DK142869B - Analogous process for preparing 2,6-dialkyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester compounds. - Google Patents

Description

(9 \ B> (11) petition 142869 DENMARK i «) mt. ci.3 c 07 0 211/90 (21) Application No. 877/74 (22) Filed on 19 · Feb. 1974 li & piII (24) Race day 19 Feb. 1974 V / (44) The application presented and the document published on 1 February 6. 1 981

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM (30) '' "

Feb 20 1975, 20425/754 JP

Mar 5 1975, 25566/734 JP Apr 20 1975, 44821/73, JP

May 11, 1975, 52507/754 JP

May 17, 19754 54959/754 JP

July 24. 1975, 83276/734 JP

Nov 29 1975, 154069/754 JP

Nov 29 1973, 154070/754 JP

(71) YAMANOUCHI PHARMACEUTICAL CO. LTD., 5-14 Nihoribashi-Honcho 2-chome, "Chuo-ku, Tokyo, JP.

(72) Inventor: Masuo Murakami, 19-1-502, Sengoku 2-chome, Bunkyo-ku, Tokyo, JP: Kbzo TakahasKi, 8574 Nishioizumi-cho, Nerima-ku, Tokyo, JP:

Mas aru Iwanami, 8-1, Nishikigaoka, Kohoku-ku, Yokohama-shi, Kanagawa, JP: Magaharu Fujimoto, 840, Hokima, Adachi-ku, Tokyo, JP: Tadao Shlba = numa, 14-32, Saiwai-cho 2 -chome, Asakl-øhi, saitama, JP: Ryufcaro Kawai, 1547-5, Koguki, Shiraoka-machi, Mlnamisalt ama-gun, saitama, TP: Toichl Takenaka, 17—18—807, Akabanedai 4-chome, Kita-ku , Tokyo, JP.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company.

(64) Analogous process for the preparation of 2,6-dialkyl-4-phenyl-1,4-dihydropyridine-5-carboxylic acid aminoalkyl ester compounds.

This invention relates to an analogous process for the preparation of novel 2,6-dialkyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester compounds having the general formula (I) as set forth in the preamble of claim 1, excellent cerebral vasculodilatory activity.

Of 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives, 4- (nitrosubstituted phenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester has long been known and is described in eg. Chem.

Ber., 20, 1338-1343 (1889) and J. Am. Chem. Soc., 71, 4003-4007 (1949). Other known examples are 1,4-dihydropyridine-3,5-dicarboxylic acid alkoxyalkyl esters, which are described in U.S. Patents Nos. 3,485,847 and 3,511,847 and German Publication Nos. 1,813,436, 2,013,431 and 2 018 738.

2 142869

Among these known compounds, 4- (2'-nitrophenyl) -2,6-dimethyl-1,4- 'dihydropyridine-3,5-dicarboxylic acid methyl ester is well known as a compound exhibiting coronary vasodilatory activity and spasmolytic activity (US Patent Nos. 3 485, 847) (approved under the name "Nifedipine" by the British Pharmacopoea Commission). It is also known that 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -3,5-pyridine-dicarboxylic acid diethyl ester has blood pressure lowering activity (see, e.g., U.S. Patent No. 3 511 847). However, it has never been known in practice that these known compounds have cerebral vasculodilatory activity.

Danish Patent Application No. 2089/73 discloses 4-phenyl-2,6-dimethyl-1,4-dihydropyridine-5-alkoxycarbonyl (or alkanoyl) -3-carboxylic acid aminoalkyl esters with cerebral vasculodilatory activity.

It has now been found according to the invention that the novel compounds of formula (I) have muscularotropic spasmolytic activity as well as a particularly prominent low toxicity cerebral vasculodilatory activity and that they produce a much stronger and longer lasting vascular dilatation than the above known compounds. Therefore, these compounds are particularly suitable for abrogating the closure of the cerebral vascular blood stream.

These nitrogen-substituted alkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acid are novel as mentioned and it was unexpected that such new compounds would appear to have the above-described activities.

The process according to the invention is characterized by the characterizing part of the claim.

In the procedure (a) of the claim, the compounds of formulas (II), (III) and (IV) are reacted in substantially equimolar conditions in an insoluble state or in a solvent such as ethanol, isopropanol, dioxane, dimethylformamide, dimethylsulfoxide and aceto -nitril. The reaction can be promoted by heating the reaction system.

As set forth in the claim, the enamine derivative of formula (IV) is prepared by reacting a β-diketone compound of formula (V) and an atm of formula (XVI) and isolating the product before use, but the following method Of course, the compound of formula (V) may be reacted with a substantially equimolar amount or an excess molar amount of the amine of formula (XVI) in a reaction vessel, preferably in the presence of an organic solvent such as ethanol. of the compound of general formula (IV), after which the compound of formula (II) and compound of formula (III) are added to the reaction mixture without isolation of compound (IV).

In the procedure (b) of the claim, the benzaldehyde derivative of formula (II) is reacted with the enamine compound of formula (VI) and the compound of formula (V) under the same conditions as in procedure (a). Similar to procedure (a), the enamine compound of formula (VI) is prepared by reacting the compound of the general formula (III) and the amine of the general formula (XVI), and the compound of the formula (II) and the compound of the formula (V) can be added to the reaction mixture without isolating the compound of formula (VI).

When the compound of formula (VI) or compound of formula (IV) is prepared by reacting the compound of formula (III) or compound of formula (V) with the compound of formula (XVI) under the above procedures, it is preferred to use the compound of formula (VI) substantially equimolar or excess amount relative to the compound of formula (III) or the compound of formula (V), and if necessary to add the compound of formula (XVI) as a solution in an organic solvent such as methanol and ethanol . In addition, if an excess amount of the compound of formula (VI) is used, it is necessary after the reaction to remove excess compound of formula (XVI) from the reaction mixture by concentration under reduced pressure before reacting the product with other reactants, i.e. the compound of formula (II) and the compound of formula (III) or the compound of formula (II) and the compound of formula (V).

142869 4

In the procedure (c) of the claim, the lower alkanoyl cinnamic acid alkyl ester of formula (Vil) R6 R3 is obtained by -CH = C-COOA-N ^ (VII) I 2 \ 4 COR ^ R * 2 3 a wherein R, R, R, R and A are as defined in the preamble of claim 1 to react with the compound of formula (IV), and by procedure (d), the compound of general formula (VIII) R COR5 (VIII) COR1 15 wherein R, R and R are as defined in the preamble of the claim to react with the compound of formula (VI).

In the procedure (e) according to the claim, the compound of the above formula (VII) is reacted with the compound of the formula (V) and the amine of the formula (XVI) and by the procedure (f) the compound of the above formula (VIII) ) to react with the compound of formula (III) and the amine of formula (XVI).

In the procedure (g) of the claim, the compound of formula (II), the compound of formula (III), the compound of formula (V) and the compound of formula (XVI) are reacted in equimolar ratios, preferably in an organic solvent.

5 142869

Finally, by the procedure set out in the claim φι), the compound of formula (II), the compound of formula (IV) and a compound of the general formula R2-COCH2-C00A-X (IX) p wherein X represents a halogen atom are reacted. and R and A are as defined in the preamble of the claim to form a compound of formula D "r6 r5oc \ cooa-x (X) k

Ί O C

wherein R, R, R, R, R and A have the meaning set forth in the preamble of claim and X has the above meaning upon which this compound is reacted with an amine of formula / R3 ΗΝΓ (XI)

V

X 4 wherein R 1 and R are as defined in the preamble of claim.

The products prepared by the various above procedures can be isolated and purified by ordinary chemical operations such as extraction, lake, gel chromatography, recrystallization and the like.

The compounds of general formula (I) may advantageously be converted into therapeutically harmless salts, e.g. salts with mineral acids such as hydrochlorides, sulfates and phosphates, or salts with organic acids such as acetates, fumarates, maleates and tartrates.

The appropriate dose of the compounds of the present invention for once-in-human administration is 0.1 - 0.5 mg by intravenous administration and 5 - 10 mg by oral administration, and dosing two or three times a day. is appropriate.

Examples of lower alkyl groups represented by R, R 4, and R 5, R 5 and R 5 in the compounds of general formula (I) may be mentioned methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, and as Examples of lower alkoxy groups represented by include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, tert-butoxy and pentyloxy. Examples of lower alkoxy groups substituted by a lower alkoxy group represented by R include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 2-methoxypropoxy, 2-propoxypropoxy, 5-methoxypene-tyloxy and 3-methoxypentyloxy. Examples of alkylene groups represented by A in the general formula (i) include methylene, ethylene, trimethylene, tetramethylene, propylene and ethylethylene.

The results of tests of the cerebral vasodilating activity of the compounds of the invention are set forth in the following table.

Method: Adult bastard dogs were anesthetized with sodium pentobarbital (30 mg / kg, - i.v.) and given artificial respiration. The vertebral blood flow was measured with an electromagnetic flow meter placed around the vessel. LD ^Q was measured using mice. The results are given in the following table.

Open NO2 R 2 OC-COO-A-N 4 HCl 11 JI p 2 · CH-TY 2 CH 3 3 3 7 142869

Sample Vertebral Blood LDj-n 5 3 4 Current Effective R A R R Dose (mg / kg, i.v.) (Mg / kg, ______ i.v.

CH2 O- -CH2CH2- O “CH2" ch3 "0.0003 - 0.01 20.7 c2h5o-" "" "" CH ^ ncho- "" CH2 "-CH2CH2CH2-" C2H5- "" 12 n -CH2CH2- CH30-Q-CH2- CH2 "" 10 C2H50- "C1-Q-CH2-" 10 n «n 0.001 - 0.01 i2 CH3-" 0 "CH2" "0.001" ° "001 40" " C1-0-CH2- "" "45

Nifedipine 0.001 - 0.01 5.6 The following are the results of comparative experiments with a number of compounds prepared according to Danish Patent Application No. 2089/73 and a number of compounds made according to the present invention with papaverine as standard. The vasodilatation and toxicity were measured in the same manner as described above, and the strength of the vasodilatation was then compared to that produced by papaverine.

8 142869

The general formula for the compounds of the invention and of Danish Patent Application No. 2089/73.

X

% 0C \ ^ K / 00RA

Cf jiC

CH ^ A CJH, J H 3

Vasodilatation LD, -n

Ra 1¾ X Strength Duration mg / £ g in <v_

Papaverin 1 - f 27.0

Compounds prepared according to Ans. No. 2089/73:

Sample no.

a -CH2CH2N-H - ° ch3 ^ rN ° 2 1 ++ 46.7

Xch3 V

b -CH-CH-N-CH, "" 10 "53.0 2 2 n. in CH3 c -CH2CH2N-CH3" "" 33.0 'C2H5 d -CH2CH2N-C2H5 "" 39.5 \ 2h5 e -CH2CH2nQ "" "33.0 f -CH2CH2CH2N— CH3" "" 29 i5

Sch3 g -CH-CH-N-CH- "" "" 301 ° I 2 \ 3 CH- CH- J. CH-I 3 h -CH2CH2N-CH3 -OCH2CH2N "1 t 70.0 XCH3 C133" -0CH3 "10 53.0 j" "OC2H5" "37 j ° k" · -OCH-CH- "n t ++ 37.0 \ Δ CH3 9 142869

Vasodilatation LD ^ q

Sample No. RA_Re X Strength Duration. l v_ 1 -CH 2 CH 2 N-CH, -OCH-CH, fl 2 fNO 2 10 T ++ 4210 2 2 S \ h 5 ^ m, "-0C (CH 3) 3" "+ f 50.0 n" -OCH 2 CH- € H3 "*" ", CH, o - ° C ^ CH2" C2H5 P "-OeH2CH2OCH2CH2CH3" "" 29.5 q “OC2H5 1 f 25.3 r" "48.1 | ^ CH3 s" - (fV001 ^ "** 28.0 T q £ || t" -and 3 "f 53.4 U" "(JV01 10 H 18.0

Xci v "- p 1 f 43.1 w -" l $ LNo2 10 H 20.5 x "" ¢ ^ ° 2 "" 53.0 F ° 2 y "" Q 0.3 + 76.6 z - ( pCH2N-CH3 "ΐφΐΝ0 10 ++ 1013 CH3 xch3 2 Z '-CH2CH2H-CH3 -CH3 β ~ Ν02" + 85.0 CH_ J

z ·· -CH2CH2 ^ d ^ j -OCH3 i ^ m2 - + H

z "-CH2CH2N— CH3" 0CH3 δ ° r3 "25 J ° \ h3 10 142869

Compounds made from Tr ..

according to the invention: vasodilatation id ^ q

Sample No. RA RB X Strength Duration mg / kg i.v.

a -CH2CH2N-H _0CH3 (Γ ^ ΓΝ ° 2 30 + Ή- 16.0

'<12- © Y

b -CH, CH, N-CH-, 200 + H4 20.7 c -CH2CH2N-C2H5 -OCH-CH3 n 13.5

V, - © X

d -CH9CH_N-CH- "" "7.4

Xch2 - ^ - ch3 e -CH2CH2N-CH3 "OVE" "8" 6 xch2 - ^ - and3 f -CH2CH2N-CH3 "OCH3" "6.0 -Q-ci g -CHOCHOCH" N-CH, -OCH -CH- "" "9.7 2 2 2 \ 2 \ 3 CB2- © ch3 h -CH2CH2N-CH3 -OCH3" "" 16.5 CH2 -® in -CH2CH2N-CH3-Coils 30 t + t 23.7

Xch2- ^ 3 j "" (prCF3 "" 14.0 kn ". A 200 ++++" ^ Γ1 ° 2 1 -CHOCHoN-CH, -OCHCH '(¾ "" 0.6 2 2' o1 - © åe3 3 ^ 1> 2 m "-CH3 jt ^ fN02 100 +++ 40.7 n -CH ~ CH_N-CH," "" "50.0 2 2 \ 3 / = rv

Cl: Papaverine = 1 s1: f: 5-10 min. ++: 10-20 min. +++: 20-30 min. ++++: 30-50 min.

11 142869

The following pharmacological data represent the cerebral vasodilatory activity, the spasmolytic activity and the acute toxicity of the compound 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3 -β- (N-benzyl-N-me thylamino) ethyl ester-5-methyl ester hydrochloride (hereinafter called compound "A") in comparison with the activities of papaverine and nifedipine.

1. Effect on cerebral circulation, heart rate and blood pressure after intravenous injection:

Method: Adult bastard dogs were anesthetized with sodium pentobarbital (30 mg / kg, i.v.) and given artificial respiration. The vertebral blood flow was measured with an electromagnetic flow meter placed around the vessel. The blood pressure of the femoral artery was measured by a pressure transducer and the heart rate by a cardio-tachometer. All agents were administered into the femoral vein.

Results: The effects of compound A, papaverine and nifedipine on the vertebral blood flow, mean blood pressure and heart rate of anesthetized dogs are listed in the following table.

Table

Mean Dose Number of animals Vertebral Mean Heart (mg / kg) i.v. blood flow blood pressure speed th # ± s.a.) (Δ mmHg (A stroke / min + s.a.) + s.a.)

Papaverin 0.1 8 22 ί 3.4 -9-1.1 8 i 1.5 0.3 8 67 - 7.1 -21 ½ 2.8 22 - 3.5 1.0 8 124 ί 13.8 -32 ± 3.5 44 in 4.8

Nifedipine 0.001 5 47 δ 13.5 -10 - 1.6 10 ± 3.5 0.003 4 104 t 25.8 -24 ± 5.9 18 3.2 3.2 6 135 ~ 28.8 -39 - 5 , 2 17 - 4.0

Compound A 0.0003 8 27 - 4.4 -1 in 0.6 4 in 1.3 0.001 8 61 t 9.5 -7 δ 1.5 12 ί 2.2 0.003 8 132 ί 13.8 -14 i 2.2 18 ± 2.0 0.01 8 200 ί 27.3 -29 - 3.6 25 - 5.3 2. Direct effect on cerebral and femoral arteries: 12 142869

To analyze the selective effect of the agents on the vasculature, the direct effect on the cerebral (vertebral artery) and peripheral (femoral artery) vascular pathway was investigated by the constant volume perfusion method.

Method: Adult bastard dogs were anesthetized with sodium pentobarbital (30 mg / kg, i.v.) and given artificial respiration. Heparin (1000 units / kg, i.v.) was used as an anticoagulant. The methods for perfusion of each artery were as follows: l) For the vertebral artery, the arterial blood that was directed from the left general carotid artery was collected by a tygon tube and perfused by a Sigma motor pump to the right vertebral artery. 2) For the femoral artery, the arterial blood flowing from the proximal femoral artery was perfused by means of the Sigma motor pump into the distal femoral artery. The 'vascular responses were expressed as changes in the perfusion pressure measured by a pressure transducer. All means were given into a rubber tube connected tightly to each artery cannula by means of a microinjector. The dose response curve for each agent was determined and the 50% effective dose (ED ED Q) for each agent was calculated when the maximum response to papaverine at 3000 µg i.a. was expressed as 100% reaction.

Results: Effects of intra-arterially administered papaverine, nifedipine and compound A on vertebral and femoral artery are listed in the following table.

Table

Vasodilatation s.a. Selectivity ratio ED, -n / Ug - (EDcn in femoral artery / ED? Q in vertebral artery

Mean Number of animals Vertebral Femoral ^ arte rie artery

Papaverine 4 72.8 - 8.71 48.8 t 3.73 0.67

Nifedipine 4 0.74 ± 0.15 0.37 ^ 0.11 0.50

Compound A 4 0.66- 0.20 0.86-0.11 1.30 3. Spasmolytic Activity: 13 142869

Methods: Isolated guinea pig ileum was suspended in Tyrodes solution using a Magnus apparatus, and muscle movements were recorded on a kymograph of an isotonic lever. Barium chloride, acetylcholine and histamine were used as agonist, and 50% inhibition by the antagonist was measured from the contraction response of the agonist.

results:

Table

Spasmolytic activity (g / ml-s.a.)

Agonist Concentrate- Papaverine Nifedipine Compound A

(g / ml) -

BaCl2 2 x 10 ~ 4 (7.2 ± 0.2) x ΙΟ'6 (3.3 ± 0.2) x 10 "9 (1.9 * 0.4) x 10 ~ 9 cholesterol" 10'7 (l, 1 * 0.1) x 10-5 (l, 6 * 1.1) x 10 ~ 8 (5.2 * l, 0) x ΗΓ9

Histamine 10 "7 (7.0 * 1.9) x 10" 6 (5.5 * 0.9) x ΙΟ "8 (1.8 ± 0.2) x 10" 9 4. Acute toxicity:

Comparison of the intravenous acute toxicity between compound A and nifedipine was performed using ICR male and bastard dogs.

Table LD (mg / kg, i.v.)

Sample Mice -3 Dogs

Compound A 20.7 6.1

Nifedipine 5.6 1.5

From the above results, the compounds prepared by the process of the invention have strong spasmolytic activity, vigorous and selective cerebral vasodilating activity and low toxicity. Therefore, they are useful in the treatment of acute attacks of occlusive cerebral vascular disease and apoplexy and postapoplectic conditions arising from cerebral vascular irregularities in both injection and long-term oral administration.

The process according to the invention is further illustrated by the following examples.

EXAMPLE 1

A mixture of 5 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester, 2.8 g of β-aminocrotonic acid isopropyl ester and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100 ° C on an oil bath. Then, by treating the product as in Example 2 below, 2.5 g of 2,6-dimethyl-4- (3 * -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-5-isopropyl ester-3 was obtained. -.β- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 171 - 175 ° C

Elemental Analysis for CggH ^N ^OgCl:

Ct (Ht) (Nt) Cl (° / o) Calcd: 61.82 6.30 7.72 6.52 Found: 61.58 6.15 7.42 6.50 Example 2

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of β-aminocrotonic acid methyl ester and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100 ° C on an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20: 1 mixture of chloroform and acetone. The eluate containing the desired product was concentrated and assayed by thin layer chromatography.

The powdered product thus obtained was dissolved in acetone and, after adjusting the solution to pH 1-2 with an ethanol solution saturated with hydrogen chloride, the solution was concentrated to give 2 g of 2,6-dimethyl-4- (3'- nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester-3- β- (N-benzylmethylamino) ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone / ether mixture;

Melting point: 136-140 ° C (decomp.)

Elemental analysis for C ^ qHHNNNC ^Cl: C t)) Htø)) Ntø) Cl tøø calculated: 60.52 5.86 8.14 6.87 Found: 60.25 5.87 7.88 6.67 In 6 ml of methanol, 2.0 g of the crystals obtained above were dissolved and the solution concentrated concentrated to reduced pressure. To the caramel-like residue thus obtained was added 10 ml of acetone and the solution was stirred under ice-cooling. There was obtained 1.5 g of the above product with a melting point of 168-170 ° C.

EXAMPLE 5

A mixture of 4.2 g of acetoacetic acid β - (N-methyl-N-phenylamino) ethyl ester, 2.05 g of β-aminocrotonic acid methyl ester and 2.68 g of m-nitrobenzaldehyde was stirred for 5 hours at 100 ° C on an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm, height 25 cm) and then eluted with a chloroform / acetone mixture in a 20: 1 volume ratio. The eluate was assayed by thin layer chromatography and the eluate containing the desired product was collected and concentrated under reduced pressure to crystallize the product. The crystals were collected and recrystallized from a mixture of ether and petroleum ether to give 0.9 g of 2,6-dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid 5-methyl ester 3-β- (N-methyl-N-phenyl) aminoethyl ester.

Melting point: 135-138 ° C.

Elemental Analysis for C25H276.36: C (%) H (%) N (%) Calculated: 64.50 5.85 9.03 Found: 64.48 5.81 8.95 Example 4 In 3 ml of isopropanol was dissolved 4.4 g of acetoacetic acid 2 - (N-benzyl-N-methylamino) ethyl ester, 2.6 g of β-aminocrotonic acid isopropyl ester and 2.7 g of o-nitrobenzaldehyde, and the solution thus prepared was heated for 5 hours to 80 ° C. . The reaction mixture was dissolved in 50 ml of chloroform, then the solution was washed with 20 ml of 10% hydrochloric acid and 20 ml of water and further with 30 ml of 10% aqueous sodium hydroxide solution and 20 ml of water. The chloroform layer thus formed was separated, dried over anhydrous magnesium sulfate, and the chloroform distilled off under reduced pressure. The residue formed was dissolved in a small amount of chloroform and the solution prepared was subjected to a silica gel column chromatography (diameter 3 cm, height 20 cm). The product was eluted with a chloroform / acetone mixture in a 20: 1 volume ratio. The eluate was examined by thin layer chromatography and the eluate containing the desired product was collected and concentrated under reduced pressure to give 2.2 g of 2,6-dimethyl-4- (2f-nitrophenyl) -1,4-dihydropyridine-3, 5-dicarboxylic acid 5-isopropyl ester 3-β- (Nb enzyl-N-methylamino) ethyl star. The product was dissolved in acetone and, after neutralizing the solution with ethanol saturated with hydrogen chloride, the solution was concentrated under reduced pressure to give the hydrochloride of the above compound.

Melting point: 208-210 ° C (decomp.).

Elemental Analysis for C «)H t )N «Cl Cl: 61.82 6.30 7.72 6.52 Found: 61.63 6.25 7.65 6.73 EXAMPLE 5 In 5 ml of isopropanol was dissolved 5 , 0 g of acetoacetic acid (N-benzyl-N-methylamino) propyl ester, 2.7 g of β-aminocrotonic acid isopropyl ester and 2.9 g of m-nitrobenzaldehyde and the solution was heated to 80 ° C for 5 hours.

Then, by treating the reaction mixture as in Example 4, 3.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester 3-9 was obtained. ^ - (N-benzyl-N-methylamino) propyl ester. The melting point of the hydrochloride of this compound was 1666-169 ° C (decomp.).

Elemental analysis for C ^H ^ gNNO OgCl: C (96) H (96) N (96) Cl (%) calcd: 62.41 6.50 7.53 6.35 found: 62.35 6.39 7, EXAMPLE 6 In 3 ml of isopropanol was dissolved 4.0 g of acetoacetic acid P- (N-benzyl-N-methylamino) ethyl ester, 2.1 g of β-aminocrotonic acid ethyl ester and 2.4 g of m-nitrobenzaldehyde. whereupon the solution was heated to 80 ° C for 5 hours.

Then, by treating the product thus obtained as in Example 4, 1.5 g of 2,6-dimethyl-4- (3, -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-ethyl ester was obtained. 3-β- (N-benzyl-N-methylamino) ethyl ester. The results of the elemental analysis on the hydrochloride of this product are as follows:

Melting point: 168-169 ° C.

Elemental Analysis for: C (%) H (9e) N (%) Cl (%) Calc'd 61.19 6.09 7.93 6.69 Found: 6.13, 6.33 7.66 6.59 Example 7 I 6 ml of isopropyl alcohol were dissolved 2.6 g of β-aminocrotonic acid β- (N-benzyl-N-methylamino) ethyl ester, 1.1 g of methyl acetoacetate and 1.5 g of m-nitrobenzaldehyde and the solution prepared was stirred for 6 hours at 85 ° C.

The reaction mixture was cooled, dissolved in 10 ml of chloroform, and the solution washed once with excess dilute hydrochloric acid and then three times with 7 ml of water each time. The resulting chloroform layer was separated, dried over anhydrous magnesium sulfate, and the chloroform then distilled off. By mixing the residue with 15 ml of ethyl acetate followed by stirring, the separated product crystallized, dried and recrystallized from acetone to give 2.4 g of 2,6-dimethyl-4- (3'-ni trophenyl) crystals. -1,4-dihydropyridine-3,5-di-carboxylic acid 5-methyl-ester-3β- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 128-132 ° C (decomp.).

Elemental analysis for C ^ gH ^ øN₂OgClCl / 2CH-CCOCH ^: C (96) H (9e) N (96) Cl (96) calculated: 60.60 6.10 7.71 6.50 found: 60.6l 6 Example 14 18 142869 In 20 ml of isopropyl alcohol was dissolved 5.0 g of p-aminocrotonic acid p-dimethylaminoethyl ester, 7.2 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and 4, 3 g of m-nitrobenzaldehyde and the resulting solution was stirred for 5 hours at 85 ° C. After completion of the reaction, the reaction mixture was cooled, dissolved in 50 ml of ethyl acetate, and the product was extracted once with excess hydrochloric acid and then three times with each. once 50 ml of water. All the extracts were combined and, after alkalizing the solution with a dilute aqueous solution of sodium hydroxide, the product was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, concentrated, purified by silica gel column chromatography using ethyl acetate as eluant, and the desired fractions were then collected. The mixture was concentrated, acidified with ethanolic hydrogen chloride and the solvent distilled off to obtain 4.0 g of crystalline powder of 2,6-dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine. -3,5-dicarboxylic acid 3-β- (N-benzyl-N-methylamino) ethyl ester 5-β- (N, N-dimethylamino) ethyl ester.

. Elemental analysis for C 29 H 38 N 4 ° 6 Cl 2: C (%) E (%) N (%) Cl (%) calculated: 57.14 6.28 9.18 11.63 found: 57.02 6.56 8.93 11.83

Nuclear Magnetic Resonance Spectrum (CDCl3): S (ppm): 2.27 (9H, -N <~ | -3 (6H) + (3H)) 2.31 (3H), 2.41 (3H) ( 2.6 - 2.8 (4H, -CH -, - N <) 3.64 (2H, -N <ch_O) 4.2 - 4.4 (4H, -COQ-CEL-) 5.28 (1H ,)

H

7.4 - 8.4 (9H, '(5H) + (φΤΤ 2 (4H)) EXAMPLE 9 In 12 ml of isopropyl alcohol, 4.0 g of acetoacetic acid p- (N-benzyl-N-methylamino) ethyl ester was dissolved , 1.22 g of m-nitrobenzaldehyde and 1.3 ml of ammonia water, and the resulting solution was stirred for 6 hours at 85 ° C. Then, by treating the reaction mixture thus obtained as in Example 8, 3.0 g of crystalline powder was obtained. of 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bi-β- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Elemental analysis for C ^H ^N ^OgClg in C (%) H (%) N (é) Cl (%) calculated: 61.31 6.17 8.17 10.34 found: 61.06 6.20 7 , 95 10.22

Magnetic Nuclear Resonance Spectrum (CDC1); 3

-CH

S (ppm): 2.16 (6H, 2.30 (6H, XX)! H H 3 3.60 m, H 2 O ~ S 2a'N <5 3.45 (4H, -N <^ h2_0 4.13 (4H, -CH 2 -CH 2 -N.)

5.08 (1H, XX

. 7.0 - 8.2 (14H, (10H) + 2 (4H) EXAMPLE 10 (a) In 5 ml of isopropanol, 3.0 g of P-chloroethyl acetoacetate, 3.3 g of m-nitrobenzaldehyde and 2, 3 g of methyl p-aminocrotonate and the solution was heated to 80 ° C for 4 hours.

The reaction mixture thus prepared was concentrated under reduced pressure, the residue dissolved in a small amount of ethyl acetate, the solution subjected to silica gel column chromatography (diameter 3.3 cm, height 20 cm), and the product then eluted with ethyl acetate. The eluents containing the desired product were collected and concentrated to give 2.0 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-p -chlorethylester-5-methyl ester

Melting point: 130-131 ° C.

Elemental Analysis for C18 H19 N2 Cl6 Cl: C (%) H (%) N (%) Cl (%) Calcd: 54.76 4.85 7.10 8.98 Found: 54.43 4.74 6.91 9.18 (b ) In 6 ml of toluene were dissolved 2.0 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester-5-methyl ester and 1.3 g of N-methylbenzylamine and the solution thus formed was heated at reflux for 5 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of chloroform and 10 ml of water, and the organic layer formed was separated and washed with 10 ml of 10% hydrochloric acid and then with water. The organic solution thus obtained was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was added to 10 ml of ethyl acetate and the mixture was stirred under cooling to crystallize 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5'-dicarboxylic acid-3-P - (N-benzyl-N-methylamino) ethyl ester 5-methyl ester hydrochloride. The product thus obtained was 1.6 g. The product, after recrystallization from a methanol / acetone mixture, had a melting point of 180-181 ° C.

Elemental analysis for C26H30N3 ° 6C1: C (%) H (%) N (%) Cl (%) calculated: 60.52 5.86 8.14 6.87 found: 60.35 5.87 7.90 6.67 (C) In 6 ml of toluene was dissolved 2.0 g of 2,6-dimethyl-4- (3,3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester-5-methyl ester and 1.2 g of benzylamine, and the solution was refluxed for 3 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of chloroform and 10 ml of water, and the resulting organic layer was separated, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to a silica gel column chromatography (diameter 4 cm, height 25 cm) and the product was eluted using a 10: 1 volume ratio of benzene and acetone. The eluate containing the desired product was examined by thin layer chromatography and collected and concentrated. under reduced pressure to obtain 0.8 g of crystalline powder of 2,6-dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- β- (N -benzylamino) ethyl ester-5-methyl ester.

Elemental analysis for Η25Η27Ν3 ° 6: C (%) H (%) N (%) calculated: 64.50 5.85 9.03 Found: 64.41 5.72 8.85

The hydrochloride of the product prepared by treating it with alcoholic hydrogen chloride showed a melting point of 128-130 ° C (dec.).

EXAMPLE 11 (a) In 10 ml of isopropanol, 3.32 g of acetoacetic acid p-chloroethyl ester, 3.0 g of m-nitrobenzaldehyde and 2.86 g of β-aminocrotonic acid isopropyl ester were dissolved and the solution was heated under reflux for 5 minutes. hours. The reaction mixture was concentrated and the residue subjected to silica gel chromatography. The product was eluted therefrom using a 10: 1 volume ratio of chloroform and acetone, the eluates containing the desired product were collected, the solvent was distilled off from the solution, and the crystals thus formed were recrystallized from a chloroform / ether mixture, 2.5 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-p-chloroethyl ester-5-isopropyl ester were obtained.

22 142869

Melting point: 140-145 ° C.

Elemental Analysis for C20H25N2 ° 6C1:

Ctø) Htø) Ntø) Cltø) calculated: 56.81 5.48 6.62 8.38 found: 56.52 5.22 6.46 8.63 (b) In 6 ml of toluene dissolved 2.0 g of 2, 6-Dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester-5-isopropyl ester and 1.4 g of N-ethylbenzylamine, and the solution was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of chloroform and 10 ml of water, and the organic layer formed was separated, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to a silica gel column chromatography (diameter 4 cm, height 25 cm), the product was eluted using a 10: 1 volume ratio of benzene and acetone, and the eluates containing the desired product were collected and concentrated under reduced pressure. The residue obtained was dissolved in ethanol and, after acidification of the solution with an ethanolic solution of hydrogen chloride, the solution was concentrated under reduced pressure. Recrystallization of the product from a chloroform / ether mixture yielded 1.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dinitropyridine-3,5-dicarboxylic acid 3-β- ( N-benzyl-N-ethylamino) ethyl ester 5-isopropyl ester hydrochloride.

Melting point: 132-135 ° C.

Elemental Analysis for Cgg H

Ctø) Htø) Ntø) Cltø) calculated: 62.41 6.50 7.53 6.35 found: 62.30 6.38 7.49 6.41 Example 12

A mixture of 5.26 g of acetoacetic acid β- (N-methyl-Nβ-methylbenzylamino) ethyl ester, 2.86 g of p-aminocrotonic acid isopropyl ester and 3.02 g of m-nitrobenzaldehyde was stirred for 6 hours at 100 ° C. on an oil bath.

After completion of the reaction, the reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm, height 25 cm), the product 23 1Λ 2 8 8 9 was eluted with a mixture of chloroform and acetone in the 20: 1 volume ratio, and the eluates containing the desired product was examined by thin layer chromatography, collected and concentrated to give 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester-3-P - (N-methyl-Np-methylbenzylamino) ethyl star.

Nuclear Magnetic Resonance Spectrum (CDCl

H

Δ (ppm): 1.09 (3H), 1.24 (3H) <4 + "> 2.2 (3H, -N <TCH) + tl 2.3 - 2.4 (9H, h3C PCH3 *" Λ ~ »•) Wv 2.62 (2H, -CH2 -K) 3.47 (2H, -N-CH2-Q-) 4.17 (2H, -CH2-CH2-N <) 4.8 - 5.1 (1H , -CH <™ 3) ΛΜ · ^ ** 2 5.10 (1H, | fT °) ή 7.13 (4H,)

H '^' H

ΛΛΤ h | NO, 7.2 - 8.2 (4H, * ηΑ + Λη)

***** I

The product was dissolved in acetone and after adjusting the prepared solution to pH 1-2 with an ethanol solution saturated with hydrogen chloride, the solution was concentrated. The residue formed was dissolved in a small amount of acetone and by adding petroleum ether to the solution, 4 g of powdered 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid was obtained. 5-isopropyl ester 3-β- (N-methyl-Nβ-methylbenzylamino) ethyl ester hydrochloride.

Elemental analysis for C 29 H 36 N 3 ° 6 Cl: C (%) H (%) N (%) Cl (%) calculated: 62.41 6.50 7.53 6.35 found: 62.61 6.69 7.23 6.35 EXAMPLE 15 U2869

A mixture of 5.0 g of acetoacetic acid β- (N-methyl-Nβ-methoxybenzylamino) ethyl ester, 2.4 g of p-aminocrotonic acid ethyl ester and 2.4 g of m-nitrobenzaldehyde was heated to 85 ° C for 5 minutes. Then, by treating the reaction mixture as in Example 13, 4.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-ethyl ester were obtained. -3-P- (N-methyl-Np-methoxy-benzylamino) ethyl ester.

Elemental analysis for C 28 H 33 N 3 ° 7: C (%) H (%) N (j) calculated; 64.23 6.35 8.03 found 64.01 6.41 '7 »85

Nuclear Magnetic Resonance Spectrum (CDCl3): δ (ppm) ϊ 1.21 (3H, -COOCH2-CH3) 2.20 (3H, -N <) 2.36 (6H, XN] +) H3C1 CE 3 / VVv 2.63 (2H, -CH2-N <) - 3-, 45 (2H,)

3.60 (3H, -O + OCH 3> Vv ^ v * 4.0 - -4-, 3 (4H, -COO-CH, -) Ah ^ 5.13 (1H, (|) ~) Γ 6.82 (2H), 7.20 (2H) ()

H H

J-irL - m «7.3 - 8.2 (4H, Q) -NO₂) 14-2869 EXAMPLE 14

A mixture of 1.5 g of m-nitrobenzaldehyde, 2.8 g of acetoacetic acid β- (N-methyl-Nβ-chlorobenzylamino) ethyl ester, 1.3 g of β-aminocrotonic acid ethyl ester and 5 ml of ethanol was stirred for 3 hours at 95 ° C. ° C.

The solvent was distilled off under reduced pressure, the residue subjected to a silica gel column chromatography, and the product eluted with a benzene / acetone mixture in the volume ratio of 10: 1. The vials containing the desired product were collected and the solvent was distilled off. The residue formed was dissolved in ethanol and after acidification of the solution with 1N ethanolic hydrogen chloride solution, the ethanol was distilled off under reduced pressure. The residue thus formed was dissolved in a small amount of acetone, and after adding ether to the solution until cloudiness formed, the solution was allowed to stand at 0 ° C to give 2.8 g of pale yellow needle-shaped crystals of 2.6 dimethyl-4- (3'-nitrophenyl) -l, 4-dihydro-pyridine-3,5-dicarboxylic acid 5-ethyl ester 3-p- (N-methyl-N p-chlorobenzyl-amino) ethyl ester hydrochloride.

Melting point: 135-139 ° C (decomp.).

Element analysis for C

C (%) H (%) N (%) Cl (%) calculated: 57.45 5.54 7.44 12.56 Found: 57.10 5.62 7.35 12.77 EXAMPLE 15 In 20 ml of isopropyl alcohol was dissolved 7.0 g of acetoacetic acid P- (N-methyl-Np-methoxybenzylamino) ethyl ester, 2.0 g of m-nitrobenzaldehyde and 2.2 ml of 28% ammonia water and the solution was stirred for 6 hours at 85 ° C. The reaction mixture was dissolved in ethyl acetate and then extracted once with excess dilute hydrochloric acid and three times with water. The extracts were combined and after alkalizing the mixture with a dilute aqueous solution of sodium hydroxide, the product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and then chloroform distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography and the product was eluted to purify with ethyl acetate. The fractions of the desired product were collected and concentrated. After acidification of the residue with 1N ethanolic hydrogen chloride solution, the solvent was distilled off under reduced pressure to give 5.0 g of crystalline powder of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-amine. dihydropyridine-5,5-dicarboxylic acid bis / β- (N-methyl-Nβ-methoxybenzylamino) ethyl ester dihydrochloride.

Elemental analysis for C ^H ^ gNNO OgClCl: C (%) H (J6) N (%) Cl (%) calculated: 59.60 6.22 7.51 9.51. Found: 59.55 6.03 7.79 9.69

Nuclear Magnetic Resonance Spectrum (DMSD-dg): S (ppm): 2.36 (6H, jLj ^) H ^ 2.64 (6H, -N <^ 3) 3.38 (4H, -CH2-N \ CH3) ΛΛνν 3/80 (6H,) 4.30 (4H, -N <CH 2 γ) 4.44 (4H, -C00CH 2 -) 5.08 (1H 'fV-a)

Sk 7.0 - 8.2 (12H, (8H) + 2 (4H)) EXAMPLE 16 In 3 ml of isopropyl alcohol was dissolved 1.6 g of o-trifluoromethylbenzaldehyde, 1.6 g of 3-aminocrotonic acid P- (N-benzyl). N-ethylamine) ethyl ester and 0.9 g of acetoacetic acid propoxyethyl ester, whereupon the solution was stirred for 14 hours at 85 ° C. The reaction mixture was concentrated, the residue dissolved; in a small amount of chloroform / acetone mixture in a 20: 1 volume ratio, and then the solution was subjected to silica gel column chromatography (diameter 3.5 cm, height 20 cm). The product was eluted with a chloroform / acetone mixture in 20: 1, 27 142869 volume ratio and the eluates containing part desired product were assayed by thin layer chromatography, collected and concentrated to give Ο, β g of 4- (2-trifluoromethylphenyl) -2 , 6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3- β- (N-benzyl-δί-thylamino) ethyl ester-S--propylethyl ester.

Elemental analysis for G3 9N2 O5 F3: C (%) H (9e) N (%) calculated: 65.23 6.68 4.76 found: 65.37 6.89 4.82

Nuclear Magnetic Resonance Spectrum (CDCl3): i (ppm); 0.84 (39, -CJ 2 Cl 2 -CH 2) 0.96 (3H,) 1.52 (2H, -0-CH 2 -CH 2 -CH 3)

1 eAW

2.26 (6H, XX) as · 3.34 2.46 (2H, -O ^ -9 ^ 2 ^ 3) 2.63 (2H, -CH2-CH2-HCCH2CH3) WVv '3.31 (2H), 3.58 (2H) (-H2C-O-CH2-) 3.57 (2H, -N <CH2_0) 4.0 - 4.2 (4H, -C00-CH2-) 5.55 (1H, θ'- · ) 7.1 - 7.6 (9H, -0 (5H) + {Qf 2 (4H) EXAMPLE · 17 ..... I1 2 3 4 H 1 1 "3 ml of isopropyl alcohol was dissolved 1.07 g of acetic acetic acid r5- ( N-methyl-2 Nβ-methylbenzylamino) ethyl ester, 0.466 g of β-aminocrotonic acid methyl ester and 0.7Q5 g of m-trifluoromethylbenzaldehyde, and the solution was heated at reflux for 6 hours. 4 cm, height 15 cm) and the eluates containing the desired product were collected and concentrated The residue thus obtained was dissolved in acetone and, after adjusting the pH of the solution to 1-2 with an ethanol solution saturated with hydrogen chloride 28, the solution On crystallization of the residue formed from acetone, 0.8 g of 2,6-dimethyl-4- (3'-trifluoromethyl) was obtained. lphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid e-5-methylester ester 3- β- (K-methyl-N-p-methylbenzylamino) ethyl st hydrochloride Melting point: 130-132 ° C.

Elemental Analysis for C28H32N2 ° 4F3C1: C (9fi) H (%) Nt0) Clt0) calculated: 60.81 5.83 5.07 6.41 found: 61 * 11 6.01 5.35 6.67 Example 18

A mixture of 1 g of acetylacetone, 0.75 ml of concentrated ammonia water, 1.5 g of m-nitrobenzaldehyde, 2.5 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and 5 ml of ethanol was heated to 90 ° C for 4 hours. After distilling off the solvent from the reaction mixture under reduced pressure, the residue was dissolved in 10 ml of ethyl acetate and the product extracted with 2N hydrochloric acid. The extract was neutralized with sodium carbonate and the product then extracted with ethyl acetate. The solvent was distilled off from the extract under reduced pressure and the resulting residue dissolved in 3 ml of ethanol. After acidification of the solution with 2N ethanolic hydrogen chloride solution, ethyl acetate was added to the solution until it became cloudy and then allowed to stand for 20 hours at 0 ° C to give 1.4 g of yellow needle-shaped crystals of 5-acetyl -2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid β- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 154 - 157 ° C (decomp.) *

Elemental Analysis for CggHH ^ øN ^O ^Cl: C (9e) Htø) Ntø) Cltø) calculated: 62.46 6.05 8.40 7.09 Found: 62.75 6.21 8.22 6.99 Example 19

To 1 g of acetylacetone was added 0.75 ml of concentrated ammonia water and 5 ml of ethanol and the mixture was stirred for 30 minutes at room temperature to give crystals. To the product was added 1.5 g of m-nitrobenzaldehyde and 2.8 g of acetoacetic acid P- (N-p-chlorobenzyl-N-methyl) ethyl ester, and the mixture was heated to 95 ° C for 4 hours. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue was subjected to silica gel column chromatography. The fractions containing the desired product were eluted with a benzene / acetone mixture in a volume ratio of 10: 1, the eluates were collected and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol and after acidification of the solution with 2N ethanolic hydrogen chloride solution, ethyl acetate was added to the solution until it became cloudy. Then, the solution was allowed to stand for 3 days at 0 ° C to give 1.2 g of yellow needle-shaped crystals of S-acetyl-Z (dimethyl-β-N-nitrophenyl) -1,4-dihydropyridine-3 -carboxylic acid-β- (N p-chlorobenzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 145-150 ° C (decomp.).

Elemental Analysis for C26H29N3 ° 5C1; C (#) H (%) N (%) Cl (%) calculated: 58.43 5.47 7.86 13.27 Found: 58.65 5.59 7.68 13.10 EXAMPLE 20 In 15 ml of isopropanol Dissolve 5.0 g of β-aminocrotonic acid N-benzyl-N-methylaminoethyl ester, 3.1 g of m-nitrobenzaldehyde and 2.0 g of acetylacetone, and then the solution is stirred for 4 hours at 85 ° C. The reaction mixture was dissolved in 40 ml of ethyl acetate and the product extracted with excess dilute hydrochloric acid and an additional three times with 40 ml of water each time. The aqueous extracts were combined and 10 g of sodium chloride was dissolved in the extract. The oily material thus formed was extracted four times, each time with 50 ml of chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and the chloroform distilled off under reduced pressure. The residue was dissolved in acetone and then ethyl acetate was added to the solution to give 5.0 g of yellow needle-shaped crystals of 5-acetyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3 -carboxylic acid P- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 154 - 157 ° C (decomp.).

EXAMPLE 21 In 20 ml of isopropyl alcohol were dissolved 2.9 g of 2-amino-2-penten-4-one, 4.41 g of m-nitrobenzaldehyde and 7.7 g of acetoacetic acid P- (N-benzyl-N-methylamino) ethyl ester, and then the solution was heated at reflux for 6 hours. To the reaction mixture was added 70 ml of ethyl acetate and, after adjusting the pH of the solution to 1-2 with 2N hydrochloric acid, the aqueous layer formed was separated. The ethyl acetate layer was extracted twice with water. The aqueous layers were combined and, after saturating the solution with sodium chloride, the product was extracted twice with chloroform. The chloroform extracts were combined and dried over anhydrous magnesium sulfate and concentrated. When a small amount of ethanol was added to the concentrate, crystals formed which were obtained by filtration and recrystallized from ethanol to give 7 g of 5-acetyl-2,6-dimethyl-4- (3'-nitrophenyl) -1 4-dihydropyridine-3-carboxylic acid p- (N-benzyl-N-methylamino) ethyl ester hydrochloride.

Melting point: 147 - 152 ° C (decomp.).

Elemental Analysis for Ο ^^ Η ^^ Ν ^ Ο ^ ΟΙ.C2H ^ 0H: C th) Htø) Ntø) Cltø) calculated: 61.77 6.62 7.67 6.79 found: 61.59 6.65 7 Example 6.4 In 3 ml of isopropanol was dissolved 1.18 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 0.48 g of 2-amino-2-penten-4-one and 0.83 g of m.p. trifluoro-methylbenzaldehyde, and then the solution was heated under reflux for 6 hours. The reaction mixture was concentrated and the residue subjected to silica gel column chromatography (dimensions 4 cm, height 15 cm). The product was eluted with a chloroform / acetone mixture in a 20: 1 volume ratio, the eluates containing the desired product were examined by thin layer chromatography, collected and concentrated. The residue formed was dissolved in acetone and, after adjusting the pH of the solution to 1-2 with an ethanol solution saturated with hydrogen chloride, the solution was concentrated. The crystals formed were recrystallized from acetone to give 1.3 g of 5-acetyl-2,6-dimethyl-4- (3trifluoromethylphenyl) -1,4-dihydro-idin-3-c arb oxy 1 acid e - β - (Nb enzyme 1-N-methylethyl) ethyl ester hydrochloride.

31 142869

Melting point: 168 - 169 ° C (decomp.).

Elemental Analysis for (%) H (tf) N (%) Cl (%) Calcd: 62.01 5.78 5.36 6.78 Found: 62.30 5.90 5.33 6.95 Example 25

A mixture of 1.0 g of o-trifluoromethylbenzaldehyde, 1.6 g of actoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and 700 mg of β-aminocrotonic acid methyl ester was stirred at 110-120 ° for 6 hours. C. The reaction mixture was dissolved in a small amount of chloroform / acetone mixture in a 20: 1 volume ratio and then the solution was subjected to silica gel column chromatography (diameter 3.5 cm, height 20 cm). The product was eluted with a chloroform / acetone mixture in a 20: 1 volume ratio and the eluates containing the desired product were examined by thin layer chromatography, collected and concentrated. The residue was dissolved in a small amount of acetone and after acidification of the solution with an ethanol solution saturated with hydrogen chloride, the solution was concentrated. The residue obtained was crystallized from an acetone / ether mixture to give 0.7 g of 2,6-dimethyl-4- (o-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-di-carboxylic acid-3 - ^ - (N-benzyl-N-methylamino) ethyl ester 5-methyl ester hydrochloride.

Melting point: 182 - 192 ° C.

Elemental analysis for C ^H ^ qIIO ^F ^Cl: C (9e) H (%) N (%) Cl (%) calculated 60.17 5.61 5.20 6.58 found: 59.93 5, EXAMPLE 24 In 3 ml of isopropyl alcohol, 1.18 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester, 0.55 g of β-aminocrotonic acid methyl ester and 0.3 g of m-trifluoromethylbenzaldehyde were dissolved. and the solution was heated to reflux for 6 hours. The reaction mixture was concentrated and the residue subjected to silica gel column chromatography (diameter 4 cm, height 15 cm). The product was then eluted with a chloroform / acetone mixture in 20: 1 v / v ratio, and the eluates containing the desired product were examined by thin layer chromatography, collected and concentrated. The residue formed was dissolved in acetone and, after adjusting the solution pH to 1-2 with an ethanol solution saturated with hydrogen chloride, the solution was concentrated.

By crystallization of the residue formed from ethyl acetate, 1.3 g of -2,6-dimethyl-4- (m-trifluoromethylphenyl) -1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-β- (N -benzyl-N-methylamino) ethyl ester 5-methyl ester hydrochloride.

Melting point: 142 - 152 ° C (decomp.).

Elemental analysis for C ^ yHHN NO ^F ^Cl: C (%) H (%) N (%) Cl (%) calculated: 60.17 5.6l 5.20 6.58 found: 60.47 5 , 63 5.49 6.71 EXAMPLE. In 3 ml of isopropyl alcohol, 1.07 g of acetoacetic acid tf- (N-benzyl-N-methylamino) propyl ester, 0.52 g of β-aminocrotonic acid ethyl ester and 0.71 g of m-trifluoromethylbenzaldehyde were dissolved and the solution was heated under reflux. 6 hours.

Then, as in Example 25, the reaction mixture was subjected to silica gel column chromatography and the eluates containing the desired product were collected and concentrated to give 0.9 g of 2.6 dimethyl-4- (m-trifluoromethylphenyl) -1,4-dihydro-4 pyridine-3,5-dicarboxylic acid 3-T - (N-benzyl-N-methylamino) propyl ester 5-ethyl ester.

Elemental analysis for: C (%) H (%) N (%) calculated: 65.65 6.27 5.28 found: 65.45 6.40 5.40

Nuclear Magnetic Resonance Spectrum (CDCl3): S (ppm): 1.2 (3H, -CH - CH) 1.79 (2H, -CH2CH2CH2-)

s **** »» JL

2.20 - 2.40 (6H, (µl); H3cechCH3 2.12 (3Hr -N

-w ~ L

2.0-2.5 (2H, -CH 2 -CH 2 -N <) λ W = 3.42 (2H, -CH 2 - +) 33 3.9 - 4.3 (4H, -CH 2 CH -CH2CH2CH2-N <) 5.1 (1H, 0 "^ ')' ', .7'1 -7-6 (9H- + ηΨΓ3 _ (5H) (4H) EXAMPLE 26 v

A mixture of 1.5 g of 2- (3'-nitrobenzylidene) acetoacetic acid P- (N-benzyl-N-methylamino) ethyl ester, 0.452 g of β-aminocrotonic acid methyl ester and 7 ml of isopropyl alcohol was heated at reflux for 6 hours. wins stirring. After cooling, the reaction mixture was mixed with 30 ml of chloroform and then with 10 ml of 2N hydrochloric acid. The mixture was shaken in a separatory funnel, washed twice with water and the resulting chloroform layer separated. The chloroform layer thus obtained was concentrated, and after adding 7 ml of ethyl acetate to the residue formed, the mixture was stirred overnight to give 1.4 g of crystals. The crystals were dissolved in methanol and, after distilling off the solvent from the solution, the residue was recrystallized from acetone to give 0.98 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3, 5-dicarboxylic acid 3-β- (N-benzyl-N-methylamino) ethyl ester-5-methyl ester hydrochloride.

Melting point: 180 - 181 ° C.

Elemental analysis for c26 H30 N3 ° 6Cl: C (%) E (%) N (%) Cl (%) calculated: 60.52 5.86 8.14 6.87 found: 60.76 5.72 8.04 7.00 EXAMPLE 27

A mixture of 1.1 g of 2- (3'-nitrobenzylidene) acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester, 0.34 g of acetoacetic acid methyl ester, 5 ml of ethanol and 0.35 ml of ammonia water was heated under reflux for 5 hours with stirring. After distilling off the solvent, the reaction mixture was treated in the same manner as in Example 27 to give 0.33 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid. 3-β- (N-benzyl-N-methylamino) ethyl ester-5-methyl ester hydrochloride, m.p. 180-181 ° C.

34 142859

The infrared absorption spectrum of this product was consistent with that of the product prepared in Example 27 · EXAMPLE 28

A mixture of 2.49 g of 2- (3-nitrobenzylidene) acetoacetic acid methyl ester, 2.48 g of p-aminocrotonic acid p- (W-benzyl-N-methylamino) ethyl ester and 8 ml of isopropyl alcohol was heated at reflux in 6 hours with stirring. After cooling, the reaction mixture was mixed with 100 ml of chloroform to dissolve the product and washed with 2N hydrochloric acid to adjust the pH of the aqueous layer to 1-2.

Then the chloroform solution was washed twice with water, dried over anhydrous sodium sulfate and concentrated. The residue formed was mixed with 20 ml of ethyl acetate to give 3.3 g of crystals. The crystals were dissolved in methanol and the solvent was distilled off to give a sticky material.

Recrystallization of the material from acetone afforded 2 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid -3- (N-benzyl-N- methylamino) ethyl ester-5-methyl ester hydrochloride, m.p. 180-181 ° C.

The infrared absorption spectrum of the product was consistent with the spectrum of the product prepared in Example 27.

EXAMPLE 29

A mixture of 2.49 g of 2- (3'-nitrobenzylidene) acetoacetic acid methyl ester, 2.49 g of acetoacetic acid P- (N-benzyl-N-methylamino) ethyl ester, 1.18 ml of ammonia water and 10 ml of ethanol was obtained. heated at reflux for 6 hours with stirring. The reaction mixture was then concentrated, the residue formed was subjected to silica gel column chromatography and the desired portions were eluted with a 10: 1 volume ratio chloroform / acetone mixture. The recovered portions were dissolved in chloroform and washed with 2N hydrochloric acid to adjust the pH of the aqueous layer to 1-2.

Then, the solution was washed twice with water and the resulting chloroform layer was separated, dried over anhydrous sodium sulfate and concentrated. When ethyl acetate was added to the residue formed, 1.1 g of crystals formed. The crystals were recovered and dissolved in methanol. By distilling off the solvent, a sticky material was obtained. Recrystallization of the material from acetone afforded 0.7 g of 2,6-dimethyl-4- (3'-nitrophenyl) 1,4-dihydorpyridine-3,5-dicarboxylic acid 3-p- (N-benzyl-N- methylamino) ethyl ester-5-methyl ester hydrochloride, m.p. 180-181 ° C.

The infrared absorption spectrum of the product was consistent with the spectrum of the compound prepared in Example 27.

EXAMPLE 50 In 7 ml of pyridine were dissolved 675 mg of methylamine hydrochloride, 2.49 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester, 1.17 g of acetoacetic acid methyl ester and 1.51 g of m-nitrobenzaldehyde. and the mixture was heated to 90 ° C for 3 hours. The reaction mixture was cooled, 30 ml of chloroform was added and the solution was washed successively with 10 ml of water, 10 ml of 2% acetic acid, 10 ml of 3% sodium hydroxide solution and 10 ml of water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated.

The residue was dissolved in a small amount of a 8: 1 volume ratio of benzene and acetone and subjected to silica gel column chromatography (diameter 4 cm, height 25 cm). The eluate was examined by thin layer chromatography and the eluates containing the desired product were collected and the combined eluates were concentrated to an oily material.

Nuclear Magnetic Resonance Spectrum: S (ppm): 2.20 (3H, -Ν <£ 5θ) 2.48 (6H, XX) .. h3c ^ ch3 / VW * AVW * »2.70 (2H, -CH2-CH2- N <) 3.20 (3H, j [NH) 3.51 (2H, -N <CH2 O) 3.67 (3H, -COc + cH3) / Wvv 4.24 (2H, -CH2-CH2- N <) 5.27 (1H,) + VNO2 7 - 8.2 (9H, (5H) + (4H)} 36 142869

The oily material was dissolved in a small amount of acetone and acidified with ethanolic hydrogen chloride to give 1.1 g of 1,2,6-trimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3, 5-dicarboxylic acid 3-β- (N-benzyl-N-methylamino) ethyl ester 5-methyl ester hydrochloride.

Elemental Analysis for C27H32N3 ° 6C1: C (%) H (%) N (tf) Cl (%) Calcd: 61.19 6.08 7.93 6.69 Found: 61.03 6.12 7.72 6.81

Infrared Absorption Spectrum: ΚΒϊτ –1 max Cm: 2950 1686 (s) 1521 (s ^ 1342 (s) / 1205 (s), 1150 (s), 1100 (m), 990 (w), 733 (w), 690 (w) Example 31 In 7 ml of pyridine were dissolved 675 mg of methylamine hydrochloride, 2.48 g of m-nitrobenzylideneacetoacetic acid methyl ester and 2.49 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and the mixture was heated to 90 ° C for 2 hours The reaction mixture was treated in the same manner as in Example 31 to give 1.2 g of 1,2,6-trimethyl-4- (3-nitrophenyl) 1,4-dihydropyridine -3,5-dicarboxylic acid -3- (N-benzyl-N-methylamino) ethyl ester-5-methyl ester hydrochloride The infrared spectrum of the product was identical to the spectrum of the compound prepared in Example 31.

EXAMPLE 32 (a) In 340 ml of isopropyl alcohol, 82 g of crude m-nitrobenzaldehyde, 135 S crude ac etoacetic acid β-(N-benzyl-N-methylamino) ethyl ester and 63 g crude β-aminocrotonic acid methyl ester were dissolved and the reaction mixture heated. under reflux for 6 hours with stirring. At the end of the reaction, 580 ml of methylene chloride was added to the reaction mixture. The solution was washed with a hydrochloric acid solution consisting of 92 ml of concentrated hydrochloric acid and 320 ml of water, then with 240 ml of water and finally with a hydrochloric acid solution consisting of 40 ml of concentrated hydrochloric acid and 240 ml of water. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off. 1500 ml of ethyl acetate was added to the residue thus obtained and the solution was stirred overnight at room temperature. The precipitate formed was collected and washed with ethyl acetate to give 200 g of crystals.

b) -l. 130 g of the crystals obtained above were suspended in 900 ml of methylene chloride and 450 ml of water was added to the suspension followed by stirring for 30 minutes. The organic layer was separated and washed twice, each with 360 ml of water and then once with a hydrochloric acid solution consisting of 22 ml of concentrated hydrochloric acid and 360 ml of water, and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off and the caramel-like residue thus obtained was dissolved in 800 ml of acetone. The solution was stirred overnight under ice-cooling to obtain 93 g of β-type crystals of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester-3 -P- (N-benzyl-N-methylamino) ethyl ester hydrochloride, which had a melting point of 168-170 ° C.

b) -2. 100 g of the crystals obtained under (a) were suspended in 700 ml of methylene chloride and 340 ml of water was added to the suspension followed by stirring for 30 minutes. The organic layer was separated and washed twice, each with 270 ml of water and once with a hydrochloric acid solution consisting of 16 ml of concentrated hydrochloric acid and 270 ml of water, after which the solution was dried over anhydrous sodium sulfate. The solvent was distilled off and the thus caramel-like residue was dissolved in 500 ml of acetone. The solution was allowed to stand overnight at room temperature. The precipitate formed was collected and washed with acetone to give 70 g of α-type crystals of 2,6-dimethyl-4- (3'-nitrophenyl) 1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester -3-p- (N-benzyl-N-methylamino) ethyl ester hydrochloride having a melting point of 179-181 ° C.

Claims (1)

Patent claim: Analogous process for preparing 2,6-dialkyl-4-phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester compounds of general formula iv R5-0O. Xy ^ 00-- 4 4 (I) i: wherein A means alkylene of 1-4 carbon atoms, R means hydrogen of 2 or alkyl of 1-4 carbon atoms, R and R which may be the same or different, means alkyl with 1-4 carbon atoms, R means a phenyl group or a benzyl group which may be substituted by an alkyl or alkoxy group having 1-4 carbon atoms or a halogen atom, 4.5 represents R hydrogen or alkyl of 1-4 carbon atoms, R means alkyl of 1-4 carbon atoms, alkoxy of 1-6 carbon atoms which may be substituted by an alkoxy group of 1-4 carbon atoms, or -O-A-NR 2 R 4, wherein A, R 1 and R 4 have the above meaning, and R 1 is nitro or trifluoromethyl or pharmaceutically acceptable acid addition salts thereof, characterized in that (a) a benzaldehyde derivative of the formula Al * I - R 6 (II) CHO C wherein R has the above meaning is reacted with a lower alkanoyl acetic acid -aminoalkyl ester of the formula V R2-CO-CH 2 CO-AN (III) R4 39 14 2 69 4 wherein R, R, R and A have the o and Enamine of the formula R 1 -C = CH-COR 1 (IV) NH-R 15 wherein R, R and R are as defined above, which enamine is prepared by reacting a compound of formula R -ch2-cor1 (V) wherein R and R are as defined above and a compound of formula r-nh2 (XVI) wherein R is as defined above, or (b) that a benzaldehyde derivative of formula f -R2 (II) CHOr wherein R ° has the meaning given above is reacted with a β-amino-acrylic acid aminoalkyl ester of the formula. R3 4 5-C = CH-C00-AN <(VI) NHR ^ R ^ 15 wherein R and R are as defined above, which β-amino-acrylic acid aminoalkyl ester is prepared by reaction of a compound of formula 3 3 Wherein R, R, R, R and A are as defined above and a β-diketone of the formula 5 R 2 CO-CH 2 COOR 1 (V) 14-COCH 2 CO-AN (III) R 4 074 wherein R, R , R and A are as defined above and a compound of formula R-NH 2 (XVI) wherein R is as defined above, or (c) a lower alkanoylcinnamic acid alkyl ester of formula "6 ff" = C-C00-AN / ^ 711 ^ \ = J COR2 ^ r4 wherein R2, R ^, R ^, R ^ and A are as defined above, reacted with an enamine derivative of the formula R1-C = CH-COR5 (IV ) NHR wherein R, R 1 and R 4 have the meaning given above, or (d) reacting a lower-alkyl styryl ketone of the formula 6CH-C-COR5 COR1 wherein R 1, R 2 and R 2 have the meaning given above with an enamine compound of the formula s # r2-c = ch-coo-an ^ (vi) j \ Wherein R, R2, R4, R4 and A are as defined above, or (e) that a lower alkanoyl cinnamic acid alkyl ester of the formula ZVV-CH = C-C00-A-NC; , (VII) \ = / éoR2 VR wherein R2, R ^, r \ R ^ and A are as defined above are reacted with a β-diketone compound of the formula r1-co-ch2-cor5 (V) wherein R1 and R has the meaning given above and an amine of formula r-nh2 (XIV) wherein R has the meaning given above, or (f) that a lower alkyl styryl ketone of formula R6 // \ y CH = C-COR5 (VIII) \ = zf COR1 wherein R 1, R 2 and R 2 have the meaning given above are reacted with a lower-alkanoyl acetic acid amino-alkyl ester of the formula r 2 -co-ch 2 -cooan 4 (III) wherein R 2, R 3, R 2 and A is as defined above and an amine of formula r-nh2 (XVI) wherein R is. or (g) that a benzaldehyde derivative of formula Q - CHO wherein R has the meaning given above is reacted with an alkanoylacetic acid aminoalkyl ester of formula / R3 R2-CO-CHO-C00-AN (III) 2 'vo A wherein R, R and R have the meaning given above, a β-diketone of the formula r1-co-ch2-co-r5 (V) wherein R 1 and R 2 have the meaning given above, and a amine of formula r-nh 2 (XVI) wherein R is as defined above, or (h) a benzaldehyde derivative of formula jT-j-R6 (II) CHO g wherein R is as defined above is reacted with an enamine with the formula