KR830002275B1 - Method for preparing 1, 4-dihydropyridine compound containing fluorine - Google Patents

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Description

Method for preparing 1, 4-dihydropyridine compound containing fluorine

The present invention relates to a process for the preparation of new fluorine-containing 1,4-dihydropyridine compounds that affect circulation and are effective in increasing coronary therapy, hypertension or peripheral blood outflow.

In the above structural formula

R is a hydrogen atom or an optionally substituted alkyl or aralkyl group,

R ¹ and R ⁶ are the same or different and are each optionally substituted alkyl group,

R ⁴ is optionally substituted with 1 or 2 identical or different substituents in an alkyl group or nitro, cyano, trifluoromethyl, halogen, azido, trifluoromethoxy, alkyl, alkoxy, alkylmercapto and SO ₂ -alkyl Aryl groups, quinolyl, pyridyl, pyrimidyl, thienyl or furyl groups, optionally substituted by alkyl or halogen,

R ⁵ represents an alkyl group optionally substituted with halogen or an aminoalkyl in which the other hydrogen atoms of the alkenyl, alkynyl, alkoxyalkyl, amino group can be replaced by one or two alkyl groups simultaneously or by aralkyl groups Represents a group or

R ² and R ³ are the same or different and are straight, branched or cyclic aliphatic having at least one perfluorinated carbon atom in which one of the two substituents is a hydrogen atom and another substituent or two substituents are substituted with 2 or 3 fluorine; Hydrocarbon group, wherein the hydrocarbon group is optionally interrupted by a -CH ₂ -X-CH ₂ -group, X is oxygen or sulfur, or R ² and R ³ together with the CH group have 4 to 7 ring numbers Forming a saturated isocyclic ring, which ring may be optionally substituted with an alkyl group containing at least one perfluorinated carbon atom and also containing one or two perfluorinated carbon atoms.

Already, 1,4-dihydropyridine carboxylic acid esters have been published which have properties effective for the circulation obtained by reacting aldehydes having β-ketocarboxylic acid esters with enaminocarboxylic acid esters (see German Publications 2,117,571 and 2,117,573). Dihydropyridine derivatives which are compounds of the invention containing perfluorinated carbon atoms in ester groups have not yet been described.

According to the present invention, the preparation of the compound of the present invention is as follows.

(a) The following formula (Ⅱ _a) 1 mole of enamine the following structural formula (Ⅲ _a) of β- keto carboxylic acid ester and one mole of the following structural formula (Ⅳ) of aldehyde and one mole of the reaction (wherein formula (Ⅲ _a) with ( Ilyne compound of formula (V _a ) formed from the compound of IV) is optionally separated and then reacted.

In the above structural formula

R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as mentioned above.

(b) the following structural formula (Ⅱ _b) enamine 1 mol of the following structural formula (Ⅲ _b) of β- keto carboxylic acid ester and one mole of the following structural formula (Ⅳ) of aldehyde and one mole of the reaction (wherein formula (Ⅲ _b) of ( Ilyne compound of formula (V _b ) formed from compound of IV) is optionally separated and then reacted.

In the above structural formula

R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as mentioned above.

Preparation processes (a) and (b) are optionally reacted at temperatures between 20 ^° and 150 ° C. in the presence of water or an inert organic solvent. If the compounds of the present invention have basic substituents, these compounds can be converted into salts of suitable organic or inorganic acids.

The compounds of the present invention and their pharmaceutically toxic acid addition salts exhibit potent pharmacological action. In particular, these compounds have a significant effect on the circulation and are preferably used to increase the amount of coronary therapy, hypertension or peripheral blood. Because of their new structure and in particular the presence of carbon atoms treated with perfluorine, the compounds of the present invention have an advantageous action. Therefore, their use represents progress in pharmacy.

Enamines of the formulas (II _a ) and (II _b ) which can be used in the present invention can be prepared by known methods from known or corresponding β-diketo compounds and amines (A. Prinner B 34,4239 / 40 (1901)).

For example:

2-trifluoro-ethyl β-aminocrotonate, 2, 2-hexa fluoro-isopropyl β-aminocrotonate, 2-difluoromethylisopropyl β-aminocrotonate, 3, 4- Penta-fluorobutyl β-aminocrotonate, 2-trifluoromethyl-cyclohexyl β-aminocrotonate, 2-trifluoroethoxy-ethylβ-aminocrotonate, methyl β-aminocroto Nitrate, ethyl β-aminocrotonate, isopropyl β-aminocrotonate, 2-benzylaminoaryl β-amino-crotonate, 2-chloroaryl β-aminocrotonate, 2-methoxymethyl β-aminocrotonate, 2-methylmercaptoethyl β-aminocrotonate, cyclohexyl β-aminocrotonate, allyl β-aminocrotonate, propargyl β-aminocrotonate, and tetrahydro- Furfuthyl β-amino-crotonate.

Β-ketocarboxylic acid esters of the general formulas (III _a ) and (III _b ) which can be used in the present invention can be prepared by known or known methods (Houben-Weyl, Methods of Organic Chemistry, Ⅶ / 4, 230). et. Seq. (1968).

For example:

Methyl acetoacetate, ethyl acetoacetate, isopropyl acetoacetate, hexyl acetoacetate, benzyl acetoacetate, cyclohexyl acetoacetate, 2-morpholinoethyl acetoacetate, 2-dimethylaminoethyl acetoacetate, 3-diethylaminopropyl acetoacetate Acetate, 2-methoxyethylacetoacetate, 2-ethoxyethyl acetoacetate, 2-isopropoxyethyl acetoacetate, 2-methylmercapto-ethyl acetoacetate, 2-benzylaminoethyl acetoacetate, 2- (α- Methylbenzyl) -amino-ethyl acetoacetate, 2- (α-methylphenethyl) -aminoethyl aceto acetate, trifluoroethyl acetoacetate, 2-hexafluoroisopropyl acetoacetate, 2, 2-hexafluoroiso Propyl acetoacetate, 3, 4-pentafluorobutyl acetoacetate, 3-diflu Romero butyl-propenyl acetoacetate, 4-trifluoromethyl-cyclohexyl acetoacetate bit, 2-Difluoro-ethoxy-ethyl acetoacetate and 2-trifluoroethyl-mercapto-ethylacetoacetate.

Aldehydes of formula (IV) which can be used in the present invention are known but can be prepared by known methods (see E. Mosetting, Org.Reactions VII, 218 et seq. (1954)).

An example is as follows.

Acetaldehyde, benzaldehyde, o-nitrobenzaldehyde, m-chlorobenzaldehyde, o-chlorobenzaldehyde, o-fluorobenzaldehyde, m-fluoromethylbenzaldehyde, m-chlorobenzaldehyde, o-trifluoro Benzaldehyde, m-trifluoromethylbenzaldehyde, o-methylbenzaldehyde, m-methylbenzaldehyde, o-methoxybenzaldehyde, m-methoxybenzaldehyde, o-trifluoroethoxybenzaldehyde, m -Trifluoroethoxy benzaldehyde, o-methylmercaptobenzaldehyde, m-methylmercapto benzaldehyde, o-cyclopropylbenzaldehyde, o-azidobenzaldehyde, β-azidobenzaldehyde, α-pyridyl Aldehyde, β-pyridylaldehyde, α-furfurol, β-furfurol, thiophen-1-aldehyde, thiophen-2-aldehyde, pyrimidine-5-aldehyde, 4-methyl-pyrimidine-5- Aldehydes, quinoline-2-aldehydes, naphthalene-1-aldehydes and naphthalene-2-aldehydes.

Diluents that can be used are water and all inert organic solvents. Mainly preferred are alcohols such as ethanol, methanol, isopropanol and ethers such as dioxane, diethylether, tetrahydrofuran, glycol monomethylether and glycol dimethylether or glacial acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile and pyridine.

The reaction temperature can vary within a relatively wide range. Generally, the reaction is carried out between 20 and 150 ° C., preferably at the boiling point of the particular solvent.

This reaction can be carried out under elevated pressure as well as standard pressure, generally at a standard pressure.

Of particular interest are compounds of the invention wherein in formula (I) R is a hydrogen atom, an alkyl group or benzyl group having 1 or 2 carbon atoms,

R ¹ and R ⁶ are the same or different and are alkyl groups having 1 to 4 carbon atoms,

R ⁴ is in each case an alkyl and alkoxy group having 1 or 2 carbon atoms in nitro, cyano, trifluoromethyl, halogen, azido, trifluoromethoxy, alkyl, alkoxy, alkylmercapto and SO ₂ -alkyl An optionally substituted phenyl group or a pyridyl group.

를 나타낸다.R ⁵ represents an alkyl group having 1 to 6 carbon atoms optionally substituted with halogen or an alkoxyalkyl, alkenyl or alkynyl group having up to 6 carbon atoms, or an amino group having 1 to 4 carbon atoms in the alkyl group Represents an aminoalkyl group in which two hydrogen atoms of the group may be replaced simultaneously or by benzyl groups by one or two alkyl groups having 1 to 4 carbon atoms

Indicates.

R ² and R ³ are the same or different in this case and only one of the two substituents is a hydrogen atom, and another substituent or two substituents in each case are substituted with 1, 2 or 3 perfluorinated with 2 or 3 fluorine Up to 6 carbon atoms containing carbon atoms are preferred and represent straight, branched or cyclic alkyl groups of up to 8 carbon atoms (where the alkyl groups are optionally interrupted by —CH ₂ —X—CH ₂ — groups and X is oxygen or sulfur Or R ² and R ³ together with the CH group form a saturated isocyclic ring having 4 to 7 rings, which contains 1, 2 or 3 perfluorinated carbon atoms and also 1 or 2 perfluorinated It may be optionally substituted with an alkyl group having 1 to 4 carbon atoms which may have a carbon atom.

In addition to those mentioned in the Examples, the following compounds according to the invention also appear as follows.

This new compound has materials that can be used as drugs. They have a broad spectrum of drug action and the following main actions are demonstrated in detail in animal experiments.

1. By parenteral oral and sublingual administration, these compounds have distinct and long lasting coronary vasodilation.

This coronary vessel's action is simultaneously enhanced by nitrite-like effects that reduce the burden on the heart.

These compounds affect or mitigate tropical deaths in terms of energy savings.

2. The excitability and stimulus-induced system by the stimulation of the heart is reduced, so there is anti-defibrillation action that can be proved as a therapeutic amount.

3. In the presence of this compound, the activity of smooth muscle in the blood vessels is significantly reduced. Such vasospasm may occur in the entire vasculature, or manifestly in somewhat isolated localized vascular regions, such as the central nervous system.

4. This compound lowers blood pressure in normal or hypertensive animals and can be used as a treatment for hypertension.

5. This compound has a strong myocardial action, particularly on the smooth muscle of the stomach, intestinal urogenital system and respiratory system.

As described above, this invention also relates to the use of the compounds of the present invention in human and veterinary medicine.

The present invention refers to a pharmaceutical mixture containing the active ingredient of the compound of the present invention in the mixing of a solid or liquefied diluent or a liquid diluent of less than 200 and more preferably a molecular weight of 200 or less without the presence of surfactants. .

The present invention refers to a pharmaceutical mixture which is sterile and physiologically contains the active ingredient of the compound of the present invention in the form of an isotonic solution.

The invention also refers to a drug in the form of a dosage unit of the compound of the invention.

The present invention also refers to drugs as tablets, dragees, capsules, pills, injections or suppositories comprising the sugar tablets and granules of the compounds of the invention.

As used herein, "drug" refers to a physically segregated portion suitable for drug administration.

Drugs in dosage unit form as used herein are administered together with the carrier, simultaneously and together in a bag, together with a daily dose or up to four times the daily dose of a compound of the present invention, or a dose up to 1/40 Suitable for physically segregated parts. Drugs can be administered once, twice, three times, four times a day, for example, relative to the daily dose, or 1/2, 1/3 or 1/4 of the daily dose. .

According to the present invention the pharmaceutical mixtures can be prepared in the form of solvents and emulsions, syrups, granules or powders, for example, containing active ingredients in sprays, lotions, suspensions, aqueous or drainage diluents, including ointments, gels, pastes, creams, aerosols. Have

Diluents used in pharmaceutical mixtures also apply to tablets, dragees, capsules and pills, which include the following:

(a) excipients and weight: for example starch, sugar, mannitol, silicic acid

(b) Binders: for example carboxymethyl celrose and other celrose derivatives, alginates, gelatin and polyvinyl pyrrolidone

(c) wetting agents, for example glycerol

(d) Degradants: for example agar, calcium carbonate, sodium bicarbonate

(e) Degradation retardants, for example paraffin

(f) absorption accelerators, eg quaternary ammonium compounds

(g) Surfactants: e.g. cetyl alcohol, glycerol monostearate

(h) adsorbents, for example kaolin and bentonite

(i) Suspending agents, for example, talc, calcium stearate and magnesium, and solid polyethyl glycol.

Tablets, dragees, capsules, pills made from the pharmaceutical mixtures of the present invention may be coated with customary coatings, shells, and protective molds containing opacifiers. These compounds are so configured that the active ingredient is liberated only or preferably in particular parts of the intestine, possibly even over a time period. The sheaths, sheaths and protective molds are made of, for example, polymeric materials or waxes. These ingredients can be made into a minimum capsule form, such as one or several diluents described above.

Diluents used in pharmaceutical mixtures are also applied to make suppositories, for example, ordinary water soluble diluents such as polyethylene glycol and fats (expensive esters of cocoa butter and 16 carbon fatty acids and 14 alcohols of carbon) or mixtures of these diluents.

Pharmaceutical mixtures of ointments, pests, creams and gels can also be used, for example, animal and vegetable fats, waxes, paraffins, starches, trigacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc, zincated or mixtures of these substances. General diluents, such as these, may be contained.

Pharmaceutical mixtures of powders and sprays may also contain common diluents such as, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder or mixtures of these materials.

Pharmaceutical mixtures of solvents and emulsions contain customary diluents such as solvents, disintegrating agents or emulsifiers, especially water, ethyl alcohol, iso Propyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butyl glycol, dimethylformamide, oil (e.g. pulverized soybean oil), glycerol, tetrahafurfurfuryl alcohol, Fatty acid esters and mixtures of polyethylene glycol and sorbitol.

Parenteral administration solutions and emulsions should be sterile and, if possible, blood extracts.

Pharmaceutical mixtures of suspensions include, for example, water, ethyl alcohol, liquid diluents such as propylene glycol, surface active agents such as ethoxylated isostearyl-alcohols, polyethylene sorbitan, sorbitan esters, and fine crystals of cellulose, aluminum-methahydroxy It contains common diluents such as side, bentonite, agar, tragacanth or mixtures.

All pharmaceutical mixtures according to the present invention may contain colorants and preservatives as well as perfumes and sweeteners such as, for example, peppermint and eucalyptus flavours and saccharin.

Pharmaceutical mixtures according to the present invention generally contain from 0.5 to 90% of the active ingredient in the total composition weight.

In addition to the compounds of the present invention, the pharmaceutical mixtures and drugs according to the present invention may contain other pharmaceutically effective compounds. Again these drugs contain some compounds of the invention.

Any diluent in the drug of the invention may be any of those mentioned above in connection with the drug mixture of the invention. These drugs are the only diluents and include solvents up to 200 molecular weight.

Separately agglomerated parts of the drug according to the invention are generally applied in the form or packaging for drug administration, for example in tablets, pills, dragees, capsules, suppositories and ampoules, including sugar-containing tablets and granules. It can be something. Some of these forms are determined to retard the release of the active ingredient. Some capsules with a protective sheath become part of a drug that is physically packed together.

The preferred daily dose for intravenous administration of the drug of the present invention is 0.25 to 5 mg of the active ingredient, oral to 2.5 to 250 mg of the active ingredient.

The pharmaceutical mixtures and drug products mentioned above are made by methods known in the art, for example, when an active ingredient is mixed with a diluent to form a pharmaceutical composition (e.g. granules) and make it into a pharmaceutical mixture (e.g. tablets). .

The present invention further provides a method for preventing, alleviating and treating the above-mentioned diseases in humans and non-human animals by administering to the animal either alone or in combination with a diluent or in the form of a drug according to the invention.

It is observed that such active compounds are administered orally, for example parenterally or topically, for example intramuscularly, intraperitoneally, subcutaneously and intravenously, particularly preferably sublingually or intravenously. Therefore, drug mixtures and drugs should preferably be suitable for oral or parenteral administration. Administration in the method of the invention is preferably oral or parenteral administration.

In general, an intravenous dose of 0.001 mg / kg to 1 mg per day more preferably 0.005 to 0.1 m, oral doses of 0.005 mg to 10 mg per kg of weight per day, more preferably 0.05 to 5 mg per day It is proved to be advantageous for this effect. Nevertheless, in particular, depending on the nature and weight of the human or animal to be treated, the function of the individual to be treated, the systematic form in which the active ingredient is administered and the manner in which it is administered and the course of the disease or the interval at which it is administered, the dose may sometimes There is a need. As such, in some cases it may be sufficient to use an amount less than the minimum mentioned above, while in other cases it may exceed the maximum mentioned above to reach the required result. Where high doses are administered, it is appropriate to distribute these amounts into several individual doses over a period of time.

The following examples demonstrate the preparation of the compounds of the present invention.

Example 1

3-ethoxycarbonyl-2, 6-dimethyl-4- (3-nitropinyl) -5-trifluoroethoxycarbonyl-1, 4-dihydropyridine

To 5 g of trifluoroethyl amino crotonate dissolved in 500 ml of ethanol, 7.3 g of ethyl m-nitrobenziridine aceto acetate was heated at reflux for 3 hours. The reaction mixture was cooled and filtered to yield 7.8 g of pale yellow crystals with a melting point of 192 ° C. and 67% of theory.

Example 2

2, 6-dimethyl-3-β-methoxyethoxycarbonyl-4- (3-nitrophenyl) -5-trifluoro ethoxycarbonyl-1, 4-dihydropyridine.

5 g of trifluoroethyl aminocrotonate was heated to reflux with 3.1 g of β-methoxyethyl m-nitrobenzylidene aceto acetate dissolved in 500 ml of propanol for 3 hours. The reaction mixture was filtered to yield 9.3 g of pale yellow crystals, 74% of theory with a melting point of 169 占 폚.

The compounds described in the table below are obtained in a similar manner as in Example (1).

Among the novel 1,4-dihydropyridine salts of the present invention, pharmaceutically harmless salts are particularly important and preferred.

The new free 1,4-dihydropyridine and their salts of general formula (I) can be internally converted in a suitable manner by internal conversion methods already known in the art.

The invention also consists of pharmaceutically possible bioprecursors of the active compounds of the invention.

As used herein, the term "pharmaceutically possible bioprecursor" of the active compound of the present invention refers to a compound which differs from the active compound but which has a structural formula which is administered to an animal or human and converted into the active compound in the body of a patient.

Claims (1)

A process for preparing 1, 4-dihydropyridine containing fluorine of the following formula (I) by reacting 1 mol of the amine of formula (II _a ) with 1 mol of the iridene compound of formula (V _a ).

Wherein R is a hydrogen atom or an optionally substituted alkyl or aralkyl group, R ¹ and R ⁶ are the same or different and each an optionally substituted alkyne group, and R ⁴ is an alkyl group or nitro, cyano, trifluoromethyl , An aryl group optionally substituted with one or two same or different substituents among halogen, azido, triurouromethoxy, alkyl, alkoxy, alkylmercapto and SO ₂ -alkyl, or a qui optionally substituted by alkyl or halogen Noyl, pyridyl, pyrimidyl, thienyl or furyl group, R ⁵ represents an alkyl group optionally substituted with halogen or an alkyl group of two hydrogen atoms of alkenyl, alkynyl, alkoxyalkyl, amino group having 1 or 2 And / or an amino alkyl group which may be substituted by one aralkyl group or a structural formula

R ² and R ³ are the same or different, a straight chain having at least one perfluorinated carbon atom in which one of the two substituents is a minor atom and the other substituent or bisubstituent is both substituted with 2 or 3 fluorine; , Branched or cyclic aliphatic hydrocarbon group, wherein the hydrocarbon group is optionally interrupted by a group of -CH ₂ -X-CH _2- , X is oxygen or sulfur, or R ² and R ³ together with the CH group are 4 To form a saturated isocyclic ring having from 7 to 7 ring members and the bicyclic may be optionally substituted with an alkyl group containing at least one perfluorinated carbon atom and also containing 1 or 2 perfluorinated carbon atoms.