Use of substituted 4-phenyl-6-amino-nicotinic acid derivatives for producing pharmaceutical compositions suitable for treatment of central nervous system and new substituted 4-phenyl-6-amino-nikotinic-acid

The invention relates in part to known substituted 4-phenyl-6-amino-nicotinic acid derivatives which are useful as medicaments. The present invention relates to novel active compounds and their preparation and their use as medicaments for modifying potassium channels, in particular for the treatment of the central nervous system.

From the literature (Collec. Czech. Chem. Commun. 56 (10). 2175-2182 (1991); Khim. Geterotsikl. Soedin (11), 1504-1508 (1984)), some 4-phenyl-3-pyridine carboxylic derivative is known but their pharmacological action is not mentioned.

It has now been found that the partially known substituted 4-phenyl-6-amino-nicotinic acid derivatives of formula (I) and salts thereof, wherein

A is a C 6 -C 10 aryl or pyridyl group optionally having up to three identical or different nitro, cyano, phenyl, halogen, trifluoromethyl, and up to 6 carbon atoms. they may be substituted with a straight or branched alkylthio group or an alkoxy group,

D is cyano or nitro,

R¹ is hydrogen or straight or branched alkyl having up to 8 carbon atoms, r 2 and R 1 are the same or different and may be hydrogen and straight or branched alkyl or acyl having up to 6 carbon atoms,

V

<img file="HUT74618A_D0001.tif" />

3 surprisingly modulate potassium channels and thus be used to treat cerebral diseases and sickle cell anemia.

Physiologically acceptable salts are preferred. These are generally salts of the compounds of the invention and of inorganic or organic acids. The inorganic acid is preferably hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, while the organic carboxylic acid or sulfonic acid is preferably acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, methanesulfonic acid, ethane sulfonic acid, , toluene sulfonic acid or naphthalene disulfonic acid.

The compounds of the present invention may exist in various stereoisomeric forms which are either mirror-reflective isomers (enantiomers) or non-reflective isomers (diastereomers). The invention encompasses individual antipodes as well as racemic forms and diastereomeric mixtures. The racemic forms and the diastereomers may be separated in conventional manner into uniform stereoisomeric components.

Preferred are compounds of the formula I and salts thereof for the treatment of cerebral diseases wherein

A is phenyl or naphthyl, optionally substituted with up to three identical or different nitro, cyano, fluoro, chloro, bromo or iodo, phenyl, trifluoromethyl and straight or branched alkylthio groups of up to 4 carbon atoms or substituted with alkoxy,

D is cyano or nitro,

R¹ is hydrogen or straight or branched chain alkyl having up to 6 carbon atoms,

R² and R³ is the same or different and may be hydrogen and a straight or branched alkyl or acyl group having up to 6 carbon atoms.

Particularly preferred are compounds of the formula I and their salts for the treatment of cerebral diseases wherein:

A is phenyl which may be optionally substituted with up to two of the same or different nitro, cyano, fluoro, chloro, bromo or iodo, phenyl, trifluoromethyl, methoxy or methylthio groups,

D is cyano or nitro,

R¹ is hydrogen or straight or branched chain alkyl having up to 4 carbon atoms,

R² and R³ is the same or different and may be hydrogen and a straight or branched alkyl or acyl group having up to 3 carbon atoms.

The compounds of formula I according to the invention have an unforeseen valuable pharmacological action

<img file="HUT74618A_D0002.tif" />

- 5 to. These compounds are modulators that are selective for high-potency calcium-dependent potassium channels (BK (Ca) channels), particularly in the central nervous system.

Based on their pharmacological activity, these compounds can be used in the preparation of pharmaceutical compositions for the treatment of degenerative diseases of the central nervous system, dementia such as post-infarction dementia (MID), primary degenerative dementia (PDD), premature or senile dementia, Alzheimer's disease, HIV dementia forms of dementia; and Parkinson's Disease, Muscle Dilated Sclerosis, Multiple Sclerosis.

These agents can also be used to treat brain dysfunction, brain psychosyndrome (OBS abbreviated to English Organic Brain Syndrom) and old-fashioned thinking! for the treatment of disorders (AAMI).

They are also suitable for the prevention and treatment of the consequences of cerebral haemorrhagic disorders such as cerebral ischemia, stroke, trauma to the skull or brain and subarachnoid hemorrhage.

They can be used to treat depression and psychosis such as schizophrenia. They are also suitable for the treatment of disorders of neuroendocrine secretion, such as neurotransmitter secretion, and related health disorders such as mania, alcoholism, drug addiction, drug mania and eating disorders. Other uses include the treatment of migraine, sleep disorders and neuropathy.

They are also suitable as analgesics.

They are also useful in the treatment of disorders of the immune system, in particular T-lymphocyte proliferation, in the smooth muscle such as the uterus, bladder and respiratory tract, and in the treatment of related diseases such as asthma and urinary incontinence, hypertension, arrhythmia, angina and diabetes. treatment.

The present invention also relates to novel compounds of formula (I): wherein:

A, D, R¹-R³ has the meaning given above, with the exception of the following compounds:

6-amino-5-cyano-2-methyl-4-phenyl-nicotinic acid ethyl ester,

6-amino-4- (4-chlorophenyl) -5-cyano-2-methyl-nicotinic acid ethyl ester,

Ethyl 6-amino-5-cyano-2-methyl-4- (4-methoxyphenyl) nicotinic acid;

6-Amino-5-cyano-2-methyl-4- (4-nitrophenyl) -nicotinic acid ethyl ester.

The invention further relates to a process for the preparation of the novel compounds of formula (Ia) and their salts, wherein the substituents have the meanings given in the following table:

<img file="HUT74618A_D0003.tif" />

<td>X, γ</td><td>R²</td><td>R³</td><td>D</td>

<td>4-CF₃, Η</td><td>H</td><td>H</td><td>νο₂</td>

<td>2-Cl, 3-Cl</td><td>H</td><td>H</td><td>νο₂</td>

<td>Η, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>3-Cl, 4-CF₃</td><td>H</td><td>H</td><td>νο₂</td>

<td>3-NO₂, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>2-CF₃, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>3-C1, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>2-C1, 3-C1</td><td>H</td><td>H</td><td>νο₂</td>

<td>2-C1, 3-C1</td><td>H</td><td>H</td><td>νο₂</td>

<td>4-OCH₃, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>4-CN, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>3-C1, H</td><td>H</td><td>H</td><td>νο₂</td>

<td>2-CF₃, 3-H</td><td>CO-CH₃</td><td>CO-CH₃</td><td>νο₂</td>

<td>2-C1, 3-C1</td><td>ch₃</td><td>Η</td><td>νο₂</td>

<td>Η, H</td><td>ch₃</td><td>H</td><td>νο₂</td>

<td>3-C1, 4-CF₃</td><td>ch₃</td><td>H</td><td>νο₂</td>

<td>4-CF₃, H</td><td>ch₃</td><td>H</td><td>νο₂</td>

<td>3-NO₂, H</td><td>ch₃</td><td>H</td><td>νο₂</td>

<td>2-CF₃, H</td><td>ch₃</td><td>Η</td><td>νο₂</td>

<td>2-C1, 3-C1</td><td>CO-CH₃</td><td>Η</td><td>νο₂</td>

<td>Η, H</td><td>CO-ch₃</td><td>Η</td><td>νο₂</td>

<td>2-CF₃, 3-H</td><td>CO-ch₃</td><td>Η</td><td>νο₂</td>

<td>2-C1, 3-C1</td><td>Η</td><td>Η</td><td>CN</td>

<td>3-NO₂, H</td><td>H</td><td>Η</td><td>CN</td>

V

<td>Χ, Υ</td><td>R²</td><td>R³</td><td>D</td>

<td>Η, Η</td><td>Η</td><td>H</td><td>CN</td>

<td>2-CF₃, Η</td><td>Η</td><td>H</td><td>CN</td>

<td>4-C1, Η</td><td>Η</td><td>H</td><td>CN</td>

<td>2-CF₃, Η</td><td>Η</td><td>H</td><td>CN</td>

<td>4-C₆H_s, Η</td><td>Η</td><td>H</td><td>CN</td>

<td>2-C1, 3-C1</td><td>-COCH₃</td><td>H</td><td>CN</td>

<td>3 ΝΟ₂, Η</td><td>-COCH₃</td><td>H</td><td>CN</td>

<td>2-CF₃, Η</td><td>-COCH₃</td><td>H</td><td>CN</td>

<td>4-CF₃, Η</td><td>-COCH₃</td><td>H</td><td>CN</td>

<td>2-C1, 3-C1</td><td>ch₃</td><td>H</td><td>CN</td>

<td>3 ΝΟ₂, Η</td><td>ch₃</td><td>H</td><td>CN</td>

<td>2-CF₃, Η</td><td>ch₃</td><td>H</td><td>CN</td>

<td>4-C1, Η</td><td>ch₃</td><td>H</td><td>CN</td>

<td>4-CF₃, Η</td><td>ch₃</td><td>H</td><td>CN</td>

<td>Η, Η</td><td>ch₃</td><td>H</td><td>CN</td>

- 9 In the preparation of the novel compounds of the formula I, a dihydropyridine derivative of the formula II, wherein

A, D, R¹-R³ R 1 is as defined above, r 4 is other than R 1 and R 4 except hydrogen¹In the inert solvent, the resulting compound is oxidized with a common oxidant such as manganese dioxide, optionally alkylated or acylated in an organic solvent and in the presence of a base and optionally hydrolyzed.

The process of the present invention is illustrated in Scheme A.

Suitable solvents are any inorganic organic solvent which does not change under the reaction conditions. Preferred are alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, and acetonitrile or amides such as hexamethyl- phosphoric triamide, or dimethylformamide, acetic acid or halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, or hydrocarbons such as benzene or toluene. Mixtures of the above solvents may also be used. Preferably, the solvent is methylene chloride.

Suitable solvents for the oxidation are any inorganic organic solvent which does not change under the reaction conditions. Preferred are alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, and acetonitrile or amides such as hexamethyl phosphoric triamide, or dimethylformamide, acetic acid or halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, or hydrocarbons such as benzene or toluene. Mixtures of the above solvents may also be used. Preferably, the solvent is methylene chloride.

The oxidizing agent is generally 2,3-dichloro-4,5-dicyano-p-benzoquinone or its derivative, pyridinium dichromate, elemental bromine or iodine or manganese dioxide. Manganese dioxide is preferred. The oxidizing agent is generally employed in an amount of from 1 to 20 mol, preferably from 1 to 5 mol, relative to 1 mol of the compound of formula II.

The reaction temperature can be varied within wide limits. Generally, it is carried out at a temperature of from 10 to 150 ° C, preferably from 20 to 100 ° C. The reaction may be carried out at atmospheric pressure, but higher or lower pressures, for example 0.5 to 3 bar, may be employed. We usually work at atmospheric pressure.

The organic solvents used in the alkylation are also customary organic solvents which do not change under the reaction conditions. Ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether are preferred; hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, and ethyl acetate , triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Mixtures of the above solvents may also be used. Dimethylformamide is preferred.

Suitable bases include an alkali metal hydride or alcohol such as potassium hydride or potassium tert-butylate, and a cyclic amine such as piperidine, dimethylaminopyridine or C 1-4 alkylamine such as triethylamine. Sodium hydride is preferred.

The reaction temperature can be varied within a wide range, generally from 10 to 150 ° C, preferably from 20 to 100 ° C, preferably at room temperature.

Alkylation is carried out in a solvent as mentioned above at a temperature of 0 to 150 ° C, preferably room temperature to 100 ° C.

The reaction may be carried out at atmospheric pressure, but lower or higher pressures, for example 0.5 to 3 bar, may be employed. We usually work at atmospheric pressure.

The base is generally employed in an amount of 1 to 5 moles, preferably 1 to 2 moles, per mole of compound to be alkylated.

Suitable bases for acylation are inorganic or organic bases. Alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxide such as barium hydroxide, alkali metal carboxylate are preferred.

<img file="HUT74618A_D0004.tif" />

12 bonates such as sodium carbonate or potassium carbonate, an alkaline earth metal carbonate such as calcium carbonate, and an organic amine such as a C 1-6 trialkylamine such as triethylamine, a heterocyclic compound such as pyridine, methylpiperidine, piperidine or morpholine. Triethylamine is preferred.

Also suitable as the solvent for acylation are any organic solvent which does not change under the reaction conditions. Preferred are ethers such as diethyl ether, dioxane, tetrahydrofuran or glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane. , carbon tetrachloride, dichloroethylene, trichlorethylene or chlorobenzene, and ethyl acetate, triethylamine, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. Mixtures of the above solvents or the acylating agent may be used. Acetic anhydride and pyridine are preferred.

The acylation is generally carried out at a temperature of from 0 to 120 ° C, preferably from 30 to 90 ° C, and at atmospheric pressure.

The saponification of the carboxylic acid ester is carried out in the usual manner by treating the ester with a common base in an inert solvent.

Any inorganic base may be used as a base in the saponification. Alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide are preferred.

- 13 roxide, potassium hydroxide or barium hydroxide, as well as alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate. Within this, sodium hydroxide or potassium hydroxide are preferred.

Suitable solvents for the saponification are water or an organic solvent commonly used for the saponification. Examples include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, ethers such as tetrahydrofuran or dioxane, and dimethylformamide or dimethylsulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferred. Mixtures of the above solvents may also be used.

The saponification is generally carried out at a temperature of from 0 to 100 ° C, preferably from 20 to 80 ° C. The saponification is generally carried out at atmospheric pressure, but lower or higher pressures, for example 0.5 to 5 bar, may also be used.

Enantiomerically pure forms may be prepared, for example, when the diastereomeric mixture of the formulas (Ia) and (Ib)

R / R¹'is an optically active ester group, is isolated by conventional means, then directly transesterified, or first chiral carboxylic acid is prepared and esterified to give the enantiomerically pure compound.

Separation of diastereomers can be accomplished by fractional crystallization, autumn chromatography, or Craig separation. The optimal method will be determined on a case-by-case basis, and it may be expedient to combine the individual methods. Particularly preferred are crystallization, Craig separation, or combinations thereof.

The enantiomerically pure compounds may also be prepared by chromatography of the racemic ester on a chiral phase.

Compounds of formula II may be prepared by, for example, the preparation of a compound of formula III wherein

E and R⁴ is as hereinbefore described for reaction with a compound of formula (IV)

R², R³ and D is in the above and above mentioned organic solvents, preferably ethanol, and optionally in the presence of a base.

The base is generally an alkali metal hydride or alcohol such as sodium hydride or potassium tert-butylate, or a cyclic amine such as piperidine, dimethylaminopyridine or C 1-4 alkylamine such as triethylamine. Piperidine, dimethylaminopyridine, pyridine, sodium hydride and potassium tert-butylate are preferred.

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

The reaction is generally carried out at atmospheric pressure, but higher or lower pressures may be employed, for example

0.5-3 bar pressures as well. We usually work at atmospheric pressure.

The reaction temperature can be varied within wide limits. Generally, temperatures of from 10 ° C to 150 ° C, preferably from 20 ° C to 100 ° C, in particular the boiling point of the solvent are employed.

The compounds of formula (III) and (IV) are known or may be prepared by conventional methods.

Biological activity can be monitored by measuring the efflux of 86rubidium on rat C6-BU1 glioma cells by a slightly modified method of Tas et al. (Neurosci. Let. 94: 279-284 (1988)).

From the data obtained, the ionomycin-induced increase in the effluent relative to the basal effluent was determined and considered as 100%. The stimulation achieved with the test drug is referenced to this value.

The invention further relates to a pharmaceutical composition comprising, in addition to an inert, non-toxic pharmaceutical carrier and excipient, one or more compounds of formula (I) / (Ia) or one or more compounds of formula (I) / (Ia). The invention further relates to a process for the preparation of such compositions.

The amount of the compounds of formula (I) / (Ia) in such compositions is from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, based on the total weight of the composition.

The pharmaceutical compositions may contain, in addition to the compounds of formula (I) / (Ia), other pharmaceutical active ingredients.

The pharmaceutical compositions of the invention may be formulated in conventional manner, optionally using, for example, carriers or excipients.

The compounds of formula (I) / (Ia) are generally administered in a daily dose of from about 0.01 to about 100 mg / kg, preferably from about 1 to about 50 mg / kg body weight, optionally in portions to achieve the desired effect.

It may be necessary, if necessary, to deviate from the amounts given above, depending on the patient being treated, his weight, the particular behavior of the drug, the type and severity of the disease being treated, the mode and time of administration and the interval.

The invention is further illustrated by the following examples, which are not to be construed as limiting the scope thereof.

Preparation of starting materials

Example I

6-Amino-4- (3-chloro-4-trifluoromethyl-phenyl) -1,4-dihydro-2-methyl-5-nitro-nicotinic acid methyl ester

15.3 g (50 mmol) of (3-chloro-4-trifluoromethylbenzylidene) -acetic acid methyl ester and 5.2 g (50 mmol) of 2-nitro-1,1-ethenediamine (R. Troschütz and A. Lückel, Arch. Pharm. (Weinheim) 324: 73-77 (1991)) are dissolved in 80 ml of ethyl alcohol and refluxed for 12 hours. After cooling, the resulting solid was filtered and washed with ethyl alcohol. 13.0 g (66% of theory) of the title compound are obtained.

Melting point: 250 ° C.

Example II

6-Acetylamino-4- (3-chloro-4-trifluoromethyl-phenyl) -1,4-dihydro-2-methyl-5-nitro-nicotinic acid methyl ester

Example I (4.0 g, 12.0 mmol) was dissolved in acetic anhydride (40 mL) and refluxed for 12 hours. The acetic anhydride was distilled off under reduced pressure and the residue was dissolved in methylene chloride and washed with a saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, concentrated and the residue is purified on Kiesel gel eluting with toluene / ethyl acetate / isopropanol (100: 10: 1). The evaporated eluate was recrystallized from ethanol to give 0.5 g (11% of theory) of the title compound.

Mp 152 ° C.

Example III

6-Amino-5-cyano-2-methyl-4- (trifluoromethyl) -1,4

dihydro-pyridine-3-carboxylic acid methyl ester

13.6 g (50 mmol) of 2-acyl (4-trifluoromethyl) phenylacetic acid methyl ester, 7.45 g (50 mmol) of cyanoacetimidic acid ethyl ester hydrochloride and 15 g of A mixture of ammonium acetate (190 mmol) in methanol (100 mL) was heated to reflux for 1 hour. After evaporation, the residue was partitioned between ice water and ethyl acetate. The organic layer was washed twice with dilute aqueous sodium bicarbonate solution and once with water, then dried over sodium carbonate and concentrated in vacuo. The residue (18.4 g) was crystallized from methanol to give 6.3 g (37% of theory) of a colorless crystal.

Melting point: 210-214 ° C.

ARC. example

6-Acetamido-5-cyano-4- (2,3-dichloro-phenyl) -2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid methyl ester

Methyl 6-amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydropyridine-3-carboxylate (6.7 g, 20 mmol) Analogously to Example III) and 33.5 ml (350 mmol) of acetic anhydride was refluxed for 30 minutes. The excess acetic anhydride was converted to methyl acetate by addition of methanol at 25 ° C. The reaction mixture was concentrated in vacuo, then taken up twice in toluene and evaporated. The residue is finally boiled in 50 ml of toluene, the precipitated crystals are filtered off and washed with toluene. 3.6 g (50% of theory) of the title compound are obtained.

Melting point: 224 DEG C. (dec.).

Example V

5-Cyano-4- (2,3-dichlorophenyl) -2-methyl-6-N-methylamino

-1,4-dihydro-pyridine-3-carboxylic acid methyl ester

2.8 g (10 mmol) methyl 2-acetyl (2,3-dichlorophenyl) acetic acid and 1.5 g (10 mol) ethyl cyanoacetimidate hydrochloride in 5 ml (33%) ethanol) (40 mmol). The mixture is heated to 46 ° C. After cooling to 30 ° C, glacial acetic acid (2.3 mL, 40 mmol) was added followed by methanol (20 mL). After refluxing for 5 hours, the mixture was diluted with ice water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The resulting amorphous residue (3.9 g) was chromatographed on 100 g of silica gel eluting with a toluene / ethyl acetate gradient. 0.5 g (10% of theory) of the title compound is obtained.

Melting point: 234-239 ° C.

Production examples

Example 1

6-Amino-2-methyl-5-nitro-4- (4-trifluoromethyl-phenyl) -nicotinic acid methyl ester

Methyl 6-amino-2-methyl-5-nitro-4- (4-trifluoromethyl) -1,4-dihydro-nicotinic acid (2.0 g, 5.6 mmol) (prepared analogously to Example I). 100 ml of methylene chloride and mixed with 10.0 g of precipitated active manganese dioxide. After stirring for 12 hours at room temperature, it was filtered through Kiesel gel with methylene chloride. The filtrate was evaporated and the residue was recrystallized from methanol. 1.4 g (70% of theory) of the title compound are obtained.

Melting point: 185-186 ° C.

In a manner analogous to Example 1, the following compounds of formula Ib can be prepared:

First spreadsheet

<td>Eg.</td><td>X</td><td>Y</td><td>Yield (¾)</td><td>Mp (° C)</td>

<td> 2 .</td><td>H</td><td>H</td><td> 70</td><td> 202-4</td>

<td> 3 .</td><td>3-C1</td><td>4-CF3</td><td> 33,5</td><td> 210-2</td>

<td> 4 .</td><td>2-C1</td><td>3-C1</td><td> 70</td><td> 178-9</td>

<td> 5 .</td><td>3-NO₂</td><td>H</td><td> 96</td><td> 175-77</td>

<td> 6.</td><td>2-CF₃</td><td>H</td><td> 41</td><td> 191</td>

<td> 7.</td><td>3-Cl</td><td>4-C1</td><td> 62</td><td> 202-3</td>

(continue table)

<td>Eg.</td><td>X</td><td>Y</td><td>Yield:</td><td>(%) Mp (° C)</td><td></td>

<td> 8 .</td><td>2-C1</td><td>3-C1</td><td> 92</td><td> 149-50</td><td>(-) enantiomer</td>

<td> 9.</td><td>2-C1</td><td>3-C1</td><td> 90</td><td> 149-50</td><td>(+) Enantiomer</td>

<td> 10 .</td><td>4-OCH₃</td><td>H</td><td> 25</td><td> 197</td><td></td>

<td> 11.</td><td>4-CN</td><td>H</td><td> 68</td><td> 205-6</td><td></td>

<td> 12 .</td><td>3-C1</td><td>2-CN</td><td> 5</td><td> 236-9</td><td></td>

13th example

Methyl 6-N, N-Diacetylamino-2-methyl-5-nitro-4- (2-trifluoromethyl-phenyl) -nicotinic acid

Example 6 (0.8 g, 2.25 mmol) was dissolved in acetic anhydride (20 mL) and refluxed overnight. After distilling off the acetic anhydride, the crystalline residue is washed with water and recrystallized from ethanol. 250 mg (28% of theory) of the title compound are obtained.

Melting point: 113 ° C.

14th example

Methyl 4- (2,3-dichlorophenyl) -2-methyl-6-N-methylamino-5-nitro-nicotinic acid

0.7 g (2 mol) of the compound of Example 4 are dissolved in 20 ml of dry dimethylformamide and mixed with 70 mg of 80% w / w sodium hydride. After stirring at room temperature for 3 hours, it is mixed with 2.5 ml of a 1M solution of methyl iodide in dimethylformamide and stirred for an additional 18 hours at room temperature. After evaporation, Kiesel gel was filtered through ethyl acetate / toluene 1:10 and the crude product (0.8 g) was purified by column chromatography eluting with ethyl acetate / toluene 1:80. 65 mg (9% of theory) of the title compound are obtained.

In a manner analogous to Example 14, the following compounds of formula Ic can be prepared:

Second spreadsheet

<td>Eg.</td><td>X</td><td>Y</td><td>Yield (%)</td><td>Op. (^eC.)</td>

<td> 15.</td><td>H</td><td>H</td><td> 20</td><td> 123-4</td>

<td> 16.</td><td>3-C1</td><td>4-CF3</td><td> 70</td><td> 148</td>

(continue table)

<td>Eg.</td><td>X</td><td>Y</td><td>Yield (%)</td><td>Mp (° C)</td>

<td> 17.</td><td>4-CF₃</td><td>H</td><td> 56</td><td> 137-8</td>

<td> 18 .</td><td>3-NO₂</td><td>H</td><td> 23</td><td> 196-7</td>

<td> 19 .</td><td>2-CF3</td><td>H</td><td> 20</td><td> 110-1</td>

20th example

6-N-Acetylamino-4- (2,3-dichloro-phenyl) -2-methyl-5-nitro-nicotinic acid methyl ester

800 mg (2 mmol) of methyl 6-N-acetylamino-4- (2,3-dichlorophenyl) -1,4-dihydro-2-methyl-5-nitronicotinic acid (prepared in analogy to Example II) ) Dissolved in 80 ml of methylene chloride and mixed with 5 g of manganese dioxide. After stirring at room temperature for 3 days, it was filtered through celite and purified by column chromatography eluting with ethyl acetate / toluene (4: 1). The evaporated eluate was recrystallized from toluene to give 302 mg (38% of theory) of the title compound.

Melting point: 195 ° C.

Similarly to Example 20, they can be prepared in Table 3

<img file="HUT74618A_D0005.tif" />

Compounds of formula (Id):

Third spreadsheet

<td>Eg.</td><td>X</td><td>Y</td><td>Yield (¾)</td><td>Mp (° C)</td>

<td> 21.</td><td>H</td><td>H</td><td> 19</td><td> 178-9</td>

<td> 22 .</td><td>2-CF₃</td><td>H</td><td> 64</td><td> 141-2</td>

23rd example

6-Amino-5-cyano-4- (2,3-dichloro-phenyl) -2-methyl-nicotinic acid methyl ester

Methyl 6-amino-5-cyano-4- (2,3-dichlorophenyl) -2-methyl-1,4-dihydro-nicotinic acid (1.0 g, 3 mmol) (prepared analogously to Example III) manganese dioxide (2.6 g, 30 mmol) in methylene chloride (20 mL) was stirred at room temperature for 70 hours. The solvent was removed in vacuo and the residue was mixed with ethyl acetate and filtered over Kieselgel. 0.6 g (60% of theory) of the title compound is obtained in the form of colorless crystals.

Melting point: 251-253 ° C.

24th example

6-Amino-5-cyano-4- (3-nitrophenyl) -2-methyl-nicotinic acid methyl ester

The title compound was prepared in an analogous manner to Example 20.

Rf 0.19 (3: 1 toluene / ethyl acetate)

Mp 202-205 ° C

Yield: 80% of theory.

Analogous to Examples 23 and 24, they can be prepared in analogy to Examples 4 and 4.

Compounds of formula (le) given in Table I:

4th spreadsheet

<td>Eg.</td><td>X, Y</td><td colspan="2">Yield (%) Op. (° C)</td>

<td> 25.</td><td>Η, H</td><td> 55</td><td> 254-8</td>

<td> 26 .</td><td>2-CF₃, H</td><td> 45</td><td> 212</td>

<td> 27.</td><td>4-Cl, H</td><td> 65</td><td> 231</td>

<td> 28.</td><td>4-CF 3, H</td><td> 85</td><td> 201-5</td>

<td> 29.</td><td>4-C₆H₅, H</td><td> 38</td><td> 241-4</td>

<img file="HUT74618A_D0006.tif" />

• · · ·

- 26 Example 30

6-Acetamido-5-cyano-4- (2,3-dichloro-phenyl) -2-methyl-l, 4-dihydro-pyridine-3-carboxylic acid methyl ester

In analogy to Example 23, 4.3 g (11 mmol) of IV. Example 10a was oxidized with manganese dioxide (10.7 g, 120 mmol). 1.4 g (34% of theory) of the title compound are obtained.

160-162 ° C (from ethyl acetate).

In a manner analogous to Example 30, compounds of formula (If) of Table 5 can be prepared:

5th spreadsheet

<td>Eg.</td><td>X, Y</td><td colspan="2">Yield (%) Op. (^eC.)</td>

<td> 31.</td><td>3-NO₂ , H</td><td> 11</td><td> 189-92</td>

<td> 32 .</td><td>2-CF₃, H</td><td> 32</td><td> 180-3</td>

<td> 33.</td><td>4-CF 3, H</td><td> 52</td><td> 139-42</td>

* · &lt;

<img file="HUT74618A_D0007.tif" />

- 27 Example 34

Methyl 5-Cyano-4- (23-dichlorophenyl) -2-methyl-6-N-methylaminopyridine-3-carboxylic acid

In analogy to Example 20, 3.5 g (10 mmol) of the compound of Example V were oxidized with 10 g (115 mmol) of manganese dioxide. 1.7 g (49% of theory) of the title compound are obtained.

In a manner analogous to Example 34, the compounds of formula (Ig) shown in Table 6 can be prepared:

6th spreadsheet

<td>Eg.</td><td>X, Y</td><td></td><td>Yield:</td><td>(%) Op. ('C)</td>

<td> 35.</td><td>3-NO₂,</td><td>H</td><td> 10</td><td> 213-4</td>

<td> 36 .</td><td>2-CF₃,</td><td>H</td><td> 64</td><td> 128-31</td>

<td> 37 .</td><td>4-C1,</td><td>H</td><td> 40</td><td> 152-4</td>

<td> 38.</td><td>4-CF 3,</td><td>H</td><td> 30</td><td> 175-9</td>

<td> 39.</td><td>Η, H</td><td></td><td> 70</td><td> 121-4</td>

Jl · · ·