Methods of obtaining derivatives of 1,4-dihydropyridines-3,5 - dicarboxylic acid in the form of the r-isomers and their salts, source and intermediate products for their production

 

(57) Abstract:

The invention relates to methods of producing new derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula I, where R1and R3the same or different and mean C1-C8-alkyl which may be substituted C1-C6-alkoxyl or hydroxyl, R2is phenyl which may be substituted with halogen or cyano. Method 1: benzylidene compound of formula II is subjected to interaction with complex ether aminocrotonic acid of the formula III in which R1and R2have the specified values, A is benzyl, in an inert solvent, if necessary, in the presence of a base, from the obtained product otscheplaut Apple imide, followed by separation of the target product in the form of a base or salt. Method 2: benzylidene compound of formula IIa is subjected to interaction with complex ether aminocrotonic acid of the formula IIIa, in which R1, R2and A have the above values, then act as described in method 1. The compounds of formula I are Ca+2antagonists and positively affect learning ability and memory function. 5 c.p. f-crystals, 2 Il.

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To get possessing biological activity phenylsilane derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid known method, in which the benzaldehyde is subjected to interaction with complex ether aciliini acid in the presence of ammonia or lower alkylamine, if necessary, in the environment of the solvent (see U.S. patent N 3966946, A 61 K 31/44, 29.06.1976 year).

The objective of the invention is to develop methods of obtaining new phenylsilane derivatives of 1,4-dihydropyridines in the form of the R-isomers or their salts.

The problem is solved by the following ways of obtaining derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula (I)

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where R1and R3the same or different and denote unbranched or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted unbranched or branched alkoxyl with 1-6 carbon atoms or hydroxyl,

R2is a radical of the formula

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R4means halogen, A. their salts.

The first way is that benzylidene compound of General formula (II)

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where R2- has the above value,

And means benzyl,

subjected to interaction with complex ether aminocrotonic acid of General formula (III)

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where R1have the above values,

in inert solvents, if necessary, in the presence of a base,

the resulting 1,4-dihydropyridines of General formula (IV)

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where R1, R2and a have the above values,

otscheplaut Apple imide under mild conditions by treatment with weak bases, followed, if necessary, the allocation of the free acid or by etherification by known methods and the desired product isolated in the form of a base or as a salt.

The second way is that benzylidene compound of General formula (IIa)

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where R1and R2have the above meaning,

subjected to interaction with complex ether aminocrotonic acid of General formula (IIIa)

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where a represents benzyl,

in inert solvents, if necessary, in the presence of a base,

and obtained according to a) and b) 1,4-dt Apple imide under mild conditions by treatment with weak bases followed, if necessary, the allocation of the free acid or by etherification by known methods and the desired product isolated in the form of a base or as a salt.

In the preferred form of salts with physiologically tolerated salts of the compounds according to the invention with inorganic acids such as, for example, hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or with organic carboxylic or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methansulfonate, vinylsulfonate, toluensulfonate or naphthalenedisulfonate.

The proposed methods are explained with the reaction scheme (see below).

The proposed methods are fundamentally suitable for the synthesis of pure enantiomers of derivatives of dihydropyridines-3,5-dicarboxylic acid.

B as a solvent during the reaction of compounds of formulas (II) and (III) suitable ethyl acetate or isopropanol.

As the solvent when the reaction of compounds of formulas (IIa) and (IIIa) are suitable, in General, in EGAT alcohols, such as, for example, methanol, ethanol, propanol or isopropanol, or ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, simple glycolytically ether, or a simple diethylethylenediamine ether, acetonitrile, or amides, such as, for example, triamide hexamethylphosphoric acid or dimethylformamide, or acetic acid, or esters, such as, for example, ethyl acetate, or a halogenated hydrocarbon, such as, for example, methylene chloride, carbon tetrachloride, or hydrocarbons, such as, for example, benzene, xylene or toluene. In addition, it is also possible to use mixtures of the mentioned solvents. Preferably use isopropanol.

The reaction temperature for both methods can vary within wide limits. Typically operate at temperatures from 20 to 120oC, preferably at 60 - 90oC.

The reaction can be conducted at atmospheric pressure and at elevated or reduced pressure (for example, 0.5 to 80 bar). Typically operate at atmospheric pressure.

Compounds of General formula (IIa) partially known or can be obtained by conventional methods, for example, by reacting the corresponding aldehydes with 2-is us.

Benzimidazole compounds of the above General formula (II) are novel and represent a further object of the invention. They can be obtained, for example, due to the fact that aldehydes of General formula (V)

R2-CHO (V)

where R2has the above value,

subjected to interaction with complex ether acetoxyl acid of General formula (VI)

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where a has the above meaning,

in inert solvents in the presence of a base and a carboxylic acid.

As the solvent usable all inert organic solvents which under the reaction conditions do not change. To them, preferably belong alcohols, such as, for example, methanol, ethanol, propanol or isopropanol, or ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, simple glycolytically ether, or a simple diethylethylenediamine ether, acetonitrile, or amides, such as, for example, triamide hexamethylphosphoric acid or dimethylformamide, or acetic acid, or esters, such as, for example, ethyl acetate, or a halogenated hydrocarbon, such as, for example, dichloromethane, carbon tetrachloride, or uglevodoroy. Preferably using dichloromethane.

As the bases are preferably suitable cyclic amines, such as, for example, piperidine, three - and dialkylamines with 1-3 carbon atoms, such as, for example, di - and triethylamine, or pyridine or dimethylaminopyridine. Preferred is pyridine.

The base is usually used in an amount of 0.01 - 0.10 mol, preferably 0.05 to 0.08 mol based on 1 mol of aldehyde.

As suitable acids preferably alkalicarbonate acids with 1-4 carbon atoms, such as, for example, acetic acid.

The acid is usually used in an amount of 0.01 - 0.1 mol, preferably 0.05 to 0.08 mol based on 1 mol of aldehyde.

The reaction temperature may vary within wide limits. Typically operate at temperatures from 20 to 120oC, preferably at 30 - 60oC.

The reaction can be conducted at atmospheric, elevated or reduced pressure (for example, 0.5 to 5 bar). Preferably operate at atmospheric pressure.

Aldehydes of General formula (V) are known or can be obtained by the known methods.

Compounds of General formula (VI) are new, you can get them due to the fact that

The solvent is usually suitable hydrocarbons, such as, for example, benzene, toluene or xylene. Preferred is toluene.

The reaction temperature can range from 90 - 140oC, preferably from 100 - 110oC.

The reaction is usually carried out at atmospheric pressure. They can, however, also carried out at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar).

The imides of the General formula (VII) partially known [see, e.g., THL 1990, 4949; J. Am. Chem. Soc. , 2589, 1989] or you can get them due to the fact that (R)-(-)-malic acid is subjected to interaction with the corresponding amines in the environment of one of the abovementioned solvents, preferably in environment, xylene, at a temperature of from 100 to 180oC, preferably at 130 - 150oC.

Diketene and 2,2,6-triethyl-1,3-dioxin-4-one are known.

Esters aminocrotonic acid of the above General formula (IIIa) are novel and represent a further object of the invention. They can be obtained, for example, due to the fact that in the process of obtaining the above-mentioned complex ester acetoxyl acid of General formula (VI) in situ add ammonia or ammonium salt.

As resimulate with ammonium salts is carried out in an environment of toluene on a water separator under conditions of phlegmy.

The reaction temperature can range from 0 - 120oC, preferably from 5 to 80oC.

The reaction is usually carried out under reduced pressure of 0.1-0.5 bar, they can, however, also carried out at atmospheric or elevated pressure (for example, when 1 to 5 bar).

As ammonium salts suitable ammonium salts of organic or inorganic acids, such as, for example, ammonium acetate or ammonium formate. Preferred is ammonium acetate.

1,4-dihydropyridines of the above General formula (IV) are novel and constitute another object of the present invention. You can get them this way.

Cleavage substituted pyrrolidin-2,5-Dion-3-yl from pure enantiomeric 1,4-dihydropyridines of General formula (IV) is conducted in the environment of one of the above inert solvents. Prefer ethyl acetate, tetrahydrofuran or mixtures thereof.

As grounds suitable carbonates of alkali metals, such as, for example, sodium carbonate or potassium carbonate, or organic bases, such as trialkylamine, for example, triethylamine, N-ethylmorpholine, N-methylpiperidine or diisopropylethylamine, or dimethylaminopyridine, 1,8-diaza - bicyclo[5.

The base is used in amounts of 1 to 5 mol, preferably 1 to 2 mol, in each case calculated on 1 mole of the pure enantiomeric compounds of General formula (IV).

The reaction temperature can range from 0 - 50oC, preferably operate at room temperature.

The reaction is usually carried out at atmospheric pressure, it can, however, also carried out at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar).

Get methods compounds are Ca2+antagonists with selectivity for Ca2+-channel L-type Central nervous system.

The selectivity exceeds the selectivity of known Ca2+- antagonistic dihydropyridines with cerebral activity, trading product nimodipine (described, for example, paved the application Germany N 2815578). This is evident, for example, when comparing the affinity of binding sites with binding of dihydropyridines in the brain and heart of rats (see Ramp D. R., Rutledge A., Janice R. A., Triggle D. J., Can. Journ. Physiol. Pharmcol. 65(1987), page 1452).

The proposed compounds have a positive effect on learning ability and memory function, as evidenced by the results of a typical viavattine prevention, experience the influence of the ability to recall, produced in automated cells by Skinner. The proposed compounds have antidepressant potential, which proved their validity in the experience Porsolt on the floating rats.

Due to their pharmacological properties you can use to obtain drugs for the treatment of Central degenerative diseases, which arise, for example, dementia such as multi-infarct dementia, primary degenerative dementia, Predtechenskaya and senile Alzheimer's disease, AIDS dementia and other types of dementia, parkinsonia disease or amyotrophic lateral sclerosis.

In addition, the active substances suitable for the treatment of brain disorders in old age, brain organic psychosyndrome, and due to the age of the memory disorders.

They are valuable for prevention, for treatment of the consequences of violation of local cerebral blood flow, such as cerebral ischemia, stroke, subarachnoid hemorrhage.

They are suitable for combating depression and mania. In addition, they can also be used to treat migraines, nabet, poisoning, micro-organisms or autoimmune diseases, painful passion and phenomenon abstinence.

Derivatives of 1,4-dihydropyridines of the above General formula (I) can represent an active ingredient of pharmaceutical compositions, which may contain at least one inert pharmaceutically suitable carrier. The active substance of the formula (I) are usually contained in the composition at a concentration of 0.1 to 99.5 wt.%, preferably 0.5 to 95 wt.%.

In addition to the active substances of the formula (I) of the proposed pharmaceutical composition can also contain other pharmaceutical active substances. Get it known techniques.

To achieve the desired results in General, it is advisable to give the active substance of the formula (I) in total amounts of about 0.01 to 100 mg, preferably about 1 to 50 mg/kg of body weight per day, optionally in the form of several individual doses.

However, if necessary, it may be appropriate to deviate from the specified number, namely depending on the type and weight of the subject to treatment of the patient, the individual behavior of the patient regarding medications, the type and severity of the disease, as pre the e source and intermediates for producing compounds of formula (I).

Example 1

(3S)-1-benzyl-3-(3-oxobutyrate)-pyrrolidin-2,5-dione

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To a solution of 9.0 g (43,8 mmol) N-benzylamine (S)-malic acid in 18 ml of xylene added by drops at 130oC 6.6 g (of 4.38 mmol) of 2,2,6-trimethyl-1,3-dioxin-4-it. The resulting acetone is distilled off from the reaction mixture. Stirred for 2 hours at 130oC, cool the reaction solution to 50oC and remove the solvent in vacuo. The residue is purified by chromatography on a column containing silica gel, and the solvent used simple diethyl ether. After separation of the eluate get to 11.8 g (93%) of the target product.

1H-NMR (CDCl3): = 2,28 (s, 3H); 2,77 (DD, J = 18 Hz, 5 Hz, 1H): 3,19 (DD, J = 8 Hz, 5 Hz, 1H); of 3.56 (s, 2H); 4,68 system (AB, 2H); 5,49 (DD, J = 8 Hz, 5 Hz, 1H); 7,25 - 7,42 h/mill (m, 5H); enol H: weak singlet at 11,68 h/mill).

Example 2

(3S)-3-(aminocrotonate)-1-benzyl-pyrrolidin-2,5-dione

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Suspension 1700 g (of 8.28 mmol) N-benzylamine (S)-malic acid 6.8 l of toluene is heated to 105oC and within approximately 20 minutes add 1447 (8,65 mmol) 85% 2,2,6 - trimethyl-1,3-dioxin-4-it, and formed the acetone is distilled off with toluene. Stirred for 2 hours at 100 - 105oC, and distilled laidout 70oC. After adding 1207 g (15.7 mmol) of ammonium acetate is heated under reflux for 3 hours at 65oC and a pressure of 250 to 300 mbar, and the water is separated. Add 3.4 liters of ethyl acetate, the resulting mixture is cooled to room temperature, washed with saturated aqueous sodium bicarbonate, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuum at 35-40oC. the Residue is served in 4.2 l of isopropanol and the solvent is distilled off in vacuum at 25-65oC. the Residue is again served in 2.5 l of isopropanol. The suspension is heated under reflux, and the solid is dissolved. After cooling down to 5-7oC add 1.8 l of water, usageprice the product is filtered, washed with 3.4 liters of a mixture of isopropanol and water in the ratio 1:1 and the resulting product is dried in vacuum at 50oC.

Output: 1990 (83%)

Melting point: 104 - 105oC

1H-NMR (CDCl3): = 1,94 (s, 3H): a 2.71 (DD, J = 18 Hz, 5 Hz, 1H); of 3.12 (DD, J = 18 Hz, 8 Hz, 1H): of 4.57 (s, 1H); 4,71 system (AB, 2H): 4,74 (s, Shir. , 1H): of 5.40 (DD, J = 8 Hz, 5 Hz, 1H); 7,20 - 7,44 h/mill (m, 5H): 7,88 h/mill (s, W, 1H).

Example 3

1-benzylpyrrolidine-2,5-Dion-3-silt ether (3'S)-2-acetyl-3- (2-chloro-3-cyano-phenyl)-2-propanolol acid

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To a solution of 12.6 g (43,6 mmol) is of piperidine and 168 mg (2.8 mmol) of glacial acetic acid. Then heated under reflux for 18 hours. After cooling to room temperature dichloromethane solution was washed with 40 ml of water, dried over sodium sulfate and concentrated in vacuum. The residue is purified by chromatography on a column containing silica gel, and the solvent used diethyl ether. After separation of the eluate get 13,0 g (68%) of the desired product as a mixture of isomers E and z

1H-NMR (CDCl3): = 2,30, of 2.51 (2s, 3H): 2,70 - 2,87 (m, 1H); is 3.08 - of 3.33 (m, 1H); 4.63 to - 4,80 (m, 2H); 5,51 - 5,69 (m, 1H); 7,27 - a 7.92 (m, 9H).

Example 4

3,5-in primary forms (4R, 3'S)-(1-benzyl-pyrrolidin-2,5-Dion-3 - yl)-(2-methoxyethyl)-4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6 - dimethyl-pyridine

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To 80,0 g (0,244 mol) of the compound of example 2 and 83,29 g (0,243 mol) of complex 2-methoxyethanol ether 2-acetyl-3-(2-chloro-3 - cyano-phenyl)-2-propanolol acids are added to 1100 ml isopropanol, the resulting mixture is heated under reflux for 8.5 hours. Cooled to room temperature, usageprice the crude product is filtered and twice washed with isopropanol, taken in an amount of 100 ml, then the crude product is dried in vacuum at 40oC. the Crude product is suspended in 200 ml of ethyl acetate, and the obtained suspension is heated out 40 ml of ethyl acetate and dried in vacuum at 50oC.

Output: of 57.8 g (41%)

Diastereomeric purity of 99.5% (certain high-performance liquid chromatography on silica gel Chiracel OD-H)

Melting point: 239 - 240oC

1H-NMR (d6-DMSO) = and 2.26 (s, 6H): 2,68 (DD, J = 18 Hz, 5 Hz, 1H); to 3.09 (DD, J = 18 Hz, 8 Hz, 1H); and 3.16 (s, 3H); 3,37 - to 3.50 (m, 2H): 3,95 - 4,12 (m, 2H); to 4.52, with 4.64 (system AB, JAB= 15 Hz, 2H); 5.25 in (s,1H); of 5.53 (DD, J = 8 Hz, 5 Hz, 1H), 7,22 - to 7.77 (m, 8H).

Option B (compounds of formulas II and III):

To 3.0 g (6,9 mmol) of the compound of example 3 and 1.1 g (6,9 mmol) of complex 2-methoxyethanol ester 3-aminocrotonic acid add 38 ml of ethyl acetate, after which the mixture is heated under reflux for 5 hours. The precipitate is filtered, washed with 3 ml of ethyl acetate and the resulting product is dried in vacuum at 40oC.

Yield: 1.3 g (33%)

Diastereomer purity: 99,5% (certain high-performance liquid chromatography on silica gel Chiracel OD-H)

Example 5

(4R)-imidazolyl-(2-methoxyethyl)-4-(2-chloro-3-cyano-phenyl)-1,4 - dihydro-2,6-dimethylpyridine-3,5-in primary forms

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73,9 g (0,128 mol) of the compound of example 4 suspendered in 480 ml of ethyl acetate and 96 ml of tetrahydrofuran, then add 29.0 ml (0,192 mol) of 1,8-diazabicyclo[5,4,0]undec-7-ene and the resulting mixture pen is stirred for 15 minutes. An ethyl acetate phase out, washed once with 150 ml of 1 N. hydrochloric acid and saturated aqueous sodium chloride and dried over sodium sulfate. The solvent is removed in vacuo and to the residue add 420 ml of ethyl acetate. After the addition of 25.0 g (0,154 mol) of N,N'- carbonyldiimidazole stirred at room temperature for 12 hours and then at 0 - 5oC for 15 minutes. Usageprice the product is filtered, washed with 25 ml of ethyl acetate and dried in vacuum.

Output: 42.6 g (76%)

Melting point: 180oC

1H-NMR (CDCl3): = 1,90 (s, 3H); 2,48 (s, 3H); up 3.22 (s, 3H): 3,40 - of 3.53 (m, 2H): 4,10 (t, 2H); to 5.58 (s, 1 H); of 6.02 (s, 1 H); was 7.08 (d, 1 H); 7,25 -7,58 (m, 4H); to $ 7.91 (s, 1 H).

The example below explains the formation of compounds of formula (I).

Example 6

(4R)-isopropyl-(2-methoxyethyl)-4-(2-chloro-3-cyano-phenyl)-1,4 - dihydro-2,6-dimethyl-pyridine-3,5-in primary forms

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and 73.2 g (166 mmol) of the compound of example 5 and of 0.93 g (7.6 mol) of N,N-dimethylaminopyridine in 530 ml of isopropanol is heated under reflux for 20 hours. The reaction mixture is cooled slowly to 0-5oC and stirred for one hour at 0 to 5oC. Bicrystalline the crude product is filtered, washed with 35 ml of cold isopropanol and dried in vacuum. After product.

Melting point: 138-140oC

[]2D0= +13,9 (C = 1, CHCl3g

1. The method of obtaining derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula I

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where R1and R3- same or different and denote unbranched or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted unbranched or branched alkoxyl with 1 to 6 carbon atoms or hydroxyl;

R2is a radical of the formula

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R4means halogen;

R5means cyano, and one of the substituents R4and R5can mean hydrogen,

or their salts, characterized in that benzylidene compound of General formula II

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where R2has a specified value:

And means benzyl,

subjected to interaction with complex ether aminocrotonic acid of General formula III

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where R1has the specified values,

in inert solvents, if necessary, in the presence of a base, derived from 1,4-dihydropyridines of General formula IV

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where R1, R2and have the specified values,

otscheplaut Apple imide under mild conditions by processing the th known methods and target product is isolated in the form of a base or as a salt.

2. The method of obtaining derivatives of 1,4-dihydropyridines-3,5-dicarboxylic acid in the form of the R-isomers of General formula I

< / BR>
where R1and R2the same or different and denote unbranched or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted unbranched or branched alkoxyl with 1 to 6 carbon atoms or hydroxyl;

R2is a radical of the formula

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R4means halogen;

R5means cyano, and one of the substituents R4and R5can mean hydrogen,

or their salts, characterized in that benzylidene compound of General formula IIa

< / BR>
where R1and R2have a specified value,

subjected to interaction with complex ether aminocrotonic acid of General formula IIIa

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where a represents benzyl,

in inert solvents, if necessary, in the presence of a base, derived from 1,4-dihydropyridines of General formula IV

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where R1, R2and have the specified values,

otscheplaut Apple imide under mild conditions by treatment with weak bases, followed, if necessary, the allocation of free acid or its known etherification with the General formula III

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where R2and As is mentioned in paragraph 1 values

as a starting product for producing compounds of the formula I

4. Ester aminocrotonic acid of General formula IIIa

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where As is specified in paragraph 1 value,

as a starting product for producing compounds of formula I.

5. 1,4-Dihydropyridines of General formula IV

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where R1, R2and As are specified in paragraph 1 values

as intermediates for producing compounds of formula I.

 

Same patents:

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Z-CH2-Y (I)

where Z stands for a group

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where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

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in which R and m have the above meanings;

Y - group

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where R is the specified value,

mixtures of their isomers or the individual is

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,

and its enantiomer, 5-(3- [(2R.) -Exo-bicyclo [2.2.1.]hept-2 - yloxy]- 4 - methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)-he, of the formula:

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in which the radicals R represent hydrogen atoms or together form a single bond; the radical R' represents a hydrogen atom or easily removable and the radicals R" are identical, represent phenyl radicals which may be substituted by a halogen atom or a methyl radical in the ortho - or meta-position, as well as their salts

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where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

R4and R5the same or different and mean a hydrogen atom, an unbranched or branched alkyl with 1-8 carbon atoms, phenyl or benzyl,

or thienyl,

R2a hydrogen atom or cycloalkyl with 5-8 carbon atoms or an unbranched or branched alkyl, alkenyl, alkadienes, or quinil with 1-10 carbon atoms, unsubstituted or once or twice substituted od the cyano and nitro-group, or unbranched or branched alkylthiol, alkoxygroup, alkoxycarbonyl, acyl or alloctype with 1-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms, fenoxaprop or phenyl, the latter is not substituted or once or twice substituted by identical or different substituents from the group comprising halogen atom, an unbranched or branched alkyl and alkoxygroup with 1-6 carbon atoms, or substituted by the group-NR4R5in which R4and R5have the above values,

R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining amino adamantane General formula AdR, where R=NH2, NHBu-t,

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which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"
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