FI56682C - FREQUENCY REFRIGERATION OF AV 2-AMINO-1,4-DIHYDROPYRIDINE - Google Patents

Description

F55F1 M {11) MONTH ».PUBLICATION

lj '' utlAggninqsskript 3vbo2 C Patent granted 10 03 1930 (^ 5) patent meddelat ^ T ^ (51) K ».lk. * / 1nt.CI. * C 07 D 211/90 ENGLISH — Fl N LAND (21) Ptt * nttlh «k« mui - PiMntaiwttknlng 772U83 (22) H »keml * ptlvl - Arattkntngtdaf 19.08.77 '(23) Alkupllvi— GUtighttsdag 02.03.73 (41) Become Public - Bllvlt offantllg 19.08.77

Patent and Registration Office .... ... . . .....

_ ^ '. (44) Date of issue of the contract. -

Patent- och register * tyraisan Anaektn utlagd och uti.ikHftm public * r »d 30.11.79 (32) (33) (31) Requested« bringHuut — Bsgird prlorltM 06.03.72

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 221067M

(71) Bayer Aktiengesellschaft, Leverkusen, Federal Republic of Germany-Förbunds-republiken Tyskland (DE) (72) Horst Meyer, Wuppertal, Friedrich Bossert, Wuppertal, Wulf Vater, Leverkusen, Kurt Stoepel, Wuppertk, Federal Republic of Germany ) (7 * 0 Oy Kolster Ab (5 * 1) Method for the preparation of 2-amino-1,1-dihydropyridines - Förfarande för framställning av 2-amino-1,1'-dihydropyridine (62) Separated from application 656/73 56681) -Avdelad frän ansokan 656/73 (utläggningsskrift 56681)

The invention relates to a process for the preparation of 2-amino-1,4-dihydropyridine derivatives of the formula R20C R h \ X> "· ί Ϊ wherein R is an alkyl group having 1 to 2 carbon atoms or a phenyl group which may be substituted by 1 to 3 carbon atoms. the same or different halogen atoms or 1-3 identical or different nitro, cyano, trifluoromethyl, azido, phenyl, alkyl, alkoxy or thioalkyl groups having an alkyl or alkoxy moiety containing 1-2 carbon atoms, or R is a naphthyl, furyl, thienyl, 3,56682 or pyrimidyl group which may be substituted by a nitro group or an alkyl or alkoxy group containing 1-2 carbon atoms or a pyridyl group which may be substituted by an alkyl group having 1-2 carbon atoms R 1 is 1-2 carbon atom ........ 2 3.

an alkyl group or a phenyl group, R and R, which may be the same or different, denote an alkyl, alkoxy, alkynyloxy or alkoxyalkyl group, the alkyl and / or alkoxy part of which contains up to 1+ carbon atoms, or an amino group or an alkylamino group, the alkyl part of which contains 1 -2 carbon atoms, or R and R together form an alkylene group containing 2-h carbon atoms.

It is known that the reaction of benzylideneacetic acid ethyl ester with aminocrotonic acid ethyl ester gives 1,1-dihydropyridines. (Knoevenagel, ~

Ber. 31, 7 ^ 3 (1898)).

According to application 656/73, 2-amino-1,1-dihydropyridine derivatives of the formula (I) are prepared by reacting an aldehyde of the formula RCHO (II) in which R is as defined above with a N-dicarbonyl compound of the formula r1coch2cgr2 (III) 1.2.

wherein R and R are as defined in formula (i) and with an amidine of the formula "2" \ - CH2 - COR "3 (V) HIT - 3 wherein R is as defined in formula (i) in an inert organic solvent at a temperature of 20-200 ° C.

The present invention is characterized in that the γ, β-unsaturated β-dioxo compound of the formula y yCOR1 RCH = C (IV) 1.2. . . .... wherein R, R and R are as defined above, are reacted with an amidine of formula

H, N

C-CH2-CO2 (V)

HIT

3 £> 6682 3. . . .

wherein R is as defined above, in an inert organic solvent at a temperature of 20-200 ° C.

The 2-amino-1,1 + -dihydropyridines of formula (i) have a potent and long-lasting arterial dilating and antihypertensive effect.

It is really surprising to find that the reaction according to the invention gives 2-amino-1,1 + -dihydropyridines of the formula (I) in such exceptionally pure and high yields, since in the prior art it must be expected that the amidine function is related to the derivatives VI: HR

^ cqr1 r2oc X * / _ RJOC-CH -c '+ RCH = cX -jf-) y "N®2 -¾0 II j R, ^» 00r3 xl c.

(VI) (cf. E.F. Silversmith, J. Qrg. Chem. 27 »1 + 090 (1962)).

The substantial advantage of the method according to the invention is that it gives exceptionally pure products with a high yield and that it can be implemented as a one-step process with low technical equipment costs and good economy.

The β, β-unsaturated dioxo compounds (IV) useful according to the invention are known or can be prepared by known methods (Qrg. Reaction XV, 20k - (1967)).

In formula V

^ J-CHg-COR ^ mr v 3 ...

R is preferably a straight-chain or branched alkyl radical having 1-U

a carbon atom, or an amino group.

, 56682

The amidines used according to the invention are known or can be prepared by known methods (S.M. Mc.

Elvain, B.E. Tate JACS. 73, 2760, 1951)).

Examples include.

amidines:

Amideacetic acid methyl ester, amideacetic acid ethyl ester, amideacetic acid n-propyl ester, amideacetic acid isopropyl ester, amideacetic acid cyclohexyl ester, amidine acetic acid (ethyl) ethyl acetate, amide acetic acid

Amidines can be used either in free form or in the form of their salts (e.g. hydrohalide). They are liberated from their salts by basic substances (e.g. alkali alcoholates).

Suitable diluents are all inert organic solvents. These preferably include alcohols such as ethanol, methanol, propanol; ethers such as dioxane, diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethylsulfoxide or acetonitrile.

Reaction temperatures can be varied over a wide range.

In general, between 20 and 250 ° C is used, preferably at the boiling point of the solvent.

The reaction can take place at normal pressure but also at elevated pressure. Usually working at normal pressure.

In carrying out the process according to the invention, each of the substances involved in the reaction is used in molar amounts.

The novel compounds of the invention are useful as medicaments. They have a wide and varied range of pharmacological action. ~

In detail, the following main claims could be demonstrated in animal experiments: 1) The compounds cause clear and long-acting coronary vasodilation when administered by injection, oral or tongue. This effect on coronary vessels is reinforced by the concomitant echelon of the ciliary heart. They affect t or others.the way the heart metabolizes as a kind of enorgius.

2) The compounds lower the blood pressure of animals with normal or hypertension and can thus be used as antihypertensive agents.

5 56682 3) The sensitivity of the irritation and excitation systems inside the heart decreases, so that an anti-atrial fibrillation effect (antifimer effect) can be demonstrated at therapeutic doses.

4) The muscle tension of the smooth muscles of the veins decreases strongly under the influence of the compounds. This vascular spasmolytic effect may occur throughout the vascular system, or it occurs more or less isolated in local vascular areas (such as the central nervous system).

5) The compounds have a strong muscle-spasmolytic effect, which is clearly manifested in the smooth musculature of the stomach, intestines, urinary tract and respiratory system.

6) The compounds affect the cholesterol or fat pattern of the blood.

The new active ingredients can be converted in a known manner into customary preparations, such as tablets, capsules, candied granules, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or diluents. In this case, the therapeutically active compound must in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve a given dosage range.

The preparations are made, for example, by diluting the active ingredient with solvents and / or carriers, optionally using emulsifying and / or dispersing agents, in which case, for example, when water is used as a diluent, organic solvents can optionally be used as co-solvents.

w Examples of excipients are:

Water, non-toxic organic solvents such as paraffins and (e.g. petroleum fractions), vegetable oils (e.g. peanut / sesame oil), alcohols (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol) , such as natural stone powders (e.g. kaolin, clays, tdJkk, liil.ua), synthetic stone powders (e.g. fine silicic acid, silicates), sugars (e.g. raw, milk and grape sugar); emulsifiers such as nonionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, alkyl sulfonate and aryl sulfonate), dispersants (e.g. lignin, sulphite, sulfite, sulfite), sulfite and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid, sodium sulfate, and sodium lauryl sulfate).

The administration takes place in the usual manner, preferably orally or by injection, in particular through the tongue or intravenously.

When used orally, the tablets may, of course, contain, in addition to the carriers mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives such as starch, preferably potato starch, gelatin and the like. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be included for tabletting purposes. In the case of liquid suspensions and / or elixirs intended for oral use, various flavoring or coloring agents may be added to the active ingredients in addition to the abovementioned excipients.

When used as an injection, suitable liquid carriers can be added to the active ingredient solutions.

In general, when administered intravenously, it has been found advantageous to use amounts of from about 0.001 to 2 mg / kg, preferably from about 0.005 to 10 mg / kg of body weight per day for effective results, and when administered orally, the dosage is about 0.1 to 20 mg. / kg, preferably 0.5-10 mg / kg body weight per day.

Nevertheless, it may be necessary to deviate from these amounts and specifically depending on the body weight or mode of administration of the test animal but also on the species and its individual attitude towards the drug or its formulation and the time or frequency of use. Thus, in some cases it is possible to cope with amounts lower than the above-mentioned minimum, while in other cases the said upper limit must be exceeded. In case of use of larger amounts, it is recommended to divide these into several single doses throughout the day. When used in humans, the same dosing interval is required. The above suggestions are also valid in spirit here.

7 56682

The coronary effect of the following examples was compared to the effect of "Per-santin", which increases oxygen saturation in the coronary sinus at an average dose of 0.3 mg / kg iv (intravenous) by 23 02%, at an iv dose of 0.4 mg / kg by about 34 02% , with a recovery time to the initial value of about 1-2 h.

Table I

Preparation Dose 0 ^ saturation Recovery time example mg / kg approx., Starting value about No. i.v. 2 ..... hours _ 2 0.02 33 2.5 5 0.03 32 3 9 0.01 23 2

The coronary effect was determined in anesthetized, cardiac catheterized mixed-breed dogs by measuring the increase in oxygen saturation in the coronary artery.

The effect of some compounds of the invention on blood pressure and toxicity are shown in Table II. The dosage given in column 3 means a decrease in blood pressure of at least 15 mm Hg in a rat with a high blood pressure.

Table II

Manufacturing Toxicity in mice Reduction of blood pressure, rat, example mg / kg orally at which it is high, dose No. mg / kg orally 1 - 1.0 2. - 0.1 3 - 1.0 5 - '* 1 , 0. '6> 1000 1.0 .9 - · 1.0 10 ·' 1.0 13 - 1.0 H - 3.1 15 * - 1.0 8

Examples of manufacturing; $ 6682

Example 1 .yv H5C200C ^ Jk ^ COOC ^ H,

H, C Λν> ΉΗ2 H

After boiling for 2 hours, a solution of 21.8 g of benzylideneacetic acid ethyl ester and 13.0 g of amideacetic acid ethyl ester in 150 ml of ethanol gave 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3 , 5-dicarboxylic acid diethyl ester, J6 ° C (alcohol), yield 67% of theory.

Example 2 ~~

Qho2

HjCOOC

XX

H, C JJ NH2.

After boiling for 1 hour, a solution of 24.9 g of 2'-nitrobenzylideneacetic acid methyl ester and 13.0 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (2'-nitrophenyl) -1,4 -dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester, mp 168 ° C (alcohol). Yield 59% of theory.

Example 3 H, C2 OO1 ^ ^ yCOOCa H.

T \ ιΓ h3

B

After boiling for 1 hour, a solution of 24.8 g of 2'-methoxybenzylideneacetic acid ethyl ester and 13.0 g of amidine acetic acid ethyl ester in 150 ml of ethanol gave 2-amino-6-methyl-4- (2'-methoxyphenyl) -1,4 -dihydropyridine-3,5-dicarboxylic acid diethyl ester, melting point 170 ° C (ethanol).

Yield 65% of theory.

Example H

S6682

Hj C2 OOC SyXxlcOOCa H,

H, C

B

After boiling for 2 hours, a solution of 23.2 g of 2-methylbenzylideneacetic acid ethyl ester and 13.0 g of amidine acetic acid ethyl ester in 150 ml of ethanol gave -2-amino-6-methyl-4- (2 * -methylphenyl) -1, 4-Dihydropyridine-3,5-, dicarboxylic acid diethyl ester, melting point 130 ° C (ethanol).

Yield 71% of theory.

^ Es imerkkl 5 ..

1 H, C, C 20 H 2 Cl 2 O 2 H 2

Ti il • HjC ^ N ^ NHa

B

After boiling for 2 hours, a solution of 24.3 g of 21-cyanobenzylideneacetic acid ethyl ester and 13.0 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (N-cyanophenyl) -1,4 -dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 208 ° C (ethanol).

Yield 54% of theory.

Example 6 ÄCF * 00C2 H3 »2

B

After boiling for 1 hour, a solution of 14.2 g of 2'-trifluoromethylbenzylideneacetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (21-trifluoromethylphenyl) -1, 4-Dihydro-_______, pyridine-3,5-dicarboxylic acid diethyl ester, mp 156 ° C (ethanol). Yield 76% of theory.

10

Example 7 Μ6β2 ζΓ1 | / Η

H3C200C

After boiling for 1 hour, a solution of 12.6 g of 3'-chlorobenzylideneacetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave -2-amino-6-methyl-4- (3 '). -chlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 157-159 ° C (ethanol).

Yield 62% of theory.

Example 8 „„ tT

'"1 1 1 1“ bUHj H-C200C v ^ N'COOC2H5 JÖ li

H, C

B

After boiling for 1 hour, a solution of 13.2 g of 4'-methylmercaptobenzylideneacetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (4'-methylmercaptophenyl) -1 , 4-Dihydro-pyridine-3,5-dicarboxylic acid diethyl ester, mp 165 ° C (ethyl acetate / petroleum ether). Yield 49% of theory.

Example 9 H5 C2 OOCv '^ V' cooc2 h,

aX

After boiling for 1 hour, a solution of 26.3 g of 3'-nitrobenzylideneacetic acid ethyl ester and 13.0 g of amidineacetic acid ethyl ester in 200 ml of ethanol gave 2-amino-6-methyl-4- (3'-nitrophenyl) -1 , 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 169 ° C (ethanol).

Yield 59% of theory.

66662

Example IQ

^ - I IMI I 1

j ^ H

H, COOC ^ JjY "C00C2 ^ h, c ^ n ^ nh2

3 H

After boiling for 1 hour, a solution of 24.9 g of 3'-nitrobenzylideneacetic acid methyl ester and 13.0 g of amidine acetic acid ethyl ester in 180 ml of ethanol gave 2-amino-6-methyl-4- (3'-nitrophenyl) -1.4 g. -dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester, mp 124 ° C. Yield 59% of theory.

Example 11 After boiling for 2 hours, a solution of 13.8 g of 3'-nitrobenzylideneacetic acid isopropyl ester and 6.5 g of amidineacetic acid ethyl ester in 150 ml of ethanol was obtained, if the N ° 2 (H3 C) 2HCO2Cl2C2Cl2 Amino-6-methyl-4- (3 * -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester -5-isopropyl ester, m.p. 206-207 ° C (alcohol). Yield 62% of theory.

^ Example 12 N ° 2 HC = C "CH2 00C C00C2 H5

H3C

B

After boiling for 1 hour, a solution of 10.9 g of 3'-nitro-benzylideneacetic acid propargyl ester and 5.2 g of amidine-56682 acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (3'-nitrophenyl) - 1,4-Dihydropyridine-3,5-cyclooxylic acid 3-ethyl ester-5-propargyl ester, pour point 18 ° C (ethanol). Yield 59% of theory.

Example 13 h3 coch2 ch2 ooqJ <? / COOC2 a, NH *

Boiling for 1 hour a solution of 14.6 g of 3'-nitrobenzylideneacetic acid γ-methoxyethyl ester and 6.5 g of amidine acetic acid ethyl ester in 150 ml of ethanol gave 2-amino-6-methyl-4- (31 -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5H-methoxyethyl ester, mp 179 ° C (ethyl acetate / petroleum ether). Yield 57% of theory.

Example 14 After boiling for 1 hour, a solution of 14.2 g of 31-nitro-61-chlorobenzylideneacetic acid methyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol was obtained. -amino-6-methyl-4- (3'-nitro-6'-chlorophenyl) -1,4-dihydropyridine-3,5-alkarboxylic acid 3-ethyl ester-5-methyl ester, m.p. 124 ° C (ethanol) . Catch 73% of theory.

13.

Example 15 S6682 After boiling for 2 hours, a solution of 10.4 g of 21-furylideneacetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol was obtained. Amino-6-methyl-4- (furyl-2 1) -1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 183 ° C (isopropanol). Yield J8% of theory.

Example 16 HC OOC COOCj H, H 0 H NH 2 After boiling for 2 hours, a solution of 14.0 g of benzylidenebenzoylacetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 150 ml of ethanol gave 2-amino-4,6-diphenyl -1,4-dihydropyridine-3,5-dicarboxylic acid ethyl ester, pour point 183 ° C (ethanol). Yield 48% of theory.

Example 17 H Cfi, E, C2 000T> Oc00C2 H3 h5c ^ nJLnh2

B

After boiling for 2 hours, a solution of 15.6 g of ethylideneacetic acid ethyl ester and 13.0 g of amideacetic acid ethyl ester in 100 ml of ethanol gave 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. , Pour point 140 ° (isopropanol). Yield 59% of theory.

14

Example 18 S6662 S 1¾ Ca OOC Vjj ^ v / CONH2 h, c ^ n ^ \ nh2 Π After 2 hours of cooking, a solution of 13.1 g of 3'-nitrobenzylideneacetic acid ethyl ester and 5.1 g of amidine acetamide in 150 ml of ethanol was obtained , 2-amino-6-methyl-5-carboxyethyl-4- (3 * -nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid amide, melting point 260 ° C (alcohol). Yield 52% of theory.

Example 19 After heating the H * C2OOC YY COOCH (CHa) 2 "3 ° NH 3 for 2 hours, a solution of 26.3 g of 3'-nitrobenzylideneacetic acid ethyl ester and 14.4 g of amidine acetic acid isopropyl ester in 250 ml of ethanol was obtained, 2-amino -6-methyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-ethyl ester, mp 175-6UC (ethanol) Yield 77% of theory.

Example 20 H, C200 (> y ^ Oc00CH (CH3) 2 H, CII NH1

Boiling for 1 hour a solution of 14.3 g of 21-trifluoromethyl-benzylideneacetic acid ethyl ester and 7.2 g of amidine-acetic acid isopropyl ester in 150 ml of ethanol gave 2-amino-6-methyl-4- (2'-trifluoromethylphenyl) -1,4- dihydropyridine-3,5-dicarboxylic acid 3'-isopropyl ester-5-ethyl ester, solid 56682 mp 106 ° C. Yield 49% of theory.

Example 21

Cr * 0 *

T H

(H5C) 2HC00C cooch (ch3) a

H c HH

After heating for 3 H * -1 h, a solution of 13.9 g of 3'-nitrobenzylideneacetic acid isopropyl ester and 7.2 g of amidine acetic acid isopropyl ester in 180 ml of ethanol gave ~ 2-amino-6-methyl-4- (3'-nitrophenyl) ) -1,4-dihydro-twidine-3,5-dicarboxylic acid diisopropyl ester, mp 122 ° C (ether).

Yield 62% of theory.

Example 2 2 ·

kJ-CN

LH

After boiling for 1 h, a solution of 12.2 g of 2'-cyanobenzylideneacetic acid ethyl ester and 7.2 g of amidineacetic acid isopropyl ester in 200 ml of ethanol, 2-amino- 6-methyl-4- (2'-cyanophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester-5-ethyl ester, pour point 200 ° C (Cisopropanol), yield 58% of theory.

Example 23

Ci N ° *

After boiling for 1 hour, a solution of 12.5 g of 3'-nitrobenzylideneacetic acid methyl ester and 7.2 g of amidineacetic acid isopropyl ester in 150 ml of ethanol, 2-amino-6 g of COOCH (CH 2) a H, C h NH * 2 was obtained. -methyl 4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-methyl ester, m.p. 167662 mp 167 ° C (ethanol). Yield 82% of theory.

Example 2H

. rrN0 '

Ha Ca 00C00CHa CH2 CH3 HjCl2H NHi

Heating for 2 hours with a solution of 13.2 g of 3 * -nitro-benzylideneacetic acid ethyl ester and 7.2 g of amidineacetic acid n-propyl ester in 200 ml of ethanol gave 2-amino-6-methyl-4- (3 '). -nitrotenyl) -1H-dihydropyridine-3,5-dicarboxylic acid (3-n-propyl ester-5-ethyl ester, mp 168 ° C (ethanol)).

Yield 79% of theory.

Example 25 (fYN0 *

Hj C8CC s / C C00CH, CH, OCH, H a

Boiling for 2 hours a solution of 13.2 g of 31-nitrobenzylideneacetic acid ethyl ester and 8.0 g of amidineacetic acid γ-methoxyethyl ester in 200 ml of ethanol gave 2-amino-6-methyl-4- (3 - nitrotenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-γ-methoxyethyl ester-5-ethyl ester, mp 17 ° C.

Yield 59% of theory. -

Example 26

Hj Ca OOC C00C2 Hj H3C ^ H N112 IT S66 £ 2

Boiling for 8 hours a solution of 13 * * g of (1'-naphthylidene) acetic acid ethyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (1'-naphthyl). ) -1H-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 1 ° C (ethanol). Yield 62% of theory.

Example 27

Svcn

After heating for 6 hours, a solution of 11.5 g of 2'-cyanobenzylideneacetic acid methyl ester and 7.2 g of amidine acetic acid isopropyl ester in 100 ml of ethanol, 2-amino-6-methyl -4- (2'-Cyanophenyl) -1H-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-methyl ester, mp 211 ° C (ethanol). Yield 72% of theory.

Example 2 8

l / I CN

After boiling for 8 hours, a solution of 11.5 g of 2'-cyanobenzylideneacetic acid methyl ester and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6- Methyl 4- (21-cyanophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester, mp 224UC (ethanol) Yield 66% of theory.

Example 29 18 56682

LJU ^ j! H, Ca OOC COOC2 H3 H.C2N2NHa

B

After heating for 8 hours, a solution of 14.8 g of 2'-biphenyl-benzylideneacetic acid ethyl ester and 6.5 g of amidineacetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-14- (21-biphenyl) -1 , β-dihydropyridine-3,5-di-β-carboxylic acid ethyl ester, pour point 182 ° C (ethanol). Yield ^ 1% of theory.

Example 30 After heating for 6 hours, a solution of 12.5 g of 3 * -nitrobenzylideneacetic acid methyl ester and 7.2 g of amidineacetic acid n-propyl ester in 100 ml of ethanol was obtained, Γ * ΎΝ ° 2 h3 cooc C00CH2 ch2 ch3 HJC. 2-Amino-6-methyl-4- (31-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-n-propyl ester-5-methyl ester, mp 155UC (ethanol). Yield 69% of theory.

Example 31

ly. S

k11

Il3 Ca OOC γγcooc2 h3

After heating for 4 hours, a solution of 12.2 g of (21-tenylidene) -acetic acid ethyl ester and 6.5 g of amideacetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (2-tenylidene) ethyl acetate. (-tenyl) -1H-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 170 ° C (ethanol). Yield 73% of theory.

Example 32

| H

(h3c) 2 N6G ^ JC ^ GÖNIIa

After heating for 8 hours, a solution of 10.9 g of benzylideneacetic acid dimethylamide and 5.0 g of amidine acetamide in 100 ml of ethanol gave 2-amino-6-methyl-4-phenyl-5-dimethylaminocarbonyl-1 , H-dihydropyridine-3-carboxylic acid amide, melting point 236 ° C (ethanol). Yield 50% of theory »

Example 33 (H, C) a NOC II5 II NU *

Heating a solution of 10.9 g of benzylenediacetic acid dimethylamide and 6.5 g of amidine acetic acid ethyl ester in 100 ml of ethanol for 6 hours gave 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine. 3,5-Dicarboxylic acid 3-ethyl ester-5-dimethylamide, mp 230 ° C (alcohol). Yield 6.1% of theory.

Example 3H

W ^ NOa i / 5Ca OOCv ^ K ^ COOCiKCHj) 2 0 & 66β2

Boiling for 6 hours a solution of 13.2 g of 2'-nitrobenzylideneacetic acid ethyl ester and 72 g of amidine acetic acid isopropyl ester in 100 ml of ethanol gave 2-amino-6-methyl-H- (2 * -nitrophenyl) -1, 4-Dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-ethyl ester, m.p. 139 ° C (isopropanol). Yield 39% of theory.

Example 35

TH

c2 OOC 1 ^ H> c H NHa

Boiling for 6 hours a solution of 13.2 g of 2'-nitrobenzylideneacetic acid ethyl ester and 6.5 g of amidineacetic acid ethyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (2'-nitrophenyl) -1 , 4-dihydropyridine-3,5-dicarboxylic acid diethyl ester, mp 159 ° C (ethanol). Yield 52% of theory.

Example 36

After heating for 8 hours, a solution of 12.5 g of 21-nitrobenzylideneacetic acid methyl ester and 7.2 g of amidine acetic acid isopropyl ester in 100 ml of ethanol gave 2-amino-6-methyl. -4- (2 1-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester 5-5-methyl ester, pour point 203μΟ (isopropanol). Yield 50% of theory.

Example 37 21 $ 6682

CN

After heating for 8 hours, a solution of 12.2 g of 2'-cyanobenzylideneacetic acid ethyl ester and 7.2 g of amidineacetic acid n-propyl ester in 100 ml of ethanol was obtained. , 2-Amino-6-methyl-4- (2'-cyanophenyl) -1H-dihydropyridine-3,5-dicarboxylic acid 3-n-propyl ester-5-ethyl ester, Solid. 182μΟ (ethanol). Yield 62% of theory.

Example 38 (H3 C) a HCOOC ^ JC ^ COOCUa CHa CH3

H, c ^ N ^ NHa H

After heating for 6 hours, a solution of 13.9 g of 3'-nitrobenzylideneacetic acid isopropyl ester and 7.2 g of amidineacetic acid n-propyl ester in 100 ml of ethanol gave 2-amino-6-methyl-4- (3 ' -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-n-propyl ester-5-isopropyl ester, - Melting point 199 ° C (isopropanol). Yield 75% of theory.

22 * 6682

Example 39 After boiling for 3 hours, a solution of 20.1 g of pyridyl-2-methylidenecyclohexane-1,3-dione and 13.0 g of amidine acetic acid ethyl ester in 200 ml of isopropanol was obtained from 2-amino-U- (0tf). -pyridyl) -1,5,5,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ester, m.p. 260 ° C. Yield 58% of theory.

Example Up

In analogy to Example 39, 21.5 g of 6-methylpyridyl-2-methylidenecyclohexane-1,3-dione and 13.0 g of amidineacetic acid ethyl ester were obtained from 2-amino-N- (61-methylpyrid-2-yl) -1, U, 5,6,7,8-Hexahydro-5-oxoquinoline-3-carboxylic acid ethyl, pour point> 260 ° C. Yield 52% of theory.

Example ^ 1

In analogy to Example 39, 2.1 g of 2-azido-benzylidene-cyclohexane-1,3-dione and 13.0 g of amidineacetic acid ethyl ester were obtained from 2-amino-N- (2-azidophenyl) -1, , 5,6,7,8-Hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester, mp 209 ° C. Blockade 71% of theory.

Claims (1)

A process for the preparation of 2-amino-1,1 + -dihydropyridine derivatives of the formula RH / r2 “\ X / ™ 3 v XX R n m2 wherein R is an alkyl group having 1 to 2 carbon atoms or a phenyl group having a substituent the support may be 1 to 3 identical or different halogen atoms or 1 to 3 identical or different nitro, cyano, trifluoromethyl, azido, phenyl, alkyl, alkoxy or thioalkyl groups, the alkyl or alkoxy part of which contains 1-2 carbon atom, or R is a naphthyl, furyl, thienyl, or pyrimidyl group which may be substituted by a nitro group or an alkyl or alkoxy group having 1 to 2 carbon atoms, or a pyridyl group which may be substituted by an alkyl group having 1 to 2 carbon atoms. ..... . With 2 l groups, R is an alkyl group having 1 to 2 carbon atoms or a phenyl group, R and 3. ..... R, which may be the same or different, denote an alkyl, alkoxy, alkynyloxy or alkoxyalkyl group, the alkyl and / or alkoxy part of which contains up to k carbon atoms, or an amino group or an alkylamino group, the alkyl part of which contains 1 -2 carbon atoms, or R and R together form an alkylene group containing 2-h carbon atoms, characterized in that the O (β-unsaturated dioxo compound of the formula> CO 2 R R = C 1 -C 3 R 2 1.2. Wherein R, R and R, as defined above, is reacted with an amidine of the formula H2Nx ^ p-CH2-COR3 (V) HN3, wherein R is as defined above, in an inert organic solvent at a temperature of 20-200 ° C.