DE2715182A1 - 2-Aminoalkyl-1,4-di:hydro-pyridine derivs. - with broad spectrum of effects on the heart and circulation, e.g. lowering blood pressure and spasmolytic effect - Google Patents

Abstract

Dihydropyridines of formula (I) and their pharmaceutically acceptable acid addn. salts are new: In (I), R1 is H, alkyl, alkoxyalkyl or aralkyl, opt. substd. in the alkyl or aryl fragments; A is opt. branched alkylene; Y and Z are each COOR2,COR2,CN or SO(n)R3; R2 is alkyl (opt. substd. by alkoxy OH, NH2, or alkylamino)alkenyl, alkynyl, alkylaminoaralkyl or aralkyl, opt. substd. as in R1; R3 is alkyl (opt. substd. by alkoxy, NH2 or alkylamino) alkenyl, aryl, or aralkyl, opt. substd. as in R1; n is 0-2. R4 is H, alkyl (opt. interrupted by O), or -ANH2; X is aryl. opt. substd. by 1-3 of phenyl, alkyl, alkenyl, alkynyl alkoxy, alkynyloxy, acyloxy, halo, CF3, CF3O,OH,NO2,CN N3,NH2 (opt. substd. by alkyl or acyl), carbalkoxy, carboxamido, sulphamido or SO(n)alkyl; or X is quinolyl, pyridyl, pyrimidyl, thienyl, furyl or pyrryl (opt. substd. by alkyl, alkylamino, NO2 or halo), or opt. substd. aralkyl cycloalkyl, cycloalkenyl or styryl. (I) have circulatory activity. The main effects are (i) powerful and sustained dilation of cardiac blood vessels reinforced by a nitrate-like effect on the heart and modification of cardiac metabolism to save energy; (ii) redn. of blood pressure in normal and hypertonic subjects; (iii) antifibrillatory effect; (iv) spasmolytic effect on smooth muscles of the vascular system, stomach, intestines, urogenital tract and respiratory system; (v) effect on blood lipid and cholesterol levels.

Description

2-alkyleneamino dihydropyridines, process for their preparation

position and their use as medicaments The present invention relates to new 2-alkyleneamino dihydropyridines, several processes for their preparation as well as their use as pharmaceuticals, especially those that influence the circulation Middle.

It has already become known that 2,6-dimethyl-4-phenyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diethyl ester is obtained when ethyl benzylidene acetoacetate is used with ß-amino-crotonic acid ethyl ester or acetoacetic acid ethyl ester and ammonia (Knoevenagel, Ber.

German chem. Ges. 31, 743 (1898)). It is also known that certain 1,4-dihydropyridines have interesting pharmacological properties (F. Bossert, W. Vater, Naturwissenschaften 58, 578 (1971).

The invention relates to new 2-alkyleneamino dihydropyridines of the formula in which R1 represents hydrogen, alkyl, alkoxyalkyl or aralkyl, the alkyl and aryl groups mentioned being optionally substituted, A represents a straight-chain or branched alkylene radical, Y and Z are identical or different and a) represent the COOR2 or COR2 group , where R2 stands for alkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, kylaminoaralkyl or aralkyl, where the mentioned alkyl and aryl radicals are optionally substituted or b) stand for a cyano radical or c) stand for the radical SO (n) stand, where R3 stands for alkyl, alkenyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, aryl or aralkyl, where the alkyl and aryl radicals mentioned are optionally substituted, n stands for O, 1 or 2, R4 stands for hydrogen, or alkyl, where the Alkyl radical is optionally substituted or interrupted by oxygen or represents the radical A-NH2, where A has the abovementioned meaning and X represents an aryl radical which optionally one to three, identical or different substituents from the group consisting of phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkynoxy, acyloxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, azido, amino, alkylamino, acylamino, carbalkoxy, carbonamido, Contains sulfoanido or SOn-alkyl (n = 0 to 2) or represents a quinolyl, pyridyl, pyrimidyl, thienyl, furyl or pyrryl radical optionally substituted by alkyl, alkylamino, nitro or halogen, or represents an optionally substituted aralkyl, cycloalkyl, cycloalkenyl or styryl radical, and their pharmaceutically acceptable acid addition salts.

It has been found that the new 2-alkyleneamino dihydropyridines of the formula I are obtained if 2-allene-phthalimido-7,4-dihydropyridine of the formula II in which R1, R4, A, X, Y. and Z have the meaning given above or R4 stands for the remainder is converted into primary anines of the formula I by hydrolysis or hydrazinolysis with elimination of the phthalic acid group, if appropriate in the presence of inert organic solvents.

By reacting the amine compounds of the formula I thus obtained with suitable organic or inorganic acids according to methods known per se obtained from those pharmaceutically unobjectionable ones which can also be used according to the invention Acid addition salts.

The compounds of the formula (I) and their pharmaceutically acceptable ones Acid addition salts show strong pharmacological effects. In particular, draw they are characterized by effects on the circulatory system and can preferably be used are called coronary drugs, antihypertensive agents and agents for increasing the peripheral blood flow. Due to their novel structure, in particular due to the better solubility of the compounds according to the invention due to the amino group and because of their versatile mode of action, the use of the inventive Compounds are an asset to pharmacy.

The phthalimido-1,4-dihydropyridines to be used as starting materials are not yet known, but can be obtained (according to German application P 2 658 183.9) by adding β-ketocarboxylic acid esters of the formula with enamines of the formula and aldehydes of the formula X-CHO (V) where the substituents A, X, Y, Z, R1 and R4 have the meaning given above, are reacted with one another.

2-Alkylenaminodihydropyridines of the formula are of particular interest (I) in which R represents hydrogen, alkyl with 1-4 carbon atoms, in particular Methyl, alkoxyalkyl with a total of 2 to 4 carbon atoms or benzyl, A for an alkylene radical with 1 - 4 carbon atoms, in particular for methylene, ethylene, Propylene, isopropylene, butylene or isobutylene, Y and Z are identical or different are and stand for the grouping COOR², where R2 stands for alkyl with 1 - 4 carbon atoms, in particular methyl, ethyl, propyl, isobutyl or for alkoxyalkyl with 2-6, in particular with 2-4 carbon atoms or for an alkylaminoalkyl or alkylaminobenzyl radical where the alkyl groups each contain 1 - 4 carbon atoms, R4 for hydrogen, alkyl with 1 - 4 carbon atoms, in particular methyl or ethyl or represents the radical A-NH2, where A has the abovementioned meaning and X stands for a phenyl radical which is optionally replaced by 1 or 2 identical or different Substituents from the group halogen, nitro, cyano, trifluoromethyl, amino, alkoxy with 1 - 4 carbon atoms, in particular methoxy and ethoxy or alkyl mercapto with 1 - 4 carbon atoms, in particular methyl mercapto or for a naphthyl, Pyridyl, thienyl, furyl or quinolyl ring.

The following compounds may be mentioned according to the invention: 2- (β-aminoethyl) -6-ethyl-4- (2-methoxy-4-fluorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid propyl ester, 2,6-diaminomethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid tert-butyl ester-5-carboxylic acid (ß-ethoxyethyl) ester, 2,6 - (-Diaminopropyl) -4-ß-pyridyl-1,4-dihydropyridine-3,5-dicarboxylic acid dibenzyl ester, 2-aminopropyl-6-propyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid butyl ester-5-carboxylic acid isopropyl ester, 2-aminomethyl-6,1-methyl-4- (3-chlorophenyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methoxypropyl ester, 2-aminomethyl-6-methyl-4- (2-nitro-4-chlorophenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-acetyl, 2,6-diaminomethyl-4- (2-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.

Unless expressly defined otherwise, this stands for Application of the term optionally substituted alkyl for straight-chain or branched alkyl, preferably having 1 to 6, especially 1 to 4 carbon atoms.

Examples are optionally substituted methyl, ethyl, n-propyl, Iso-propyl, n-butyl, iso-butyl and tert-butyl called.

The optionally substituted alkenyl is straight-chain or branched alkenyl with preferably 2 to 6, in particular 2 to 4 carbon atoms. Examples are optionally substituted ethenyl, propenyl- (1), propenyl- (2) and butenyl- (3) called.

Optionally substituted alkynyl is straight-chain or branched alkynyl having preferably 2 to 6, in particular 2 to 4 carbon atoms. Examples are optionally substituted ethynyl, propynyl- <1), propynyl- (2) and butynyl- (3) called.

Optionally substituted aryl are preferably optionally called substituted phenyl or naphthyl.

Aralkyl is optionally substituted with aralkyl 6 or 10, in particular 6 carbon atoms in the aryl part, preferably 1 to 4, in particular 1 to 2 carbon atoms in the alkyl part, with the aryl part and / or the alkyl part is substituted. Optionally substituted may be mentioned as examples Benzyl and phenethyl.

The halogen is preferably fluorine, chlorine, bromine and iodine, in particular Fluorine and chlorine.

Alkylamino preferably represents monoalkylamino or dialkylamino each having 1 to 4, in particular 1 or 2, carbon atoms in the alkyl part. Exemplary are called monomethylamino, N, N-dimethylamino, methyl-ethylamino, Methyl-benzylamino, n-butylamino. The carbalkoxy radicals mentioned preferably contain 2 to 4, especially 2 or 3 carbon atoms. Carbomethoxy may be mentioned by way of example and carboethoxy.

The alkoxyalkyl substituents mentioned preferably contain 1 or 2 carbon atoms in the alkyl part and 1 to 3 carbon atoms in the alkoxy part. Exemplary may be mentioned methoxyethyl, ethoxymethyl, propoxyethyl.

The salts of the 1,4-dihydropyridine derivatives according to the invention are according to well known methods, e.g. B. by dissolving the base in ether and adding the solution made with suitable acids.

As inorganic and organic acids that interact with the dihydropyridines of the formula (I) form physiologically acceptable acid addition salts are exemplary called: hydrohalic acids such as hydrochloric and hydrobromic acid, in particular Hydrochloric acid, phosphoric acids, sulfuric acid, nitric acid, mono- and bifunctional Carboxylic acids and hydroxycarboxylic acids such as acetic acid, maleic acid, succinic acid, Fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, 1,5-naphthalenedicarboxylic acid and naphthalene disulfonic acid.

Water and all inert solvents are used as diluents during production organic solvents in question. These preferably include alcohols, e.g. lower ones Alkyl alcohols with preferably 1 to 4 carbon atoms, such as Ethanol, Methanol, isopropanol, ethers, e.g. lower dialkyl ethers (preferably 3 to 5 carbon atoms), such as diethyl ether or ring ethers such as tetrahydrofuran, dioxane, lower aliphatic Carboxylic acids (preferably 2 to 5 carbon atoms), such as acetic acid, propionic acid, lower dialkylformamides (preferably 1 or 2 carbon atoms per alkyl group), such as dimethylformamide, lower alkyl nitriles (preferably 2 to 4 carbon atoms), such as acetonitrile, dimethyl sulfoxide, liquid heteroaromatic bases such as pyridine, as well as mixtures of these solvents including water with one another.

The reaction temperatures can be varied within a relatively wide range will. In general, the temperature is between about 20 and about 150.degree. C., preferably between 50 and 100 ° C, especially at the boiling point of the solvent used.

The reaction can be carried out under normal pressure, but also under increased pressure will. In general, normal pressure is used.

The new compounds are used as drugs, especially as vascular and active ingredients influencing the circulation can be used.

The compounds of the invention are broad and versatile pharmacological spectrum of activity.

In detail, the compounds according to the invention have the following main effects on: 1. The new compounds cause parenteral, oral and perlingual administration a clear and long-lasting expansion of the coronary vessels.

This effect on the coronary vessels is caused by a simultaneous Nitrite-like heart-relieving effect increased. They influence or change the metabolism in terms of energy savings.

2. The new compounds lower blood pressure from normotensive and hypertensive animals and can thus be used as antihypertensive agents.

3. The excitability of the stimulation and conduction system inside the heart is lowered so that one is detectable in therapeutic doses Anti-flicker effect results.

4. The tone of the smooth muscles of the vessels is under the action of connections greatly reduced. This vasospasmolytic effect can occur throughout Vascular system take place or more or less isolated in circumscribed vascular areas (such as the central nervous system) manifest.

5. The compounds have strong muscular-spasmolytic effects, those on the smooth muscles of the stomach, intestinal tract, and urogenital tract of the respiratory system become clear.

6. The compounds influence the cholesterol resp.

Blood lipid levels.

The new compounds are therefore for prevention, improvement or Suitable for curing diseases, in which in particular the above-mentioned effects are desired.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carriers one or contain several compounds of the formula (I) and / or their salts or those from one or more compounds of the formula (I) and / or their salts exist and Process for the manufacture of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts z. B. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, whose active ingredient content corresponds to a fraction or a multiple of a single dose. The dosage units can be, for. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or Contain 1/4 of a single dose. A single dose preferably contains the amount Active ingredient that is administered in one application and that usually corresponds to a whole, corresponds to half a day or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of any kind to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules, pills, granules, suppositories, solutions, suspensions and emulsions called.

Tablets, coated tablets, capsules, pills and granules can be the or contain the active ingredients in addition to the usual carriers, such as a) fillers and extenders, z. B. starches, lactose, cane sugar, glucose, mannitol and silica, b) binders, z. B. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, c) humectants, z. B. glycerin, d) disintegrants, e.g. B. agar agar, calcium carbonate and sodium bicarbonate, e) solution retarders, e.g. B. paraffin, and f) absorption accelerators, e.g. B. quaternary Ammonium compounds, g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, h) Adsorbents, e.g. B. kaolin and bentonite, and i) lubricants, e.g. B. Talc, Calcium and magnesium stearate and solid polyethylene glycols or mixtures of the below a) - i) listed substances.

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings and casings, optionally containing opacifying agents be and also be composed so that they only or the active ingredient or preferably in a certain part of the intestinal tract, possibly delayed give off, with such as embedding compounds. B.

Polymer substances and waxes can be used.

The active ingredient (s) can optionally be combined with one or more of the above-mentioned carriers are also in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble ones or contain water-insoluble carriers, e.g. B. polyethylene glycols, fats, z. B. cocoa fat, and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures these substances.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the customary carriers such as solvents, solubilizers and emulsifiers, e.g. B. 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 oil, olive oil, castor oil and sesame oil, glycerine, Glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can include the usual carriers, such as liquid diluents, e.g. B.

Water, ethyl alcohol, propylene glycol, suspending agents, e.g. B.

ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants and preservatives as well as odor and taste improving additives, z. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. contain saccharin.

The therapeutically active compounds are intended to be in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95 percent by weight of the total mixture be.

The pharmaceutical preparations listed above can except Compounds of the formula (I) and / or their salts as well as other pharmaceutical active ingredients contain.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, for. B. by mixing the or the active ingredients with the carrier or carriers.

The present invention also includes the use of the compounds of the formula (I) and / or their salts and of pharmaceutical preparations which contain one or more compounds of the formula (I) and / or their salts, in of human and veterinary medicine to prevent, ameliorate and / or cure the above listed diseases.

The active ingredients or the pharmaceutical preparations can preferably orally, parenterally and / or rectally, preferably orally and parenterally, in particular administered perlingually and intravenously.

In general, it has proven advantageous to use the Active ingredients for parenteral (intravenous) administration in amounts of about 0.01 to about 50, preferably 0.1 up to 5 mg / kg body weight every 24 hours and for oral administration in amounts of about 0.1 to about 100, preferably 1 to 30 mg / kg body weight per 24 hours, if necessary in the form of several single doses to be administered to achieve the desired results. Contains a single item the active ingredient (s), preferably in amounts of about 0.005 to 50, in particular 0.5 to 20 mg / kg body weight. However, it may be required of the above Dosages vary, depending on the type and body weight the object to be treated, the type and severity of the disease, the type of Preparation and application of the drug as well as the period or interval, within which the administration takes place. So it may be sufficient in some cases be able to manage with less than the above-mentioned amount of active ingredient, while in in other cases the amount of active ingredient listed above must be exceeded. the Determination of the required optimal dosage and type of application of the Active ingredients can easily be made by any person skilled in the art on the basis of their specialist knowledge.

Preparation Examples Example 1 2-Aminomethyl-6-methyl-4- (2'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.

14 g of 2-phthalimidomethyl-6-methyl-4- (2-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are heated with the addition of 5 cc of hydrazine hydrate in 150 cc of ethanol for 2 - 3 hours to boil, sucks hot and again after cooling and concentrates in a vacuum.

Crystals yellow from ether, melting point 134-136 ° C., yield: 65%.

The following compounds were obtained in the same way: Example 2 2-aminomethyl-6-methyl-4- (3'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester M.p. 140-1420C (ether), yield: 70%.

By boiling 22 g of 2-phthalimidomethyl-6-methyl-4- (3'-chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester for 3 hours and 11 g of hydrazine hydrate in 250 cc of ethanol.

Example 3 2-Aminomethyl-6-methyl-4- (3'-chlorophenyl) -i, 4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4- (3'-chlorophenyl) -1, 4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester and 22 cc of hydrazine hydrate in 500 cc of ethanol.

Light yellow crystals (ether) with a melting point of 128-1300C. Yield: 60%.

Example 4 2-Aminomethyl-6-methyl-4- (2'-nitrophenyl) -i, 4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester and 22 cc of hydrazine hydrate in 500 cc of ethanol.

Light yellow crystals with a melting point of 134-1360C. Yield: 40%.

Example 5 2-Aminomethyl-6-methyl-4- (4'-methoxyphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 0.2 mol of 2-phthalimidomethyl-6-methyl-4- (2'-methoxyphenyl) -3,5-dicarboxylic acid diethyl ester-1,4-dihydropyridine and 22 cc of hydrazine hydrate in 500 cc of ethanol.

Yellow crystals (ether) with a melting point of 78-800C Yield: 65 t.

Example 6 2-Aminomethyl-6-methyl-4- (2'-trifluoromethylphenyl) -1,4 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4- (2'-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 22 cc of llydrazine hydrate in 500 cc of ethanol.

Light yellow crystals of melting point 136-1380C (ether) Yield: 50%.

Example 7 2-Aminomethyl-6-methyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4- (3'-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid diethyl ester-5-carboxylic acid methyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Light yellow crystals of melting point 137-1380C (ether) Yield: 40% Example 8 2-Aminomethyl-6-methyl-4- (a-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4-t (αpyridyl) - (pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 9 2-Aminomethyl-6-methyl-4- (β-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4- (ß-pyridy 1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 10 2-Aminomethyl-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 0.1 mol of 2-phthalimidomethyl-6-methyl-4-phenyl-1 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 11 2-Aminomethyl-6-methyl-4- (2'-methoxyphenyl) -1,4-dihydropyridine-3-carboxylic acid methyl ester-5-carboxylic acid ethyl ester from 2-phthalimidomethyl-6-methyl-4- (2'-methoxyphenyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 12 2-Aminomethyl-6-methy1-4- (2'-methylmercaptophenyl) -1 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 2-phthalimidomethyl-6-methyl-4- (2'-methylmercaptophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of tlydrazine hydrate in 500 cc of ethanol.

Example 13 2-Aminomethyl-6-methyl-4- (2'-nitro-3'-methoxyphenyl) -1,4-dihydropyridine -3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester from 2-phthalimidomethyl-6-methyl-4- (2'-nitro-3'-methoxyphenyl) -1,4-dihydropyridine-3-carboxylic acid ethyl ester-5-carboxylic acid methyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 14 2-Aminomethyl-6-methyl-4- (4'-nitrophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 2-phthalimidomethyl-6-methyl-4- (4'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol Example 15 2-aminomethyl-6-methyl-4- ( , + t-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 2-phthalimidomethyl-6-methyl-4- (t-pyridyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 16 2-Aminomethyl-6-methyl-4- (4'-fluorophenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 2-phthalimidomethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Example 17 2-Aminomethyl-6-methyl-4- (3'-cyanophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester from 2-phthalimidomethyl-6-methyl-4- (3'-cyanophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 20 cc of hydrazine hydrate in 500 cc of ethanol.

Yellowish crystals with a melting point of 110-1120C. Yield: 50%.

Example 18 2,6- (Diaminomethyl) -4- (2'-chlorophenyl) -1,4-dihydropyridine-5,5-dicarboxylic acid diethyl ester 20 g of 2,6- (diphthalimldomethyl) -4- (2'-chlorophenyl) 1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are heated in 600 cc of ethanol with the addition of 12 cc of hydrazine hydrate for 3 hours then off in the cold and evaporate iV.

Light yellow crystals (ether) with a melting point of 1150C Yield: 40%

Claims (7)

Claims 1. 2-alkyleneamino dihydropyridines of the formula in which R1 stands for hydrogen, alkyl, alkoxyalkyl or aralkyl, the alkyl and aryl groups mentioned being optionally substituted, A stands for a straight-chain or branched alkylene radical, Y and Z are identical or different and a) stand for the grouping COOR2 or COR2 , where R2 stands for alkyl, alkenyl, alkynyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkylaminoaralkyl or aralkyl, the alkyl and aryl radicals mentioned being optionally substituted or b) stands for a cyano radical or c) for the radical SO (n) R3 stands, where stands for alkyl, alkenyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, aryl or aralkyl, the mentioned alkyl and aryl radicals being optionally substituted. n is 0, 1 or 2, R4 is hydrogen or alkyl, where the alkyl radical is optionally substituted or interrupted by oxygen or represents the radical A-NH2, where A has the abovementioned meaning and X stands for an aryl radical which may optionally contain one to three, identical or different Substituents from the group phenyl, alkyl, alkenyl, alkynyl, alkoxy, alkynoxy, Acyloxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, cyano, azido, Amino, alkylamino, acylamino, carbalkoxy, carbonamido, sulfonsmido or SOn-alkyl (n = O to 2) or for one optionally by alkyl, alkylamino, nitro or halogen-substituted quinolyl, pyridyl, pyrimidyl, thienyl, furyl or Pyrryl radical, or an optionally substituted aralkyl, cycloalkyl, Cycloalkenyl or styryl radical, as well as their pharmaceutically acceptable acid addition salts. 2. Process for the preparation of 2-alkyleneamino dihydropyridines according to Claim 1, characterized in that 2-alkylen-phthalimido-1,4-dihydropyridines of the formula II in which R1, R4, A, X, Y: Ufld Z have the meaning given above or R4 stands for the remainder is converted into primary anines of the formula I by hydrolysis or hydrazinolysis with elimination of the phthalic acid group, if appropriate in the presence of inert organic solvents, and these are optionally reacted with organic or inorganic acids to form pharmaceutically acceptable acid addition salts. 3. 2-alkyleneamino dihydropyridines of the formula I. in which R1 represents hydrogen, alkyl with 1-4 carbon atoms, in particular methyl, alkoxyalkyl with a total of 2 to 4 carbon atoms or benzyl, A represents an alkylene radical with 1-4 carbon atoms, in particular methylene, ethylene, propylene, isopropylene, butylene or isobutylene Y and Z are identical or different and stand for the grouping COOR², where R² stands for alkyl with 1-4 carbon atoms, in particular methyl, ethyl, propyl, isobutyl or for alkoxyalkyl with 2-6, especially with 2-4 carbon atoms or for an alkylaminoalkyl or alkylaminobenzyl radical where the alkyl groups each contain 1-4 carbon atoms, R4 stands for hydrogen, alkyl with 1-4 carbon atoms, in particular methyl or ethyl, or for the radical A-NH2, where A has the abovementioned meaning and X stands for is a phenyl radical which is optionally substituted by 1 or 2 identical or different substituents from the group consisting of halogen, nitro, cyano, trifluoromethyl, A mino, alkoxy with 1-4 carbon atoms, especially methoxy and ethoxy or alkylmercapto with 1-4 carbon atoms, especially methylmercapto, or a naphthyl, pyridyl, thienyl, furyl or quinolyl ring. 4. A pharmaceutical agent containing a 2-alkyleneamino dihydropyridine according to claim 1. 5. A method for the manufacture of a pharmaceutical agent, thereby characterized in that 2-alkyleneamino dihydropyridines according to claim 1 with suitable Auxiliary and carrier materials mixed. 6. Use of 2-alkyleneamino dihydropyridines according to Claim 1 for the treatment of circulatory diseases. 7. A method for the treatment of circulatory diseases, characterized in that that 2-alkyleneamino dihydropyridines according to claim 1 humans or animals if necessary applied.