CS258499B2 - Method of new dihydropyridine-lactols production - Google Patents

Abstract

Process for the production of new dihydropyridine lactols of formula (I) in which R · * · means a phenyl group which is optionally substituted with nitro, chloro, trifluoromethyl or alkyl with 1 to 3 carbon atoms, R2 represents C 1 -C 4 alkyl, which is optionally substituted with alkoxy with 1 or 2 carbon atoms; alkyl having 1 to 3 atoms carbon, and R4 is alkyl C 1 -C 4 isomers, mixtures of isomers, racemates or optical antipodes as well as their physiologically Salty salts, characterized in that to formyl derivatives of formula II it is treated in inert organic solvents or in water first with base and then acid. Produced compounds are used as medicaments, in particular for the treatment of diabetes

Description

The present invention relates to a process for the production of novel dihydropyridine lactols having valuable pharmacological properties, in particular, to lower blood sugar and to have effects on the circulatory system. The compounds produced can therefore be used as medicaments.

It has been found that the dihydropyridine lactols of formula (I)

in which r! represents a phenyl group which is optionally substituted by nitro, chloro, trifluoromethyl or C1-C3 alkyl,

R is C 1 -C 4 alkyl optionally substituted with C 1 or C 2 alkoxy, □

R is C 1 -C 3 alkyl and

R represents a C 1 -C 4 alkyl group, in the form of its isomers, mixtures of isomers, optical antipodes or racemates, as well as in the form of its physiologically acceptable salts, having valuable pharmacological properties, in particular reducing blood sugar and beneficially affecting the circulatory system.

The compounds of the invention may exist in the form of their salts. In general, these salts are compounds of the invention with inorganic or organic acids. However, physiologically acceptable salts of the compounds according to the invention with inorganic or organic acids are preferred. Examples are: hydrohalides, hydrogen sulphates, sulphates, hydrogenphosphates, acetates, maleates, citrates, fumarates, tartrates, lactates or benzoates.

The compounds of the invention exist in stereoisomeric forms, which either behave as image and mirror image (enantiomers) or do not behave as image and mirror image (diastereomers). The invention relates to both antipodes and racemates, as well as mixtures of diastereomers. Like the diastereomers, the racemic forms can be separated into stereoisomerically uniform components in a known manner (cf. E. L. Eliel, Stereoohemistry of Carbon Compounds, McGraw Hill, 1962).

The object of the present invention is a process for the preparation of the novel dihydropyridinolactols of the formula (I), characterized in that the formyl derivatives of the formula (II ⁾ by ₂ c,

R ³

CO ₂ R ⁶

CHO (li) in which

4

R to R are as defined above and

R is a straight or branched alkyl group having up to 8 carbon atoms, reacted in inert organic solvents or in water with a base first and then with an acid.

The preparation of the compounds of formula I according to the invention can be illustrated by the following reaction scheme:

Suitable solvents for the process according to the invention are water and all organic solvents which are inert under reaction conditions. These preferably include alcohols, such as methanol, ethanol, propanol or isopropyl alcohol, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide or hexamethyltriophosphoric triamide. Mixtures of the solvents mentioned may also be used.

Suitable bases for the process according to the invention are all customary inorganic or organic bases. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium methoxide or potassium tert-butoxide, alkali metals such as sodium, alkali metal hydrides such as sodium hydride or potassium hydride, alkali metal amides such as sodium amide or lithium diisopropylamide.

Suitable acids are the customary organic or inorganic acids. These preferably include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic carboxylic acids such as acetic acid.

The process according to the invention is carried out by first reacting the formyl derivative of the formula II in the abovementioned solvents with 100 to 5 mol, preferably 50 to 10 mol, of base, based on 1 mol of the formyl derivative, and then treating the reaction mixture with acids. The working up of the reaction mixture is carried out in a customary manner and by one skilled in the art.

The reaction is generally carried out at temperatures of from 0 to 150 ° C, preferably at temperatures of 20 to 100 ° C.

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

The starting compounds of the formula II are known or can be prepared by known methods (cf. DOS 26 29 892).

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

Said compounds reduce blood sugar and can be used to treat diabetes.

The blood sugar lowering effect was tested for the test compounds on male Wistar rats weighing between 140 and 190 g. For this purpose, rats were weighed for 18 hours prior to administration of the test substances, divided into groups of 6 and allowed to fast. Test substances are suspended in an aqueous 0.75% tragacanth suspension immediately prior to application using an agitator (Ultra-Turrax). Application of the tragacanth suspension (control animals) or substances suspended in the tragacanth is carried out by a swallowing probe.

Blood collection is performed in each rat at 30, 60 and 120 minutes after retro-orbital venous plexus application. 30 µl of blood was collected each time using an automatic device and the proteins were removed with 0.3 ml uranyl acetate (0.16%). After centrifugation, the glucose content is determined photometrically in the supernatant by the glucosoxidase method using 4-aminophenazone as a color indicator. Evaluation of the results is carried out by means of the Student's t-test, p = ≥ 0.05 being chosen as the significance limit.

Substances which cause a significant reduction in blood sugar concentration of at least 10 J at a certain point in time compared to a control group that only received a tragacanth suspension are reported to be effective.

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

Tabulkal

Compound Decrease in blood sugar concentration as a percentage of control (from Example No.) ^{* 1} 10 mg / kg po

29

34

The present invention also relates to pharmaceutical compositions comprising, in addition to non-toxic, inert, pharmaceutically acceptable carriers, one or more active ingredients produced by the process of the invention or consisting of one or more active ingredients produced by the process of the invention. The invention also encompasses the preparation of such compositions.

Pharmaceutical preparations in unit dosage forms also belong to the present invention. This means that the unit-dose preparations, for example tablets, dragees, capsules, pills, suppositories and ampoules, contain the active ingredient in an amount corresponding to a certain part or several times a single dose. The dosage units may comprise, for example

1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 single dose. A single dose preferably contains an amount of the active ingredient to be administered when administered, which usually corresponds to the whole, one-half or one-third or one-quarter of the daily dose.

Non-toxic, inert, pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and auxiliaries of any kind used in the preparation of such formulations.

Preferred pharmaceutical preparations include tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions.

Tablets, dragees, capsules, pills, and granules may contain the active ingredient (s) in addition to the usual carriers such as:

(a) fillers and extenders, such as starch, lactose, cane sugar, glucose, mannitol and silicic acid;

b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,

(c) moisture-retaining agents, such as glycerol;

(d) disintegrants, such as agar-agar, calcium carbonate and sodium bicarbonate;

(e) dissolution retardants such as paraffin; and

(f) resorption accelerators, such as quaternary ammonium compounds;

g) wetting agents, for example cetyl alcohol, glycerin monostearate,

(h) adsorbents such as kaolin and bentonite; and

i) lubricants, for example talc, calcium stearic acid and magnesium stearic acid, and solid polyethylene glycols, or mixtures of the compounds of a) to i).

Tablets, dragees, capsules, pills and granules may be provided with the usual coatings and coatings, optionally containing repeating agents, and which are also formulated such that the active ingredient (s) are dispensed only or preferably in a certain part of the intestinal tract, optionally wherein, for example, polymeric substances and waxes can be used as auxiliary insulating materials.

The active compound (s) may optionally be present in the form of microcapsules with one or more of the abovementioned carriers.

suppositories may contain, in addition to the active ingredient or in addition to the active ingredients, customary water-soluble or water-insoluble carriers, such as polyethylene glycols, fats, for example cocoa fat and higher esters (for example esters of C14 alcohol and C16 fatty acids); mixtures of these substances.

The solutions and emulsions may contain, in addition to the active ingredient, conventional carriers such as solvents, co-solvents and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils , in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures thereof.

For parenteral administration, solutions and emulsions can also be used in sterile as well as isotonic form for blood.

The suspensions may contain, in addition to the active compound (s), conventional carriers such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitan esters and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or agar of these substances.

Said compositions may also contain coloring agents, preservatives, as well as flavor enhancers, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.

The therapeutically active compounds should be present in the above pharmaceutical preparations preferably in a concentration of from about 0.1 to 99.5%, preferably from about 0.5 to 95% by weight, based on the weight of the total composition.

In addition to the active compounds according to the invention, the aforementioned pharmaceutical preparations can also contain other pharmaceutically active compounds.

The aforementioned pharmaceutical preparations are prepared in a customary manner according to known methods, for example by mixing the active substance (s) with the carrier or carriers.

The present invention also relates to the use of a compound of formula I and / or salts thereof, as well as pharmaceutical compositions containing the compounds of formula I and / or salts thereof, in human and veterinary medicine for the prophylaxis, amelioration and / or treatment of the above diseases.

In general, both in human medicine and in veterinary medicine, it has proven to be advantageous for β to administer an active compound of the invention or active compounds of the invention in a total amount of from about 0.01 to about 200 mg / kg, preferably in an amount of 0, 1 to 50 mg / kg body weight within 24 hours, optionally in the form of several individual doses to achieve the desired results.

However, it may also be necessary to deviate from the above dosage, depending on the type and body weight of the object being treated, the type and severity of the disease, the type of preparation and the mode of administration, as well as the time or time interval during which application performed. Thus, in some cases less than the abovementioned amount of active substance may be sufficient, while in other cases the abovementioned amount of active substance must be exceeded. However, it is well within the skill of one of ordinary skill in the art to ascertain the optimum dosage and mode of administration of the active ingredients.

Examples illustrating the production method

Example 1

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

1-ethyl-2-formyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-5-isopropyl ester is introduced in 40 mmol of 2N potassium hydroxide solution and the mixture was briefly heated to 50 ° C in a water bath and then allowed to stir for 1 hour at room temperature. The solution obtained is clarified by the addition of activated carbon and acidified with hydrochloric acid and the precipitate is filtered off.

@ 1 H-NMR (CDCl3) .delta. 0.8 (d, 3H), 1.1 (a, 3H); 1.3 (t, 3H), , 2, 3 (s, 3H), 3.4-4.0 (m, wide. 2H), , 4, 7 (m, 1H), 5.1 (s, 1H), , 5.9 (with, 1H) , 6.2 (with, wide, 1H), 7.3-8.3 (m. 4H)

The following compounds were also prepared in an analogous manner to that described in Example 1.

Example 2

4- (2-Chloro-phenyl) -1-ethyl-7-hydroxy-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro [1,4-b] pyridine-3-carboxylic acid isopropyl ester

145-147 ° C.

Example 3

4- (2-Chloro-phenyl) -1-ethyl-7-hydroxy-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro [3,4-b] pyridine-3-carboxylic acid ethyl ester

h ₃ ch ₂ co ₂ c. ÍI Ί TÍlT T ^CI h ₃ c JI u 1 CH, AND OH 1 ch ₃ Yield: 13% of theory (amorphous product). Mass spectrum: 377 (10 & lt ^{; +} & gt ^; , M ^& lt ^{; +} & gt ^; ), 348 (20%) 304 (10), 266 (100), 29 (40%)

Example 4

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

Yield: 30%.

Mass Spectrum: 371 (15% M ⁺ ), 328 (25%), 280 (80%), 278 (100%), 192 (20%), 164 (20%), 42 (50t), 29 (35%) »).

Example 5

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

Yield: 35%.

@ ¹ H-NMR (CDCl3) .delta. 0.8 (d, 3H), 1.1 (d, 3H), 1.3 (t,

3H), 2.3 (s, 3H), 3.5-3.9 (s, broad, 2H), 4.8 (hept, 1H), 5.3 (s, 1H),

5.9 (s, 1H), 6.1 (s, Broad, 1H), 7.2-7.6 (m, 4H).

Claims (2)

A process for the preparation of the novel dihydropyridinolactols of the general formula I (I) in which "1 represents a phenyl group which is optionally substituted by nitro, chlorine, trifluoromethyl or an alkyl group having 1 to 3 carbon atoms" means an alkyl group having 1 to 4 carbon atoms, which is optionally substituted by alkoxy having 1 or 2 carbon atoms means an alkyl group having 1 to 3 carbon atoms and is an alkyl group having 1 to 4 carbon atoms. in the form of their isomers, mixtures of isomers, racemates or optical antipodes, as well as their physiologically acceptable salts, characterized in that the formyl derivatives of the general formula II in which: R ⁴ to R ⁴ are as defined above, and R ⁵ represents a straight or branched alkyl group having up to 8 carbon atoms, acting in inert organic solvents or water first with a base and then with an acid. Process according to claim 1, characterized in that the inert organic solvents used are alcohols, ethers, in particular diethyl ether, dioxane and tetrahydrofuran, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide or hexamethyltriamide phosphoric acid.