Derivatives of 4-aryl-6-aminonicotinic acid and their salts

The invention relates to a pyridine derivative, in particular to novel nicotinic acid derivatives with valuable biological properties.

Collect sources. Czech. Chem. Comun. 56 (10), p. 2175 - 82, 1991 and Chem. heterocycle. combined. (11), pp. 1504 - 8, 1984 are known pyridine derivatives which are substituted ethyl esters of nicotinic acid, wherein the substituents are indicated as methyl (position 2), phenyl (in position 4), unsubstituted or substituted in the 4-position by chlorine or methoxy, or nitro, cyano (in position 5) and an amino group (position 6).

These sources do not contain data intended substituted ethyl esters of nicotinic acid.

The object of the invention to provide novel substituted nicotinic acid derivatives, possessing biological activity, in particular exhibiting modulirueschee potassium tubules action.

The problem is solved provides 4-aryl-6-amino-nicotinic acid derivative of general formula (I) wherein A - phenyl, unsubstituted or substituted 1 - 3 times by identical or different substituents from the group consisting of nitro, cyano, phenyl, halogen and trifluoromethyl, or straight or branched alkylthio group having 1-6 carbon atoms or a straight-chain or branched alkoxy group having 1-6 carbon atoms, D - cyano or nitro, R1 - hydrogen or a linear or branched alkyl group having 1 - 8 carbon atoms, R2 and R3 are the same or different and hydrogen or straight-chain or branched alkyl having 1-6 carbon atoms or a linear or branched acyl group having 1-6 carbon atoms, wherein when A is phenyl, unsubstituted or substituted in the 4-position by chlorine, methoxy or nitro, D - cyano and R2 and R3 are identical and are hydrogen, then R1 is not a radical is ethyl, and their salts.

<IMG>

As preferred salts of physiologically acceptable salts. Preferred are salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acids or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, fenilsulfokislota, toluenesulphonic acid or naphthalenedisulphonic acid.

Preferred are compounds of general formula (I), where A - phenyl, unsubstituted or substituted 1 - 3 times by identical or different substituents from the group consisting of nitro, cyano, fluorine, chlorine, bromine, iodine, phenyl and trifluoromethyl or straight-chain or branched alkylthio with 1-4 carbon atoms, or straight-chain or branched alkoxy with 1-4 carbon atoms, D - cyano or nitro, R1 - hydrogen or a linear or razvletvlenny alkyl of 1-6 carbon atoms, R2 and R3 are identical or different and denote hydrogen or straight-chain or branched alkyl having 1-4 carbon atoms or a linear or branched acyl group having 1-4 carbon atoms, wherein when A is phenyl, unsubstituted or substituted in the 4-position by chlorine, methoxy or nitro, D - cyano and R2 and R3 are identical and are hydrogen, then R1 is not a radical is ethyl, and salts thereof.

Especially preferred are compounds of general formula (I), where A - phenyl, unsubstituted or substituted by 1 - 2 identical or different radicals from the group consisting of nitro, cyano, fluorine, chlorine, bromine, iodine, phenyl, trifluoromethyl, methoxy and methylthio, D - cyano or nitro, R1 - hydrogen or a linear or razvletvlenny alkyl of 1-4 carbon atoms, R2 and R3 are identical or different and denote hydrogen or straight-chain or branched alkyl having 1-3 carbon atoms or a linear or razvletvlenny acyl having 1 - 3 carbon atoms carbon, wherein if A is phenyl, unsubstituted or substituted in the 4-position by chlorine, methoxy or nitro, D - cyano and R2 and R3 are the same and are hydrogen, then R1 is not a radical is ethyl, and salts thereof.

As already mentioned, the compounds of general formula (I) have a modulating action of potassium tubules and are thus suitable for use in the fight against cerebral disease and sickle cell anemia. In particular they are modulators of tubules having selectivity for calcium-dependent potassium tubules high conductivity, in particular of the central nervous system.

On the basis of these pharmacological properties, they are suitable for the preparation of medicaments for the treatment of degenerative diseases of the central nervous system such as, for example, dementia as multi-infarct dementia, primary degenerative dementia, presenile and senile dementia (Alzheimer's disease), dementia of AIDS, and other types of dementia, additionally for the treatment of Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

In addition, the new compounds are useful for the treatment of functional weakness of the brain in old age, mozgoorganicheskogo psihosindroma and memory disorders in old age.

They are useful to prevent, treat and combat the effects of cerebral circulatory disorders such as, for example, cerebral ischemia, stroke, traumatic brain injury and subarachnoid hemorrhage.

In addition, they are useful for the treatment of depressions and psychoses, for example schizophrenia, and also for the treatment of disorders of neuroendocrine secretion, the secretion of neurotransmitters and related health problems, such as, for example, mania, alcoholism, drug abuse, painful desire or painful relation to food. Further scope of applicability of the novel compounds are treatment of migraine, sleep disorders, neuropathies. In addition, they are useful as analgesics.

Possible to apply the new compounds for the treatment of disorders of the immune system, in particular the proliferation of T-lymphocytes, and for influencing the smooth muskulyaturu, in particular of uterus, urinary bladder and bronchial tract and for the treatment of related diseases, for example asthma and urinary incontinence, and for the treatment of high blood pressure, arrhythmia, angina and diabetes.

The biological activity of the compounds of formula (I) is illustrated by the following experiment.

Vydelenie86 rubidium glioma cells from C6-BU1 experiments were performed with minor modifications according to the method Tas et al. (Neurosci. Lett. 94 pp. 279-284 (1988)). For this purpose, isolated from rat glioma cells C6-BU1. As obtained by liquid scintillation data were read ionomycin induced increase in basal allocation through the selection, which take 100%. Stimulation in the presence of the test substance is assigned to this value. In this experiment the compounds of Examples 1 and 2 showed a stimulating effect at concentrations of 10-6 mol.

The compounds of formula (I) belong to the category of low-toxic compounds.

The new compounds of general formula (I) can be prepared, for example, by oxidizing dihydropyridines of general formula (II) wherein A, D, R1-R3 are as defined above R4 has the abovementioned meaning R1, but does not represent hydrogen, a typical oxidizing agent, preferably manganese dioxide, in inert solvent followed, if necessary, alkylating or acylating the product obtained, or by hydrolysis of the resulting ester, if appropriate in organic solvents and in the presence of a base.

<IMG>

This method is illustrated reaction scheme shown at the end of the description.

Suitable solvents are all inert organic solvents which do not change under the reaction conditions. Preferred solvents are alcohols such as methanol, ethanol, propanol or isopropanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, acetonitrile, amides such as hexamethylphosphoric triamide or dimethylformamide, acetic acid, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, hydrocarbons such as benzene or toluene. It is also possible to use mixtures of the solvents mentioned. Particularly preferred is methylene chloride.

Suitable oxidizing agents generally suitable 2,3-dichloro-4,5-dicyano-p-benzoquinone and derivatives, pyridinium dichromate, elemental bromine or iodine and manganese dioxide. Preferred is manganese dioxide.

The oxidizing agent is in general employed in an amount of 1 - 20 mol, preferably 1 - 5 mol, per 1 mol of the compound of general formula (II).

The reaction temperatures can be varied within a wide range. In general, at temperatures of between + 10oC and + 150oC, preferably between + 20oC and + 100C, in particular at room temperature.

The reactions can be carried out at atmospheric pressure or at elevated or reduced pressure (eg 0.5 - 3 bar). In general operate at atmospheric pressure.

Suitable solvents for the alkylation are also suitable conventional organic solvents which do not change under the reaction conditions. Preferred solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trihlormetran, tetrachloromethane, dichloroethylene , trichlorethylene or chlorobenzene, ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Preferred is dimethylformamide.

Suitable bases are generally suitable hydrides or alkali metal alcoholates, such as sodium hydride or potassium t-butoxide, cyclic amines such as piperidine, dimethylaminopyridine or alkyl with 1 - 4 carbon atoms, for example triethylamine. Preferred is sodium hydride.

The reaction temperatures can be varied within a wide range. In general, at temperatures of between + 10oC and + 150oC, preferably between + 20oC and + 100C, in particular at room temperature.

Alkylation of the abovementioned solvents in the medium is carried out at temperatures ranging from 0oC to + 150oC, preferably at room temperature up to + 100C.

The reactions can be carried out at atmospheric pressure or at elevated or reduced pressure (eg 0.5 - 3 bar). In general operate at atmospheric pressure.

The base is in general employed in an amount of 1 - 5 mol, preferably 1 - 2 mol, relative to 1 mol of a compound which is alkylated.

As suitable bases for the acylation are inorganic or organic bases. Preferred bases are alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal, such as, for example, barium hydroxide, alkali metal carbonates, such as, for example, sodium carbonate or potassium carbonate, alkaline earth metal, such as, for example, calcium carbonate, or organic amines such as, e.g., trialkylamines having 1-6 carbon atoms in each alkyl part, in particular triethylamine, or heterocycles such as pyridine, methylpiperidine, piperidine or morpholine. Particularly preferred is triethylamine.

Solvents suitable for the acylation are also customary organic solvents which do not change under the reaction conditions. Preferred solvents are ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halogenated hydrocarbons such as dichloromethane, trihlormetran, tetrachloromethane, dichloroethylene , trichlorethylene or chlorobenzene, ethyl acetate, triethylamine, pyridine, dimethyl sulphoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned or appropriate acylating agent may also be used as a solvent. Preferred are acetic anhydride and pyridine.

The acylation is generally carried out at temperatures ranging from 0oC to + 120C, preferably from + 30oC to + 90oC, and atmospheric pressure.

Saponification of esters of carboxylic acids by known methods by treatment with standard bases in inert solvents.

Suitable bases for the saponification standard suitable for this reaction, inorganic bases. Preferred bases are alkali or alkaline earth metals, such as, for example, sodium hydroxide, potassium or barium, or alkali metal carbonates such as sodium or potassium carbonate, or sodium bicarbonate. Especially preferred are sodium hydroxide or potassium hydroxide.

Solvents suitable for saponification water or standard for this reaction, organic solvents. Preferred solvents are alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. Particularly preferred are alcohols such as methanol, ethanol, propanol or isopropanol. It is also possible to use mixtures of the solvents mentioned, saponification is generally carried out at temperatures ranging from 0oC to + 100C, preferably from + 20oC to + 80oC.

In general, the saponification is carried out at atmospheric pressure. However, one can also work at reduced pressure or at elevated pressure (e.g. from 0.5 to 5 bar).

Compounds of general formula (II) can be prepared, for example, by reacting the compounds of general formula (III) where E and R4 have the abovementioned meaning, with compounds of general formula (IV) wherein R2, R3 and D have the abovementioned meaning, in one of the abovementioned organic solvents, preferably in ethanol, and if appropriate in the presence of a base.

<IMG>

<IMG>

Suitable bases are generally suitable hydrides or alkali metal alkoxides such as, for example, sodium hydride or potassium t-butoxide, or cyclic amines, such as, for example, piperidine, dimethylaminopyridine or alkyl of 1-4 carbon atoms, for example triethylamine. Preferred are piperidine, dimethylaminopyridine, pyridine, sodium hydride and potassium t-butoxide.

The base is in general employed in an amount of 1 - 5 mol, preferably 1 - 2 mol, relative to 1 mol of the compound of general formula (III).

The reactions can be carried out at atmospheric pressure or at elevated or reduced pressure (eg 0.5 - 3 bar). In general operate at atmospheric pressure.

The reaction temperatures can be varied within a wide range. In general, at temperatures of between + 10oC and + 150oC, preferably between + 20oC and + 100C, in particular at the boiling temperature of the corresponding solvent.

Compounds of general formulas (III) and (IV) are known or can be prepared by well known methods.

When used as a medicament the compounds of general formula (I) preferably provide in total amounts from about 0.01 mg / kg to about 100 mg / kg, preferably in total amounts of about 1 mg / kg to about 50 mg / kg body weight body weight per day, optionally in the form of several individual doses, to achieve the desired result.

However, may also be advantageous deviation from the abovementioned quantities, namely depending on the species and body weight of the patient, on the individual response to the drug, the type and severity of the disease, the type of composition and applications, and the time or interval of medication cottages.

The following examples illustrate the preparation of compounds of the above formula (I).

Starting compounds EXAMPLE I Methyl 6-amino-4- (3-chloro-4-trifluoromethylphenyl) - 1,4-dihydro-2-methyl-5-nitronikotinovoy acid 15.3 g (50 mmol) methyl ester of (3 chloro-4- triftormetilbenziliden) atsetuksusnoy acid and 5.2 g (50 mmol) of 2- nitro-1,1-etendiamina dissolved in 80 ml of ethanol and the reaction mixture was heated under reflux for 12 hours. After cooling, the resulting solid was filtered off and washed with ethanol. Obtained 13.0 g (66% of theory) of the title compound.

<IMG>

Etc .: 250oC EXAMPLE II Methyl 6-acetylamino-4- (3-chloro-4- acid 4.0 g (12.0 mmol) of the compound of Example 1 was dissolved in 40 ml of acetic anhydride and heated to reflux for 12 hours. Then, acetic anhydride was distilled off under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulphate, concentrated and the residue was purified by chromatography on silica gel using as eluent a mixture of toluene, ethyl acetate and isopropanol in a ratio of 100: 10: 1. The eluate is concentrated and recrystallized from ethanol. 0.5 g (11% theory) of the title compound.

<IMG>

Etc .: 152oC Example III Methyl 6-amino-5-cyano-2-methyl-4- (trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylic acid 13.6 g (50 mmol) of methyl 2-acetyl- (4-trifluoromethyl) phenylacetic acid, 7.45 g (50 mmol) of the ethyl ester tsianatsetimidnoy acid and 15 g (190 mmol) of ammonium acetate in 100 mL of methanol was refluxed for one hour. After concentrating the residue was partitioned between ice water and ethyl acetate. The organic phase was washed twice with dilute aqueous sodium bicarbonate solution and once with water, dried over sodium carbonate and concentrated in vacuo. Crystallization of the residue (18.4 g) from methanol gave 6.3 g (37% of theory) of colorless crystals.

<IMG>

Etc .: 210 - 214oC EXAMPLE IV Methyl 6-acetamido-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid 6.7 g of ( 20 mmol) of methyl 6-amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylic acid (preparation analogous to Example III) and 33.5 ml ( 350 mmol) of acetic anhydride was heated at reflux for 30 minutes. The excess acetic anhydride is converted into methyl acetate by reacting methanol with stirring at 25oC. The reaction solution was evaporated in vacuo and the resulting residue was purified twice with toluene in vacuo. The residue is boiled with 50 ml of toluene, the separated crystals are filtered and washed with toluene.

<IMG>

Yield: 3.6 g (50% of theory) etc .: 224oC (dec.) EXAMPLE V Methyl 5-cyano-4- (2,3-dichlorophenyl) -2-methyl-6- N-methylamino 1,4-dihydropyridine-3-carboxylic acid 2.8 g (10 mmol) of methyl 2-acetyl (2,3-dichlorophenyl) acetic acid and 1.5 g (10 mmol) of the ethyl ester tsianatsetimidovoy acid mixed with 5 ml (40 mmol) of 33% ethanolic methylamine solution. The mixture was heated to 46oC. After cooling to 30oC to the mixture was added 2.3 ml (40 mmol) of glacial acetic acid and then 20 ml of methanol. After refluxing for 5 hours, the reaction solution was mixed with ice water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under reduced pressure, and the obtained 3.9 g of amorphous residue, which was purified by chromatography on 100 g of silica gel using as eluent a mixture of toluene and ethyl acetate (used as a gradient).

<IMG>

Yield: 0.5 g (10% of theory) of crystals etc .: 234 - 239oC final products EXAMPLE 1 Methyl 6-amino-2-methyl-5-nitro-4- (4- trifluoromethylphenyl) -nikotinovoy acid 2 0 g (5.6 mmol) of methyl 6-amino-2-methyl-5-nitro-4- (4-trifluoromethyl-1,4-dihydro) -nikotinovoy acid (prepared as in Example 1) was dissolved in 100 ml of methylene chloride and mixed with 10.0 g of precipitated, active manganese dioxide. Stir at room temperature for 12 hours. The reaction mixture was subjected to chromatography using as eluent methylene chloride. The eluate was concentrated and the residue is recrystallized from methanol. 1.4 g (70% of theory) of the title compound.

<IMG>

Etc .: 185 - 186oC prepared analogously to Example 1 in Table 1 compound.

EXAMPLE 13 Methyl 6-N, N-diacetylamino-2-methyl-5-nitro-4- (2-trifluoromethylphenyl) -nikotinovoy acid 0.8 g (2.25 mmol) of the compound of Example 6 dissolved in 20 ml of acetic anhydride and overnight heated under reflux. After distilling off the acetic anhydride, the crystalline residue was washed with water and recrystallized from ethanol. Obtained 250 mg (28% of theory) of the title compound.

<IMG>