CS250694B2 - Method of 1-alkylsubstituted 1,4-dihydropyridinelactones production - Google Patents

Description

The present invention relates to a process for the preparation of novel 1-alkyl-substituted 1,4-dihydropyridine lactones which have valuable pharmacological properties and can be used as medicaments.

The new compounds correspond to the following general formula (I)

in which

R represents a chlorine atom, a fluorine atom, a bromine atom, a methyl group, a methylthio group, a cyano group, a trifluoromethyl group or a nitro group,

R ¹ is hydrogen, chlorine or fluorine,

R ² represents an alkyl group having 1 to 6 carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms in the alkyl and alkoxy moiety, alkylthioalkyl having 1 to 4 carbon atoms in each alkyl moiety, phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety a (C 1 -C 6) alkyl group which is optionally interrupted by SO or 2 oxygen atoms,

R ³ represents a methyl group, a methoxymethyl group or a dimethylaminoethyl group,

R ⁴ represents a C 1 -C 3 alkyl, allyl, optionally carboxy, -CO-OC 2 H 5, hydroxy or C 1 -C 3 dialkylamino group substituted with 1 to 3 carbon atoms in the alkyl moieties, in the form of isomers, mixtures of isomers, racemates and optical antipodes, with the proviso that R is not a trifluoromethyl group when R ² is an ethyl group.

Particular preference is given to those compounds of the formula I in which:

R is trifluoromethyl, cyano, chloro, fluoro, bromo, methyl or methylthio,

R ¹ represents a hydrogen or chlorine atom,

R ² represents an alkyl group having 1 to 6 carbon atoms which is optionally interrupted by two oxygen atoms or -SO- or represents phenylalkyl having 1 or 2 carbon atoms in the alkyl part,

R ³ represents a methyl group, a methoxymethyl group or a dimethylaminoethyl group,

R ⁴ is C 1 -C 3 alkyl or allyl, except for compounds in which R is trifluoromethyl when R ² is ethyl.

The compounds of the formula I can be prepared according to the invention by the formation of dihydropyridines of the formula XII in which:

R, R ^1, R ^2, R ³ and R ⁴ are as defined above,

R ⁵ has the same meaning as R ² and R ⁸ is halogen, preferably chloro or bromo, or is -O-R ⁷ , wherein R ⁷ is the usual alcohol protecting group, cyclized at a temperature of 20 to 300 ° C.

Using specific starting materials, the compounds of formula I can be prepared as shown in the following reaction scheme:

The cyclization according to the invention can also be carried out without solvents. Suitable solvents are, if appropriate, all customary inert organic solvents. These preferably include aromatic hydrocarbons such as benzene, toluene or xylene, tetralin, petroleum fractions, ethers such as dioxane, tetrahydrofuran, glycol mono- or diethyl ethers, halogenated hydrocarbons such as di-, tri- or carbon tetrachloride, di- or trichlorethylene; diglym.

The cyclization is carried out in a temperature range of from 20 ° C to 300 ° C, preferably at temperatures from 40 ° C to 250 ° C.

The cyclization can also be carried out at atmospheric, elevated or reduced pressure. Generally, the process is carried out at atmospheric pressure.

Acids, bases, fluoride or hydrogen can optionally be used as auxiliary agents in the process according to the invention.

The starting compound of formula XII, wherein R ⁸ is -O-R ⁷ are known or can be prepared by known processes. The starting compound of formula XII, wherein R ⁸ is halogen, preferably chlorine, bromine, are novel and can be prepared such that the 1,4-dihydropyridines of the general formula XIII

in which

R, R ¹ to R ⁵ are as defined above, act with halogenating agents in the presence of inert organic solvents or fall in the presence of radical forming agents

Suitable solvents are all organic solvents, but preferably halogenated hydrocarbons such as di-, trine or carbon tetrachloride.

Suitable halogenating agents are all conventional halogenating agents. Preferred halogenating agents are chlorine, bromine, N-chlorosuccinimide or N-bromosuccinimide, optionally in the presence of radical forming agents such as azo-bis-isobutyric acid nitrile, dibenzoyl peroxide or light.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at temperatures between 0 ° C and 120 ° C, preferably at the boiling point of the solvent used.

The reaction can be carried out at atmospheric pressure but also at elevated pressure. Generally, the process is carried out at atmospheric pressure.

The ratio of the reactants is arbitrary, but equimolar amounts are preferably used.

The compounds of formula (I) produced by the process of the invention exhibit a valuable spectrum of pharmacological effects.

With a non-deleterious effect on the circulatory system, these substances reduce blood sugar and can therefore be used to treat diabetes.

The compounds produced by the process of the invention can be converted into conventional means, such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, in a known manner using inert, non-toxic pharmaceutically acceptable carriers or solvents. The therapeutically active compound is to be present in each case in a concentration of from about 0.5 to 90% by weight, based on the total weight of the mixture, i.e. in an amount sufficient to achieve the said dosage range.

These compositions are prepared, for example, by mixing the active compounds with solvents and / or carriers, optionally with emulsifiers and / or dispersants, whereby organic solvents can optionally be used as co-solvents when water is used as the diluent.

Excipients which may be mentioned are, for example:

water, nontoxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. a mixture of peanut and sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol), solid carriers such as natural stone flours (for example kaolin, alumina, talc, chalk), synthetic stone flours (for example highly dispersed silicic acid, silicate, sugars (for example cane sugar, lactose and grape sugar), emulsifiers (for example polyoxyethylene fatty acid esters), polyoxyethylene fatty alcohol ethers, alkylsulfonates arylsulfonates, dispersants (e.g., lignin, sulfite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

Administration is carried out in a conventional manner, preferably orally or parenterally, in particular perlingually or intravenously. In the case of oral administration, the tablets can of course also contain, in addition to the aforesaid carriers, additives such as sodium citrate, kialcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin, etc. In addition, lubricants such as magnesium stearate , sodium lauryl sulfate and talc to prepare tablets. In the case of aqueous suspensions and / or elixirs which are intended for oral use, various flavor enhancers or colorants may be added to the active ingredients in addition to the abovementioned excipients.

For parenteral administration, solutions of the active compounds using suitable liquid carriers can be used.

In general, it has proven advantageous to administer, when administered orally, from about 0.01 to 200 mg of active ingredient per kg body weight, preferably from 0.1 to 50 mg / kg body weight, for effective results.

Nevertheless, it may be desirable to deviate from this range, depending on the body weight of the test animal or the mode of administration, but also on the animal species and its individual behavior towards the medicament, the type of preparation and the time and the interval at which the application is executed. Thus, in some cases it may be sufficient to use less than the abovementioned minimum amounts, while in other cases the above-mentioned maximum limits must be exceeded. In the case of administration of larger amounts, it is advisable to administer this amount during the day in several individual doses. For administration in human medicine, the same dose range is contemplated. Accordingly, the above also applies.

The following examples illustrate the invention but do not limit it in any way:

Example 1

4- (2-chlorophenyl) -2,6-dimethyl-1-ethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diisopropyl ester was boiled in carbon tetrachloride along with 10 mmol of N-bromosuccinimide and a catalytic amount of azodiisobutyronitrile overnight. Then, the reaction mixture is filtered, the filtrate is concentrated and the residue is chromatographed on silica gel.

Melting point: 110-112 ° C.

Example 2

4- (2-chlorophenyl) -2,6-dimethyl-1-ethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester was reacted in an analogous manner to that described in Example 1. The reaction mixture was also worked up in an analogous manner. as in Example 1. Melting point: 140-142 ° C.

Example 3

mmol of 2-acetoxy-4- (2-chlorophenyl) -6-methyl-3,5-dicarboxylic acid (3-ethyl-, 5-isopropyl) ester is deprotonated in dimethylformamide with 50 mmol of sodium hydride, then 50 mmol are added of ethyl iodide and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated on a rotary evaporator, the residue was dissolved in ethanol, an aqueous hydrochloric acid solution was added to the solution, and the mixture was boiled for 1 hour. Then the reaction mixture is concentrated and the product is recrystallized.

Melting point: 110-111 ° C.

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Note to the table:

Example 38 mass spectrum:

423 (M &lt; + &gt;),

406 (90%)

378, 332, 316, 312, 288, 248, 222, 177, 75.

Example 35

1-Ethyl-2-methyl-4- (2-trifluoromethylphenyl) -5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid methyl ester.

This compound was prepared in an analogous manner to that described in Examples 1 to 15

3.

Melting point: 150-152 ° C.

Example 36

1-Allyl-2-methyl-4- (2-trifluoromethylphenyl) -5-oxo-1,4,5,7-tetrahydrofuran [3,4-b] pyridine-3-carboxylic acid methyl ester

The procedure is as described in Examples 1-3. The product is obtained as an amorphous substance.

¹ H-NMR (CDCl 3): δ =

2.4 (s. 3H),

3.5 (s. 3H);

4.1 (m, 2H).

4.7 (s, 2H).

5.4 (d, 2H).

5.8 - 6.0 (m, 1H);

7.3-7.7 (m, 4H) ppm.

Example 37

4- (2-Chloro-phenyl) -1,2-dimethyl-5-oxo-1,4,5,7-tetrahydro-furo [3,4-b] pyridine-3-carboxylic acid propyl ester

The procedure is as described in Examples 1 to 3.

Melting point 173-177 ° C.

The compounds of Examples 38-41 were also prepared in an analogous manner to those described in Examples 1-3.

and

OH

Melting point: 140-143 ° C (from methanol) Example 39

C / V, ^C 2.M5 ·

Melting point: 134-137 ° C.

Example 40

C / 70 ° _X ť °

Melting point: amorphous product.

280694

Mass Spectrum: (DCI, with isobutane)

415 (50%)

386 (100%),

369 (20%)

355 (10%)

327 (10%).

Example 41

Melting point: 115-118 ° C.

The blood sugar lowering effect of the test substances was tested in male rats (Wistar strain) weighing between 140 grams and 190 g. For this purpose, rats were weighed and divided into groups of 6 specimens 18 hours prior to administration and kept fasted. Test substances were suspended in 0.75% aqueous tragacant suspension immediately prior to application with an Ultra-Turrax. Application of the tragacanth suspension (control animals) or test substances suspended in the tragacanth suspension is carried out by means of a probe into the esophagus.

Blood was collected from each rat at intervals of 12, 30, 60 and 120 minutes after application from the retro-orbital venous plexus. Using an automatic device, 30 μϊ of blood is drawn and the protein is deprived of protein by 0.3 mol of uranyl acetate (0.16 percent). After centrifugation, the upper layer was photometrically determined for glucose by the glucosoxidase method using 4-aminophenazone as a coloring agent.

Evaluation of the results is carried out by means of the t-test (according to Student), where a value of p < 0.05 is chosen as a statistically significant limit.

Test substances that cause a statistically significant reduction in blood glucose concentration of at least 10% in rats over a period of time are compared to a control group given only a suspension of tragacanth.

The following Table 1 contains the observed changes in blood glucose concentrations as a percentage of control.

Table 1 substance decrease in blood glucose concentration (from Example No.) in percentage of control

Claims (4)

A process for the preparation of 1-alkyl-substituted 1,4-dihydropyridine lactones of the general formula I wherein: R represents a chlorine atom, a fluorine atom, a bromine atom, a methyl group, a methylthio group, a cyano group, a trifluoromethyl group or a nitro group, R ¹ is hydrogen, chlorine or fluorine, R ² represents an alkyl group having 1 to 6 carbon atoms, alkoxyalkyl with 1 I INVENTION up to 4 carbon atoms in the alkyl and alkoxy moieties, an alkylthioalkyl of 1 to 4 carbon atoms in both alkyl moieties, a phenylalkyl of 1 to 4 carbon atoms in the alkyl moiety, an alkyl group of 1 to 6 carbon atoms optionally interrupted by SO or 2 oxygen atoms, R ³ represents a methyl group, a methoxymethyl group or a dimethylaminoethyl group, R ⁴ is C 1 -C 3 alkyl, allyl, optionally carboxy, -COCO-OC 2 H 5, hydroxy or C 1 -C 3 dialkylamino substituted C 1 -C 3 alkyl in the form of isomers, mixtures of isomers, racemates and optical antipodes, with the proviso that R is not a trifluoromethyl group when R ² is an ethyl group, characterized in that the dihydropyridines of formula XII R 'Y ^!! R OOC Λ 1 i and ^R 'i / · K. | (R 1 in which R, R ^1, R ^2, R ³ and R ⁴ are as defined above, R ⁵ has the same meaning as R ² a R ⁸ is halogen, preferably chlorine or bromine, or is -O-R ⁷ , wherein R ⁷ is the usual alcohol protecting group, cyclizes at a temperature of from 20 to 300 ° C. 2. A process according to claim 1, wherein the corresponding compounds of formula (XII) are used as starting materials to give compounds of formula (I) in which: R is trifluoromethyl, cyano, chloro, fluoro, bromo, methyl or methylthio, R ¹ represents a hydrogen atom or a chlorine atom, R ² represents an alkyl group having 1 to 6 carbon atoms which is optionally interrupted by two oxygen atoms or -SO- or represents phenylalkyl having 1 or 2 carbon atoms in the alkyl part, R ³ is methyl, metho14 xymethylovou group or dimethylaminoethyl, R ⁴ is C 1 -C 3 alkyl or allyl, except for compounds in which R is trifluoromethyl when R ² is ethyl. 3. A process according to claim 1 wherein the corresponding compounds of formula (XII) are used as starting materials to give 4- (2-chlorophenyl) -1-ethyl-2-methyl-5-oxo-1,4,5-isopropyl ester. 7-tetrahydrofuro (3,4-b) pyriride-3-carboxylic acid. 4. The process of claim 1, wherein the corresponding compounds of formula XII are used as starting materials to give 4- (2-chlorophenyl) -1-ethyl-2-methyl-5-oxo-1,4,5 ethyl ester, 7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid, 4- (2-chlorophenyl) -1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuran [ethoxy] ethyl ester [3] 4-b] pyridine-3-carboxylic acid, 4- (2-chlorophenyl) -1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuran [3,4-b] isobutyl ester pyridine-3-carboxylic acid, 4- (2-methylphenyl) -1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro [3,4-] pyridine-3-carboxylic acid isopropyl ester or 4- (2-cyanophenyl) -1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid isopropyl ester.