DE3816360A1 - (-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylates - Google Patents

Abstract

(-)-Menthyl 2-amino-1,4-dihydropyridinedicarboxylates of the formula (I), <IMAGE> in which the substituents and symbols have the meanings given in the description, are novel compounds possessing surprising pharmacological properties.

Description

Field of application of the invention

The invention relates to new amines, processes for their preparation, their use and medicines containing them. The compounds of the invention are used in the pharmaceutical industry for the manufacture of pharmaceuticals.

Known technical background

It is known that certain 1,4-dihydropyridine derivatives substituted in various ways have pharmacologically useful properties. Surprisingly it has now been found that the new compounds described in more detail below have particularly interesting pharmacological properties, by which they differ from the compounds of the prior art in an advantageous manner Differentiate way.

Description of the invention

The invention relates to new amines of the formula I.

wherein Cy is a cycle of the formula

represents in which Y represents oxygen (O), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula

means

R1 means amino (NH₂), R2 is hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 represents a (-) menthyl radical, R4 and R5 are the same or different and are hydrogen, hydroxy, halogen, Nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, in whole or in part 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl substituted by fluorine, Amino or mono- or di-1-4C-alkylamino mean and R61-6C-alkyl or 3-7C-alkoxyalkyl means

and the salts of these compounds.

1-6C-alkyl is straight-chain or branched and means, for example, one Hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, Isopropyl or especially ethyl or methyl radical.

3-7C-Alkoxyalkyl stands for example for an ethoxyethyl, propoxyethyl, Isopropoxyethyl, butoxyethyl, methoxypropyl, 2-methoxy-1-methylethyl, 2- Ethoxy-1-methylethyl or in particular methoxyethyl radical.

The (-) - menthyl residue is the residue derived from (1R: 3R: 4S) -p-menthanol- (3).

Halogen in the sense of the invention means bromine, fluorine and especially chlorine.  

1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl or in particular Methyl residue.

1-4C-alkoxy contains one of the above in addition to the oxygen atom 1-4C alkyl groups. The methoxy and ethoxy radicals are preferred.

All or part of fluorine-substituted 1-4C-alkoxy is, for example 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular Difluoromethoxy.

1-4C-Alkoxycarbonyl contains one of the above in addition to the carbonyl group 1-4C alkoxy groups. The methoxycarbonyl and the ethoxycarbonyl radical are preferred.

2-5C-acyl contains one of the above in addition to the carbonyl group 1-4C alkyl groups. The acetyl radical is preferred.

Mono- or di-1-4C-alkylamino contains one or two in addition to the nitrogen atom the aforementioned 1-4C-alkyl radicals. Di-1-4C-alkylamino is preferred, and here in particular dimethyl-, diethyl- or diisopropylamino.

All salts with acids can be considered as salts. They are particularly worth mentioning pharmacologically acceptable salts commonly used in the pharmaceutical industry used inorganic and organic acids. Pharmacological incompatible salts, for example in the manufacture of the invention Industrial-scale compounds initially arise as process products can, by methods known to those skilled in pharmacological tolerated salts transferred. Water-soluble, for example, are suitable as such and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, Hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, Hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, Succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate, but also salts with bumetanide, Furosemide, azosemide, galosemide, besunid, piretanide, etacrynic acid, tienilic acid or 4-chloro-sulfamoyl-benzoic acid.  

Compounds according to the invention which are to be emphasized are those of the formula I in which

CyPhenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl or benzoxdiazolyl, R1 means amino (NH₂), R2 means methyl or ethyl, R3 represents a (-) menthyl residue and R6 denotes methyl, ethyl or isopropyl,

and their salts.

Preferred compounds according to the invention are those of the formula I in which

Cy3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylphenyl means R1 means amino (NH₂), R2Methyl means R3 represents a (-) menthyl residue and R6 denotes methyl or ethyl,

and their salts.

The following compounds may be mentioned as examples:
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3- (propyl-2) ester,
2-amino-1,4-dihydro-6-methyl-4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-difluoromethoxyphenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-difluoromethoxyphenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methylpyridin-3,5-dicarb-one acid 5-ethyl-3 - (-) - menthyl ester,
2-amino-4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-pyridyl) pyridine-3,5-dicarboxylic acid - 5 - (-) - methyl 3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-trifluoromethylphenyl) pyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
2-amino-4- (2,3-dichlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5-(-) - menthyl-3-methyl ester,
2-amino-4- (2,1,3-benzoxdiazol-4-yl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5-(-) - menthyl-3-methyl ester,
2-amino-1,4-dihydro-6-methyl-4- (2-pyridyl) pyridine-3,5-dicarboxylic acid - 3-ethyl-5 - (-) - menthyl ester,
2-amino-4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid, 3-ethyl-5 - (-) - menthyl ester,
2-amino-4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylic acid 5 - (-) - menthyl-3-methyl ester,
and their salts.

The compounds of formula I have at least four centers of chirality, and three in the (-) - menthyl radical and one in the 4-position of the 1,4-dihydropyridine ring. The invention encompasses both all enantiomers and all diastereomers as well as racemates and mixtures of compounds of formula I. The compounds of formula I with different configuration in the 4-position of the dihydropyridine ring and in the rest of the molecule of the same configuration are diastereomeric to each other.

Another object of the invention is a method for producing the invention Compounds and their salts. The process is characterized by that he  

• a) cinnamic acid derivatives of the formula II with amidines of the formula III or
• b) keto compounds of the formula IV with amidines of the formula III and aldehydes of the formula V implemented and, if desired, subsequently obtained salts converted into the free bases or bases obtained into the salts, where Cy, R1, R2, R3, R4, R5 and R6 have the meanings given above and where the starting compounds are used as such or in the form of their salts .

Refinements of the method are those in which in the formulas II to V the substituents or symbols Cy, R1, R2, R3, R4, R5 and R6 which in the sub- and secondary claims have the meanings given.

The process according to variants a and b is carried out in suitable, preferably inert organic solvents. Examples include alcohols, such as t-butanol, methanol, isopropanol or in particular ethanol, hydrocarbons, such as toluene or xylene, ethers such as dioxane, diethyl ether, tetrahydrofuran, Glycol monoethyl ether, glycol dimethyl ether or other, for example polar solvents such as dimethylformamide, dimethyl sulfoxide, acetonitrile or Hexamethylphosphoric triamide, or chlorinated hydrocarbons such as methylene chloride, Chloroform or tetrachlorethylene.

The reaction temperatures - depending on the reactivity of the starting materials - in one vary wide range. In general, the reaction at temperatures between 20 ° C and 150 ° C, preferably between 20 ° C and 100 ° C, especially at the boiling point of the solvent used.

The method according to the invention according to variant a is carried out in Presence of a base, for example in the presence of an alkali alcoholate, such as Sodium methylate or sodium ethylate.

The substances according to the invention are isolated and purified in known way z. B. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or one of the usual cleaning methods, such as column chromatography on a suitable support. The separation of diasteromers is carried out in a manner known to those skilled in the art, for example by recrystallization or by chromatography.

Acid addition salts are obtained by dissolving the free base in a suitable one Solvents, e.g. B. in a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (Ethanol, isopropanol), which contains the desired acid or which the desired Acid is then added.  

The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent obtained for the addition salt or by evaporating the solvent.

Salts obtained can by alkalization, e.g. B. with aqueous ammonia solution, be converted into the free bases, which in turn into acid addition salts can be transferred. In this way, pharmacologically tolerated acid addition salts in pharmacologically tolerated acid addition salts convert.

The starting compounds are known from the literature or can be obtained in analogy to those known from the literature Methods are made. The cinnamic acid derivatives II can for example in analogy to G. Jones ["The Knoevenagel Condensation" in Org. Reactions, Vol. XV, 204f (1967)]. The amidines III can according to H. Yamanaka et al., Heterocycles 1976, 1854. The keto compounds IV can according to D. Borrmann ["implementation of diketene with alcohols, Phenols and Mercaptans "in Houben-Weyl, Methods of Organic Chemistry, Vol. VII / 4, 230ff (1968)] or Y. Oikawa et al [J. Org. Chem. 43, 2087 (1978)] will.

The above manufacturing processes are given for illustration only, and the preparation of the compounds of formula I according to the invention not limited to these procedures. Rather, every modification is this Process in the same way for the preparation of the compounds according to the invention applicable.

The following production examples are intended to explain the invention in more detail without restrict them. Mp. Means melting point, h stands for hours, min for Minutes, Kp. Stands for boiling point, dec. means decomposition.

Examples End products 1. 2-amino-1,4-dihydro-6-methyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-ethyl-5 - (-) - menthyl ester

To 18.67 g of ethyl amidinoacetate and 8.33 g of 2-acetyl-3- (3-nitrophenyl) - acrylic acid - (-) - menthyl ester in 80 ml of ethanol is added dropwise at the boiling point sodium ethylate solution prepared from 1.15 g sodium and 50 ml ethanol within of 60 min and the reaction mixture is then refluxed for a further 2 h. After concentrating the reaction mixture, the residue obtained is between Ethyl acetate, sodium hydrogen carbonate solution and then water distributed. The organic phase is concentrated after drying over sodium sulfate and chromatograph the residue obtained on a silica gel column with dichloromethane-ethanol (99 + 1) as the eluent. The restricted product fraction gives 19 g of a solidly foamed residue, in diethyl ether / petroleum ether is recrystallized. The title compound is obtained as a fine colorless Needles with a melting point of 154-55 ° C. Yield: 17.1 g.  

Output connections A. 2-Acetyl-3- (3-nitrophenyl) acrylic acid - (-) - menthyl ester

15.6 g of acetoacetic acid - (-) - menthyl ester and 9.8 g of 3-nitrobenzaldehyde are in 160 ml of benzene are mixed with 8 ml of glacial acetic acid and 0.7 ml of piperidine and then the mixture heated to boiling on the water separator under reflux until about 1.2 ml of water. After cooling the solution with water and dilute sodium hydrogen carbonate solution, over sodium sulfate dried and concentrated to dryness in vacuo. The remaining tough, yellow-orange oil is reacted further without further purification.  

Industrial applicability

The compounds of the formula I according to the invention and their salts have valuable ones Properties that make them commercially usable. You pose in particular effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds of the invention, the paired is with a low toxicity, is particularly evident in a slow entering, strong and long-lasting lowering of blood pressure. Furthermore the compounds according to the invention have an inhibitory effect on calcium influx as well as a promoting effect on the potassium outflow of cells, smooth muscle relaxing and peripheral, coronary, cerebral and renal vasodilator as well salidiuretic, antithrombotic, antiarteriosclerotic and inexpensive hemorheological properties.

In its excellent effectiveness, which is paired with a low toxicity and the absence of significant side effects, the invention differs Connections in a surprising and advantageous manner from the Prior art compounds.

The fact that the inventive (-) - menthyl ester a much stronger and especially longer lasting Effect as the known methyl or ethyl esters, but also as the enantiomers (+) - Show menthyl ester. The latter fact in particular was for the Specialist not predictable because of the in the European patent application 26 317 results were to be expected that the pharmacological Not effective due to the different configuration in the chiral Ester residue, but only by the configuration of the carbon in the 4-position of the dihydropyridine ring is affected.

Examples of advantageous properties of the compounds I are: the extent of the drop in blood pressure, the prolonged persistence of the drop in blood pressure, the good controllability of lowering blood pressure, the surprisingly low and at repeated dosing heart rate increase, the excellent Bioavailability, the wide therapeutic range, the lack of central side effects, the lack of kinetic interactions with other substances, the absence a development of tolerance, the balanced physical properties and the great stability.  

The excellent activity of the compounds of the formula I according to the invention and their salts allow their use in human medicine, being used as an indication especially primary (essential) and secondary, arterial and pulmonary Hypertensions of all degrees of severity, coronary heart diseases (coronary insufficiency, Angina pectoris, myocardial infarction, etc.), peripheral and cerebral circulation disorders (Stroke, temporary cerebral circulatory disorders, migraines, Dizziness, renal artery narrowing etc.), hypertrophic cardiomyopathy, heart failure, Diseases based on increased water and sodium retention and diseases that are based on an increased calcium influx, such as e.g. B. Spasms of smooth muscle organs (respiratory tract, gastrointestinal tract, urogenital tract etc.) as well as arrhythmia, arteriosclerosis and cell damage of various Genesis (e.g. hypoxia) can be considered.

Another object of the invention is therefore a method for treatment of mammals, especially humans suffering from any of the above diseases are ill. The method is characterized in that the sick Individual a therapeutically effective and pharmacologically acceptable Amount of one or more compounds of formula I administered.

The invention also relates to the compounds of the formula I for use in the treatment of the diseases mentioned.

The invention also encompasses the use of compounds of the formula I in the manufacture of medicines to combat the diseases mentioned be used.

Another object of the invention are pharmaceuticals, the one or more Contain compounds of general formula I.

The pharmaceuticals are manufactured according to methods known per se and familiar to the person skilled in the art produced. The medicinal products according to the invention are pharmacological active compounds (= active ingredients) either as such or preferably in Combination with suitable pharmaceutical excipients in the form of tablets, Coated tablets, capsules, suppositories, plasters (e.g. as TTS), emulsions, suspensions, Aerosols, sprays, ointments, creams, gels or solutions are used, wherein the active ingredient content is advantageously between 0.1 and 95%.

Which excipients are suitable for the desired pharmaceutical formulations are familiar to a person skilled in the art on the basis of his specialist knowledge. In addition to solvents,  Gel formers, suppository bases, tablet excipients and other active substances For example, antioxidants, dispersants, emulsifiers, Defoamers, flavoring agents, preservatives, solubilizers, Dyes or in particular permeation promoters and complexing agents (e.g. cyclodextrins) can be used.

The active substances can be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).

In general, it has proven advantageous in human medicine that or the active ingredients when administered orally in a daily dose of about 0.01 to about 10, preferably 0.05 to 5 mg / kg body weight, if desired in the form of several, preferably 1 to 4 single doses to achieve the desired result to administer. With parenteral treatment, similar or (especially when the active ingredients are administered intravenously) lower doses are used. With creeping dosage if a lower dose is given at the start of treatment, then slowly switched to a higher dose. After reaching the desired therapeutic success will go back to a lower dose.

The determination of the optimal dosage and type of application required The active ingredients can easily be used by any specialist on the basis of their specialist knowledge respectively.

Should the compounds of the invention and / or their salts for treatment of the diseases mentioned, the pharmaceutical preparations also one or more other pharmacologically active ingredients other groups of drugs, such as other vasodilators, antihypertensives, alpha-1 receptor blockers, alpha-2 receptor stimulators, beta-1 receptor blockers, beta-2 receptor stimulators, ACE inhibitors, nitro compounds, cardiotonics, Diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, anticoagulants, Anticholinergics, methylxanthines, antiarrhythmics, antihistamines, dipamine stimulators, Serotonin receptor blockers etc., such as nifedipine, dihydralazine, Prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, Digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, Polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, Total rauwolfia alkaloids, acetylsalicylic acid, bezafibrate, warfarin, Atropine, theophylline, lidocaine, astemizole, bromocryptine, ketanserin etc. included.  

pharmacology

The antihypertensive activity of the compounds according to the invention can be modeled the spontaneously hypertensive rat can be detected.

The compounds listed below are used to determine the antihypertensive effect in the indicated doses on four consecutive days on 6 each male rats (strain SHR / N / Ibm / Bm, 250-350 g) with genetically determined high pressure (systolic blood pressure <180 mm Hg) once a day by gavage administered. The blood pressure is measured 6 and possibly 2 or 24 hours after substance administration.

The blood pressure measurement is carried out in a warming chamber at 36 ° C to achieve better blood flow to the tail artery. For this, the animals placed in perforated sheet metal cages and 20-40 minutes after warming up measured. To measure the systolic arterial pressure, a ring-shaped cuff with inflatable rubber membrane to prevent the Blood circulation and a ring-shaped piezocrystal transducer to record the Pulse waves pushed onto the tail. After the blood flow has been stopped in the tail artery the cuff pressure is continuously reduced. The return of the pulse waves at pressure relief is automatically as systolic blood pressure recognized and printed out (Bühler, R. et al .: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th international symposium on rats with spontaneous hypertension and related studies, Rascher, R. et al. [Eds.], Schattauer Verlag, Stuttgart, New York, 1982, pp. 410-413). Pulse signals and pressure curve are used for evaluation recorded graphically.

To get used to the measuring process, the animals are given 14 days before the substance test trained. In the second week of training, blood pressure pre-values are collected. Animal groups that received substance are tested against a control group. In the table below, the examined connections are shown by running Numbers marked that match the respective sample numbers.  

Table I gives the percentages for the representatives of the compounds according to the invention Lowering blood pressure (BP) after oral administration in the rat again.

Table I

% Changes (BP) in genetically hypertensive rats after a single po application daily for four consecutive days (N = 6 / dose).

Claims (7)

1. New amines of the formula I wherein Cy is a cycle of the formula represents in which Y represents oxygen (O), sulfur (S), vinylene (-CH = CH-), azomethine (-CH = N-) or a group of the formula means, R1 means amino (NH₂), means hydrogen, 1-6C-alkyl or 3-7C-alkoxyalkyl, R3 represents a (-) - menthyl radical, R4 and R5 are identical or different and are hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5-C-acyl, amino or mono- or di-1-4C-alkylamino mean and R61-6C-alkyl or 3-7C-alkoxyalkyl means, and the salts of these compounds. 2. Compounds of formula I according to claim 1, wherein CyPhenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2- (1,1,2,2-tetrafluoroethoxy) phenyl, 3- (1,1,2,2-tetrafluoroethoxy) phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-pyridyl, 3-pyridyl or benzoxdiazolyl, R1 means amino (NH₂), R2 means methyl or ethyl, R3 represents a (-) menthyl residue and R6 denotes methyl, ethyl or isopropyl, and their salts. 3. Compounds of formula I according to claim 1, wherein Cy3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylphenyl means R1 means amino (NH₂), R2Methyl means R3 represents a (-) menthyl residue and R6 means methyl or ethyl, and their salts. 4. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

• a) cinnamic acid derivatives of the formula II with amidines of the formula III or
• b) keto compounds of the formula IV with amidines of the formula III and aldehydes of the formula V implemented and, if desired, subsequently obtained salts converted into the free bases or bases obtained into the salts, where Cy, R1, R2, R3, R4, R5 and R6 have the meanings given in claim 1 and wherein the starting compounds as such or in the form of their salts be used.

5. Medicament containing one or more compounds according to one or several of claims 1 to 3 and / or their pharmacologically acceptable salts. 6. Compounds according to one or more of claims 1 to 3 and their pharmacological tolerable salts for use in the treatment and / or prophylaxis hypertension, coronary artery disease, peripheral and cerebral Circulatory disorders and / or diseases based on increased water or Sodium retention based. 7. Use of compounds according to one or more of claims 1 to 3 and their pharmacologically acceptable salts for the manufacture of pharmaceuticals for the treatment and / or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulation disorders and / or diseases, based on increased water or sodium retention.