 540 mg of 4'-[(2-amino-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzimidazole.

Melting point > 250oC.

Elemental analysis data (C31H24N4O2S HBr):

Calculated,%: C 62.31, N 4 the dart TMS):

2.8-3.4 (total 3H), 5.0 (1H), 6.6-7.8 (total 16H), 8.16 (1H, m), 10.27 (1H, s).

MC (FAB): 517 (M++ 1).

Example 2

After dissolving 500 mg of 2-phenyl-4'[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl] benzanilide in a mixed solvent consisting of 15 ml of chloroform and 1.5 ml of ethyl acetate, the resulting solution was mixed with 560 mg of copper bromide (II) and subjected to heating under reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, was filtered, the insoluble materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in a mixed solvent consisting of 10 ml of 2-propyl alcohol and 2 ml of methyl alcohol and the resulting solution was mixed with 155 mg guanidinoacetic and subjected to 6-hour heating under reflux. During this heating to precipitate colorless crystals. After cooling the reaction solution in an ice bath, the crystals were filtered off and washed nebolshogo alcohol, resulting in 452 mg of 4'-[(2-guanidino-5,6-dihydro-4H-thiazolo[5.4-d] [1] -benzazepin-6-yl) carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Melting point > 250oC.

1H-NMR (M. D. in DMSO-d6internal standard TMC):

2.9 - 3.5 (total 3H), 4.95 (1H), 6.7-7.8 (total 16H), 8.18 (total 5H), 10.32 (1H, c).

MC (FAB): 559 (M++ 1).

Example 3

Repeating the reaction of example 1, except that the starting material used 470 mg of 2-(4-were)-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl] benzanilide, the resulting reaction solution was concentrated, and the residue was subjected to phase separation using ethyl acetate and aqueous sodium bicarbonate solution. Separating an ethyl acetate layer was dried over magnesium sulfate and then concentrated. The residue was recrystallized from ethyl acetate, resulting in 358 mg of 4'-[(2-amino-5,6-dihydro-4H-thiazolo[5.4-d][1]benzazepin-6-yl)carbonyl]- 2-(4-were)benzanilide.

Physico-chemical properties:

Melting point 161-163oC.

Elemental analysis data (C32H26N4O2S):

Calculated,%: C, 72.43, H 4.94, N 10.56, S 6.04

On the (1H), 6.72 (1H, m), 6.8 - 7.7 (total 14H), 8.18 (1H, m), 10.29 (1H, s).

MC (FAB): 531 (M++ 1).

Example 4

Using 400 mg of 2-(4-were)-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide as source material, repeating the procedure of example 2, resulting in 392 mg of 4'-[(2-guanidino-5,6-dihydro-1H-thiazolo[5.4-d] [1] benzazepin-6-yl)carbonyl] -2- (4-were)-benzenemethanamine.

Physico-chemical properties:

Melting point > 230oC.

Elemental analysis data (C33H28N6O2S memorial plaques in DMSO-d6internal standard TMC):

2.27 (3H, c), 3.30 (total 3H), 6.7-7.8 (total 15H), 7.92 (total 4H), by 8.22 (1H, m), 10.29 (1H, s).

MC (FAB): 573 (M++ 1).

Example 5

After dissolving 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent consisting of 15 ml of chloroform and 2 ml of ethyl acetate, the resulting solution was mixed with 390 mg of copper bromide (II) and subjected to 3 hours of heating under reflux with vigorous stirring. After the reaction solution to room temperature, removed by filtration of insoluble materials. The obtained filtrate was washed with a saturated aqueous solution bicarbonat pressure and then was evaporated to dryness, using a vacuum pump. The resulting solid was dissolved in 20 ml of 2-propyl alcohol, and the resulting solution was mixed with 372 mg 4-imidazolidinylideneamino and subjected to 24-hour heating under reflux. After the reaction solution to room temperature, kept the solvent and the obtained residue was mixed with chloroform and saturated aqueous sodium bicarbonate solution to separate the organic layer, which was then washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then deleted from all of the solvent by distillation under reduced pressure. The resulting residue was subjected to column chromatography on silica gel with elution with a mixture (25: 1) chloroform - methyl alcohol. The obtained eluate in chloroform was mixed with 5 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate was removed by distillation, the solvent, and the resulting residue was recrystallized from a mixture of ethanol-diethyl ether, resulting in 262 mg of 4'-[(4-imidazolidinyl)-5,6-dihydro-4H-thiazolo[5.4-d[1] benzazepin-6-yl) carbonyl]-2-2HCl.

Physico-chemical properties:

T is 2HCl 1,5 H2O):

Calculated,%: C 61.67, H 4.73, N 10.27, S 4.70, Cl 10.40

Found,%: C, 61.82, H 4.37, N 10.27, S 4.79, Cl 10.30

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

3.04 (1H, m), 3.37 (2H, m), 4.56 (2H, s), 5.00 (1H, m), 6.78 (1H, d), 6.90 (2H, d), 7.08 (1H, t), 7.25-7.69 (total 14H), 8.29 (1H, d), 10.35 (1H, s) 14.59 (1H, s).

MC (FAB): 582 (M++ 1).

Example 6

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide and 262 mg of 4-(2-methylimidazole)diacetylhydrazine, repeating the procedure of example 5, resulting in 263 mg 4'-[(2-[4-(2-methylimidazole)methyl] -5,6-dihydro-4H-thiazolo[5.4-d][1] benzazepin-6-yl]carbonyl]-2-phenylbenzene 2HCl.

Physico-chemical properties:

Melting point 197-200oC.

Elemental analysis data (C36H29N5O2S 2HCl 1.5 H2O):

Calculated,%: C, 62.97, H 4.82, N 10.20, 4.67 S, Cl 10.33

Found,%: C, 62.75, H 4.62, N 10.24, S 4.73, Cl 9.99

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

2.56 (3H, c), 3.05 (1H, m), 3.36 (2H, m), 4.48 (2H, s), 5.00 (1H. m), 6.79 (1H. d), 6.90 (2H, d), 7.09 (1H, t), 7.25-7.58 (total 13H), 8.33 (1H, d), 10.34 (1H, s), 14.20 (1H, s).

MC (FAB): 596 (M++ 1).

Example 7

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide and 370 mg of 2-pyridylthio from a mixture of chloroform-diethyl ether, receiving 300 mg of 4'[[2-(2-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5.4-d][1]-benzazepin-6-yl] carbonyl]-2-phenylbenzene.

Physico-chemical properties:

Melting point 215-218oC.

Elemental analysis data (C37H28N4O2S):

Calculated,%: C, 74.98, H 4.76, N 9.45, S 5.41

Found,%: C, 74.69, H 4.68, N 9.32, S 5.39

1H-NMR ( M. D. in CDCl3internal standard TMC):

3.10 (2H, m), 3.49 (1H, m), 4.56 (2H, s), 5.17 (1H, DD), 6.66 (1H, d), 6.85 (1H, d), 6.96-7.10 (5H, m), 7.22-7.49 (total 8H), 7.46 (1H, t), 7.53 (1H, t), 7.61 (1H, t), 7.86 (1H, d), 8.42 (1H, d), 8.63 (1H, d).

MC (FAB): 593 (M++ 1).

Example 8

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide and 400 mg of 3-pyridylacetonitrile, repeating the procedure of example 5, resulting in 100 mg 4'-[[2-(4-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl] carbonyl]-2-phenylbenzimidazole in the form of an amorphous solid.

Physico-chemical properties:

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

3.03 (1H, m), 3.29 (2H, m), 4.66 (2H, s), 4.99 (1H, d), 6.78 (1H, d), 6.89 (2H, d), 7.08 (1H, t), 7.25-7.58 (total 12H), 8.03 (1H, t), 8.25 (1H, d), 8.60 (1H, d), 8.85 (1H, d), 9.04 (1H, s), 10.32 (1H, s).

MS (FAB): 593 (M++ 1).

Example 9
is potentiometrically, repeating the procedure of example 5, and the obtained residue was recrystallize from a mixture of methyl alcohol-diethyl ether, resulting in 360 mg 4'-[[2-(3-morpholinopropan)-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl]carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Melting point 215-218oC.

Elemental analysis data (C38H36N4O3S1.6H2O):

Calculated,%: C, 62.48, H 5.68, N 7.67, S 4.39, Cl 9.71

Found,%: C at 62.13, H 5.59, N 7.45, S 4.38, Cl 9.16

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.27 (2H, m), 3.06-3.29 (total 9H), 3.45 (2H, m), 3.85 (1H, m), 3.85 (3H, m), 3.95 (2H, m), 5.00 (1H, m), 6.79 (1H, d), 6.90 (2H, d), 7.08 (1H, t), 7.25-7.57 (total 12H), 8.25 (1H, d), 10.34 (1H, s).

MS (FAB): 629 (M++ 1).

Example 10

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl]benzanilide and 300 mg dimethylaminoethylmethacrylate, and ethyl alcohol as solvent in the reaction, repeating the procedure of example 5, and the resulting residue was recrystallized from a mixture of ethyl acetate-diethyl ether, resulting in 300 mg of 4'-[(2-diethylaminoethylamine-5,6-dihydro-4H-thiazolo[5.4-d] [1]-benzazepin-6-yl)the carbonyl]-2-2HCl.

Physico-helicesN5O2S3H2O):

Calculated,%: C at 58.82, H 5.78, N 9.80, S 4.49, Cl 9.92

Found,%: C, 58.60, H 5.40, N 9.73, S 4.53, Cl 9.51

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.85 (6H, s), 3.02 (2H, m), 3.19 (1H, m), 3.37 (2H, t), 3.76 (2H, m), 4.97 (1H, m), 6.74 (1H, d), 6.93 (2H, d), 7.04 (1H, t), 7.24-7.48 (total 12H), 8.24 (1H, d), 10.35 (1H, s), 10.59 (1H, s).

MC (FAB): 514 (M++ 1).

Example 11

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide and 204 mg of dimethylaminoacetonitrile, repeating the procedure of example 5, resulting in 167 mg of 4' -[(2-dimethylamino-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl) carbonyl-2-phenylbenzimidazole in the form of an amorphous solid.

Physico-chemical properties:

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

3.04 (1H, m), 3.12 (6H, s), 3.29 (2H, d), 4.96 (1H, m), 6.73 (1H, d), 6.92 (2H, d), 7.04 (1H, t), 7.24-7.58 (total 12H), 8.24 (1H, d), 10.33 (1H, s).

MC (FAB): 545 (M++ 1).

Example 12

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl]benzanilide and 285 mg of dimethylaminoacetonitrile, repeating the procedure of example 5, resulting in 212 mg 4'-[[2-(3-dimethylaminopropyl)-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl]carbonyl]-2-Hairdryer1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.19 (2H, m), 2.79 (6H, s), 3.10 (3H, m), 3.18 (2H, t), 3.27 (2H, m), 5.04 (1H, m), 6.77 (1H, d), 6.90 (2H, d), 7.08 (1H, t), 7.25-7.58 (total 12H), 8.35 (1H, d), 10.33 (1H, s).

MS (FAB): 587 (M++ 1).

Example 13

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide and 185 mg of 2-carboxypropanoyl, repeating the procedure of example 5, and the resulting free base was recrystallized from a mixture of methyl alcohol-diethyl ether, resulting in 186 mg of 4'-[(2-methyl-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene.

Physico-chemical properties:

Melting point 165-168oC.

Elemental analysis data (C32H25N3O2S memorial plaques DMSO-d6, internal standard TMS):

2.75 (3H, s), 3.07-3.19 (2H, m), 3.55 (1H, m), 5.20 (1H, m), 6.65 (1H, d), 6.85 (2H, d), 6.96-6.99 (3H, m), 7.01-7.85 (total 9H), 8.38 (1H, d), 8.39 (1H, d).

MS (FAB): 516 (M++ 1).

Example 14

(1) After dissolution 461 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent consisting of 14 ml of chloroform and 1.4 ml of ethyl acetate, the resulting solution was mixed with 560 mg of copper bromide (II) and subjected to 3-hour heating with Oh was removed by filtration of insoluble materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 12 ml of 2-propyl alcohol, and the resulting solution was mixed with 220 mg of telemediated and subjected to 6-hour heating under reflux. During this heating was allocated to precipitate colorless crystals. After the reaction solution in an ice bath, the crystals were filtered and washed with a small volume of cold 2-propyl alcohol, resulting in 410 mg of 4'-[(2-phthalimidomethyl-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene.

Physico-chemical properties:

1H-NMR ( M. D. CDCl3, internal standard TMS):

2.8-3.8 (total 3H), 5.21 (2H, s), 6.64 (1H, DD), 6.75 - 8.1 (total 19H), 8.40 (1H, DD).

MS (FAB) : 661 (M++ 1).

(2) After the suspension of 390 mg of 4'-[(2-phthalimidomethyl-5,6-dihydro-4H-thiazolo[5.4-d] [1]benzazepin-6-yl)carbonyl]-2-phenylbenzene in 20 ml of methyl alcohol, the resulting suspension was mixed with 1.2 ml of a mixed solvent consisting of 40 mass is actionnow the mixture was concentrated, and the obtained residue was purified by column chromatography on silica gel (chloroform:methyl alcohol = 20:1). Obtained solid substance was dissolved in 3.5 ml of methyl alcohol and the resulting solution was mixed with a solution of 4 N. hydrochloric acid-ethyl acetate and then with acetonitrile to provide sediment. The precipitate was filtered and washed with a small volume of acetonitrile, resulting in 200 mg of 4'-[(2-aminomethyl-5,6-dihydro-4H-thiazolo[5.4-d] [1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Purity after HPLC: >96%; ODS-80TM (Tosoh).

1H-NMR ( M. D. DMSO-d6, internal standard TMS):

2.51 (1H, m), 3.09 (1H, m), 3.36 (total 2H), 4.47 (2H, s), 5.02 (1H), 6.85 (2H), 7.11 (1H, t), 7.2-7.7 (total 13H), 7.9 (1H), 8.45 (1H, d), 8.81 (2H), 10.35 (1H, s).

MS (FAB): 531 (M++ 1).

Example 15

Using 400 mg of 2-phenyl-4'[(5-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl) carbonyl] benzanilide and 300 mg of 3-phthalimidopropyl, repeating the procedure of example 14, receiving the 135 mg 4'[(2-amino-ethyl-5,6-dihydro-4H-thiazolo[5.4-d] [1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Purity after HPLC: >91%; ODS-TM (is), 6.77 (1H, d), 6.91 (2H, d), 7.09 (1H, t), 7.54-7.58 (total 12H), 8.14 (1H, W), 8.38 (1H, d), 10.33 (1H, s).

MS (FAB) : 545 (M++ 1).

Example 16

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl] benzanilide and 376 mg of 4-phthalimidobutyl, repeating the procedure of example 14 was obtained using a mixture of ethanol-ethyl acetate as solvent for recrystallization, 193 mg of 4'[(3-aminopropyl-5,6 - dihydro-4H-thiazolo[5.4-d] [1]benzazepin-6-yl)carbonyl]-2 - phenylbenzimidazole.

Physico-chemical properties:

Melting point 185-188oC.

Elemental analysis data (C34H30N4O2SH2O):

Calculated,%: C, 62.50, H 5.29, N 8.41, S 6.39, Cl 7.90

Found,%: C at 62.27, H 5.09, N 8.51, S 5.17, Cl 8.15

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.09 (2H, m), 2.97 (2H, m), 3.05 (1H, m), 3.10 (1H, t), 3.34 (2H, m), 5.01 (1H, m), 6.77 (1H, d), 6.89 (2H, d), 7.08 (1H, t), 7.26-7.58 (total 12H), 7.99 (2H, W), 8.33 (1H, d), 10.33 (1H, s).

MS (FAB): 559 (M++ 1).

Example 17

After the dissolution of 176 mg of tert-butoxycarbonylamino, 205 mg of 1-hydroxybenzotriazole and 0.15 ml of N-methylmorpholine in 3.5 ml of dichloromethane to the resulting solution was added with stirring in an ice bath, 192 mg of 1-ethyl-3-(2-dimethylamino the traditional solution, again cooled in an ice bath, was added dropwise 4 ml of dichloromethane, in which has been dissolved 400 mg of 4'-[(2-amino-5,6-dihydro-4H-thiazolo[5.4-d] [1] benzazepin-6-yl)carbonyl] -2-phenylbenzimidazole described in example 1, and 0.103 ml of triethylamine, after which the mixture was stirred overnight at room temperature. The reaction solution was mixed with water, stirred for 60 minutes and then subjected to a phase separation. Separated dichloromethane layer was washed its saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride (once each solution) and then dried over anhydrous magnesium sulfate. Removing by distillation the solvent, the resulting residue is suspended in 3 ml of methyl alcohol. Cooling in an ice bath, the suspension was mixed with 4.4. ml of a mixture of 4 N. hydrochloric acid-dioxane and stirred for 3 hours. After that, the reaction solution was concentrated, and the residue was recrystallized from 2-propyl alcohol, receiving 250 mg of 4'-[(2-glycylamino-5,6-dihydro-4H-thiazolo[5.4-d] [1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazole 2-propyl alcohol.

Physico-chemical properties:

The temperature of the O):

Calculated,%: C, 64.51, H 5.41, N 10.45, S 4.78, Cl 5.29

Found,%: C, 64.35, H 5.19, N 10.20, S 4.80, Cl 5.10

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

1.04 (6H, d), 3.80 (1H, m), 5.05 (1H), 6.7-7.8 (total 16H), 8.24 (1H, DD), 10.30 (1H, s).

MC (FAB): 574 (M++1).

Example 18

After dissolving 500 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl] carbonyl] benzanilide in a mixed solvent consisting of 15 ml of chloroform and 1.5 ml of ethyl acetate, the resulting solution was mixed with 560 g of copper bromide (II) and subjected to heating under reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, removed by filtration of insoluble materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 10 ml of acetonitrile, and the resulting solution was mixed with 750 mg of potassium carbonate and 510 mg of acetamidomalonate and subjected to 90 minutes of heating under reflux with vigorous stirring. After ohlazhdenie what drove under reduced pressure the solvent. The obtained residue was dissolved in chloroform, after which the resulting solution was washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel (chloroform:methyl alcohol = 20:1), resulting in, in order of elution, 4'-[(2-methyl-5,6-dihydro-4H-oxazolo[4.5-d] - [1]benzazepin-6-yl)carbonyl] -2-phenylbenzene and 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]benzazepin-6-yl) carbonyl]-2-phenylbenzene.

4'-[(2-Methyl-5,6-dihydro-4H-oxazolo[4.5-d][1] benzazepin-6-yl)carbonyl] -2 - phenylbenzene recrystallized from ethyl acetate, resulting in 40 mg of crystals (example 18 (1)).

4'-[(2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl) carbonyl] - 2-phenylbenzene was dissolved in 5 ml of ethanol, the resulting solution was mixed with 0.19 ml of a mixture of 4h. hydrochloric acid-ethyl acetate and cooled in an ice bath, then filtered, precipitated in the sediment crystals and washed with a small volume of ethanol, resulting in 220 mg of 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl] -2-phenylbenzimidazole (example 18(2)).

Physico-chemical properties:
the of 234-236oC.

1H-NMR ( M. D. in CDCl3, internal standard TMS):

2.57 (3H, s), 2.90 (2H, m), 3.27 (1H,m), 5.17 (1H,m), 6.66 (1H, d), 6.8 -7.0 (total 6H), 7.23 (1H), 7.3 -7.6 (total 8H), 7.7 - 7.9 (total 2H).

MC (FAB): 500 (M++1).

(Cl):499 (M+).

MS high resolution (FAB):

Found: 500.200597

Calculated: 500.197417

The empirical formula C32H25N3O3.

4'[(2-Methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]benzazepin-6-yl)carbonyl] -2-phenylbenzimidazole

Melting point > 230oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.70 (3H, s), 2.99 (1H, t), 3.17 (2H, m), 4.99 (1H, m), 6.8 - 7.0 (total 3H), 7.14 (1H, t), 7.2 - 7.7 (total 12H), 8.02 (1H, d), 10.31 (1H, s), 14.6 (total 2H).

MS (FAB): 499 (M++1).

(Cl): 498 (M+).

MS high resolution (FAB):

Found: 499.215808

Calculated: 499.213401

The empirical formula C32H26N4O2.

Example 19. After dissolving 800 mg of 2-(4-were)-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent consisting of 24 ml of chloroform and 2.4 ml of ethyl acetate, the resulting solution was mixed with 560 g of copper bromide (II) and subjected to heating under reflux for 3 chasovnya insoluble materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 16 ml of acetonitrile, and the resulting solution was mixed with 1.17 g of potassium carbonate and 800 mg acetamidomalonate and subjected to 120 minutes of heating under reflux with vigorous stirring. After cooling the reaction solution to room temperature was removed by filtration of insoluble materials, and then drove away under reduced pressure the solvent. The obtained residue was dissolved in chloroform, after which the resulting solution was washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel (chloroform:methyl alcohol + 30: 1), resulting in, in order of elution, 2-(4-were)-4-[(2-methyl-5,6-dihydro-4H-oxazolo[4.5-d] [1] benzazepin-6-yl)carbonyl]benzanilide (example 19(1) and 2(4-were)-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1] benzazepin-6-yl)carbonyl]benzanilide.

2-(4-METI what about alcohol, the resulting solution was mixed with 0.37 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and cooled in an ice bath, then filtered, precipitated in the sediment crystals and washed with a small volume of ethanol, resulting in 500 mg of 2-(4-were)-4'[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl)carbonyl] benzenedicarboxamide (example 19(2)).

Physico-chemical properties:

2-(4-Were)-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1] benzazepin-6-yl)carbonyl]benzoylhydrazone

Melting point 220-223oC

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.25 (3H, s), 2.67 (3H, s), 3.02 (1H, m), 3.16 (2H, m), 4.99 (1H, m), 6.8 - 7.0 (total 3H), 7.15 (total 3H), 7.2 - 7.6 (total 9H), 8.04 (1H, d), 10.33 (1H, s), 14.6 (total 2H).

MS (FAB) : 513 (M++1).

Example 20

After dissolving 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent consisting of 15 ml of chloroform and 2 ml of ethyl acetate, the resulting solution was mixed with 390 g of copper bromide (II) and subjected to heating under reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, removed by filtration nerby the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting substance was dissolved in 20 ml of acetonitrile, and the resulting solution was mixed with 1.1 g of potassium carbonate and 371 mg of ethylcarbodiimide and subjected to 1-hour heating under reflux with vigorous stirring. After filtration of the reaction solution from the obtained filtrate drove the solvent, and the obtained residue was mixed with saturated aqueous sodium bicarbonate and chloroform to separate the organic layer, which was then washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to column chromatography on silica gel with elution mixed solvent of chloroform-methyl alcohol (20:1). The obtained eluate was mixed with 5 ml of a mixture of 4h. hydrochloric acid-ethyl acetate and cooled in an ice bath, then filtered, precipitated precipitated crystals exposed them to recrystallization using ethyl alcohol as a solvent for recrystallization, and the result was 248 mg of 4'-[(2-ethyl-1,4,5,6-tet the properties:

Melting point > 230oC.

The data of elementary analysis (C33H28N4C2HCl 1.6 H2O):

Calculated,%: C at 68.59, H 5.62, N 9.69, Cl 6.13

Found,%: C, 68.28, H 5.54, N 9.62, Cl 6.48

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

1.38 (3H, t), 2.99 (1H, t), 3.08 (2H, HF), 3.12 (2H, m), 4.98 (1H, m), 6.76 (1H, d), 6.93 (2H, d), 7.14 (1H, t), 7.26 - 7.58 (total 12H), 8.13 (1H, d), 10.31 (1H, s), 14.70 (1H, Shir.).

MS (FAB): 513 (M++1).

Example 21

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H - 1-benzazepin-1-yl)carbonyl] benzanilide, 597 mg propellerclearance and 1.2 g of potassium carbonate, repeating the procedure of example 20, resulting in (using as solvent for the recrystallization mixture ethylacetoacetate alcohol) 243 mg of 4'-[(2-propyl-1,4,5,6-tetrahydroimidazo[4.5-d][1] benzazepin - 6-yl)carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Melting point > 230oC.

Elemental analysis data (C34H30N4O2HCl2H2O):

Calculated,%: C, 68.16, H 5.89, N 9.35, Cl 5.92

Found,%: C, 68.86, H 5.61, N 9.62, Cl 6.00

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

1.00 (3H, t), 1.80 (2H, HF), 2.99 (3H, m), 3.56 (2H, m), 4.99 (1H, m), 6.86 (1H, d), 6.93 (2H/BR> Using 400 mg of 1-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide, 576 mg benzylcarbamoyl and 740 mg of potassium carbonate, repeating the procedure of example 20, resulting in (using as solvent for the recrystallization of a mixture of ethyl acetate-ethanol) 225 mg of 4'-[(2-benzyl-1,4,5,6 - tetrahydroimidazo[4.5-d] [1]benzazepin-6-yl)carbonyl]-2 - phenylbenzimidazole.

Physico-chemical properties:

Melting point > 230oC.

Elemental analysis data (C38H30N4O2HCl1.5H2O):

Calculated,%: C, 71.52, H 5.37, N 8.78, Cl 5.56

Found,%: C, 71.55, H 5.22, N 8.82, Cl 5.59

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

2.97 (1H, m), 3.09 (2H, m), 3.41 (2H, s), 4.96 (1H, m), 6.86 - 7.58 (total 22H), 8.14 (1H, d), 10.32 (1H, s), 15.00 (1H, Shir.).

MC (FAB): 575 (M++1).

Example 23

Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl] benzanilide, 585 mg of cyclopropanecarbonyl and 750 mg of potassium carbonate, repeating the procedure of example 20, resulting in (using as solvent for the recrystallization of a mixture of ethyl acetate-ethanol) 276 mg of 4'-[(2-cyclopropyl-1,4,5,6 - tetrahydroimidazo[4,5-d][1]benzea melting point > 230oC

Elemental analysis data (C34H28N4O2HCl1.5H2O

Calculated,%: C, 69.44, H 5.48, N 9.53, Cl 6.03

Found,%: C, 69.10, H 5.39, N 9.42, Cl 6.15

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

1.28 - 1.37 (total 4H), 1.99 (1H, m), 2.96 (1H, m), 3.09 (1H, m), 4.96 (1H, m), 6.83 (1H, d), 6.94 (2H, d), 7.12 (1H, t), 721 - 7.58 (total 12H), 8.17 (1H, d), 10.33 (1H, s), 14.60 (1H Shir.).

MC(FAB): 525 (M++1).

Reference example 5

Using on-methylbenzoic acid and 1-(4-aminobenzoyl)-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-source materials, repeated the procedure of reference example 3, and the obtained 2-methyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl]benzene.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3internal standard TMC):

2.47 (3H, s), 2.90 (2H, m), 4.1 (2H), 6.8 (1H, m), 7.1 - 7.7 (total 10H), 7.82 (2H).

MC (EI): 398 (M+).

Reference examples 6 to 11

The following compounds were obtained as described in referential example 5.

Reference example 6.

2-Isopropyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl]benzanilide

Reference example 7

2-Methoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl] benzanilide


2 Isopropoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl)benzanilide

Reference example 10

2-Methyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl] phenylacetamide

Reference example 11

2-Methoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 - benzazepin-1-yl)carbonyl] phenylacetamide

Reference example 12

In 17 ml of dichloromethane was dissolved 1.67 g of 2'-methoxydiphenyl-4-icarbonell acid, and the resulting solution was added with cooling in an ice bath 0.95 ml oxalicacid and a catalytically effective amount of dimethylformamide, after which the resulting mixture was brought to room temperature. After completion of the foaming, concentrated reaction solution under reduced pressure and was twice subjected him azeotropic treatment with toluene. The resulting residue was dissolved in 8.4 ml of dichloromethane, and the resulting solution was added dropwise, with cooling in an ice bath, to a solution obtained by dissolving 1.0 g of 5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin and 1.53 ml of triethylamine in 10 ml of dichloromethane. The reaction solution was heated to room temperature and stirred for another 1 hour. The resulting reaction solution was mixed with water and subjected to phase separated aqueous sodium bicarbonate solution and was dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was led from toluene, resulting in 1.65 g of 1-(2'-methoxydiphenyl-4-yl-carbonyl)-5-oxo-2,3,4,5-tetrahydro-1H - 1-benzazepine as crude crystals.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3internal standard TMC):

2.17 (2H, m), 2.93 (2H, m), 3.75 (3H, s), 6.7 - 7.7 (total 8H), 7.79 (1H, d), 7.89 (2H), 8.21 (1H, d).

MC (EI): 371 (M+).

Example 24

After dissolving 2.0 g of 2-methyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-benzazepin-1-yl)carbonyl] benzanilide in a mixed solvent consisting of 30 ml of chloroform and 3 ml of ethyl acetate, the resulting solution was mixed with 2.47 g of copper bromide (II) and subjected to 3 hours of heating under reflux with vigorous stirring. After the reaction solution to room temperature, removed by filtration of insoluble materials. The filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 80 ml of chloroform, and the resulting solution was mixed Com in a stream of argon. The resulting reaction solution was mixed with water and subjected to phase separation to separate the organic layer, which was then dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the obtained residue was led from toluene, resulting in 1.41 g of 2-methyl-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1]benzazepin-6-yl)carbonyl]benzanilide. A portion (1.0 g) of this compound was dissolved in 10 ml of ethanol, mixed with 0.86 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and recrystallized, resulting in 860 mg of 2-methyl-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]benzazepin - 6-yl)carbonyl]benzenedicarboxamide.

Physico-chemical properties:

Melting point >230oC.

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

2.33 (3H, s), 2.70 (3H, s), 3.00 (2H, t), 5.0 (1H, m), 6.99 (2H, d), 7.14 (1H, t), 7.27 (1H, t), 8.17 (1H, d), 10.40 (1H, s), 14.9 (1H, Shir.).

MC(FAB): 437 (M++1).

Example 25

From 2.0 g of 2-methoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl]benzanilide, obtained by repeating the procedure of example 24, 890 mg of the crude crystals from 400 mg which received 360 mg of 2-methoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo the tour melting point >210oC

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

2.69 (3H, s), 3.00 (1H, t), 3.85 (3H, s), 5.01 (1H, m), 6.88 (1H, d), 7.36 (1H, t), 7.48 (1H, t), 8.14 (1H, d), 10.20 (1H, s) 14.83 (1H, Shir).

MC(FAB): 453 (M++1).

Example 26

From 2.0 g of 2-ethoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl) carbonyl]benzanilide obtained by repeating the procedure of example 24, 927 mg of the crude crystals from 500 mg of which received 465 mg of 2-ethoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl)carbonyl] benzenedicarboxamide.

Physico-chemical properties:

Melting point >220oC.

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1.344 (3H, t), 2.70 (3H, s), 3.00 (1H, t), 4.16 (3H, HF), 5.02 (1H, m), 6.88 (1H, d), 7.03 (3H, m), 7.13 (1H, t), 7.35 (1H, t), 7.46 (1H, t), 7.54 (1H, d), 8.18 (1H, d), 10.19 (1H, s), at 14.86 (1H, Shir.).

MC (FAB): 467 (M++ 1).

Example 27

Portion (410 mg) of bromine, dissolved in 2 ml of chloroform, gradually (over about 60 minutes) was added dropwise to 20 ml of a chloroform solution containing 1.0 g of 2-isopropoxy-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1 benzazepin-1-yl)carbonyl)benzanilide at room temperature. After confirming the disappearance of the color of bromine, washed reaction solution saturated aqueous solution of the bicarbonate pressure and then was evaporated to dryness, using a vacuum pump. The obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 1.10 g of acetamidomalonate and 2.25 g of potassium carbonate and subjected to 20-hour reflux in a stream of argon. The resulting reaction solution was mixed with water and, stirring, was filtered phase precipitate a solid, which is then suspended in 20 ml of ethanol, mixed with 0.58 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and recrystallized, receiving 600 mg 2-isopropoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo [4.5-d][1]benzazepin-6-yl)carbonyl]benzenedicarboxamide.

Physico-chemical properties:

Melting point > 300oC.

1H-NMR ( M. D. in DMSO-d6internal standard TMC): 1.30 (6H, d), 2.68 (2H, s), 3.02 (1H, t), 4.72 (1H, q), 5.0 (1H, m), 6.89 (1H, d), 7.37 (1H, t), 7.65 (1H, d), 8.10 (1H, d), 10.18 (1H, s), 14.7 (1H, Shir.).

MC (FAB): 481 (M++ 1).

Example 28

Portion (1.32 g) of bromine, dissolved in 6.6 ml of chloroform, gradually (over about 60 minutes) was added dropwise to 36 ml of a chloroform solution containing 3.55 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] -2-isopropoxybenzonitrile, when the first sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 5.0 g of cyclopropanecarbonitrile and 8.02 g of potassium carbonate and subjected to 20-hour reflux in a stream of argon. The resulting reaction solution was mixed with water for phase separation, and the separated organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the obtained residue was led from toluene, with a 2.96 g of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl) carbonyl]-2-isopropoxybenzonitrile. Part (1.08 g) of this compound was dissolved in 20 ml of ethyl alcohol was mixed with 0.8 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and recrystallized, resulting received 916 mg of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1]benzazepin-6-yl) -carbonyl]-2-isopropoxybenzonitrile.

Physico-chemical properties:

Melting point > 210oC.

1H-), 6.87 (1H, d), 7.37 (1H, t), 7.66 (1H, d), 8.17 (1H, d), 10.18 (1H, s), 14.4 (1H, Shir.).

MC (FAB): 507 (M++ 1).

Example 29

Of 5.0 g of 2-fluoro-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide obtained by repeating the procedure of example 24, 4.76 g of the crude crystals, 1.0 g of which received 1.02 g of 2-fluoro-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl)carbonyl] benzenedicarboxamide.

Physico-chemical properties:

Melting point > 270oC.

1H-NMR ( M. D. in DMSO-d6internal standard TMC): 2.70 (3H, s), 3.01 (1H, t), 5.02 (1H, m), 6.87 (1H, d), 7.02 (2H, m), 7.14 (1H, t), 8.18 (1H, d), 10.55 (1H, s), 14.8 (1H, Shir.).

MC (FAB): 440 (M++ 1).

Example 30

To 20 ml of tertrahydrofuran ring of a solution containing 1.0 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] -2-isopropylbenzene, was added with cooling in an ice bath 793 mg phenyltrimethylammonium, and the resulting mixture was heated to room temperature. After about 60 minutes, after confirming the disappearance of the color of bromine, was carried out by filtration. The filtered material was washed with tetrahydrofuran, and the filtrate was combined and concentrated. The resulting residue was dissolved in chloroform, washed with water is atok still was evaporated to dryness using a vacuum pump. Obtained with the solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 1.11 g of acetamidomalonate and 2.26 g of potassium carbonate and subjected to heating under reflux in a stream of argon. The resulting reaction solution was mixed with water for phase separation, and separating the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the obtained residue was led from toluene, receiving 640 mg of 2-isopropoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]benzazepin-6-yl) carbonyl]benzanilide. Part (563 mg) of this compound was dissolved in 5.5 ml of ethyl alcohol was mixed with 0.45 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and recrystallized, resulting received 400 mg of 2-isopropyl-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]-benzazepin-6-yl) carbonyl]benzenedicarboxamide.

Physico-chemical properties:

Melting point 251 - 253oC.

1H-NMR ( in DMSO-d6internal standard TMC):

1.18 (6H, t), 3.00 (1H, t), 3.38 (2H, W), 5.0 (1H, m), 6.89 (1H, d), 7.16 (1H, t), 7.55 (2H, d), 8.11 (1H, d), 10.47 (1H, s), 14.7 (1H, Shir.).

MC (FAB): 465 (M++ 1).

Example 31

From 2.0 g of example 30, 1.19 g of the crude crystals, 1.19 g are obtained 1.25 g of 2-methoxy-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1]benzazepin-6-yl) carbonyl]phenylacetylglutamine.

Physico-chemical properties:

Melting point > 200oC.

1H-NMR ( in DMSO-d6internal standard TMC):

2.68 (3H, s), 2.98 (1H, t), 3.60 (2H, s), 3.73 (3H, s), 5.0 (1H, m), 7.12 (1H, t), 8.10 (1H, d), 10.26 (1H, s), 14.7 (2H, W).

MC (FAB): 467 (M++ 1).

Example 32

From 2.0 g of 2-methyl-2'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] phenylacetylide obtained by repeating the procedure of example 30, 1.26 g of the crude crystals from 1.2 g which received 898 mg of 2-methyl-4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl) carbonyl]phenylacetylglutamine.

Physico-chemical properties:

Melting point 201 - 203oC.

1H-NMR ( M. D. in DMSO-d6internal standard TMC):

2.25 (3H, c), 2.68 (3H, c), 2.98 (1H, t), 3.66 (2H, s), 5.0 (1H, m), 6.90 (1H, d), 7.34 (1H, t), 8.09 (1H, d), 10.44 (1H, s), 14.7 (2H, W).

MC (FAB): 451 (M++ 1).

Example 33

A portion (3 ml) chloroform solution containing 300 mg of bromine, gradually (over about 60 minutes) was added dropwise at room temperature to 700 mg of 1-(2'-methoxide is novenia color of bromine, washed reaction solution, saturated aqueous sodium bicarbonate. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. The resulting solid was dissolved in 28 ml of chloroform, and the resulting solution was mixed with 714 mg acetamidomalonate and 1.46 g of potassium carbonate and subjected to 20-hour reflux in a stream of argon. The resulting reaction solution was mixed with water for phase separation, and separating the organic layer was dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was purified by column chromatography on silica gel (chloroform: methyl alcohol = 20:1) with, in order of elution, 210 mg (vitreous solid) 6-[(2'-methoxy-4-diphenylol)carbonyl] -2-methyl-5,6-dihydro-4H-oxazolo[4.5-d][1] benzazepine (example 33(1) and 390 mg (vitreous solid) 6-[(2'-methoxy-4-diphenylol)carbonyl]-2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1] benzazepine.

6-[(2'-Methoxy-4-diphenylol)carbonyl] -2-methyl-1,4,5,6-tetrahydroimidazo [4.5-d][1] benzazepine was dissolved in 4.8 ml of ethanol, the solution was mixed with 0.44 m is what the resulting crystals were filtered off and washed with a small volume of ethyl alcohol, resulting in 260 mg of 6-[(2'-methoxy-4-diphenylol)carbonyl] -2-methyl-1,4,5,6-tetrahydroimidazo [4.5-d]-[1]benzenedimethanamine (example 33(2)).

Physico-chemical properties:

6-[(2'-methoxy-4-diphenylol)carbonyl] -2-methyl-5,6-dihydro-4H-oxazolo [4.5-d][1]benzazepin

1H-NMR ( M. D. in CDCl3internal standard TMC):

2.57 (3H, s), 3.73 (3H, s), 5.22 (1H, m), 6.78 (1H, DD), 7.82 (1H, DD).

MC (EI): 410 (M+).

6-[(2'-methoxy-4-diphenylol)carbonyl] -2-methyl-1,4,5,6 - tetrahydroimidazo[4.5-d] [1] benzenepropanoic

Melting point > 240oC.

1H-NMR ( M. D. in DMSO-D6, internal standard TMS):

2.69 (3H, s), 3.03 (1H, t), 3.70 (3H, s), 5.02 (1H, m), 6.9-7.4 (total 11H), 8.12 (1H, d), 14.7 (total 2H).

MC (EI): 409 (M+).

Example 34

A portion (1.0 g) of the crude crystals of 2-fluoro-4'-[(2-methyl - 1,4,5,6-tetrahydroimidazo [5.4-d] [1] benzazepin-6-yl)carbonyl]- benzanilide obtained in example 39, and 1.1 g of 2-ethylimidazole was dissolved in 5 ml of dimethyl sulfoxide and stirred for 24 hours at 120oC. the Reaction solution was added water and was extracted twice with chloroform. The chloroform layers were combined, washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. By removing solvent system chloroform-methyl alcohol-28% aqueous ammonia (10:1:0.1), and the result obtained 1.02 g of a glassy solid. This compound was dissolved in 20 ml of ethanol, mixed with 1.42 ml of a mixture of 4 N. hydrochloric acid-ethyl acetate and then concentrated. The obtained residue was converted into amorphous powder, using isopropyl alcohol, and then was filtered, resulting in 460 mg of 2-(2-ethyl-1H-imidazol-1-yl)-4'-(2-methyl-1,4,5,6-tetrahydroimidazo [4.5-d] [1] benzazepin-6-yl)carbonyl]benzanilide 2HCl.

Physico-chemical properties:

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.70 (3H, s), 3.01 (1H, t), 5.02 (1H, m), 7.12 (1H, t), 8.24 (1H, d), 10.93 (1H, s).

MC (FAB): 517 (M++ 1).

Reference example 13

In 35 ml of dry chloroform was dissolved 5.46 g of 3-phthalimidopropyl, was added to a solution of 1.76 ml of ethanol, after which the resulting mixture was barbotirovany 30 minutes hydrochloric acid with cooling in an ice bath and then was stirred for 12 hours. Mixed reaction solution with diethyl ether, and the resultant of this precipitate was filtered and dissolved in 150 ml of ethanol, after which the resulting solution was mixed with 3 g of ammonium carbonate and stirred at room temperature for 24 hours. Drove races is himicheskie properties:

MC (FAB): 218 (M++ 1).

Reference example 14

Using 2.963 g of 4-phthalimidobutyl as source material, repeating the procedure of reference example 13 and as a result got 3.162 g of 4-phthalimidobutyl 1/2 carbonate.

Physico-chemical properties:

MC (FAB): 232 (M++ 1).

Reference example 15

Using 4.472 g 5-palmitoylcarnitine as source material, repeating the procedure of reference example 13 and as a result got 4.364 g 5-phthalimidomethyl 1/2 carbonate.

Physico-chemical properties:

MC (FAB): 245 (M++ 1).

Reference example 16

After the dissolution of 3.03 g of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro - 1H-1-benzazepin-1-yl)carbonyl]benzanilide in a mixed solvent consisting of 120 ml of chloroform and 15 ml of ethyl acetate, the resulting solution was mixed with 2.95 g of copper bromide (II), and was subjected to reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, was filtered, the insoluble materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, the Yu (500 mg) obtained in this foamy substance was dissolved in 150 ml of chloroform, and the resulting solution was mixed with 900 mg of potassium carbonate and 1.3 g of 3-phthalimidopropyl 1/2 carbonate obtained in reference example 13, and subjected to 16-hour reflux. After the reaction solution to room temperature, removed by filtration of insoluble materials. The resulting filtrate was mixed with saturated aqueous sodium bicarbonate. The obtained organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After distillation under reduced pressure of the solvent, the obtained residue was subjected to column chromatography on silica gel, resulting in a received 221 mg 4'-[(2-(2-phthalimidomethyl)-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepin-6-yl]carbonyl]-2-phenylbenzene from the eluate chloroform-methyl alcohol (50:1).

Physico-chemical properties:

MC (FAB): 658 (M++ 1).

Reference example 17

After the dissolution of 3.03 g of 2-phenyl-4'-[(5-oxo-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide in a mixed solvent consisting of 120 ml of chloroform and 15 ml of ethyl acetate, the resulting solution was mixed with 2.95 g of copper bromide and subjected to reflux for 3 hours preemie materials. The obtained filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. Using 500 mg of the resulting foam substances and 1.758 g of 4-phthalimidobutyl 1/2 carbonate obtained in reference example 14, as starting materials, repeating the procedure as in reference example 16, and the received 389 mg 4'-[(2-(3-phthalimidopropyl)- 1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl]carbonyl]- 2-phenylbenzene.

Physico-chemical properties:

MC (FAB): 672 (M++ 1).

Reference example 18

After the dissolution of 3.03 g of 2-phenyl-4'-[(5-oxo-2,3,4,5 - tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide in a mixed solvent consisting of 120 ml of chloroform and 15 ml of ethyl acetate, the resulting solution was mixed with 2.95 g of copper bromide and subjected to reflux for 3 hours under vigorous stirring. After the reaction solution to room temperature, was filtered, the insoluble materials. The obtained filtrate was washed with a saturated aqueous solution bicarbonat pressure and then evaporated to dryness using a vacuum pump. Using 500 mg of the resulting foam substances and 1.424 g 5-phthalimidomethyl 1/2 carbonate obtained in reference example 15, as starting materials, repeating the procedure as in reference example 16, and the result was 316 mg 4'-[(2-(4-phthalimidobutyl)- 1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl]carbonyl] - 2-phenylbenzene.

Physico-chemical properties:

MC (FAB): 686 (M++ 1).

Reference example 19

In a stream of argon was dissolved in 10 ml of tetrahydrofuran, 60% sodium hydride, and the resulting solution was mixed with 2.0 g of benzylcyanide, stirred 1 hour at room temperature, even mixed with 3.69 g of 1,4-dibromobutane and the mixture was stirred 16 hours at room temperature. The reaction mixture was mixed with water and ethyl acetate, separating the resulting organic layer was washed its saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure the resulting residue was subjected to column chromatography on silica gel, hexane and the resulting eluate was mixed with 45 ml of sulfuric acid and within 24 hours was heated under reflux. the value of the aqueous layer, which is then mixed with concentrated hydrochloric acid and ethyl acetate, and the obtained organic layer was separated, washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removing the solvent by distillation under reduced pressure, received 978 mg 1-phenylcyclohexanecarboxylic acid.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS):

1.84-2.08 (8H, m), 7.21-7.45 (4H, m).

MC (EI): 190 (M+).

Reference example 20

Using 2.0 g of benzylcyanide and 3.9 g of 1,5-dibromethane, repeating the procedure of reference example 19 and the result was 980 mg 1-phenylcyclohexanecarboxylic acid.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS):

1.26-1.87 (10H, m), 7.22-7.52 (4H, m).

MC (EI): 204 (M+).

Reference example 21

In 20 ml of dichloromethane was mixed 978 mg 1-phenylcyclohexanecarboxylic acid obtained in reference example 19, with 0.7 ml of oxanilide and was stirred for 1 hour in an ice bath. After removal of the solvent, the obtained residue was dissolved in 10 ml of dichloromethane and added to 20 ml dichlormethane was stirred 3 hours at room temperature. The resulting reaction solution was mixed with saturated aqueous sodium carbonate to separate the organic layer, which was then washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Removing the solvent by distillation under reduced pressure, the obtained residue was subjected to column chromatography on silica gel, and as a result received 759 mg of 1-[4-(1 - vinylcyclopentane-1-yl)aminobenzoyl] -5-oxo-2,3,4,5-1H-1-benzazepine from the eluate chloroform-methyl alcohol (50 : 1).

Physico-chemical properties:

MC (FAB): 453 (M++ 1).

Reference example 22

Using 980 mg 1-phenylcyclohexanecarboxylic acid and 1.2 g of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-she as starting materials, repeated the procedure of reference example 21, and as a result received 1.453 g of 1-[4-(1-phenylcyclohexane-1-yl) aminobenzoyl]-5-oxo-2,3,4,5-1H-1-benzazepine.

Physico-chemical properties:

MC (FAB): 467 (M++ 1).

Reference example 23

After dissolution 2.966 g (1-(4-nitrobenzoyl)-2,3,4,5 - tetrahydro-1H-1-benzazepin-5-it is in a mixed solvent consisting of 925 ml of chloroform and 9.2 ml of ethyl acetate, the resulting solution was mixed with 5.34 g brome adiv the reaction solution to room temperature, was filtered, the insoluble materials and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. Obtained solid substance was dissolved in 250 ml of chloroform, and the resulting solution was mixed with 10.5 g of potassium carbonate and 5.12 g of acetamidomalonate and subjected to 20-hour reflux. After the reaction solution to room temperature, removed by filtration of insoluble materials, and the obtained filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distillation under reduced pressure of the solvent, the obtained residue was subjected to column chromatography on silica gel, resulting in a received 2.077 g of 6-(4-nitrobenzoyl)-2-methyl-1,4,5,6-tetrahydroimidazo [4,5-d] [1] benzazepine from the eluate chloroform-methyl alcohol (30:1)

Physico-chemical properties:

MC (FAB): 349 (M++ 1).

Reference example 24

In a stream of argon suspended 144 mg of a 60% nagpra cooling in an ice bath) solution, obtained by dissolving 500 mg of 6-(4-nitrobenzoyl)-2-methyl - 1,4,5,6-tetrahydroimidazo-[4,5-d][1] benzazepine in 20 ml of N,N-dimethylformamide. After 1 hour stirring at room temperature the reaction solution was mixed with 0.11 ml under the conditions and stirred 24 hours at room temperature. Mixed reaction solution with water and chloroform, and the obtained organic layer was separated, washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent by distillation under reduced pressure, the obtained residue was subjected to column chromatography on silica gel, resulting in 351 mg of 6-(4-nitrobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepine from the eluate chloroform-methyl alcohol (30:1).

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS): 2.37 (3H, s), 2.85 - 2.90 (1H, m), 3.12 (1H, m), 3.36 - 3.51 (1H, m), 3.59 (3H, s), 5.14 - 5.17 (1H, DD), 6.57 (1H, d), 6.83 (1H, t), 7.22 - 7.26 (3H, m), 7.92 (2H, d), 7.26 (1H, d).

MS (FAB): 303 (m++ 1).

Reference example 25

In 50 ml of methyl alcohol was dissolved 1.421 g of 6-(4-nitrobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d][1] benzazepine, and the resulting solution was mixed with 300 mg of palladium on coal is literaly and the obtained filtrate was concentrated, receiving 571 mg of 6-(4-aminobenzoyl)-2,3-dimethyl-3,4,5,6 - tetrahydroimidazo[4,5-d] [1]benzazepine.

Physico-chemical properties:

MC (FAB): (M++ 1).

Example 35

In 10 ml of methyl alcohol was dissolved 392 mg 4'-[(2-(2-phthalimidomethyl)-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)carbonyl]-2-phenylbenzene obtained in reference example 16, and the resulting solution was mixed with 10 ml of a solution of methylamine methyl alcohol and stirred at room temperature for 4 hours. The reaction solution was mixed with chloroform and 1 N. hydrochloric acid for the separation of the aqueous layer, which was then mixed with chloroform and neutralized 1 N. sodium hydroxide to separate the organic layer. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then solvent was removed by distillation under reduced pressure. The residue was dissolved in a small volume of ethyl acetate and mixed with a mixture of 4 N. hydrochloric acid-ethyl acetate, and after washing the resulting precipitate with ethanol received 70 mg 4'-[(2-(2-aminoethyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1] benzazepin-6-yl)carbonyl]-2-phenylbenzo DMSO-d6, internal standard TMS): 1.44 - 1.64 (3H, m), 2.06 - 2.11 (2H, m), 2.26 - 2.30 (2H, m), 4.96 (1H, m), 6.86 - 7.58 (total 17H), 8.14 (1H, d), 15.0 (1H, Shir.).

MC (FAB): 528 (M++ 1).

Example 36

Using 389 mg 4'-[[2-(3-phthalimidopropyl)-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl] carbonyl] -2-phenylbenzene obtained in reference example 17, as the source material, repeating the procedure of example 35, and the obtained product was subjected to recrystallization from a mixture of ethyl acetate-ethyl alcohol, resulting in 90 mg 4'-[[2-(3-aminopropyl)-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl] carbonyl]-2-phenylbenzene 2HCl.

Physico-chemical properties:

Melting point 220 - 223oC,

Elemental analysis data (C34H31N5O22HCl 3H2O):

Calculated,%: C, 60.79, H 5.88, N 10.37, Cl 10.60

Found,%: C at 60.51, H 5.76, N 9.94, Cl 10.30

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

1.44 - 1.64 (3H, m), 2.14 - 2.17 (2H, m), 3.40 - 3.45 (4H, m), 4.96 (1H, m), 6.82 - 7.54 (total 17H), 8.14 (1H, d), 15.0 (1H, Shir.).

MC (FAB): 542 (M++ 1).

Example 37

Using 316 mg 4'-[[2-(3-phthalimidobutyl)-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl] carbonyl] -2-phenylbenzene obtained in reference example 18, as the source is idazo[4,5-d] [1] benzazepin-6-yl]carbonyl]-2-phenylbenzene 2HCl in the form of amorphous powder.

Physico-chemical properties:

Purity after HPLC: > 90% (TOSOH ODS-80T).

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

1.20 - 1.26 (2H, m), 1.44 - 1.64 (3H, m), 2.14 - 2.17 (2H, m), 3.40 - 3.43 (4H, Shir), 4.99 (1H, m), 6.86 - 7.58 (total 17H), 8.14 (1H, d), 15.0 (1H, Shir.).

MC (FAB): 556 (M++ 1).

Example 38

After the dissolution of 726 mg of 1-[4-(1-vinylcyclopentane-1-yl)- carboxybenzoyl] -5-oxo-2,3,4,5-1H-1-benzazepine obtained in reference example 21, in a mixed solvent consisting of 35 ml of chloroform and 4 ml of ethyl acetate, the resulting solution was mixed with 717 mg of copper bromide and subjected to reflux for 1 hour under vigorous stirring. After the reaction solution to room temperature, was filtered, the insoluble materials and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and then was evaporated to dryness using a vacuum pump. Obtained solid substance was dissolved in 50 ml of chloroform, and the resulting solution was mixed with 1.6 g of potassium carbonate and 780 mg acetamidomalonate and subjected to 20-hour heated with education is workie materials, and the obtained filtrate was washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distillation under reduced pressure of the solvent, the obtained residue was subjected to column chromatography on silica gel, eluate chloroformmethanol alcohol (30:1) were mixed in ethyl acetate) with a mixture of 4 N. hydrochloric acid-ethyl acetate, and then the residue obtained after removal of the solvent, recrystallized from ethanol, and the result was 181 mg of N-[4-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d][1] benzazepin-6-yl)carbonyl]phenylcyclopropanecarboxylic.

Physico-chemical properties:

Melting point 213-216oC.

Elemental analysis data (C31H30N4O2HCl 2.5 H2O):

Calculated,%: C, 65.08, H 6.34, N 9.79, Cl 6.20

Found,%: C, 65.09, H 5.98, N 9.73, Cl 6.28

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

1.54 - 1.64 (8H, m), 1.90 - 2.00 (1H, m), 3.68 (3H, s), 2.97 - 3.12 (2H, m), 4.99 (1H, m), 6.82 - 7.41 (total 13H), 8.08 (1H, d), 14.6 (1H, Shir.).

MC (FAB): 491 (M++ 1).

Example 39

Using 1.38 mg of 1-[4-(1-phenylcyclohexane-1-yl)carboxamidates]-5-oxo - 2,4,5,6-1H-benzazepine,38, and as a result received 877 mg of N-[4-[(2-methyl-1,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-6-yl) carbonyl] phenyl]-1-phenylcyclohexanecarboxylic.

Physico-chemical properties:

Melting point 222-225oC.

Elemental analysis data (C32H32N4O2HCl 1.4 H2O):

Calculated,%: C, 67.87, H 6.37, N 9.89, Cl 6.26

Found, %: C, 67.53, H 6.76, N 9.64, Cl 6.21

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 1.27 - 1.73 (10H, m), 1.90 - 2.00 (1H, m), 3.68 (3H, s), 2.97 - 3.12 (2H, m), 4.99 (1H, m), 6.82 - 7.41 (total 13H), 8.08 (1H, d), 14.6 (1H, Shir.).

MC (FAB): 505 (M++ 1).

Example 40

In 30 ml of dichloromethane was dissolved 512 mg on-vinylbenzoic acid, and the resulting solution, cooling in an ice bath, mixed with 0.45 ml of oxanilide and was stirred for 1 hour. After removal of the solvent under reduced pressure the resulting residue was dissolved in 10 ml of dichloromethane and stirring at Delaney bath, was added dropwise to 30 ml of dichloromethane solution containing, 571 mg of 6-(4-aminobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4.5-d] [1]benzazepine and 0.72 ml of triethylamine. After warming up to room temperature, the reaction solution was stirred for 6 hours. The resulting reaction Rustem washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Removing the solvent by distillation under reduced pressure, subjected the resulting residue column chromatography on silica gel, the resulting eluate chloroformmethanol alcohol (30:1) was mixed with a mixture of 4 N. hydrochloric acid-ethyl acetate, after which the residue obtained after distillation of the solvent was recrystallized from a mixture of ethanol-diethyl ether, which resulted in 230 mg of 4'-[(2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4.5-d] [1] benzazepin-4-yl] carbonyl]-2-phenylbenzimidazole.

Physico-chemical properties:

Melting point 195-198oC.

Elemental analysis data (C33H28N4O21.1 HCl 2.8 H20):

Calculated,%: C, 65.71, H 5.80, N 9.29, Cl 6.47

Found,%: C, 65.73, H 5.61, N 9.82, Cl 6.96

1H-NMR ( M. D. in DMSO-d6, internal standard TMS): 2.37 (3H, s), 2.85 - 2.90 (1H, m), 3.12 (1H, m), 3.36 - 3.51 (1H, m), 3.59 (3H, s), 5.14 - 5.17 (1H, Shir), 6.72 - 7.57 (total 17H), 8.02 (1H, d).

MC (FAB): 513 (M++ 1).

Reference example 26

In 15 ml of methylene chloride was dissolved 3.0 g of o-vinylbenzoic acid, and the resulting solution was added under cooling in an ice bath catalytically effective amount of dimethylformamide and 1.98 g of thionyl chloride. After a gradual poëles what drove under reduced pressure the solvent. The obtained residue was mixed with 15 ml of benzene and again concentrated under reduced pressure. Obtained oily material was dissolved in 20 ml of acetone and mixed, while cooling in an ice bath, with 2.08 g of p-aminobenzoic acid and 2.02 g of N,N-dimethylaniline, after which the resulting mixture was gradually warmed to room temperature. After 1.5 hours stirring at this temperature, the reaction solution was mixed with 20 ml of water, and the precipitated residue was filtered. Drying it under reduced pressure, got 4.52 g of 4-(difen-2-incarnational)benzoic acid as a white crystalline powder.

Physico-chemical properties:

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

7.28 - 7.61 (9H), 7.66 (2H, d), 7.86 (2H, d), 10.57 (1H, s).

MC (E1): 317 (M+).

Reference example 27

In 5 ml of methylene chloride was dissolved 500 mg of 4-(difen-2-incarnational)benzoic acid, and the resulting solution was added under cooling in an ice bath catalytically effective amount of dimethylformamide and 220 mg of oxalicacid. After gradually warming up to room temperature the reaction mixture was stirred at this temperature for 1.5 hours, then drove under eigenem pressure. Obtained oily material was dissolved in 5 ml of methylene chloride to obtain a solution of the acid chloride.

Cooling in an ice bath, this resulting solution of the hydrochloride was added to 2.5 ml methylenchloride solution containing 254 mg of 5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 149 mg of pyridine. After gradually warming up to room temperature the reaction mixture was stirred at this temperature for approximately 2 hours. The resulting reaction solution was mixed with 5 ml of methylene chloride and 10 ml of water to separate the organic layer, which was then washed with 10 ml of diluted hydrochloric acid and 10 ml of 5% aqueous sodium carbonate solution. After concentrating the organic layer under reduced pressure the resulting amorphous powder was subjected to column chromatography on silica gel (eluent was a mixture of methylene chloride : ethyl acetate = 6 : 1) to capture fractions containing the target compound, and then drove from fractions of solvent, got 530 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide in the form of amorphous powder.

Physico-chemical properties:

1H-NMR ( M. D. in CDCl3, internal standard TMS):

2.1 the on-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl] benzanilide in 40 ml of chloroform, the resulting solution was mixed with 1.92 g of perbromide of pyridinesulfonamide and stirred at 40oC for 60 minutes. After cooling to room temperature the reaction solution was washed twice with water and then dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was dissolved in 120 ml of chloroform, and the resulting solution was mixed with 2.7 g of acetamidomalonate and 5.52 g of potassium carbonate and subjected to 20-hour reflux in a stream of argon. The resulting reaction solution was mixed with water and subjected to phase separation to separate the chloroform layer was then dried over anhydrous magnesium sulfate. After removal of the solvent, the obtained residue was recrystallized from methyl alcohol, resulting in 2.09 g of 4'[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl) carbonyl] -2-phenylbenzene. This connection has led from 31.5 ml of ethyl alcohol and 27.2 ml of 1 N. hydrochloric acid, which gave crude crystals ( crystal) 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl) carbonyl]-2-phenylbenzimidazole. These crystals are suspended in 45 ml of acetonitrile was heated under reflux for 30 minutes, cooled, filtered and dried, resulting in crude crystals ( -Crist who was lagali, was filtered and dried, which resulted in 1.6 g of 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1]benzazepin-6-yl) carbonyl]-2-phenylbenzimidazole in the form of crystals (crystal).

Physico-chemical properties (crystal):

Melting point

1H-NMR ( M. D. in DMSO-d6, internal standard TMS):

2.66 (3H, s), 3.00 (1H, t), 4.99 (1H, m), 6.89 (2H), 7.14 (1H, t), 8.02 (1H, d), 10.31 (1H, s), 14.6 (1H, Shir.).

MC (E1): 498 (M+).

Examples of the manufacture of dosage forms

Injection solutions

The composition of

Part 1:

The compound of the present invention is 1.5 mg

Lactic acid, 0.2 mg

Lactose - 200.0 mg

Distilled water for injection, 2.0 ml, in General

Part 2:

The compound of the present invention is 1.5 mg

Lactic acid, 0.2 mg

Glycerin with 52.0 mg

Distilled water for injection, 2.0 ml, in General

Approximately 300 ml of distilled water for injection containing 0.75 g of compound of the present invention and 0.1 g of lactic acid, was mixed with about 500 ml of distilled water for injection containing 100 g of lactose (or 26 g of glycerol), and the mixture was stirred. The contents of the resulting mixture was dissolved by heating the mixture at 6 is actor was filtered through a membrane filter, filled in 2 ml ampoules, which were then sealed and sterilized, and the solution in each vial contains 1.5 mg of the compound of the present invention.

Tablets

The composition of

[Tablet]

The compound of the present invention is 5.0 mg

Lactose and 73.2 mg

Corn starch - 18,3 mg

Hydroxypropylcellulose - 3.0 mg

Magnesium stearate 0.5 mg

Total - 100.0 mg

[Floor]

The hypromellose 2910 - 2.5 mg

Polyethylene glycol 6000 0.5 mg

Talc - 0.7 mg

The titanium oxide - 0.3 mg

Total - 4.0 mg

A total 104,0 mg

25 g of compound of the present invention was mixed with 366 g of lactose, and crushed into a powder using a grinding device Sample Mill (production F. "Hosokawa Micron"). After uniform mixing 391 grams of this powdered mixture with 91.5 g of corn starch was carried out by granulating the mixture by spraying it 150 g of a 10% aqueous solution of hydroxypropylcellulose in a granulating machine fluidized bed (production F. "Okawara Mfg."). After drying the obtained granules were passed through a sieve of 24 mesh, was mixed with 2.5 g of magnesium stearate and then extruded into tablets each weighing 100 mg) on a rotary tablet machine (made in the obtained tablets were sprayed 154 g of an aqueous solution for coating, containing 12.5 g of hydroxypropylcellulose, 2.5 g of polyethylene glycol 6000, 3.5 g of talc and 1.5 g of titanium oxide, resulting in the obtained film-coated tablets, each of which contained 4 mg film coating and 5.0 mg of the compound of the present invention.

1. Derived benzazepine with condensed nitrogen-containing aromatic 5-membered ring or its salt of the General formula I

< / BR>
where the ring is nitrogen-containing aromatic 5-membered ring having at least 1 nitrogen atom and one oxygen atom or sulfur represented by the formula

< / BR>
where X1X3one of them is a group =N-, and the other is a group-NR5-, -O - or-S-;

X2group =CR6-;

R5is a hydrogen atom, a lower alkyl group;

R6-, a) a hydrogen atom; b) a lower alkyl group, unsubstituted or substituted by the following groups: amino, morpholinopropan, 1-piperazinilnom group, which optionally may be substituted by a lower alkyl group on the nitrogen atom of the ring, phenyl, imidazolidine, peredelnoj groups, which may optionally be substituted lower alkyl group; (C) cycloalkyl group having from 3 to 8 carbon atoms; (d) amine is ut optionally be substituted amino group; mono - or di - lower alkylaminocarbonyl; piperidino; morpholino group; or 1-piperazinilnom group, which optionally may be substituted by a lower alkyl group); (e) guanidinium or (f) a hydroxyl group, a lower CNS group, lower allylthiourea;

R1and R2the same and represent a hydrogen atom;

And is a single bond, a group represented by the formula

-NHCO-(CR3R4)n,

n = 0 or 1;

R3, R4may be the same or different and each represents a hydrogen atom, a lower alkyl group (provided that R3, R4may together form a lower alkylenes group having 2 to 7 carbon atoms);

the ring is a benzene ring which may have optionally from 1 to 5 substituents selected from the group: a) a lower alkyl group, b) unsubstituted lower alkoxygroup, C) halogen atom, (d) phenyl group, which optionally may be substituted by a lower alkyl group, and (e) imidazolidine group, which optionally may be substituted by a lower alkyl group.

2. Derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle or its salt is otvagnoe benzazepine with condensed nitrogen-containing aromatic 5-membered ring or its salt under item 1, where the specified ring is a benzene ring, unsubstituted or substituted lower alkyl substituted phenyl group.

4. Derived benzazepine under item 1, which is 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazol or its salt.

5. Derived benzazepine under item 1, which is 4'-[(2-ethyl-1,4,5,6-tetrahydroimidazo[4,5-d] [1] benzazepin-6-yl)carbonyl] -2-phenylbenzimidazol or its salt.

6. Derived benzazepine under item 1, which is 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazol or its salt.

7. Derived benzazepine under item 1, which is 4'-[(2-propyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzimidazol or its salt.

8. Pharmaceutical composition having antagonistic activity against Organisatorische containing an effective amount of a derivative benzazepine with condensed nitrogen-containing 5-membered ring or its salt, specified in paragraph 1, as an active ingredient and pharmaceutically acceptable carriers, diluents or excipients.

9. 4-(Biphenyl-2-ylcarbonyl)benzoic acid.

 

Same patents:

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

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

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

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

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

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

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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

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

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

(I)

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

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

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

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

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

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

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

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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

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

The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions
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