Derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2 in the form of mixtures of their isomers

 

(57) Abstract:

Describes new derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1, 2 the General formula I, where R1is phenyl, unsubstituted or substituted 1-5 identical or different residues from the group comprising nitro, halogen, trifluoromethyl; R2and R3the same or different and are each alkyl or alkoxy with 1-8 carbon atoms; and -- the number 1, 2 or 3; R4- methyl R3R4westaustralian-CH2-CH2-CH2-or-CH2- (CH3)2-CH2- in the form of mixtures of their isomers. These compounds exhibit biological activity, in particular demonstrate the selectivity with respect to dependent calcium potassium channels of high conductivity. 3 C.p. f-crystals, 4 PL.

The invention relates to new nitrogen-containing heterocyclic compounds with valuable biological properties, in particular to new derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, possessing biological activity.

Known derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, possessing biological activity, in particular fleischerei range of derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, possessing biological activity.

The problem is solved proposed derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2 General formula (I)

< / BR>
where R1is phenyl, unsubstituted or substituted by 1 to 5 identical or different residues from the group comprising nitro, halogen, trifluoromethyl,

R2and R3the same or different and are each alkyl or alkoxy with 1 to 8 carbon atoms,

a - number 1, 2 or 3,

R4- methyl, or

R3and R4together form a residue of formula-CH2-CH2-CH2- or-CH2-C(CH3)2-CH2-,

in the form of mixtures of their isomers.

In the first group of preferred derivatives of 1,4 - dihydropyridines with a cyclic bridge in positions 1,2 General formula (I) include compounds in which

R1is phenyl, unsubstituted or substituted by 1 to 3 identical or different residues from the group comprising nitro, fluorine, chlorine, bromine, trifluoromethyl,

R2and R3the same or different and are each alkyl or alkoxy with 1 to 4 carbon atoms,

a - the number 1 or 2,

R4- methyl, or

R3and R4together form a residue of formula-CH2-CH2- the foam is preferred derivatives of 1,4 - dihydropyridines with a cyclic bridge in positions 1,2 General formula (I) includes compounds have

R1is phenyl, unsubstituted or substituted by 1 or 2 identical or different residues from the group comprising nitro, fluorine, chlorine, bromine, iodine, trifluoromethyl,

R2and R3the same or different and are each methyl, ethyl or methoxy,

a - the number 1 or 2,

R4- methyl, or

R3and R4together form a residue of formula-CH2-CH2-CH2- or-CH2C(CH3)2-CH2-,

in the form of mixtures of their isomers.

Particularly preferred derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2 General formula (I) selected from the group including

complex dimethyl 7-(2,3-dichlorophenyl)-5-methyl-1,2,3,7 - tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl 5-methyl-7-(4-triptoreline)-1,2,3,7 - tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl 7-(4-chlorophenyl)-5-methyl-1,2,3,7 - tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl ester 2-(4-chlorophenyl)-4-methyl-2,6,7,8,9-Penta - hydrogenbased-1,3-dicarboxylic acid,

1-[6-acetyl-5-methyl-7-(4-nitrophenyl)-1,2,3,7-tetrahydroquinolin-8-yl] -Etalon,

1-[6-acetyl-7-(3,4-dichlorophenyl)-5-methyl-1,2,3,7-tetrahydroquinolin - 8-yl]a-triptoreline)-1,2,3,7 - tetrahydroquinolin-8 - yl]-Etalon,

1-[6-acetyl-7-(4-chloro-3-triptoreline)-5-methyl-1,2,3,7 - tetrahydroquinolin-8-yl]alanon,

methyl ester of 6-(3-nitrophenyl)-7-oxo-1,2,3,4,6,7,8,9,10 - nonhydrophilic[1,2-a]quinoline-5-carboxylic acid,

methyl ester of 6-(4-chlorophenyl)-7-oxo-1,2,3,4,6,7,8,9,10 - nonhydrophilic[1,2-a]quinoline-5-carboxylic acid,

methyl ester of 6-(2,3-dichlorophenyl)-7-oxo-1,2,3,4,6,7,8,9,10 - nonhydrophilic[1,2-a]quinoline-5-carboxylic acid,

methyl ester 5-(4-chlorophenyl)-6-oxo-1,2,3,5,6,7,8,9 - octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(2,3-dichlorophenyl)-6-oxo-1,2,3,5,6,7,8,9 - octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(4-chlorophenyl)-8,8-dimethyl-6-oxo-1,2,3,5,6, 7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(2,3-dichlorophenyl)-8,8-dimethyl-6-oxo - 1,2,3,5,6,7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(3-nitrophenyl)-6-oxo-1,2,3,5,6,7,8,9 - octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester of 6-acetyl-7-(2,3-dichlorophenyl)-5-methyl-1,2,3,7 - tetrahydroquinolin-8-carboxylic acid,

methyl ester of 6-acetyl-7-(4-chlorophenyl)-5-methyl-1,2,3,7 - tetrahydroquinolin-8-carbon actions in particular represent modulators channels with unexpected selective effect on the dependent calcium potassium channels of high conductivity, in particular potassium channels in the Central nervous system.

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, amyotrophic lateral sclerosis or multiple sclerosis.

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

They are suitable for prevention, for treatment of the consequences of violation of local cerebral blood flow, such as cerebral ischemia, stroke, trauma to the skull and brain and subarachnoid hemorrhage.

They are valuable tools to combat depression and psychosis, neprimetnoy secretion and associated health disorders, as, for example, mania, alcoholism, drug abuse, painful passion or morbid appetite. They can also be used to treat migraine, sleep disorders, neuropathies, and also as a sedative.

In addition, the proposed active agent suitable for treating disorders of the immune system, in particular the proliferation of T-lymphocytes, to impact on the smooth musculature, particularly the uterus, bladder and bronchial tract, and for treatment of related diseases, such as, for example, asthma, urinary incontinence, and treatment of arrhythmia, angina and diabetes.

Derivatives of 1,4-dihydropyridines of the above General formula (I) can be obtained due to the fact that

(A) if R3and R4mean radical open-chain aldehydes of General formula (II)

F1-CHO, (II)

where R1has the above value,

subjected to interaction with dioxo-compounds of General formula (III)

< / BR>
where R3and R4have the above meaning,

in inert solvents, optionally in the presence of a base, get benzylidene compounds of General formula (IV)

< / BR>
where R1, R3and R4have higher amines of General formula (V)

< / BR>
where R2and a have the above meaning,

in inert solvents, or

(B) if R3and R4together form one of the above rings, aldehydes of General formula (II) is subjected to interaction with compounds of General formula (VI)

< / BR>
where R3and R4together denote a residue of formula-CH2-CH2-CH2- or - CH2-C(CH3)-CH3,

and cyclic amines of the above General formula (V),

in the environment of the solvent, optionally in the presence of a base.

The above methods are explained by the following reaction scheme (see below).

As solvents in the implementation of the first and second stages of the method (A) will normally be all inert organic solvents which are not changed under the reaction conditions. To them, preferably belong alcohols, such as methanol, ethanol, propanol or isopropanol, or ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, simple glycol dimethyl ether or simple diethylethylenediamine ether, acetonitrile, acetone, or amides, such as, for example, triamide hexamethylphosphoric acid or Dimethylol is whether hydrocarbons, such as, for example, benzene or toluene, pyridine or acetic acid. The preferred implementation of the first stage are methylene chloride and pyridine, and the second stage - dimethylformamide.

As the basis of the first stage is usually suitable carbonates or alkali metal alcoholate, such as, for example, carbonate or potassium tert.butyl potassium, or cyclic amines, such as piperidine or dimethylaminopyridine or pyridine, or alkylamines followed with 1-4 carbon atoms, such as, for example, triethylamine.

When carrying out the above methods, the ratio of reactants is any. However, usually work with molar amounts of the reactants.

The reaction temperature can vary within wide limits. Typically operate at temperatures from 10 to 200oC, preferably from 20 to 100oC, in particular at the boiling temperature of the corresponding solvent.

The reaction can be conducted at atmospheric or at elevated or reduced pressure (for example, 0.5 to 3 bar). Typically operate at atmospheric pressure.

The above solvents are also suitable as solvents in the process (B). Predpochtitelen. Typically operate at temperatures from 10 to 200oC, preferably from 20 to 150oC, in particular at the boiling temperature of the corresponding solvent.

Compounds of General formula (II), (III), (IV), (V) and (VI) by themselves are known and can be obtained by the known methods.

The biological activity of the proposed compounds of General formula (I) is illustrated by the following experience.

Experience

Selection86rubidium from Gymnich cells C6-BU1

The experiment was carried out with minor modifications according to the method of the TAS and others (Neurosci. Lett. 94, pages 279-284, (1988)). This used isolated from rats glimne cells C6-BU1. Obtained by liquid scintillation data relied caused by ionomycin increased secretions through the basal allocation that take over 100%. Stimulation in the presence of the investigated substances were related to this value.

Determined concentration of the compounds of examples 5.9 and 14 nmol, which takes place stimulation. It was $ 540, 56 and 81 nmol, respectively.

Derivatives of 1,4-dihydropyridines of General formula (I) belong to the category of low-toxic substances.

To achieve the desired result in General proved to be expedient to give Akti is - 50 mg/kg of body weight per day, if necessary in the form of several individual doses.

Can be also useful deviation from these quantities, namely depending on the type and weight of the patient's body, from his reaction to medication, the type and severity of the disease, type of preparation and method of application, and the time or interval, where they perform the cottage.

The following examples illustrate how to obtain derivatives of 1,4-dihydropyridines of the above formula (I).

The source connection

An example of a

Methyl ester of 2-acetyl-3-(2,3-dichlorophenyl)-acrylic acid

< / BR>
17.5 g (100 mmol) of 2,3-dichlorobenzaldehyde and 11.6 g (100 mmol) of a compound methyl ester acetoxyl acid in 350 ml of methylene chloride is boiled on a water separator for 3 hours in the presence of 1 ml of piperidine and 0.5 ml of acetic acid. After that, the reaction mixture is washed twice with water, dried over magnesium sulfate and concentrated. The remainder vykristallizovyvalas from a simple mixture of petroleum ether and diethyl ether.

Yield: 15.0 g (55%)

Example B

3-(4-nitrobenzylidene)-pentane-2,4-dione

< / BR>
to 30.2 g (0.2 mol) of 4-nitrobenzaldehyde and 30.0 g (0.3 mol) of acetylacetone was dissolved in 200 ml isop a water bath until a clear solution is formed, then stirred for 4 hours at room temperature. Usageprice the product is sucked off. After washing with isopropanol and diethyl ether get 39,0 g (84%) of target compound.

Target products

Example 1

Complex dimethyl 7-(2,3-dichlorophenyl)-5-methyl-1,2,3,7 - tetrahydroindole-6,8-dicarboxylic acid

< / BR>
2.7 g (10 mmol) of a compound methyl ester 2-acetyl-3-(2,3 - dichlorophenyl)acrylic acid in 50 ml of isopropanol is heated under reflux for 12 hours. Then the reaction mixture is cooled to room temperature, add 20 ml of petroleum ether, the precipitate is sucked off and recrystallized from isopropanol. Receive 1.5 g (37%) of target compound.

Mass spectrum: 395

Rf= 0,33 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 1:1)

Melting point: 173oC

Analogously to example 1 are shown in table 1 compounds, and in the case of a = 2 the process is carried out in the presence of complex methyl ester piperidine-2-ilidene-acetic acid.

Example 5

1-[6-acetyl-5-methyl-7-(4-nitrophenyl)-1,2,3,7-tetrahydroquinolin - 8-yl] alanon

< / BR>
of 4.66 g (20 mmol) of the compound of example B and 2.50 g (20 the th reaction mixture was concentrated and purified by chromatography using as eluent a mixture of methylene chloride and complex ethyl ester of acetic acid in the ratio 10:1. From complex ethyl ester acetic acid crystallized 4.6 g (75%) of target compound.

Mass spectrum: 340

Rf= 0,16 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 1:1)

In table 2 connections get analogously to example 5.

Example 10

Methyl ester of 6-(3-nitrophenyl)-7-oxo-1,2,3,4,6,7, 8,9,10-nonhydro-pyrido[1,2-a]quinoline-5-carboxylic acid

< / BR>
4,28 g (28.3 mmol) of 3-nitrobenzaldehyde, 3,17 g (28.3 mmol) of cyclohexane-1,3-dione and 4.5 g (28.3 mmol) of a compound methyl ester piperidine-2-ilidene-acetic acid in 80 ml of dimethylformamide is heated under reflux for 4 hours, after which the reaction mixture is condensed, distilled twice in the presence of toluene and purified on silica gel using as eluent a mixture of petroleum ether and methylene chloride in the ratio of 2: 1. Productstream fraction is thickened and vykristallizovyvalas of diethyl ether. Obtain 2.1 g of the target compound.

Mass spectrum: 382

Rf= 0,23

Analogously to example 10 get listed in table 3 connection, in the case a = 1 the process is carried out in the presence of complex methyl ester pyrrole the l - 1,2,3,7-tetrahydroquinolin-8-carboxylic acid

< / BR>
to 2.57 g (10 mmol) of the compound of example and 1.4 g (10 mmol) of a compound methyl ether pyrrolidin-2-ilidene-acetic acid is dissolved in pyridine, after which the reaction mixture is heated at 100oC for 12 hours. The reaction solution is cooled, twice distilled in the presence of toluene, the residue is purified by flash chromatography using as eluent a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio of 8: 1. The target connection vykristallizovyvalas of diethyl ether. Receive 250 mg (7%) of the target product

Rf= 0,50 (a mixture of petroleum ether and complex ethyl ester of acetic acid in the ratio 1:1)

Mass spectrum: 379

Table 4 provides the connection get analogously to example 18.

1. Derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1, 2 the General formula I

< / BR>
where R1is phenyl, unsubstituted or substituted by 1 to 5 identical or different residues from the group comprising nitro, halogen, trifluoromethyl;

R2and R3the same or different and are each alkyl or alkoxy with 1 to 8 carbon atoms;

and the number 1, 2 or 3;

R4- methyl, or

R3and R4together education is RME mixture of their isomers.

2. Derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1, 2 the General formula I on p. 1, where R1is phenyl, unsubstituted or substituted by 1 to 3 identical or different residues from the group comprising nitro, fluorine, chlorine, bromine, trifluoromethyl; R2and R3the same or different and are each alkyl or alkoxy with 1 to 4 carbon atoms; and is the number 1 or 2; R4is methyl, or R3and R4together form a residue of formula-CH2-CH2-CH2- or-CH2- (CH3)2-CH2- in the form of mixtures of their isomers.

3. Derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1, 2 the General formula I on p. 1, where R1is phenyl, unsubstituted or substituted by 1 or 2 identical or different residues from the group comprising nitro, fluorine, chlorine, bromine, iodine, trifluoromethyl; R2and R3the same or different and are each methyl, ethyl or methoxy; and - the number 1 or 2; R4is methyl, or R3and R4together form a residue of formula-CH2-CH2-CH2- or-CH2- (CH3)2-CH2- in the form of mixtures of their isomers.

4. Derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1, 2 the General formula I under item 1, which is 2,3-dichlorophenyl)-5-methyl-1,2,3,7-tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl 5-methyl-7-(4-triptoreline)-1,2,3,7-tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl 7-(4-chlorophenyl)-5-methyl-1,2,3,7-tetrahydroindole-6,8-dicarboxylic acid,

complex dimethyl ester 2-(4-chlorophenyl)-4-methyl-2,6,7,8,9-Penta-hydrogenolysis-1,3-dicarboxylic acid,

1-[6-acetyl-5-methyl-7-(4-nitrophenyl)-1,2,3,7-tetrahydroquinolin-8-yl] -Etalon,

1-[6-acetyl-7-(3,4-dichlorophenyl)-5-methyl-1,2,3,7-tetrahydroquinolin-8-yl]-Etalon,

1-[6-acetyl-7-(2,3-dichlorophenyl)-5-methyl-1,2,3,7-tetrahydroquinolin-8-yl]-Etalon,

1-[6-acetyl-5-methyl-7-(4-triptoreline)-1,2,3,7-tetrahydroquinolin-8-yl]-Etalon,

1-[6-acetyl-7-(4-chloro-3-triptoreline)-5-methyl-1,2,3,7-tetrahydroquinolin-8-yl]-Etalon,

methyl ester of 6-(3-nitrophenyl)-7-oxo-1,2,3,4,6,7,8,9,10-nonhydro-pyrido[1,2-a]quinoline-5-carboxylic acid,

methyl ester of 6-(4-chlorophenyl)-7-oxo-1,2,3,4,6,7,8,9,10-nonhydro-pyrido[1,2-a]quinoline-5-carboxylic acid,

methyl ester of 6-(2,3-dichlorophenyl)-7-oxo-1,2,3,4,6,7,8,9,10-nonhydro-pyrido[1,2-a]quinoline-5-carboxylic acid,

methyl ester 5-(4-chlorophenyl)-6-oxo-1,2,3,5,6,7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(2,3-dichlorophenyl)-8,8-dimethyl-6-oxo-1,2,3,5,6,7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(2,3-dichlorophenyl)-8,8-dimethyl-6-oxo-1,2,3,5,6,7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester 5-(3-nitrophenyl)-6-oxo-1,2,3,5,6,7,8,9-octahedral[1,2-a]quinoline-4-carboxylic acid,

methyl ester of 6-acetyl-7-(2,3-dichlorophenyl)-5-methyl-1,2,3,7-tetrahydroquinolin-8-carboxylic acid,

methyl ester of 6-acetyl-7-(4-chlorophenyl)-5-methyl-1,2,3,7-tetrahydroquinolin-8-carboxylic acid.

 

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< / BR>
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