Derivatives of diazepinone, methods for their preparation and pharmaceutical composition

 

(57) Abstract:

Usage: in medicine, because they have antimuskarinovoe act occurs activity. The inventive product: derivatives of diazepinone formula I, where X is the group = CH or a nitrogen atom, if B denotes the divalent residue of the formula /a/, l = 1, 2, 3, m = 1, 2, n = 1 to 4, R1- H or C1-C6alkyl and the other Reagent 1: compound of formula II. Reagent 2: carboxylic acid. The pharmaceutical composition antimuskarinovoe act occurs with activity contains odnoprovodnoi of diazepinone formula I in an effective amount and a pharmaceutically acceptable carrier. 4 S. p. f-crystals, 2 tab.

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl A carbon unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or different and denote hydrogen atoms or halogen, or a methyl or ethyl group, metoxygroup or ethoxypropan,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action.

New derivatives of diazepinone General formula (I) can be obtained with known methods, for example, by the following reactions.

a) Substituted basis, condensed diazepinones General formula (II)

< / BR>
in which X, B, l, m, n and R1have the above values,

the defined values

or its reactive derivative.

As a reactive carboxylic acid derivative of General formula (III) include, for example, its esters, such as, for example, it is difficult methyl, ethyl or benzyl ester, its difficult thioethers, such as its complex methylthioethyl or Utilitaire, its galodamadruga, for example the acid chloride, anhydrides or imidazolides.

Interaction expediently carried out in an environment of solvent such as methylene chloride, chloroform, carbon tetrachloride, simple ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, if necessary in the presence of activating acid agent or a dehydrating agent, for example in the presence of a complex of ethyl ether Harborview acid, thionyl chloride, phosphorus trichloride, palpations phosphorus, N,N'-dicyclohexylcarbodiimide, N-oxysuccinimide and N,N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole or N,N'-conidiomata or triphenylphosphine in carbon tetrachloride, and if necessary in the presence of inorganic bases such as, for example, sodium carbonate, or tertiary organic bases and temperatures from -25oC to 150oC, but preferably at a temperature of from -10oC to the boiling point of the used solvent. The interaction can also be carried out without solvent. Furthermore, formed in the interaction of water can be removed by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves.

For example, the interaction can be done with halogenerator acid in an inert solvent, for example a simple ether, toluene, methylene chloride or etc., at a temperature of from -50oC to the boiling point of the reaction mixture, preferably from 0oC to 50oC and preferably in the presence of binding halogenation agent, for example a tertiary amine, sodium carbonate or calcium. You can use not only the free amines of General formula (II), and their salts, which are in situ under the influence of the added auxiliary bases give amines.

The interaction is carried out, for example, at a temperature of phlegmy in the presence imidazoline or carbodiimide and a solvent having a high boiling point, for example in the environment will xiaodonghai the acylation derivative of carboxylic acid of General formula (V)

< / BR>
in which l, m, n, R1and R2have the above values, and

Nu means nucleofuge group or tsepliaeva group.

The interaction of compounds of General formula (IV) with a derivative of the acid of General formula (V) is carried out in a generally known methods. Tsepliaeva group Nu is a group which together with the carbonyl group to which it is linked, forms a reactive carboxylic acid derivative. As reactive derivatives of carboxylic acids include, for example, galodamadruga acid, its esters, anhydrides or mixed anhydrides formed from salts of the corresponding acids (Nu OH) and anhydrides of the acids, for example phosphorus oxychloride, tetrachlorinated diphosphorous acid or esters Harborview acid, or salts of N-alkyl-2-acroceridae formed by the interaction of compounds of General formula (V) (Nu OH) with salts of N-alkyl-2-halogenopyrimidines.

Preferably the interaction of exercise with mixed anhydrides of strong mineral acids, in particular dichlorophosphino acid. If necessary, the interaction is carried out in the presence of an acid binding agent (acceptor, proo metal, as, for example, sodium carbonate or potassium bicarbonate, tertiary organic amines such as pyridine, triethylamine, ethyldiethanolamine, 4-(dimethylamino)pyridine, or sodium hydride. The interaction is carried out at a temperature of from -25oC to 130oC in inert solvent. As the inert solvent can be used, for example, chlorinated aliphatic hydrocarbons such as methylene chloride or 1,2-di-chlorate, ethers, open-chain or cyclic ethers, such as, for example, a simple diethyl ether, tetrahydrofuran or 1,4-dioxane, aromatic hydrocarbons such as benzene, toluene, xylene or o-dichlorobenzene, polar aprotic solvents such as acetonitrile, dimethylformamide or triamide hexamethylphosphoric acid, or mixtures thereof. Depending on the type and quantity of used acylation agent of General formula (V) response time varies between 15 minutes and 80 hours. There is no need to obtain compounds of General formula (V) in pure form, they can in a known manner to obtain in situ.

Thus obtained the Foundation of the General formula (I) can then be translated into their acid additive salt, or received acid-addition the E. of salt.

The proposed new condensed diazepinones General formula (I) contain up to two independent chiral carbon atom. As a further chiral element you should consider himself acylated tricycle, which can exist in two forms, one form is similar to the mirror image of the other. From the properties of the tricycle depends on the answer to the question whether the limit of energy for inversion at this center is so high that the individual isomers are stable at room temperature and that they can be clearly identified. It turned out that in the compounds of General formula (I) in which X represents a nitrogen atom and which is unsubstituted in the positions adjacent to diazepinone ring, the activation energy is reduced so that at room temperature the presence of diastereomers is not possible to prove, and their separation impossible.

Thus, the proposed new condensed diazepinones General formula (I) contain up to three chiral elements, and one of them may be unstable at room temperature configuration. Therefore, such compounds can exist in different diastereomeric forms and/or as an enantiomeric (+)- and (-)-forms. The present invention relates to individual some the properties, for example, by fractional recrystallization from a suitable solvent by liquid chromatography under pressure, chromatography on a column or gas chromatography.

Separation may resulting racemates of compounds of General formula (I) can be accomplished by known techniques, for example using an optically active acid, such as tartaric acid, ( + ) - or (- ) form or its derivative, for example diatsetilvinny acid or monomethylfumarate (+)- or (- ) form or camphor sulfonic acids (+)-form.

According to a known method of separating isomers of a racemate of compounds of General formula (I) is subjected to interaction with equimolar amounts of one of these optically active acids in the environment of the solvent, and the resulting crystalline diastereomeric salt separated due to their different solubility. This interaction can be realized in the environment of any solvent in which the solubility of salts is sufficiently different. It is preferable to use methanol, ethanol or their mixture, for example, in a volume ratio of 50 to 50. After that, each of the diastereomeric salts is dissolved in water and neutralized by adding a base, for example, ptx2">

Only one enantiomer or a mixture of two optically active diastereomeric compounds of General formula (I) obtained by the above-described synthesis with only one corresponding enantiomer.

The original compound of General formula (II) can be obtained, for example, as follows:

(Aminoalkyl)pyridine of General formula (VI)

< / BR>
in which n and R1have the above values (such compounds are known from the literature, and partly they can be purchased in trade),

in a known manner is subjected to interaction with tert.butoxycarbonyl, resulting in a gain of compounds of General formula (VII)

< / BR>
The catalytic hydrogenation of these compounds by known methods, for example in ethanol solution of hydrochloric acid and acetic acid, in the presence of platinum oxide (IV) are compounds of General formula (VIII)

< / BR>
This connection is then subjected to interaction with halogenation General formula (IX)

< / BR>
in which X, B and m have the above meanings, and

Nal means chlorine atom, bromine or iodine.

Specified amination is carried out in an inert solvent at a temperature of from -10oC to the boiling point of impolitely (VIII), or with 1-2 mol Deut. amine of General formula (VIII), and in the presence of an auxiliary base. In General, the solvent can be used, for example, chlorinated hydrocarbons such as methylene chloride, chloroform or dichloroethane, ethers, open-chain or cyclic ethers, such as, for example, a simple diethyl ether, tetrahydrofuran or dioxane, aromatic hydrocarbons, such as benzene, toluene, xylene, chlorobenzene or pyridine, alcohols, such as ethanol or isopropanol, ketones, such as acetone, acetonitrile, dimethylformamide or 1,3-dimethyl-2-imidazolidinone. As an auxiliary base can be called, for example, tertiary organic bases, such as triethylamine, N-methylpiperidine, diethylaniline, pyridine and 4-(dimethylamino) pyridine, or inorganic bases, such as carbonates, bicarbonates, hydroxides or oxides of alkali or alkaline-earth metals. If necessary, the reaction can be accelerated by adding an alkali metal iodide.

You get a connection General formula (X)

,

in which the residues B, X, R1, m and n have the above values,

from which by using, for example, the bro who headed the remainder of that resulting in the receive connection of General formula (II).

Suitable activated carboxylic acid of formula (III) are obtained by known techniques in the reaction mixture.

Diazepinone General formula (IV) are known from the literature.

Derivatives of carboxylic acids of General formula (V), where Nu denotes CNS group, produced by the interaction of the substituted piperidino obla formula (VIII) with the corresponding esters of halogenecarbonate, if necessary, using additional auxiliary bases, such as triethylamine, or catalysts, for example Triton B. the result of the saponification of the resulting ester, such as barite water, get a carboxylic acid of General formula (V), where Nu denotes a hydroxyl group. Thus obtained carboxylic acid are used as starting compounds to obtain derivatives containing other nucleofugal group, for example, golodnikov acid of formula (V).

Further objects of the invention are drugs, containing at least one derivative of diazepinone General formula (I), a mixture of its isomers or its individual isomers Il the m transfer in conventional pharmaceutical preparations, for example, solutions, suppositories, tablets, pills, capsules or tea preparations. The dose usually is 0.02 to 5 mg, preferably of 0.02 to 2.5 mg, in particular of 0.05 to 1.0 mg of active substance per 1 kg of body weight per day, and, if necessary, to achieve the desired effect of a given dose given several, preferably 1 to 3 portions.

New diazepinone General formula (I) and their acid additive salts possess valuable properties. For example, they are best selectivity for the receptor M2heart, and therefore can be used as vagal regulators rhythm for the treatment of bradycardia and bradyarrhythmia in medicine and veterinary.

Research van Halldora and fan Tsvetana (see K. Th. van Geldorp, thesis: "Characterization of Muscarinic Receptors in the Vascular System", Amsterdam, 1988; K. Th. van Geldorp, D. Davidenko and P. A. van Cvitan, Eur. J. Pharmacol, No 150, pages 197 to 199, 1988; K. Th. van Geldorp and P. A. van Cvitan, Naunyn Schmiedeberg''s Arch. Pharmacol. No 339, pp. 403 408, 1989) showed that muscarinic receptors in the basal arteries responsible for the contraction of blood vessels, are receptor type M2. Therefore, we can assume that antagonists of M2reduce the tone of cerebral blood vessels and, thus, with the s receptor leads to the prevention of sdavleni and to improve or normalize caused by arteriosclerosis of circulatory disorders in the brain. The proposed new connection is especially suitable for improvement or normalization caused by arteriosclerosis of circulatory disorders in the brain.

A series of compounds of General formula (I) due to the high lipophilia shows a good ability to pass through the Central nervous system and is therefore suitable for the treatment of Central nervous system diseases, in particular Alzheimer's disease. Senile dementia of Alzheimer's type degeneration of cholinergic neurons, in particular in the projections Amonov horns and cortical projections, leads to a decrease of the release of the neurotransmitter acetylcholine. Blocking the presynaptic autoreceptors leads to the break of the mechanism of the negative feedback that neurotransmitter carry on still intact neurons, and causes an increase in the release of acetylcholine, resulting in excitation of postsynaptic receptors (see D. C. Mash, D. L. Flynn, and L. T. Potter, No Science 228, pages 115 to 117, 1985; E. K. Perry, and others Can. J. Neurol. Sci. No 13, page 521 527, 1986; M Sarter and other TINS, No 11, pp. 13 17, 1988). Thus, the proposed compounds suitable for use in geriatrics and significantly increase the ability to learn and improve memory.

In D. the surveys by binding to muscarinic receptors

Rats-males kind of Wistar type Chbb: strain THOM weighing 180 to 220 g were killed by a blow to the head. Selected the cerebral cortex, heart, and salivary gland, which was washed and homogenized in a 20-fold volume of HEPES buffer (20 mm 4-(2-oxyethyl)-1-piperazineethanesulfonic, 100 mm sodium chloride, 10 mm magnesium chloride, pH 7.5) using a centrifuge brand Ultra-Turrax at maximum speed, component 60 g. The resulting homogenizate was diluted to a concentration of 1 to 500, in terms of the original amount of tissue. To study the binding of 1Nm [3H]pirenzepine (3,22 thousand becquerels per mmol), bind to receptors M1cortex, and 0.3 nm [3H] HMC (3H-N-methylscopolamine) (2,64 thousand becquerels per mmol), bind to receptors of the heart and salivary glands were incubated at room temperature together with of 0.35, 0.30 0.20 mg of protein per sample (0.5 ml) of the heart, salivary gland and cerebral cortex. With [3H]pirenzepinom were incubated for 90 minutes, and with [3H]HMC - within 40 minutes. The concentration of protein was determined by the method of Lowry and others (J. Biol. Chem. No 93, page 265). The incubation was ended by rapid filtration through the Mat of glass fibers. Double-washed for 10 Sekou is giving night was shaken with 4 ml of scintillation fluid, and the scintillation read device brand Packard C. All experiments were performed 3 times. Nonspecific binding was defined as the radioactivity that was contacted in the presence of 1 μm (-)-3-hinokitiol-benzilate. Data binding was analyzed using the computer by nonlinear analysis according to the method of "least-square curve fitting" (see Heinzel, , 1982, Pharmacokinetics during Drug Development: Data Analysis and Evaluation Techniques, edited by G. Boltser and Th. M. van Rossum, publisher Gustav-Springer-Verlag, page 207). Dissociation constants (KD) were calculated on the basis of the CT values50according to Chaney and Prusoff (Biochem. Pharmacol. No 22, page 3099, 1973). The results are shown in table 1.

B: Study raise the blood pressure action

A principle.

Arecoline has and can raise the blood pressure effects (Central action), and blood pressure-lowering effect (peripheral action). Peripheral effect of block N-methylscopolamine, due to which there is only the Central effect of arecoline. With the ability to pass in the brain antimuskarinovoe act occurs substances block this Central effect.

Method.

Rats-males weighing 300 g narcoticyou intraperitoneal giving urethane in to oxygen (80 times per minute). Blood pressure after insertion of the cannula in the carotid artery is recorded by a pressure sensor mark bell and Howell type 4-327-I. the compounds appliciruut through the jugular vein, namely in the amount of 0.5 mol per kg of Prior experience animals given 0.5 mg / kg of N-methyl-scopolamine. The application of arecoline (each time 0.3 mg per kg of body weight) carried out every 15 minutes. After receiving two comparative data analyzed connection give by injection of increasing doses, each time for 5 minutes before re-application of arecoline.

The results obtained were compared with the average value of the original data, and they are determined in braking. Get experience with the use of arecoline data are shown in table 2.

In the above-described methods investigated, for example, the following compounds of formula (I):

And 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino]-propyl]-1-piperidinyl]acetyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

B 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino]-propyl] -1-piperidinyl]acetyl]-6N-pyrido[2,3 - b][1,4]benzodiazepin-6-he

In 5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxobutyl)ethylamino]butyl]-1-piperidinyl]acetyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

G of 5,11-dihydro-8-chloro-11 D 5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl)-ethylamino] -propyl]-1-piperidinyl]acetyl-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

E 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1 - oxopropyl)ethylamino]propyl] -1-piperidinyl]acetyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

W 5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] propyl]-1-piperidinyl]acetyl]-6N-pyrido[2,3-b][1,4]benzodiazepine-6-he

These compounds were compared with the known compound 3 (U.S. patent N 4550107, class A 61 K 31/55; C 07 D 521/00, 1985) and with the known compounds I-K (application EP-A2-0402734, class A 61 K 31/55, 1990).

C 11-[[2-[(diethylamino)methyl]-1 - piperidinyl]acetyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

And ()-9-chloro-11-[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro-6H-pyridine[2,3-b][1,4]benzodiazepine-6-he

Th Methanesulfonate 5,11-dihydro-11-[[[2-[2-[(dipropylamino)methyl]-1-piperidinyl]ethyl]amino]carbonyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-it

To 5,11-dihydro-11-[1-oxo-6-(1-piperidinyl)-1-hexyl]-6H-pyrido[2,3-b] [1,4]-benzodiazepine-10-he

The results are shown in the following tables 1 and 2.

Shown in table 1 data show that new connections And W have extreme selectivity of M1/M2in the range of 10 35. This ratio means that the corresponding compounds possess high selectivity M2and thus, they are capable of is s M1. In contrast to this, comparative compounds C To have only vaguely pronounced selectivity of M1/M2with a ratio of selectivity <6,6. A comparison of the selectivity shows that new diazepinone General formula (I) have clear advantages over the comparative compounds.

An important condition for the applicability of the compounds for treating diseases of the Central nervous system lying about their ability to pass through the brain. The above experience is by definition the ability to pass through the Central nervous system clearly shows that new connections And W is capable of braking the Central effect caused by arecoline (see table 2). This is only possible due to good ability to pass through the Central nervous system. In contrast to this studied comparative compounds C - K having values of the ED50>10 mg/kg (intravenous), do not show any effect on the high blood pressure caused by arecoline. This clearly proved that the known compounds have significantly less ability to pass on the Central nervous system.

The following examples illustrate how the proposed method.

P3-b][1,4]-benzodiazepine-6-he

1.48 g (0.01 mol) of acid chloride of 2,2-dimethylmaleic acid, dissolved in 20 ml of tetrahydrofuran, with stirring and at ambient temperature drops added to a solution of 4.2 g (0.01 mol) of 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl-6H - pyrido[2,3-b][1,4]benzodiazepine-6-it and 2 ml of triethylamine in 150 ml of tetrahydrofuran. For completion of the reaction solution further stirred at a temperature of 50oC for one hour. After cooling, is filtered off from the precipitated hydrochloride of triethylamine, and the filtrate concentrated to dryness in a rotary evaporator created using water-jet pump vacuum. For purification, the residue is dissolved in ethyl ether complex of acetic acid. The resulting solution was shaken twice with 10% hydrochloric acid, the organic phase is separated and the aqueous phase is alkalinized by addition of concentrated ammonia. Then the aqueous phase is twice extracted with complex ethyl ester of acetic acid. The organic phase is dried over sodium sulfate and vacuum concentrated to dryness. The resulting residue was dispersed in the environment of complex ethyl ester acetic acid, resulting in crystallization. Get colorless crystals with a melting point of 136 138oC.

Yield: 62%

Example 3.

The dihydrochloride 5,11-dihydro-11-[[4-[3-[(4-methoxybenzoyl) ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3 - b][1,4]-benzodiazepine-6-it

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 4-methoxybenzoic acid. The free base is dissolved in ethyl ether complex of acetic acid and the hydrochloride precipitated by adding ethereal hydrochloric acid. As a result of recrystallization from ethanol obtain the desired compound in the form of colorless crystals with a melting point of 163 165oC (from ethanol).

Yield: 81%

Example 4.

The dihydrochloride 5,11-and

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride 3,4-dimethoxybenzoic acid. The free base is dissolved in ethyl ether complex of acetic acid and the hydrochloride precipitated by adding ethereal hydrochloric acid. The desired compound obtained as colorless crystals with a melting point of 160 162oC (from ethanol).

Yield: 78% of theory.

Example 5.

The dihydrochloride 5,11-dihydro-11-[[4-[3-[(phenylacetyl)ethylamino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-it.

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and phenylacetylide. The free base is purified by chromatography on silica gel (Merck, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester of acetic acid and methanol in the ratio of 98 to 2. The dihydrochloride is obtained by further processing of ethereal hydrochloric acid.

Yield: 24% of theory.

Colorless crystals with a melting point of 149 152oC (from ethanol).
The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she acetylchloride with yield 56% of theory.

Colorless crystals with a melting point of 178 180oC (complex ethyl ester of acetic acid).

Example 7.

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxo-propyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she carboxylic pavlinovoi acid with a yield of 61% of theory.

Colorless crystals with a melting point of 154 -155oC (complex ethyl ester of acetic acid).

Example 8.

5,11-dihydro-11-[[2-[2-[(benzoyl)methylamino] ethyl]-1-piperidinyl]acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

A mixture of 9.5 g (0,033 mol) of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b] [1,4] benzodiazepine-6-it is, of 9.8 g (0.04 mol) of 2-[2[(benzoyl)methylamino]ethyl] piperidine, of 4.2 g (0.04 mol) of sodium carbonate and 300 ml of acetonitrile is heated under reflux for 10 hours Then the reaction mixture is filtered and the filtrate is vacuum concentrated μm) using as eluent a mixture of methylene chloride, methanol, cyclohexane, ammonia and a complex ester of acetic acid in the ratio 68:15:15:2: 500.

Colorless crystals with a melting point of 115 -130oC.

Yield: 3.8 g (25% of theory).

Example 9.

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido [2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylvaleric acid with a yield of 62% of theory. Colorless crystals with a melting point of 138 to 140oC (from simple diethyl ether).

Example 10.

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxopropyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl)-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she carboxylic pavlinovoi acid with a yield of 77% of theory.

Colorless crystals with a melting point of 168 170oC (complex ethyl ester of acetic acid).

Example 11.

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino]-propyl] is 1 of 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4] benzodiazepine-6-she and the acid chloride of 2,2-dimethylmaleic acid with a yield of 36% of theory. Colorless crystals with a melting point of 173 and 174oC (from simple diisopropyl ether).

Example 12.

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino)] -propyl]-1-piperidinyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylvaleric acid with a yield of 70%

Colorless crystals with a melting point 172 173oC (complex ethyl ester of acetic acid).

Fumarate given target product has a melting point of 128 130oC.

Example 13.

5,11-dihydro-8-chloro-11-[[4-[3-[(cyclopropanecarbonyl)ethylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)drank]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4] benzodiazepine-6-she carboxylic cyclopropanecarbonyl acid with a yield of 76% of theory.

Colorless crystals with a melting point of 136 138oC (from a simple mixture of diethyl ether and complex ethyl ester of acetic acid).

Example 14.

5,11-dihydro-8-mate the Get analogously to example 1 from 5,11-dihydro-8-methyl-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-she carboxylic pavlinovoi acid with a yield of 23% of theory.

Colorless crystals with a melting point of 177 179oC (from acetonitrile).

Example 15.

5,11-dihydro-9-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-9-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl]-6H-pyrido[2,3-b][1,4] benzodiazepine-6-she and the acid chloride of 2,2-dimethylvaleric acid. Purify by chromatography on silica gel (Merck, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester of acetic acid and ammonia in the ratio of 10:0,1.

Yield: 48% of theory.

Colorless crystals with a melting point of 150 -152oC (from simple diethyl ether).

Example 16.

5,11-dihyro-9-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-9-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylmaleic acid. The basis purify by chromatography on silica gel (Merck, particle size of 30 to 60 μm) using cachestore.

Colorless crystals with a melting point of 123 -125oC (from simple diethyl ether).

Example 17.

5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H - pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-methyl-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl]-6H-pyrido [2,3-b] [1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylmaleic acid. Purify by chromatography on silica gel (Baker, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester of acetic acid and ammonia in the ratio of 10:0,1.

Yield: 41% of theory.

Colorless crystals with a melting point of 97 -99oC (complex ethyl ester of acetic acid).

Example 18.

5,11-dihydro-8-methyl-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11 - dihydro-8-methyl-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylvaleric acid. Purify by chromatography on silica gel (Baker, grain value 30 60 attachment 10:0,1.

Yield: 28% of theory.

Colorless crystals with a melting point of 83 -85oC (complex ethyl ester of acetic acid).

Example 19.

5,11-dihydro-8-chloro-11-[[4-[3-[(2,2-dimethyl-1-oxo-4-penten-1-yl)ethylamino] propyl-1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from the acid chloride of 2,2-dimethyl-4-pentenol acid and 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl]-6H - pyrido[2,3-b][1,4]benzodiazepine-6-it. Purify by chromatography on silica gel (Baker, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester acetic acid, methanol, cyclohexane and ammonia in the ratio of 8: 1:1:0,1.

Yield: 88% of theory.

Colorless crystals with a melting point of 157 -158oC (from simple diethyl ether).

Example 20.

5,11-dihydro-8-chloro-11-[[4-[3-[(cyclohexylcarbonyl)ethylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4] benzodiazepine-6-she carboxylic cyclohexanecarbonyl kiloe eluent complex mixture of ethyl ester of acetic acid, methanol, cyclohexane and ammonia in the ratio of 8:1:1:0,1.

Yield: 70% of theory.

Colorless crystals with a melting point of 162 -163oC (from simple diethyl ether).

Example 21.

5,11-dihydro-8-chloro-11-[[4-[3-[(1-oxobutyl)ethylamino] -propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she and valerianic acid chloride acid. Purify by chromatography on silica gel (Baker, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester acetic acid, methanol, cyclohexane and ammonia in the ratio of 8:1:1:0,1.

Yield: 73% of theory.

Colorless crystals with a melting point of 150 152oC (from simple diethyl ether).

Example 22.

5,11-dihydro-8-chloro-11-[[4-[3-[(1-oxobutyl)ethylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4] benzodiazepine-6-she carboxylic sour oil is escutia crystals with a melting point of 152 154oC (from simple diethyl ether).

Example 23.

5,11-dihydro-8-chloro-11-[[4-[3-(1-oxopropyl)ethylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4] benzodiazepine-6-she and propionic acid chloride acid. Purify by chromatography on silica gel analogously to example 21.

Yield: 77% of theory.

Colorless crystals with a melting point of 141 143oC (from porous diethyl ether).

Example 24.

5,11-dihydro-11-[[4-[3-[(1-oxopropyl)ethylamino] -propyl]-1-piperidinyl] acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and propionic acid chloride acid. Purify by chromatography on silica gel analogously to example 21.

Yield: 50% theory.

Colorless crystals with a melting point of 123 125oC (and simple diethyl ether).

Example 25.

5,11-dihydro-11-[[4-[3-[(1-oxobutyl)ethylamino] -propyl] -1-piperidinyl] acetyl]-6H-pyrido-[2,3)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she carboxylic acid oil. Purify by chromatography on silica gel analogously to example 21.

Yield: 61% of theory.

Colorless crystals with a melting point 174 175oC (from simple diethyl ether).

Example 26.

5,11-dihydro-11-[[4-[3-[(1-oxobutyl)ethylamino] -propyl]-1-piperidinyl] acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

The desired connection receive analogously to example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and valerianic acid chloride acid. Purify by chromatography on silica gel analogously to example 21.

Yield: 64% of theory.

Colorless crystals with a melting point 167 168oC (from simple diethyl ether).

Example 27.

5,11-dihydro-8-chloro-11-[[4-[3-[(1-methylcyclohexylamine)-ethylamino] propyl]-1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

A solution of 313 mg (2.2 mmol) of 1-methylcyclohexanecarboxylic acid and 340 mg (3.0 mmol) of N, N'-carbonyldiimidazole in 20 ml of tetrahydrofuran with stirring is heated at a temperature of 45oC for one hour. Then add 920 mg (2 mmol) of 5,11-dihydro-8-chloro-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-it, and the floor of the ion mixture is then poured into a saturated solution of sodium chloride, the organic phase is separated and vacuum concentrated to dryness. The resulting residue partitioned between water and complex ethyl ester acetic acid, and then the phase of the complex ethyl ester acetic acid is evaporated in a vacuum. The resulting crude product is purified by chromatography on silica gel (Baker, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester acetic acid, methanol and ammonia in the ratio of 9 to 10.1. Obtain 130 mg (11% of theory) of the desired compound as an amorphous product.

The value of Rfin the thin-layer chromatography of 0.4 (silicagel plates by Merck, eluent: a mixture of methylene chloride, cyclohexane, methanol and ammonia in the ratio of 680 150 150 20).

Example 28.

5,11-dihydro-8-chloro-11-[[4-[3-[(tricyclo[3,3,1,13,7] Oct-1-yl-carbonyl)ethylamino]propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-8-chloro-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-she carboxylic tricyclo[3,3,1,13,7]decane-1-carboxylic acid with a yield of 20% theory. Purify by chromatography on silica gel (Baker) using as ale is P CLASS="ptx2">

The value of Rfin the thin-layer chromatography of 0.65 (silicagel plates by Merck, eluent: a mixture of methylene chloride, cyclohexane, methanol and ammonia in the ratio of 680 150 150 20).

Example 29.

5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxopropyl)-ethylamino] butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11- [[4-[4-(ethylamino)butyl)-1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4] benzodiazepine-6-she carboxylic pavlinovoi acid with a yield of 62% of theory.

Colorless crystals with a melting point of 206 207oC (complex ethyl ester of acetic acid).

Example 30.

5,11-dihydro-11-[[4-[4-[(cyclopropanecarbonyl)-ethylamino] butyl] -1-piperidinyl]acetyl]-6H - pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11-[[4-[4-(ethylamino)butyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she carboxylic cyclopropanecarbonyl acid with a yield of 67% of theory.

Colorless crystals with a melting point of 202 204oC (complex ethyl ester of acetic acid).

Example 31.

5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxobutyl)-ethylamino]butyl]-1-piperidinyl]are the-1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylmaleic acid with a yield of 64% of theory.

Colorless crystals with a melting point of 153 -155oC (from simple diethyl ether).

Example 32.

5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxobutyl)-ethylamino] butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11-[[4-[4-(ethylamino)butyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethylvaleric acid with a yield of 69% of theory.

Colorless crystals with a melting point of 168 -169oC (complex ethyl ester of acetic acid).

Example 33.

5,11-dihydro-11-[[4-[4-[(3,4-dimethoxybenzoyl)-ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11-[[4-[4-(ethylamino)butyl] -1-piperidyl] acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride 3,4-dimethoxybenzoic acid with a yield of 67% of theory.

Colorless crystals with a melting point of 132 -135oC (complex ethyl ester of acetic acid).

Example 34.

5,11-dihydro-8-chloro-11-[[4-[4-[(2,2-dimethyl-1-oxopropyl)-ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-8-the OIC acid with a yield of 55% of theory.

Colorless crystals with a melting point of 205 -207oC (complex ethyl ester of acetic acid).

Example 35.

5,11-dihydro-8-chloro-11-[[4-[4-[(2,2-dimethyl-1-oxobutyl)-ethylamino]butyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-8-chloro-11-[[4-[4-(ethylamino)butyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she and the acid chloride of 2,2 - dimethylvaleric acid to yield 60% of theory.

Colorless crystals with a melting point of 149 151 polyurthaneoC (complex ethyl ester of acetic acid).

Example 36.

4,9-dihydro-3-methyl-4-[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino] propyl]-1-piperidinyl]acetyl]-10H-thieno[3,4-b][1,5]benzodiazepine-10-he

Get analogously to example 1 from 4,9-dihydro-3-methyl-4-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl]-10H-thieno[3,4 - b][1,5]benzodiazepine-10-she and the acid chloride of 2,2-dimethylmaleic acid with a yield of 19% of theory.

Colorless crystals with a melting point of 207 -208oC (from acetonitrile).

Example 37.

4,9-dihydro-3-methyl-4-[[4-[3-[(2,2-dimethyl-1-oxopropyl)-ethylamino] propyl]-1-piperidinyl]acetyl]-10H-thieno[3,4-b][1,5]benzodiazepine-10-he

Get analogously to example 1 hydride pavlinovoi acid, with 29% of theory.

Colorless crystals with a melting point of 188 -189oC(from acetonitrile).

Example 38.

5,11-dihydro-11-[[4-[2-[(benzoyl)methylamino] ethyl]-1-piperidinyl]acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11-[[4-[2-(methylamino)ethyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b] [1,4]benzodiazepine-6-she and benzoyl chloride to yield 80% of theory.

Colorless crystals with a melting point of 120 -122oC(complex ethyl ester of acetic acid).

Example 39.

5,11-dihydro-11-[[4-[[(acetyl)methylamino] methyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-he.

Get analogously to example 1 from 5,11-dihydro-11-[[4-[(methylamino)methyl] -1-piperidinyl] acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-she acetylchloride with yield 83% of theory.

Colorless crystals with a melting point 242 243oC (complex ethyl ester of acetic acid).

Example 40.

3-chloro-4-[[4-[3-[(2,2-dimethyl-1-oxopropyl)ethylamino]propyl]-1-piperidinyl] acetyl] -1-methyl-1,4,9,10-tetrahydropyrrolo[3,2-b] [1,5]benzodiazepine-10-he

Get analogously to example 1 from 3-chloro-4-[[4-[3-(ethylamino)propyl]-1-piperidinyl] acetyl]-1-methyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]bentchi melting 150 151oC (complex ethyl ester of acetic acid).

Example 41.

6,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino] propyl] -1-piperidinyl]acetyl]-5H-pyrido[2,3-b][1,4]benzodiazepine-5-he

Get analogously to example 1 from 6,11-dihydro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl] acetyl] -5H-pyrido[2,3-b][1,5]benzodiazepine-5-she and the acid chloride of 2,2-dimethylvaleric acid with a yield of 44%

The value of Rfin the thin-layer chromatography: 0,6 (silicagel plates by Merck, eluent: a mixture of methylene chloride, cyclohexane, methanol and ammonia in the ratio 6,8:1,5:1,5:0,2).

Example 42.

5,11-dihydro-8-chloro-11[[4-[3-[(2,2-dimethyl-1-oxobutyl)-ethylamino] propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-he

To a solution of 0.52 g (4 mmol) of 2,2-dimethylvaleric acid and 0.54 g (4 mmol) of 1-oxibendazole in 50 ml of tetrahydrofuran with stirring and at a temperature of 0oC type of 0.82 g (4 mmol) N, N'-dicyclohexylcarbodiimide. Continue to stir at the same temperature for 30 minutes, and then add 1.8 g (4 mmol) of 5,11-dihydro-8-chloro-11-[[4-[3-(ethylamino)propyl] -1-piperidinyl]-acetyl]-6H - pyrido[2,3-b][1,4]benzodiazepine-6-it. Additionally stirred at room temperature the Residue purified by chromatography on silica gel (Baker) using as eluent a mixture of complex ethyl ester acetic acid, methanol, cyclohexane and ammonia in the ratio of 8:1:1:0,1. Get colorless crystals with a melting point 172 173oC (complex ethyl ester of acetic acid).

Yield: 160 mg=7% of theory.

According to its physical and chemical properties and spectroscopy results obtained according to this example, the connection is quite identical with the obtained according to example 12 of the connection.

Example 43.

5,11-dihydro-11[[3-[3-[(benzoyl)methylamino] -propyl] -1-piperidinyl]acetyl]-6H-pirado-[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b] [1,4] benzodiazepine-6-it 3-[3[(benzoyl)methylamino]propyl]piperidine. Purify by chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in the ratio of 99:1.

Yield: 43% of theory.

Colorless crystals with a melting point of 172 -173oC.

Example 44.

5,11-dihydro-11-[[3-[3-[(acetyl)methylamino] -propyl] -1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b] [1,4]benzodiazepine-6-it 3-[3- [(acetyl)methylamino]propyl]piperidine. Purify by chromatography ivydene amount of methanol.

Yield: 23% of theory.

Colorless crystals with a melting point of 170 -172oC.

Example 45.

5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxobutyl)amino]-propyl]-1-piperidinyl]acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-he

Get analogously to example 1 from 5,11-dihydro-11-[[4-(3-aminopropyl)-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepine-6-she and the acid chloride of 2,2-dimethyl-valerianic acid with a yield of 64% of theory.

Colorless crystals with a melting point of 150 -152oC (complex ethyl ester of acetic acid).

Example 46.

5,10-dihydro-5[[4-[3-[(2,2-dimethyl-1-oxobutyl)ethylamino]-propyl]-1-piperidinyl] acetyl]-11H-dibenzo-[b,e][1,4] diazepin-11-he

Get analogously to example 1 from 5,10-dihydro-5-[[4-[3-ethylamino]propyl] -1-piperidinyl]acetyl]-11H-dibenzo [b,e] [1,4]diazepin-11-it.

Purify by chromatography on silica gel (form Merck, particle size of 30 to 60 μm) using as eluent a mixture of complex ethyl ester of acetic acid and ammonia in the ratio of 10:0,1.

The yield of the desired product in the form of racemate: 53% of theory.

Colorless crystals with a melting point of 124 126oC (from simple diethyl ether).

The value of Rfthe return of telengard, cyclohexane, methanol and ammonia in the ratio 6,8:1,5:1,5:0,2).

The separation of the racemate.

152 mg of racemate in 20 µl of a mixture of ethanol and n-hexane in a volume ratio 3: 7 served on the column size 250 x 10 mm, containing silica has a particle size of 10 μm. As the mobile phase used a mixture of ethanol and n-hexane in a volume ratio 3:7. Chromatography is carried out at a speed of 2 ml/min at a pressure of 1.3 MPa. Photometric detection was performed at 260 nm. Both enantiomers are characterized by the following retention times: 10,4 min for (-)-enantiomer, 14 min for (+)-enantiomer.

The following examples illustrate how the proposed drug and its production method.

Example 47.

Tablets containing 5 mg of 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxo-butyl)ethyl-amino]propyl)-1-piperidinyl]acetyl]-6H-pyrido [2,3-b][1,4] benzodiazepin-6-it

Structure.

1 tablet contains:

Active substance 5.0 mg

Lactose 148,0 mg

Potato starch 65,0 mg

Magnesium stearate 2.0 mg 220,0 mg

A method of obtaining the drug.

From potato starch by heating get 10% mucilage. The active substance, lactose and the rest of the potato starch , 45oWith, once again grind through the above sieve, mixed with magnesium stearate and pressed into tablets.

The weight of one tablet 220 mg

The punch diameter 9 mm

Example 48.

Tablets containing 5 mg of 5,11-dihydro-11-[[4-[3-[(2,2-dimethyl-1-oxo-butyl)ethyl-amino] propyl] -1-piperidinyl] acetyl]-6H-pyrido [2,3-b][1,4]benzodiazepine-6-it

Obtained according to example 47 tablets in a known manner provided with a shell composed primarily of sugar and talc. The finished tablets are polished with the use of beeswax.

The weight of one tablets: 300 mg

Example 49.

Ampoules containing 10 mg of the dihydrochloride 5,11-dihydro-11-[[4-[4-[(2,2-dimethyl-1-oxo-pentyl)ethyl-amino] butyl] -1-piperidinyl] -acetyl] -6H-pyrido[2,3-b][1,4]benzodiazepine-6-it

Structure.

1 ampoule contains:

Active substance 10.0 mg

Sodium chloride 8.0 mg

Distilled water Up to 1 ml

A method of obtaining the drug.

The active ingredient and the sodium chloride are dissolved in distilled water, and then add distilled water to achieve the specified volume. The solution is sterile-filtered and poured the vials with a capacity of 1 ml.

Sterilization: 20 minutes at a temperature of 120
Structure.

1 suppository contains:

Active ingredient 20.0 mg

The material for the manufacture of suppositories (e.g., brand Witepsol W 45) - 1680,0 mg 1700,0 mg

A method of obtaining the drug.

Pulverized into pulverized powder of the active substance is suspended in the mass for the manufacture of suppositories, melted and cooled to a temperature of 40oC. the resulting mass at a temperature of 37oC served slightly cooled molds for the manufacture of suppositories.

The weight of one suppository: 1.7 grams

Example 51.

Drops containing the dihydrochloride 5,11-dihydro-11-[[4-(4-[(2,2-dimethyl-1-oxo-pentyl)ethyl-amino]butyl]-1-piperidinyl]-acetyl]-6H-pyrido[2,3-b][1,4] benzodiazepine-6-it

Structure.

100 ml solution for drops contain:

Methyl ester of p-oksibenzoynoy acid 0.035 g

Complex propyl ester of p-oksibenzoynoy acid 0.015 g

Anise oil 0.05 g

Menthol 0.06 g

Pure ethanol 10.0 g

Active ingredient 0.5 g

Cyclamate sodium 1.0 g

Glycerin 15.0 g

Distilled water To 100.0 ml

A method of obtaining the drug.

The active substance and sodium cyclamate are dissolved in about 70 ml distill in ethanol and receive the solution was added with stirring to the aqueous solution. Then add distilled water to reach a volume of 100 ml and filtered to lack of solid particles.

1. Derivatives of diazepinone General formula I

< / BR>
where In one of the divalent residues and) g)

< / BR>
X group CH or a nitrogen atom, if the divalent residue (a);

l integer 1, 2 or 3;

m is an integer 1 or 2;

n is an integer 1 to 4;

R1a hydrogen atom or an unbranched or branched C1-C6-alkyl;

R2a hydrogen atom, an unbranched or branched C2- C8-alkyl, unbranched or branched C4- C6alkenyl, C3C7-cycloalkyl, unsubstituted or substituted C1C3-alkyl, substituted, phenyl, substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1-3 carbon atoms in the alkyl part, unsubstituted or substituted stands, or methoxy group, or a halogen atom;

R3and R4the same or different hydrogen atoms or halogen, or a methyl or ethyl group, metoxygroup or ethoxypropan;

R5a hydrogen atom or a chlorine or methyl;

R6and R7the same or different hydrogen atoms and is of the Windows, or their individual isomers and their salts with inorganic or organic acids.

2. The pharmaceutical composition antimuskarinovoe act occurs with activity, containing at least one derivative of diazepinone and a pharmaceutically acceptable carrier, characterized in that as a derivative of diazepinone contains a compound of General formula I on p. 1 in a therapeutically effective amount.

3. The method of obtaining derivatives of diazepinone General formula I,

< / BR>
where B is one of the divalent residues and) g)

< / BR>
X group CH or a nitrogen atom, if the divalent residue (a);

l integer 1, 2 or

m is an integer 1 or 2;

n is an integer 1 to 4;

R1a hydrogen atom or an unbranched or branched C1C6-alkyl;

R2a hydrogen atom, an unbranched or branched C2- C8-alkyl, unbranched or branched C4- C6alkenyl, C3C7-cycloalkyl, unsubstituted or substituted C1C3- alkyl, substituted, phenyl, substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1-3 carbon atoms in the alkyl part, unsubstituted or substituted m is an ode or halogen, or a methyl or ethyl group, metoxygroup or ethoxypropan;

R5a hydrogen atom or a chlorine or methyl;

R6and R7the same or different hydrogen atoms or C1C3-alkali, and

R7may also indicate a halogen atom,

or their salts with inorganic or organic acids, characterized in that the compound of General formula II

< / BR>
where X, l, n, R1these values,

subjected to interaction with the carboxylic acid of General formula III

< / BR>
where R2has the specified values,

or its reactive derivative in the solvent environment at temperatures up to the boiling point of the reaction mixture, followed, if necessary, by separation of the individual isomers and the selection of the target product in free form or in the form of an acid additive salt.

4. The method of obtaining derivatives of diazepinone General formula I

< / BR>
where In one of the divalent residues and) g)

< / BR>
X group CH or a nitrogen atom, if denotes the divalent residue (a);

l integer 1, 2 or 3;

m is an integer 1 or 2;

n is an integer 1 to 4;

R1a hydrogen atom or an unbranched or branched C1C-6-alkyl;

R2ATO is B>4- C6alkenyl,3C7-cycloalkyl, unsubstituted or substituted C1C3-alkyl, substituted, phenyl, substituted by one or two methyl groups or methoxypropane or one halogen atom, or a C1C3phenylalkyl in the alkyl part, unsubstituted or substituted stands or methoxy group or a halogen atom;

R3and R4the same or different hydrogen atoms or halogen, or a methyl or ethyl group, metoxygroup or ethoxypropan;

R5a hydrogen atom or a chlorine or methyl;

R6and R7the same or different hydrogen atoms or C1C3-alkali, and R7may also indicate a halogen atom,

or their salts with inorganic or organic acids, characterized in that the compound of General formula IV

< / BR>
where X and b have the above meanings, is subjected to the interaction with the carboxylic acid derivative of General formula V

< / BR>
where l, m, n, R1, R2have the specified values;

Nu nucleophilic group,

in the environment of the solvent, followed, if necessary, by separation of the individual isomers and the selection of the target product in free form or in the form of acid-

 

Same patents:

The invention relates to medicine, namely, neurology

The invention relates to organic chemistry, specifically to new biologically active compounds derived from polyunsaturated fatty acids, hydroxypregnenolone fatty acids and prostaglandins of General formula I:

< / BR>
where R the rest prostaglandin formula:

< / BR>
where one of the two groups at C-9 atom (R1or R2) a hydrogen atom, and the other hydroxyl (R2or R1or R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-11 of the atom (R3or R4) a hydrogen atom, and the other hydroxyl (R4or R3or R3and R4together form a keto or hydroxyisopropyl; provided that R3and R4do not form a keto or hydroxyisopropyl when R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-15 atom (R5or6) a hydrogen atom, and the other (R6or R5) hydroxyl or fluorine atom; the symbolrepresents a single or a CIS-double bond; or R is the residue of a prostaglandin of the formula:

represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or provided that if7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond; and where one of the two groups at C-15 atom (R9or R10) a hydrogen atom, and the other (R10or R9) hydroxyl;

or R the rest of the prostaglandin type I formula:

< / BR>
where the group Q at C-5 of the atom the atom is iodine or bromine, the symbolrepresents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond;

or R residue of the unsaturated fatty acids of the formula:

< / BR>
where a 0 6, f 1 6, 1 7, provided that the total carbon chain length from 18 to 22 carbon atoms;

or R residue hydroxy acid of the formula:

< / BR>
where m 1 7 x 0 4, k 0 4, n is 0 to 3, provided that the total carbon chain length from 18 to 22 carbon atoms, and str is

The invention relates to gastroenterology

The invention relates to new heterocyclic compounds having valuable biological properties, in particular to derive dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN иNOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS

The invention relates to medicine and can be used to treat conditions involving increased adhesion - aggregation of platelets and for preservation of platelet-rich plasma

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

- aminopropionic)-5h-dibenz[b, f] azepine with antiarrhythmic activity" target="_blank">

The invention relates to new chemical compounds of a number of dibenz (b, f) azepine, namely 3-carbalkoxy-5- (-aminopropionic)-5H-dibenz (b, f) azepine General formula

where (a) X=-CH2-CH2-, R1=R2=CH3, R3=H, n=1;

b) X=-CH2-CH2-, R1=CH3, R2=CH2CH2OH, R3=H, n=1;

C) X=-CH2-CH2-, R1=C2H5, R2=R3=H, n=1;

g) X=-CH2-CH2-, R1=C2H5, R2=CH3, R3=H, n=0 or 1;

d) X=-CH2-CH2-, R1=R2=C2H5, R3=H, n=1;

e) X=-CH2-CH2-, R1=C2H5, R2=H-C3H7, R3=H, n=1;

W) X=-CH2-CH2-, R1=C2H5, R2=R3=CH3n=1;

C) X=-CH2-CH2-, R1=R2=R3=C2H5n=1;

and) X=-CH2-CH2-, R1=C2H5, R2and R3together = -(CH2)2O(CH2)2-, n=1;

K) X=-CH2-CH2-, R1=ISO-C3H7, R2=CH3, R3=H, n=0;

l) X=-CH2-CH2-5, R2=CH3, R3=H, n=0;

n) X=-CH=CH-, R1=R2=C2H5, R3=H, n=1,

that possess antiarrhythmic effect and can find application in medicine

The invention relates to medicine, namely to obstetrics
The invention relates to medicine and veterinary medicine, namely to the new immune modulating drug on the basis of N-metrocable-9-acridone and physiologically active monosaccharides, various buildings

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-/D-glyukopiranozil/ammonium-2-/acridin-9-one-10-Il/acetate] -cycloferon, and can be used for the treatment of acquired immunodeficiency syndromes (AIDS), including HIV-related

The invention relates to medicine, namely to the production of medicines on the basis of [N-methyl-N-/D-glyukopiranozil/ammonium-9-one-10-Il/acetate] -cycloferon, and can be used for the treatment of multiple sclerosis
The invention relates to veterinary pharmacology, in particular to methods of treatment of acute respiratory infections in young farm animals

The invention relates to new mevalonate with pyrazolopyrimidine ring, processes for their preparation, pharmaceutical compositions containing them and their pharmaceutical use, especially as antihyperlipidemic, hypolipoproteinemia and antiatherosclerotic agents, and to intermediate products useful for their preparation and methods of producing such intermediates

The invention relates to medicine and the new original antihistaminics, anti-allergic drug containing salt Hinkley-3-diphenylcarbinol

The invention relates to an agent against human immunodeficiency virus (HIV)
Up!