NO871284L - NEW OPTICAL ACTIVE CONNECTION. - Google Patents

Description

The invention relates to a method for the production of

a new optically active compound. The new compound is used in the pharmaceutical industry in the manufacture of drugs.

It is known that certain 4-position substituted 1,4-dihydropyridine derivatives exhibit pharmacologically useful properties. Furthermore, it is known that these 1,4-dihydropyridine derivatives - provided they are differently (unsymmetrically) substituted in positions 2 and 6 and/or in positions 3 and 5 - exhibit a chirality center in position 4. It is also known that the pharmacological properties of the 1,4-dihydropyridines can be influenced by the absolute configuration in the 4-position. Surprisingly, it was now found that the pure enantiomer of a chiral dihydropyridine, described in more detail below, exhibits an unexpectedly strong pharmacological activity, through which it differs from the hitherto known enantiomers dihydropyridines in a surprising way.

The subject of the invention is a process for the preparation of the enantiomer of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyrldine-3,5-dicarboxylic acid-3-methyl-5-[3-(4 ,4-diphenylpiperidyl-1)-propyl]ester, which rotates the linearly polarized light with a wavelength of 589 nm in the (+) direction, i.e.

(+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4-diphenylpiperidyl-1) -propyl ester and its salts.

Without taking into account the absolute configuration in the 4-position of the 1,4-dihydropyridine, the compound produced according to the invention is described by the following

formula:

As salts, all salts with acids come into consideration. Particular mention should be made of the pharmaceutically acceptable salts of inorganic and organic acids which are usually used in the pharmaceutical industry. Pharmacologically intolerable salts, which can for example be formed during the production of the compound according to the invention on an industrial scale as process products, are converted into pharmacologically tolerable salts by methods known to a person skilled in the art. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, phenisoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate, methembonate, stearate, tosylate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, or mesylate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide , ethacrynic acid, thienilic acid or 4-chloro-sulfamoyl-benzoic acid.

The method in accordance with the invention is characterized by reacting (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-methyl- 5-[3-(4,4-diphenylpiperidinyl-1)-propyl]-ester with an enantiomerically pure optically active acid, separates the obtained diastereomeric salts, liberating (+ )-1,4-dihydro-2,6-dimethyl- 4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4-diphenylpiperidinyl-1)-propyl]-ester from the desired diastereomeric salt by addition of base and optionally transfers this in a salt.

Examples of optically active acids include di-0,0'-p-toluoyltartaric acid and especially di-0,0'-benzoyltartaric acid. Recrystallization is preferably suitable as a separation method.

The configurationally uniform diastereomeric salts separated by these methods are transferred by the addition of preferably inorganic bases, such as e.g. ammonia, or by means of basic ion exchangers in the optically active enantiomerically pure compounds according to the invention.

The isolation and purification of the compounds which can be produced according to the invention follows in a manner known per se, e.g. so that the solvent is removed destillatively in vacuum and the residue thus formed is recrystallized in a suitable solvent or the residue is subjected to one of the usual purification methods, such as column chromatography on a suitable support material.

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

The salts are recovered by filtration, reprecipitation and precipitation with a non-solvent for the addition salt, or by evaporation of the solvent.

Formed salts can be transferred into the free bases by alkalization, e.g. with aqueous ammonia solution, and the free bases can again be transferred into acid addition salts. In this way, pharmacologically intolerable acid addition salts can be transferred into pharmacologically tolerable acid addition salts.

The preparation of the racemate which is the basis of the compound that can be prepared according to the invention, i.e. the preparation of the 1:1 mixture with the corresponding

(-)-enantiomers are described in the examples.

The following production examples shall describe the invention in more detail, without limiting it. Temp. means melting point, h stands for hours, kp stands for boiling point, split means cleavage.

Examples

1. (+)- 1. 4- dlhydro- 2. 6- dlmetvl- 4-( 3- nltrophenvl)- pyridine- 3, 5- dlcarboxylic acid- 3- methyl- 5- r3-( 4, 4. diphenylpiperidyl- 1 )-propyl ester hydrochloride

4.53 g of 3-nitrobenzaldehyde, 3.45 g of 3-aminocrotonic acid methyl ester and 11.38 g of acetoacetic acid-[3-(4,4-diphenylpiperidyl-1)-propyl]-ester in 100 ml of 2-propanol are heated overnight by boiling under reflux. The cooled solution is evaporated to dryness and the remaining residue is chromatographed over a silica gel column with ethyl acetate as eluent. After evaporation, the uniform product fractions leave a solid foamed residue, which is dissolved in methanol and ethereal hydrochloric acid is added. The solution is evaporated, and the remaining solid residue is taken up in a little methanol and the title substance is precipitated by adding petroleum ether.

m.p. from 135 °C (dec.), yield: 9.3 g.

The free base of the title compound, which is necessary for the en-antiomer separation, is obtained when the foamed solid residue remaining after evaporation of the condensation mixture is taken up in a little methylene chloride, after addition of diisopropyl ether to remaining fine haze, the base crystallizes as fine small plates when stored in a refrigerator,

m.p. 145-147 °C.

The output connections are made as follows:

a) acetoacetic acid- f3-(4, 4-diphenylpiperidyl-l)-propyll-ester

Dissolve 23.6 g of 3-(4,4-diphenylpiperidyl-1)-propanol in 1000 ml

abs. toluene and, with stirring, 16 ml of a 50% diketene solution in acetone are added. After standing at room temperature for several days (ts control), the mixture is evaporated and the residue is dried under high vacuum. The remaining pale yellow thin liquid oil is used without further purification in the next

steps.

b) 3-(4.4-diphen.ylpiperidyl-1)-propanol

40 g of 4,4-diphenylpiperidine, 24.7 g of 3-bromopropanol, 116.4 g of powdered calcium carbonate and approx. Boil 1 g of potassium iodide under reflux and with vigorous stirring in 500 ml of a 1:1 mixture of dioxane and 1-butanol for approx. 48 hours. After cooling, the mixture is filtered and the filtrate is evaporated. The oily residue is dissolved in acetic acid ethyl ester and the solution

filtered again. After evaporation of the filtrate to dryness, the product is obtained as a yellow, oily residue, which slowly becomes a waxy solid. Yield: 44.8 g. With ethereal hydrochloric acid, the hydrochloride is obtained, which is recrystallized in 2-propanol.

m.p.: 226-227 °C.

Alternatively, starting compound b) is prepared by adding 352 g of 4,4-diphenylpiperidine, 128 g of sodium hydroxide granules, 2.5 l of methyl chloride, 500 ml of water, 218 g of 3-bromo-1-propanol and catalytic amounts of a phase transfer catalyst (e.g. .benzyltrimethylammonium chloride) is heated to reflux for 10 hours. The separated organic phase is washed with water, the combined aqueous phases are extracted with methylene chloride. After drying the combined organic phases with sodium sulfate, the clear brown solution is evaporated to dryness. The resinous brown residue is taken up in 4.5 1 of boiling pertoliter (boiling range 100-140°C), the solution is filtered hot to remove insoluble residues and cooled. After standing overnight, the starting compound is obtained as a free base in colorless, coarse crystals.

M.p.: 97°C. Yield: 303 g.

2. (+)-!. 4. dihydro- 2. 6- dimethyl- 4-( 3- phenyl)- pyrlidine-3, 5- dlcarboxylic acid- 3- methyl- 5- r3-( 4, 4- diphenylplperidyl-- 1)- propyl- ester-( + )- di- 0. 0'- benzoyl tartrate

18.2 g (+)-1,4-dihydro-2,6-dimethyl-4-(3--nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4 -diphenylpiperidyl-1)-propyl]-ester and 11.29 g of commercially available d-(+)-di-0,0'-benzoyltartaric acid hydrate (in the present example with specific rotation [o<]<23>d= + 106°C (C= 5^ethanol) is dissolved together in 100 ml of methanol. The clear solution is then evaporated to dryness, and the crystalline residue formed is recrystallized in the heat in a mixture of 280 ml of chloroform and 20 ml of methanol. After slowly cooling the solution a first crystallisate with mp 143-144C is obtained, yield approx. 14 g (coarse, slightly yellow needles),

[°G<23>D= +48° (c = 5, ethanol)]. Renewed recrystallization of the first crystallisate in chloroform/methanol gives a second crystallisate with m.p. 145-146°C, yield approx. 12 g [(coarse, slightly yellow needles, [a]<23>p = +49°(c = 5, ethanol)) Further recrystallization of the second crystallisate in chloroform/methanol gives a third crystallisate with mp 147-148° C,

yield: approx. 9 g [coarse, yellowish needles, [a]<23>j) = +50°

( c = 5 , ethanol)] .

When using D-(+)-di-0,0'-benzoyltartaric acid with higher optical purity, the specific rotations for the formed salts rise accordingly. 3. ( + )-!. 4- dihydro- 2. 6- dimethyl- 4-( 3- nitrophenyl)- pyridln 3. 5- dicarboxylic acid- 3- methyl- 5- r3-( 4. 4- diphenylpiperidyl-- 1 )- propyl- ester- hydrochloride

4.84 g of third crystallisate from example 2 is dissolved in 100 ml of dichloromethane and extracted three times with 50 ml of semi-concentrated aqueous ammonia solution. The aqueous phase is extracted again with respectively 50 ml of dichloromethane and the combined organic phases are washed twice with respectively 100 ml of water and then dried with sodium sulphate. After complete evaporation of the dichloromethane solution, the formed solid residue is dissolved in approx. 5 ml of methanol and add ethereal hydrochloric acid to the solution. The solution is evaporated on

again completely to dryness, and the solid residue formed is dissolved hot in 9 ml of dioxane. After cooling the solution, the title compound is obtained as fine needle tufts, m.p. 142°C to 162°C, slow liquefaction.. Yield: 3.1 g [a]<22>D= +13.9°

(c = 1, methanol).

When using d-( + )-di-0,0'-benzoyltartaric acid with higher optical purity, the specific rotation of the title compound rises.

The compound which can be produced according to the invention and its salts possess valuable properties which make them industrially useful. They are particularly effective vasodilators with coronary therapeutic properties. The pharmacological activity of the compounds which can be prepared according to the invention is particularly evident in a slow-onset, strong and long-lasting lowering of blood pressure. In addition to this, the compound that can be produced according to the invention has an inhibitory effect on calcium influx as well as a strengthening effect on potassium outflow from cells, smooth muscle relaxant and peripheral, coronary, cerebral and renal blood vessel dilator, as well as salidiuretic, antithrombotic, antiarteriosclerotic and favorable hemorheological properties.

In its excellent activity which occurs next to a low toxicity and absence of significant side effects, the compound which can be prepared according to the invention differs surprisingly and advantageously from compounds according to the state of the art. In particular, the compound also differs surprisingly from its corresponding racemate, (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5 -[3-(4,4-diphenylpiperidyl-1)-propyl]-ester.

As advantageous properties of the compound, for example, the following should be mentioned: the extent of the blood pressure reduction, the long duration of the blood pressure reduction, the good controllability of the blood pressure reduction, the surprisingly low and small increase in heart rate that disappears with repeated administration, the excellent bioavailability, the large therapeutic range, the absence of central side effects, absence of kinetic interactions with other substances, absence of tolerance development, balanced physical properties and good stability.

The excellent effect of the compound and its salts enables their use in human medicine, partly as an indication in particular primary (essential) and secondary, arterial and pulmonary hypertension of all types, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction, etc.) , peripheral and cerebral circulation disorders (stroke, temporary cerebral circulation disorders, migraine, dizziness, renal artery narrowing, etc.), hypertrophic cardiomyopathies, thyroid insufficiency, diseases resulting from excessive water and sodium retention and diseases resulting from a increased calcium influx such as e.g. spasms in smooth muscle organs (airways, stomach/intestinal tract, urogenital tract etc.) as well as arrhythmias, arteriosclerosis and cell damage of various origins (e.g. hypoxia).

Likewise, the invention encompasses the use of the compound which can be prepared according to the invention and its pharmacologically tolerable salts in the preparation of medicines, which can be used in the fight against the aforementioned diseases.

The medicines are produced in a manner known per se to a professional. As drugs, the pharmacologically active compound and/or its pharmacologically tolerable salts (active substances) are used either as such or preferably in combination with suitable pharmaceutical excipients, such as tablets, dragees, capsules, suppositories, plasters (e.g. as TTS), emulsions , suspensions, aerosols, sprays, ointments, creams, gels or solutions, where the content of the active substance is preferably between 0.1 and 95% by weight.

Which excipients are suitable for the desired medication formulation is known to a person skilled in the art. In addition to solvents, gel formers, suppository bases, tablets, excipients and other carriers for active substances, for example antioxidants, dispersants, emulsifiers, defoamers, flavourings, preservatives, solubilizers, dyes or especially permeation promoters and complex formers can be used (e.g. .eg cyclodextrins).

The active substances can be used orally, rectally, per inhalation or parenterally (especially perlingually, intravenously or percutaneously).

In general, it has been shown to be advantageous in human medicine to administer the active substance or substances orally in a daily dose of approx. 0.01 - 10, preferably 0.05 - 5 mg/kg body weight, if desired in the form of several, preferably 1 to 4 single administrations to achieve the desired result. In the case of parenteral treatment, a similar, respectively (particularly intravenous administration of the active substance) usually lower dosage can be used. With slow dosing (einschleichende Dosierung), a lower dose is administered at the beginning of the treatment, then it is slowly increased to a higher dose. After achieving the desired therapeutic effect, it is returned to a lower dose.

The determination of the required optimum dosage and type of application of the active substance can easily be carried out by the person skilled in the art due to his knowledge.

If the compound that can be produced according to the invention and/or its pharmacologically tolerable salts is to be used in the treatment of the aforementioned diseases, the pharmaceutical preparations may also contain one or more other pharmacologically active ingredients from other drug groups, such as other vasodilators, antihypertensives, and 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, dopamine stimulators, serotonin receptor blocking agents such as nifedipine, dihydralazine. prazisin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbidine nitrate, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, polythiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, rauwolfia alkaloids, actylsalicylic acid, bezafibrate, warfarin, atropine, theophylline, lidocaine, aste-mizole, bromocriptine, ketanserin, etc.

The antihypertensive activity of the compound which can be prepared according to the invention can be shown in the spontaneously hypertensive rat model.

To determine the anti-hypertensive effect, the compound is administered in the listed doses to 6 and 12 awake male rats (strain SKR/N/Ibm/Bm, 350-400 g) with genetically determined hypertension (mean arterial pressure 160-200 mmHg) intravenously by injection and by a catheter in the jugular vein, respectively. intragastrically using an esophageal tube. Measurement of blood pressure is carried out continuously up to 6 hours after substance administration via a catheter placed in the aorta abdominalis and conventional pressure recording using a piezo-electric pressure transducer. The blood pressure values are recorded at small time intervals for up to 60 minutes after substance administration (1, 3, 5, 10, 15, 30, 45, 60 min) after i.v. administration, respectively 5, 10, 20, 30, 40, 50 and 60 minutes after p.o. administration) and then at hourly intervals up to 360 minutes after administration. As a measure of the change in blood pressure due to substance administration, the AUC (area under the curve) is then determined

for a) the time period 0-60 minutes and b) 60-360 minutes after substance administration.

Tables I and II show the average lowering of blood pressure (mmHg) for the compound that can be prepared according to the invention (compound no. 1), as well as the corresponding racemate (compound no. 2) in the two mentioned sub-periods after i.v. (table I) respectively p.o. substance administration (Table II).

Claims (4)

1. A process for the preparation of (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4 ,4-diphenyl-piperidyl-1)-propyl]-ester and its salts, characterized by reacting (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylic acid-3-methyl-5-[3-(4,4,-diphenylpiperidyl-1)-propyl]-ester with an enantiomerically pure optically active acid, separates the diastereomers formed, frees from the desired diastereomer (+) -1,4-dihydro-2,6-dimethyl-4-(3-nitro-enyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4-diphenylpiperidyl-1)- propyl]ester by adding a base and optionally transferring this into a salt. 2. Method according to claim 1, characterized in that the enantiomerically pure optically active acid is (+)-di-0,0'-benzoyltartaric acid. 3. Use of (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4, 4-diphenylpiperidyl-1)-propyl]ester and its pharmacologically tolerable salts in the manufacture of drugs for the treatment and/or prevention of hypertension, coronary heart disease, peripheral and cerebral circulation disorders and/or diseases resulting from increased water or sodium retention. 4. Procedure for the production of drugs containing (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3- (4,4-diphenylpiperidyl-1)-propyl] ester and/or its pharmacologically tolerable salts, characterized by mixing (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4-diphenylpiperidyl-1)-pyridine-3,5-dicarboxylic acid-3-methyl-5-[3-(4,4-diphenylpiperidyl -1)propyl]-ester and/or its pharmacologically tolerable salts with a galenic excipient and transfer this into a formulation common to medicines.