SU1258324A3 - Versions of method for producing dihydropyridine derivatives - Google Patents

Abstract

1. The method of obtaining digipropyridine derivatives of the general formula Be BC-A - cG) n- (UWN-AP {) (L2b, where R, R and R are the same or different and each of them is alkyl, cycloalkyl or alkoxyalkyl; the same or different and each of them is hydrogen, halogen, nitro group, trifluoromethyl group, alkyl, cycloalkyl, alkoxy group, cyano group, alkoxycarbonyl group or alkylthio group; RJ is hydrogen, alkyl, cycloalkyl, aralkyl, arip or A - alkylene group; Ar - aryl or pyridyl group; m - an integer of 1-3; n - a simple integer O 2, characterized in that then the compound of the general form ya l CO / COOH1 IV) where R, and Rj have the indicated meanings, act with ammonia, the resulting product is reacted with the compound of the general formula (V) and with the compound of the general formula COO-A-b1 (CHL-AG - iCHjb (VI)

Description

where R ,, R ,, Rj, „X, A, ra and n

have the indicated meanings

2, Method for preparing dihydropyridine derivatives of general formula

r V.-PF

SSS

and with a compound of the general formula

de R, Rj and R, R and Ry

same or different and each of them is alkyl, cycloalkyl or alkoxyalkyl; each of them is the same or different and each of them is hydrogen, halogen, nitro, trifluoromethyl group, alkoxy group, cyano group, alkoxycarbonyl group, or alkyl group;

g is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; X is oxygen or sulfur, a vinylene group, an azomethine group, or a group of the formula

G; o (in or (; s

(jxJ- | q

(iin

A is an alkylene Ar is an aryl or pyridyl group; m is an integer of 1-3; n is a simple integer

0-2,

It is distinguished by the fact that a compound of the general formula

1258324

act with ammonia, the resulting product is reacted with a compound of the general formula

r V.-PF

SSS

(V)

(Iv)

where R ,, R, R,

Rg and X have the indicated meanings.

3, Method for preparing dihydropyridine derivatives of general formula

RS

W

 1 g

200C DL COO-A- l () N- (

high / low (I)

: m) p-Ar

n

de R ,, Rj

and R, are the same or different.

and each of them is alkyl, cycloalkyl or alkoxyalkyl; R. and Ry are the same or different.

and each of them is hydrogen, halogen, nitro, trifluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl, or alkylthio;

Rg is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl;

X is oxygen or sulfur, a vinylene group, an azomethine group, or a group of the formula

СОО-А - () к- (СН) п-Аг

Vg

(Sno)

vm

Nb

(Vi)

where R ,, R, A,

type of

have the indicated meanings.

or

/

N

S (SP

L is an alkylene group; Ar is an aryl or pyridyl group;

tt is an integer of 1-3;

n is a simple integer O-2,

characterized in that the compound of general formula

what ia

А-Т () к- (СН) п-Аг (

I

R.

(Vi)

where R ,, R, A, type

have the indicated meanings

they act with ammonia, the product being called up is treated with the compound obtained by reacting the compound of the general formula

,

(V)

0

(Iv)

Rft eno

with a compound of the general formula

COOR2 1

where r

R and X have the indicated meanings. 4. The method of obtaining derivatives

dihydropyridine General formula 95

- hydrogen, alkyl, cyclo

alkyl, aralkyl, aryl or pyridyl;

oxygen or sulfur, a vinylenic group, an azomethine group, or a group

V t

) 0 (I) or) S

  ii

(1st U

A is an alkylene group; Ag - aryl or pryndnlna

Group;

w is an integer of 1 - 3 j n is a simple integer of O - 2, characterized in that the compound of the general formula

/ COOI n

1 iv),

where R, and Rj have the indicated meanings, act with ammonia, the product thus formed is treated with a compound obtained by reacting a compound of the general formula

H1

A-vfyN-Wn-AT

Bj - Wb a)

H

D6 R ,, Rj

and R, 5

the same or different and each of them is alkyl, cycloalkyl or alkoxy-alkyl;

are the same or different and each of them is hydrogen, halogen, nitro, trifluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, apkoxycarbonyl, or alkylthio;

(V)

with a compound of the general formula

A-1 /) N- (CH) n-Ar

sn4p j;

(Vi)

where R ,, R,

R rfi

X, A, type have the indicated meanings.

The invention relates to the field of production of new dihydropyridine derivatives of the general formula (I)

; 0 (-A-1) y- (UWN-Ag I (R6

where R ,, Rj N

and R- and Rg

same or different and each of them is alkyl, cycloalkyl or alkoxy-alkyl;

one are single or different and each of them is hydrogen, halogen, nitro group, trifluoromethyl and a group, alkyl, cycloalkyl, alkoxy group, cyano group, alkoxycarbonyl group or alkylthio group;

R, is hydrogen, LKIL, cycloalkyl, aralkyl, aryl or pyridyl; oxygen or sulfur, a vinylene group, an azomethine group, or a group of formula (II) or (III)

G

 U

A is an alkylene group; Ar - aryl or pyridyl

Group;

m is an integer of 1 - 3; p - simple integer O-2. The purpose of the invention is the development of a method for the preparation of new dihydropyridine derivatives with a pronounced vasodilating effect and low toxicity, based on known methods. EXAMPLE 1 A mixture of w-nitrobenzaldehyde (2.66 g), 2- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate (6.09 g), methyl-3-aminocrotonate (2.03 d) and isopropyl alcohol (25 ml) is refluxed for 6 hours. Then the solvent is distilled off and the residue is purified by column chromatography on silica gel (250 g), using as

eluent solvent system, hexane - ethyl acetate (1: 1). The resulting oily substance is dissolved in a small amount of isopropyl ether and, with cooling in an ice bath and stirring, hexane is added to the resulting solution. When this occurs, precipitation of a powdery precipitate (7.35 g; 75.27, from

0 theory) 2- (4-benzhydryl-1-piperazinyl) ethyl methyl-2,6-dimethyl-A- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate. A part of this powdered product was recrystallized from an isopropyl ether-hexane mixture, resulting in a light yellow crystalline substance with mp. 102-104 0.

The spectrum of proton magnetic resonance (PMR spectrum) in deuterated chloroform (CBCI) D: 2-26-2.49 (8H, multi-bullet); 2.33 (6H, singlet); 2.57 (2H, triplet); 3.60 (SA, singlet); 4, t5 (2H, triplet,);

5 4.18 (2H, singlet); 5.08 (W, singlet); 5.77 (1H, singlet); 7.11 - 8.12 (14H, multiplet).

Calculated,%: C 68.83; H 6.27; 0 N 9.17.

Found,%: C 68.97; H 6.27; N 9 „05.

The free base thus obtained (3.90 g) is dissolved in dichloromethane (10 ml) and to this solution. a small excess of a solution of hydrogen chloride in dioxane is added. After cooling in an ice bath, a few drops of water are added to the reaction mixture, and it is also stirred while cooling in an ice bath. The crystalline precipitate thus formed is separated by filtration and washed with DIETOSH10THE ether, resulting in the desired 2- (4-benzhydryl-1-piperazinyl) ethyl-methyl-2,6-dimetcp-4- (3-nitrophensh1) -1 , 4-dihydropyridine-3,5-dicarboxylate dihydrohporid with a yield of 4.23 g (94.4% of theory) i This product is dissolved in dichloromethane containing a small amount of methanol. Then the solvent is distilled off, the residue is dissolved in ethyl 5 acetate and after adding water. the mixture was left to stand in an ice bath. The result of the nejJe crystallization procedure is to obtain

five

0

five

light yellow crystalline product having so pl, 167-170 G.,

Calculated,%: C 59.90; H 6.03; N 7.99,

C dNvzK About HCl-EjO

Found,%: C 60.06; H 5.97; N 7.84.

Example 2: A mixture of m-nitrobenz aldehyde, 2- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate and ethyl 3-aminocrotonate is heated in isopropyl alcohol under reflux, as in the example 1, resulting in 2- (4-benz-Tidryl- | -piperazinyl) ethyl-ethyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5- dicarboxylate as a light yellow powdery substance with so pl. 80-82 s (sintering). The yield of the product is 48.3% of the theoretically possible.

Infrared spectrum (IR), taken to disperse the product in liquid paraffin, 3320, 1695, 1680.

HMR-spectrum (CDC1,), 8: 1.18 (3N, triplet,,,); 2.33 (6H, singlet, C-CH); 4.08 (2H, quadruplet,,,); 4.15 {2H, triplet, -СООСН -СН, -); 4.18 (1H, singlet,

VcH); 5.08 (IH, singlet, -H); 5.79 (1I, singlet, NH).

Calculated,%: C 69.21; H 6.45; 35 N 8.97.

C, sH, oN, Ofi

Found,%: G 68.81; H 6.63;

N 8.72.

40

PRI me R 3. A mixture of o-nitrobenzaldehyde, 2- (4-benzhydryl-1-piperazinnl) ethyl acetoacetate and metip-3-aminocrotonate is heated in isopropyl alcohol as in Example 1, then 45 the resulting product is treated a methanol solution of hydrogen chloride, yielding the desired 2- {4-benzhydryl-1-piperazinyl) ethnp-methyl-2,6-dimethyl-4- (2-nitrophenyl) - 50 1,4-dihydropyridine- 3,5-dicarboxylate dihydrochloride monohydrate as a light yellow crystalline substance, having so pl. 1b2-1b4 with. Yield 11.4%, 55

Calculated,%: C 59.90; H 6.03; N 7.99.

C ,, H, aN, Oj ,. 2HC1-

five

50

five

0

Found,%: C 60,12; H 6.15; N 7.89.

Example 4. A mixture of o-chlorobenzaldehyde, 2- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol as in Example 1, resulting in the desired 2- (4-benz - hydryl-1-piperazinyl) etsh1-methyl-4- (2-chlorophenyl) -2, b-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in the form of a light yellow powdery product with so pl. 81-83 ° C (caking). The product yield of 30.8% of theoretically possible.

IR spectrum in vaseline oil, cm-: 3320, 1680.

HMR spectrum (CDC1,), 6: 2.26 (6H, singlet, C-CH,); 3.56 (SN, Singlet, SOOCH,); 4J2 (2H, triplet, Jb,. -COOCH-CHj-); 4.17 (1H, singlet,

N-C); 5.36 (1H, singlet, C ,, - H); 5.63 (1H, singlet, W).

Calculated,%: C 70.04; H 6.38; N 7.00.

Сз, Н, 8С1Ы, 0,

Found,%: C 69.84; H 6.45; N 6.83.

EXAMPLE 5 A mixture of o-chlorobenzaldehyde, 2- (4-benzhydrin-1-1-piperazinyl) ethyl acetoacetate, and methyl 3-ay1-nocrotonate is heated in isopropyl alcohol in analogy to Example 1, resulting in the desired 2- (4-benzhydryl-1-piperazinyl) ztll-ethyl-4- (2-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powdery substance m.p. C (with sintering), Yield 34.7%.

IR spectrum in liquid paraffin,: 3320, 1690, 1680.

1 H-NMR (CDC1,), 8: 1.17 (3N, triplet,, -CHjCH,); 2.20 (6H, singlet, C-CH3); 4.20 (1H, singlet, VCH); (1I, singlet, S.-H); 6.37 (1H, singlet, NH).

Calculated,%: C, 70.40; H 6.56; N 6.84.

C ,, 04

Found,%: C 70,12; H 6.77; N 6.57.

EXAMPLE 6 A mixture of 2,3-dichlorobenzaldehyde, 2- (4-benzhydrin-1-1-piperazine), ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol as in Example 1, resulting in a target 2 - (4-benzhydrin-1-1-piperazinyl) ethylmethyl-4- (2,3-di A101 phenyl) -2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylate in the form of a light yellow powder substances with so pl. SA-SS C (with sintering), the product yield is 31.6% of the theoretically possible.

IR spectrum in petroleum jelly, cm: 3320, 1730, 1690.

HMR spectrum (in chloroform), S: 2.28 (6H, singlet, C — CH,); 3.58 (SN, singlet. -СООСН,); 4, t5 (2H, triplet,, -COOCHjCHi); 4.19 (1H, singlet, iN-CHC) j 5.45 (W, Siiglet, S. -H); 5.61 (1H, syn

GLET, N).

Calculated,%: C, 66.24; H 5j88j N 6.62.

C ,, 04

Found,%: C 66.38; H 5.99; N6.37.

Example 7. A mixture of 2,3-dichlorobenzaldehyde, 2- (4-bezhydryl-1-piperazinyl) ethyl acetate and methyl 3-aminocrotonate is heated in isopropyl alcohol in analogy to example 1, having obtained as a result the target 2- (4-benz-g1adril-1-piperazinsht) ethyl-ethnl-4- (2,3-dichlorophen l) -2,6-dime tnl-1,4-dihydropyridine-3 5-dicarboxylate

in the form of a light yellow powdery substance with so pl. 87-89 C (with sintering). The output of 30.7%.

IR spectrum in vaseline oil, cm: 3335, 1695, 1680.

PMR spectrum (in deuterium chloroform), S: 1.15 (3N, triplet,,,; 3.25 (6H, singlet, C-CH,); 4.16 (1H, singlet, N-CHC); 5, 41 (1H, singlet, C (4) -H); 5.96 (W, singlet, NH),

Calculated,%: C, 66.66; H 6.06; N 6.48.

C, H ,, C1, N, 0,

Found,%: C, 66.32; H 5.97; N 6.27.

PRI me R 8. A mixture of meta-nitro-benzaldehyde, (4,4-difluorobenz Hydrile) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol, similarly to Example 1. Having finally obtained the target (4.4 -difluorobenzhydryl) -1-piperizinyl} methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-carboxylate in the form of a light yellow powdery substance with mp . 68-72 C (with sintering).

The product yield of 33.3%. This product is treated with a solution of hydrogen chloride in methanol and receive colorless prism crystals of the corresponding dihydrochloride with T. pl, 190-193 C.

Calculated,%: C 58.42; H 5.35: N 7.79.

Ci5H, 6F, N, 06-2HCl

Found,%: C 58.45; H 5.38; N 7.44 ..

EXAMPLE 9 A mixture of meta-nitro-benzaldehyde, (4,4-dimethyl-b-8-hydroxy) -1-piperazinyl ethyl acetate-acetate and matil-3-aminocro tonate is heated in isopropyl alcohol under conditions similar to example 1 , having received as a result the target (4, dimethylbenegidrnl) -1-piperaznnl1 ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate in the form of light - yellow powdered substance with so pl. 83-87 ° C (with sintering). Yield 53.1%.

IR spectrum in petroleum jelly,: 3330, 1695, 1680 (shoulder).

HMR spectrum (in deutero-chloroform), R: 2.32 (6H, singlet, d-CH,); 2.36

(W, sdglet, - -ON,); 3.60 (MN,

singlet, -COOCH,). 4.10 H, singlet, N-CHC); 4.14 C2H, triplet,, -COOCHrCHj-); 5.09 (1H, singlet, C (4) H); 5.84 (1H, broad singlet, NH).

Calculated,%: C 69.57; H 6.63; N 8.77.

, N, Os

Found,%: C 69.88; H 6.82; N 8.42.

PRI me R 10. A mixture of meta-nitrobexzaldehyde, 2-f4- (4,4-dimethoxy-benzhydryn-1) -1-piperazinyl | The ethyl acetoacetate and methyl 3-aminocrotonate are heated in isopropyl alcohol under conditions similar to example 1, resulting in a floor; take into account the desired 2-f4- (4,4-dimethoxybenzhydryl) -1-piperazinyl} 3 til-me Tyl-2,6-dime-Tyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powdery substance with so pl. 76-80 ° C (with sintering). The product yield of 39.3%.

JK-spectr in petrolatum, 3330, 1695, 1680 (shoulder).

PMR spectrum (in deuterochporoform) J S: 2.36 (6H, singlet, 9-CH,), 57

(SN, singlet, -СООСН,); 3.75 (6H, singlet, -OCHj); 4.11 (1H, singlet, -SNA); 4.15 (2H, triplet, -COqCH-CH-i-); 5.08 (TN, singlet,); 5.80 (1H, broad syn

GL, NH).

Calculated,%: C 66.25-, H 6.31; N 8.35.

C ,,, 0

Found,%: C 66.22; H 6.41;

N 8.12.

EXAMPLE 11 A mixture of ortho-nitro-benzaldehyde, (4,4-difluorobenz hydrile) -1-piperazini.p of ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol 1 under conditions analogous to example 1, in as a result, the target (4,4-difluorobenzhydryr-1) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (2-nitrophenyl) -1,4-dihydropyridine 3, 5-dicarboxylate is obtained in the form of a light yellow powder with m.p. 90-93 C (with sintering). Vyshd product 21.3% of theoretically possible.

IR spectrum taken from a sample obtained by pressing a fine product with potassium bromide: 3350, 1695.

HMR spectrum (in deuterium chloroform), 8: 2.26 (MN, singlet,); 2.31 (SN, singlet, -CH,); 3.53 (SN, singlet, -СООСН,); 4.0-4.3 (3N, multiplet, N-CHC "- -COOCHj-CHj-); 5.72 (1H, singlet,); 5.77 (W, broad singlet, NH).

Calculated,%: C 65.01; H 5.61; N 8.66.

C ,, H, FjN, Oj

Found,%: C 65.40; H 5.60;

N 8.39.

EXAMPLE 12 A mixture of m-nitrobenzaldehyde, (4,4-dichlorobenz hydrile) -1-piperazinyl ethyl ethane acetate and methyl 3-aminocrotonate was heated in isopropyl alcohol under the conditions of Example 1, resulting in the target (4,4-dichlorobenzhydryl) -1-piperazinylP ethylmethyl-2,6-di methyl-4- (3-nitrophensh1) -1,4-dihydropyridine-3,5-dicarboxylate in the form of light yellow powder with m.p. 83-87 ° C (with sintering). The product yield 57.8% of theoretically possible. Then this product is treated with a solution of hydrogen chloride in ethanol, resulting in a result, respectively. corresponding disulfate salt (dihydrochloride). Recrystallization of this salt from a mixture of ethanol - diethyl ether gave light yellow prismatic crystals with m.p. 208-21I C.

Calculated,%: C 55.86; H 5.09; N 7.45.

C H ClN Oj-2HC1

Found,%: C 56.00; H 5.34; N 7.38.

Example 13. A mixture of 2,3-dichlorobenzaldehyde, (4,4-difluorobenzhydryl) -1-piperazinyl | ethyl acetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under the conditions of example 1, resulting in the target (4,4-difluoro-benzhydryl) -1-pyrazinyl ethyl methyl-4- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powdered substance with so pl. 90-93 C (with sintering). The yield of this product is 52.9% of the theoretically possible.

The IR spectrum of the sample obtained by pelleting with KBG, cm: 3340, 1695.

HMR spectrum (in Deuterochloroform), S: 2.28 (6H, singlet, -f-CH,); 3.57 (SN, singlet, -sos,); 4.12 (2H, triplet,, -COOCHjCHi); 4.16 (1H, singlet,; ::; Y-CH ;;); 5.42 (1H, singlet, C (-H); 5.70 (1H, broad singlet, NH).

Calculated,%: C 62.69; H 5.26; N 6.27.

С „Н„ С1,, 04

Found,%: C 62.77; H 5.50; N 6.06.

Example 14. A mixture of 2,3-dichlorobenzapydehyde, (4,4-dichlorobenz hydrile) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under the conditions of example 1, resulting in a resultant ( 4,4-Dichlorobenzhydryl) -1-piperazinyl ethnp-methyl-4- (2,3-dichlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in the form of light - yellow powdery substance with so pl. 104-107 C (with sintering). The product yield of 43.2% of theoretically possible.

The IR spectrum of the sample obtained by pelletizing a fine product with KBG: 3340, 1695.

HMR spectrum (in chloroform), S: 2.27 (6H, singlet, C-CH,); 3.57 (SN, singlet, -СООСН,); 4.12 (2H,

triplet, -COOCHj-CH -); 4.18 (1H singlet, N-CHO; 5.43 OH, singlet, i5i4j-H) .; 5.70 (1H, broad singlet, NHr.

Calculated,%: C 59.76; H 5.01; N 5.97.

С „Н ,, С1, К, 0,

Found,%: C 59.52; H 4.97; N 5.75.

Example 15 A mixture of m-nitro-benzaldehyde, 2- (4-benzhydryl-homo-piperaein-1-yl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in iso-propyl alcohol under conditions analogous to example 1, as a result of go get the target 2- (4-benzhydryl-homopiperazin-1-yl) ethyl-methyl-2,6-di methyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate in the form of light yellow powdery substance with TopPL. 60-63 C (with sintering). Product code 31.7%.

The IR spectrum of the sample obtained by pressing the product with KBG, cm: 3330, 1690.

HMR spectrum (in chloroform), S: 2.33 (6H, singlet, d-CH,); 3.60 (SA, singlet); 4.12 (2H, triplet,); 4.57 (1H, singlet,) n-CH; ); 5.10 (1H, singlet, C, -H); 5.92 (1H, singlet, NH).

Calculated,%: C 69, -21; H 6.45; N 8.97.

C ,, H ,, N, 0,

 Found,% g C 69.24; H 6.51; N 8.77.

Example 16. A mixture of meta-nitro-benzaldehyde, (4-fluorophenyl) -1-piperazinyl ztilacetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, then the resulting product is treated with a solution of hydrogen chloride in dioxane, resulting in obtaining the target hydrochloride (4-fluorophenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5 dicarbo xylate as a light yellow powdered product having so pl. 108-110 ° C. The product yield is 76.4% of theory.

HSR spectrum in deuterated dimethylsulfoxide (DMSO-d), S: 2.30 (3N, singlet, 9-CH,); 2.38 (3N, syn-gl, C-CH); 3.60 (SN, Singlet, -СООСН); 4.48 (2H, multiplet, -COOCHfCH, -); 5.03 (1H, singlet, C,

,

five

 O - 5

thirty

35

- 50

55).

10 C, 56.71; H 5.78;

Calculated

9.45.

Cj8H ,, FN 04-HCl-H G Found,%: C 56.78; H 5.85;

N 9.35. ,

Example 17. A mixture of m-nitrobenzalcehyde, (3-chlorophenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a resultant (3-chloro) phenyl) -1-piperazinyl-ethyl-methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dica: rboxilate in the form of a light yellow powdery substance with so pl. 65-68 with (with sintering). The yield of this product is 29.0% of the theoretically possible.

IR specter in vaseline oil, CM V: 3300.

HMR-spectrum (in deuterium chloroform), S: 2.34 (3N, sing et, C-CH,); 2.36 (SN, singlet, C-CHT); 3.63 (SN, Singlet, -СООСН,); 4.21 (2H, triplet,, -СООСН-СНг-); 5.12 (1H, singlet, C (c) -H); 5.89 (1I, singlet, NH).

Calculated,%: C 63.26; H 6.22; N 10.18.

,, CIN; O,

Found,%: C 63.33; H 6.43; N 9.83.

Example 18. A mixture of m-nitro-benzaldehyde, 2-4- (3-trifluoromethylphenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a yield of target methyl (3-trifluoromethylphenyl) -1-piperazinyl ethyl -2,6-dimethyl-4- (3-nitrophensh1) - 1,4-dihydropyridine-3, 5-dicarboxylate and in the form of a light yellow powdery substance c. 95-97 ° C (with sintering). The product yield 82,7.

JK-spectrum of the product dispersion in vaseline oil: 3345, 1695, 1645.

PMR spectrum of a solution of the product in deuterochloroform} 5: 2.34 (6H, singlet, -CH)); 3.64 (SN, Singlet, -СООСН,); 4.21 (2H, triplet,, 5, -COOCH-CHj-); 5.11 (1H, singlet, C (, - H), 6.39 (1H, singlet, W).

Calcd., 7; C, 59.18; H 5.31; N9.5-2,

 Oi

and

Found,%: C 59.15; H 5.53; N 9.43.

Example 19. A mixture of meta-nitro-benzaldehyde, (2-methoxyphenyl) 1-pygerasinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, resulting in a target (2-methoxyfennp) - 1-piperazinc ethyl-methyl-2,6-dimethyl-4- (3-yitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powdery substance with m.p. 58 C (caking). The product yield of 55.6%. . 1 H NMR spectrum (in deuterium chloroform; i: 2.34 (6H, singlet, C — CH,); 3.63 EG, singlet, –CII,); 3.83 (3N, singlet, -OSK,); 4.21 (2H, triplet,, -COOCHi-CHj, -); 5.14 (W, singlet C {4GN); 6, (W, singlet, NH).

Calculated,%: C 63.26; H 6.22; N 10.18.

with „n„ n, o.,

Found,%: C 63.33; H 6.43; N 9.83.

EXAMPLE 20 A mixture of meta-nitro-benzaldehyde, 2- (4-benzyl-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, in As a result, target 2- (4-benzine 1-1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5-dicarbr-xylate are obtained in the form of light - yellow powdery substance with mp 106-108 C (with sintering). The product yield is 86.0%

The IR spectrum of the dispersion of the product in liquid paraffin, cm: 3325.

HMR spectrum (in chloroform), 5: 2.33 (6H, singlet, C-CH,); 3.46 (2H, singlet,); 3.61 (SN, singlet, -sosen,); 4.14 (2H, triplet, -COOCHfCH -); 5.09 (1H, singlet Cj, -H), 5G82 (1H, singlet, NH).

Calculated,%: C 65.15; H 6.41; N 10.48.

Found%

C, 64.93; H 6.57; N 10.48.

Example 21: A mixture of meta-nitro-benzaldehyde, (2-pyridyl) -1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example t, as a result of which target methyl is obtained ( 2-pyridnp) 10

15

25832412

1-piperazinyl ethyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5 dicarboxylate as a light yellow powdery substance having so pl. 53-56 ° C (with sintering). Yield 54.5%.

IR spectrum of product dispersion in liquid paraffin, cm: 3280.

roiP-spectrum (in deuterium chloroform), S: 2.35 (3N, singlet,) 2.37 (3N, singlet, C-CH,); 3.64 (3N, CH-glg, -COOCH,), 21 (2H, triplet,, -COOCH-H: Ng-); 5.13 (1H, singlet, C (4) -H); 5.77 (1H, singlet, NH).

Calculated,%: C 62, .18; H 5.99; 13.43.

N

,, N, 06

Found,%: C 62.20; H 6.07; N 13.03.

Example 22. A mixture of m-chlorobenzaldehyde, 2- (4-benzhydryl-1-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, resulting in a target 2- (4- benzhydryn-1-piperazinyl) ethylmethyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylate as a light yellow powdery substance with mp. 74-80 ° C (with sintering). The yield of this product is 28.3% of the theoretically possible.

IR spectrum of the product dispersion in liquid paraffin,: 3325, 1695, 1680.

HMR-spectrum (in deuterium chloroform), S: 2.32 (6H, singlet, -C-SI,); 3.60 (SN, singlet, -sos,); 4.96 (1H, singlet, C (4j-H); 5.64 (1H, broad singlet, NH).

Calculated,%: C 70.04; H 6.38; N 7.00.

C, yH, gClN, 04

Found %: C, 70.15; H 6.29; N 7.18.

EXAMPLE 23 A mixture of m-trifluoromethylbenzaldehyde, 2- (4-benzhydryl-1-piperaeinyl) ethyl acetoacetate, and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, whereby receive target 2- (4-benzhydryl-1-piperazinyl) ethyl-methyl-2,6-dimethyl-4- (3-trifluoromethylphenyl) - 1,4-dihydropyridine-3, 5-dicarboxylate in the form of a light yellow powdery substance with m.p. 70-72 C. Exit

ether. The desired disolic acid salt of the said product is obtained in the form of a colorless crystalline substance having a mp. 168-170 C.

Calculated,%: C 60.42; H 5.77; N 5.87.

C jH5gF, N, 04-2HCl, -1 / 2HjO Found;%: C 60.52; H 5.49; N 5.66.

Found,%: C 72.08; H 6.73; 5 N, 94.

131258324

product 52.5%. Then this product is Calculated,%: C 72.06; H 6, is treated with a solution of chloro-N 9.89. hydrogen sulfide in methanol and the separated dihydrochloride is recrystallized from methanol – diethyl

Example 26. First Stage. 1. Piperidine (2 drops) is added to a mixture of neta-nitrobenzaldehyde (307 mg), 2- (4-benzhydryn-1-piperazinyl) ethyl acetoacetate (668 mg) and benzene 10 ash (20 ml) and the mixture is boiled t for 2 hours with a Dean-stark nozzle for water purification by azeotropic distillation with benzene. After cooling

And pmimep 24. A mixture of 2,3-dipore-} 5 the reaction mixture was washed with benzaldehyde water, (4,4-dimethylbenz- and dried over anhydrous sulfate sodium hydroxy) -1-piperazinyl} ethyl acetatetate and ethyl 3-aminocrotonate is heated

in isopropyl alcohol under conditions.

and then the solvent is distilled off in vacuo. In the residue, crude 2- (4-benzhydryl-1-piperazinyl) ethyl is obtained analogous to Example 1, as a result of which 20 2- (3 nyrobroxylidene) acetodedetate are obtained, which gives the desired (4,4-di as an oil.

methylbenzhydryl) -1-piperazinyl} ethyl-AM is the spectrum of the product (in deuterochloethyl ethyl 4- (2,3-dichlorophenyl) -2.6-dimesh-1-form), & : 2.38 (SN, singlet,, 4-dihydropyridine-3,5-dicarboxylate SOSY); 4.14-4.53 (3N, multiplet, S form of light yellow powder, 25-COOCH-CH -, UN-CH); 7.10-8.75 (14H,

multiplet). This product is used to carry out the next stage of the reaction process without further purification.

30 Second Stage. The oily product (total amount), p & lucent on the previous step, and methyl 3-aminocrotonate (280 mg) are dissolved in iso substance with m.p. 85-88 with (with sintering). The product yield of 27.3% from

theoretically possible.

IR spectrum of the product dispersion in liquid paraffin, cm: 3330, 1690.

propyl alcohol (10 ml) and solution

PF spectrum (in deuterium chloroform), S: 1.14 (3N, triplet,, CHj-GH,); 2.25 (12H, Singlet, C-CH,), 4.05

(2H, quadruplet ,, ,,); 4.08 35 by reflux condenser (1H, singlet, N-CH); 4.08 (2H, for 2 hours. Then a Triplet solvent,, -COOCH-CHj-); 5.41 was distilled off and the residue was purified column- (1H, singlet, C {, j-H); 5.68 (1H, ears, “chromatography on a slice gel. Early singlet, No.). In the end, the desired 2- (4-benz hydrogen-1-piperazinyl) ethyl-methyl 2-2.6-dimethyl-4- (3 -nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate with a yield of 725 mg (67.6%). Next, this product is subjected to the same treatment as 2 in example 1, resulting in a semi-calculated,%. C, 67.45; H 6.41; N6.21. . S, SN, STC, 04

Found,%: C 67.29; H 6.27; N 6.00.

A mixture of nicotine aldehyde, 2- (4-benzhydryl-1-shterasinyl) ethyl acetoacetate and methyl 3-iinocrotonate is heated in isopropanol under the conditions analogous to example 1, resulting in a yield of target 2- (4-benzhydryl-1-piperazins) ethyl methyl-2,6-dimethyl-4- (3-pyridyl) -1,4-dihydropyridine-3, 5-dicarboxylate. Recrystallization of the resulting product from methanol gave colorless crystals with mp. 227-228 s, product yield 46.3%.

Found,%: C 72.08; H 6.73; N, 94.

Calculated,%: C 72.06; H 6.76 N 9.89.

Example 26. First stage 1. To a mixture of neta-nitrobenzaldegy (307 mg), 2- (4-benzhydry -1-pipenyl) ethyl acetoacetate (668 mg) and ash (20 ml) are added piperidium (2 drops) and a mixture of bales t for 2 hours with a Dyne-stark nozzle for averaging azeotropic distribution with benzene for water. After cooled

propyl alcohol (10 ml) and solution

the desired disol salt (digidrochloride). Recrystallization of this salt leads to the preparation of a light yellow crystalline substance with mp. 1b6-1v9 S.

The JK spectrum and PMR spectrum of this compound are identical with the spectra of the dihydrochloride monohydrate product obtained in Example 1.

Example 27. First Stage. To a solution of 2- (4-benzhydryl-1-piperag eninyl) ethyl acetoacetate (3.21 tons, -, 9 ethanol (5 ml), a 20% solution of ammonia in ethanol (15 ml) was added and the mixture was left overnight in a refrigerator. Then the solvent and ammonia are distilled off in vacuo and the residue gives crude 2- (4-benzhydryl-1-piperazinyl) ethyl-3-aminocrotonate as an oil.

The second stage. The oil obtained in the previous step, meta-nitrobenzaldehyde (6.88 g) and methyl acetoacetate (1.15 g) is dissolved in isopropyl alcohol (1L ml), the solution is heated under reflux with stirring for 6 hours. Then the solvent was distilled off and the residue was purified by column chromatography. The product thus obtained is subjected to further processing in the same manner as in Example 1 to obtain the corresponding hydrochloric acid salt (hydrochloride). Crystals of monohydrate dihydrochloride 2- (4-6 benzhydryl-1-piperaenoyl) ethylmethyl-2,6-dimethyl-4- (3 nitrophenyl) - 1,4-dihydropyridine-3, 5-dicarboxylate are obtained with a yield of 1.06 g (17.8% of theory) The resulting product has so pl. 166-170 C. The IR and PMR spectra of this compound are identical to the spectra of the compound obtained in Example 1.

P R and M er 28i A mixture of m-chlorobenzaldehyde, 2- (4-benzhydryl-1-piperaeinyl) ethyl acetoacetate and ethyl 3-aminocrotocate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in the desired 2- (4-benzhydryl-1-piperazinyl) ethyl-ethyl-4- (3-hLF) 1 2 b -dimethyl-1,4-dihydropyridine-3,5-dicarboxylate is obtained in the form of yellow

powdered product with so pl.

72-75 ° C (with sintering). Yield 43.3%. This product is dissolved in a small amount of ethanol and a small amount of ethanolic chlorine / hydrogen solution is added to the resulting solution, after which the mixture is left to stand in a refrigerator. The crystalline precipitate formed is dissolved in chloroform-methanol (3: 1 by volume) and the solution is concentrated in vacuo. The addition of ethyl acetate to a concentrated solution leads to the formation of a crystalline precipitate of 2- (4-benzhydryl-1-piperazinyl) ethyl-ethyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3 dihydrochloride , 5-dicarboxylate having m.p. 179-182 s.

five

5 0 5

five

Included,%: C 62.93; H 6.16; N 6.12.

C, j, H4o. 2HC1

Found,%: C 62.67; H 6.44; N 6.00.

Example 29. A mixture of p-chlorobenz-apdehyde, 2- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate and ethyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a desired 2 - (4-benzhydryl-1-piperizinyl) ethyl-ethyl-4- (4-chlorophenyl) -2,6-dimethyl-1,4-dngyropyridia-3, 5- dicarboxylate as a yellow noponica with t. square 75-79 ° C (with sintering). A product yield of 32.8% of theoretically possible.

IR spectrum of the product dispersion in liquid paraffin,: 3300, 1685, 1670.

PMR spectrum (in deuterium chloroform), 5: 1.17 (MN, triplet,, 5, —CH. —CH); 2.28 (6H, singlet, “j: -CR,); 4.95 (1H, singlet, C, -H); 5.77 (1H, broad singlet, NH).

Calculated,%: C, 70.40; H 6.56; N 6.84.

C ,, 04

Found,%: C 70.04; H 6.51; N 6.82.

EXAMPLE 30 A mixture of meta-nitro-benzaldehyde, 2- (4-benzhydryn-1-1-piperazinyl) ethyl acetoacetate, and 2-methoxyethyl-3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1 , resulting in a desired 2- (4-benzhydryl-1-piperazinyl) ethyl-2-methoxy-ethyl-2,6-dimethyl-4 - (3 -nitrophenyl) -1,4-di-hydropyridine-3 , 5-dicarboxylate as a light yellow powdery substance with so pl. 62-6b with (with sintering). The yield of this product is 19.5% of the theoretically possible,

IR spectrum of the product dispersion in liquid paraffin, cm: 3300, 1685, 1675.

HMR spectrum (in chloroform), 8: 2.33 (6H, singlet, f-CH,); 2.50 (2H, triplet,, -CHj-CH); 3.29 (SN, singlet, -SUNC); 3.49 (2H, triplet,, 5, -C% CH, 0-); 5.08 (1H, singlet, C (4) H); 5.77 (1H, broad singlet, NH).

, Calculated,%; C, 67.87; N 8.56.

17

C, 67.69; H 6.49;

31. A mixture of meta-nitro Found,%: N 8.30.

Example

 benzaldehyde, 2-G4- (4,4-dimethylben9hydryl) -1-piperazinyl ethyl acetate-acetate and ethyl-3-aminocrotonate are heated in isopropyl alcohol under conditions similar to example 1, resulting in a desired 2- C4- ( 4,4-dimethylbenzhydryl) -1-pipe rasinyl 2 ethyl-ethyl-2,6-dimethyl-4- (3-nitrophenyl) -, 4-dihydropyridine-355-dicarboxylate as a light yellow powdery substance with mp

258324

Calculated% 1 N 6.22.

C, 69.32; H

6.56;

ten

Found,%: C 69.23; H 6.55; N 6.07.

Example 33 A mixture of m-chlorobenzaldehyde, (4,4-dimethylbenzhydryl) -1-piperazinyl ethyl acetoacetate and ethyl 3-aminocrotonate was heated in isopropyl alcohol under conditions similar to Example 1, resulting in a the desired 2- f4- (4,4-dimethylbenzhydryl) -1-pipera 82-85 ° C (with sintering). The yield indicated is zinyl ethyl ethesch 1-4 g (3-chlorophenyl) -2,6% product 50.8% of theoretically Dimethyl-1,4-dihydropyridine-3,5-di-possible. Carboxylate as colorless by the IR spectrum of the dispersion of the product in the Wah-α-Cone-like substance with t; w1. 79zelinov oil, cm: 3330, 1685.

1 H NMR spectrum (in deuterium chloroform), 20 S: 1.19 (3N, triplet, α, pH-CH,); 2.26 (6H, singlet, C-CH,); 2.33 (6H, singlet,); 4, b5 (2H, quartet,, -C% CH,); 4.10 (14, N-CH singlet; T; 4.12 (2H, triplet, -COOC% CH -); 5.07 (W, singlet, C (4) H); 5.75 (1H, broad singlet, NH) ..

C 69.92} H, 6.79;

Calculated

N 8.58.

Found%:

N8.25.

B1 ° C (with sintering). The yield of this product is 48.4% of theory.

IR spectrum of the product dispersion in liquid paraffin,: 3330, 1680.

PMR spectrum (in chloroform), B: 1.16 (3N, triplet, J-7,,); 25 2.22 (6H, singlet, f-CH,); 2.28 (6H, singlet, C-CH,); 4.05 (2H, quadruplet,,,); 4.08 (W, singlet, N-CH); 4.11 (2H, triplet,, -COOCHj-CHj-); 4.93 (1H, singlet.

C, 69.94; H 6.75;

C (4) H); 5.64 (1H, broad syn30)

GL, NH).

Calculated,%: C 71.07; H 6.91; N 6.54.

C, gH 4-ClN, 04

EXAMPLE 32. A mixture of m-trifluoromethylbenzaldehyde, (4,4-dimethylbenzhydryl) -1-piperazinyl ethyl acetoacetate and ethyl 3-aminocrotonate are heated in isopropyl alcohol under conditions similar to example 1, resulting in Desired 2 f4- (4,4-dimethylbenzhydryl) -1-piperazinyl ETSh1-Etil-2,6-dimethyl-4- {3-trifluoromethylfevil) -, 4-dihydropyriindin-3,5-dicarboxylate as colorless powdered product with m.p. 74-77 C (with sintering). The product yield of 44.1% of theory.

IR spectrum of product dispersion in liquid paraffin, cm: 3320, 680.

PMR spectrum (in deuterium chloroform), 8: 1.17 (MN, triplet,,,); 2.26 (6H, singlet, p-CH) j 2,, 32 (6H, singlet, -CH); 4, -05 (2H quadruplet, -CH-CH,); 4.10 (1H, singlet, N-CHt); 4.12 (2H, triplet,, -COOCHj-CHj-); 5.02 (W, singlet, C (, - H); 5.65 (1H, broad singlet, W),

258324

Calculated% 1 N 6.22.

Found,%: C 69.23; H 6.55; N 6.07.

Example 33 A mixture of m-chlorobenzaldehyde, (4,4-dimethylbenzhydryl) -1-piperazinyl ethyl acetoacetate and ethyl 3-aminocrotonate was heated in isopropyl alcohol under conditions similar to Example 1, resulting in a the desired 2- f4- (4,4-dimethylbenzhydryl) -1-pipera-Roshkoobrazny substance with t; Sh1. 790

B1 ° C (with sintering). The yield of this product is 48.4% of theory.

IR spectrum of the product dispersion in liquid paraffin,: 3330, 1680.

PMR spectrum (in chloroform), B: 1.16 (3N, triplet, J-7,,); 5 2.22 (6H, singlet, f-CH,); 2.28 (6H, singlet, C-CH,); 4.05 (2H, quadruplet,,,); 4.08 (W, singlet, N-CH); 4.11 (2H, triplet,, -COOCHj-CHj-); 4.93 (1H, singlet.

five

Q

0

C (4) H); 5.64 (1H, broad synN

0)

GL, NH).

Calculated,%: C 71.07; H 6.91; N 6.54.

C, gH 4-ClN, 04

Found,%: C 71.19; H 6.87; .

EXAMPLE 34. A mixture of meta-anisic aldehyde, (4,4-dimethylbenzhydryl) -1-piperazinyl1-ethyl acetate, and 3m-3-amcocrotonate is heated in isopropyl alcohol under conditions similar to example 1, resulting in get the desired (4,4-dimethylbenzhydryl) -1-piperazi-yl1-ethyl-ethyl-4- (3-methoxyphenyl) -2,6-dimethyl-1,4-dihydropyridi-3, 5-dicarboxylate .pl. 75- (with sintering). The yield of this product is 42.2% of the theoretically possible.

IR spectrum of the product dispersion in liquid paraffin, cm: 3330, 1690.

PMR spectrum (in deuterium chloroform, S: 1.18 (3N, triplet,, -CHfCH,); 5 2.25 (6H, singlet, 9-CH,); 2.27 (3N, singlet, -f-CH ,); 2.29 (EG, singlet, C-CH) j 3.68 (EG, singlet, OCH,); 4.05 (2H, quadruplet.

1912 832420.

,) 4.09 (IH, singlet, C-CHC); 1 H NMR spectrum (in deuterium chloroform), 4.14 (2H, triplet, -COOCH CH -); 8: 1,15 (ЗН, triplet,,

4.96 (1H, singlet, C (4) -H); (1H,

Upshrennye Eletlet, NH).

Calculated,%: C 73.44; H 7.43; N 6.59.

Found,%: C 73.09; H 6.64; N 6.41.

PRI me R 35. A mixture of m-methoxycarbonylbenzaldehyde, (4,4 - dimethylbenzhydryl) -1-piperazinyl of ethyl acetoacetate and ethyl 3-aminocrotonate is heated in isopropyl alcohol

2.24 (6H, singlet, 9-CH,); 2.29 (6H singlet, C-CH); 4.03 (2H, quad 5 plet ,, ,,); 4.11 (1H, singlet,: jN-CHO; 4.13 (2H, triplet,, -COOCHj CH -); 5.01 (1H, singlet C (4) -H); 5.77 (1H, broad singlet, NH).

to Calculated,%; C, 74.02; H 7.01; N 8.86.

С, Н „Н404

Found,%: C 74.07; H 7.22; N 9.06 ..

under the conditions analogous to example 1, 15, as a result, the desired (4,4-dimethylbenzhydryl) -1-piperazinyl} ethyl ethyl-4- (3-methoxycarbonylphenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylate in the form of a light-20 lo yellow powder, having so pl. 80-83 ° C (with sintering). Vkod specified product 47.5% of theory.

IR spectrum of the product dispersion in liquid paraffin,: 3330, 1720, 25 1690.

PMR spectrum (in deuterium chloroform), 8: 1.17 (MN, triplet, J 7, -CH-CH,); 2.25 (6H, singlet, C-CHi); 2,3G

II p. 37. The mixture of m-nitrobenzaldehyde, 3- (4-benegryl-1-riperazinyl) -propyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, as a result which gives the desired 3- (4-benzhydryl. 1-piperazinyl) propyl-methyl-2,6-dime-. Tyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as an oil. Then this product is treated with a methanol solution of hydrogen chloride. Recrystallization of the isolated hydrochloric acid salt from methanol yields the desired dihydrochlo (bN, singlet, 3.83 (3N, read in the form of light yellow crystalglobe, -sin,), 03 (2H, quadruplet, lytic product with m.p. 168-173 S., -CHj CH,); 4.10 (Ø, singlet, iN-CHvJ, 4.10 (2H, triplet,, -COOCHj- € H, -); 5.00 (Ш, singlet , C0) 5.78 (1H, broad singlet, 35 NH).

Calculated,%: C 72.12; H 7.12; . €.

tricheskogo product with so pl.

The product yield of 34.3%.

Calculated,%: C, 61.19; H 6.13;

N 7.93

 2HC1. 1 / 2HgO Found%: C 61.09; H 6.07; 7.93.

N

Example 38. A mixture of m-chlorobenzaldehyde, 3- (4-benzhydryl-1-piperazinyl) propyl acetoacetate and methyl g3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a desired 3- ( 4-benzhydryl-1-piperazinyl) propyl-methyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxyllate as an oil. This product is then treated with a solution of hydrogen chloride in methanol, the separated hydrochloric acid salt is recrystallized from methanol, and the desired dihydrochloride of the indicated compound is obtained as a colorless crystalline substance with mp. 169-172 C. The yield is about 45.6%.

C, H, N, 0 “Found,%: N 6.12.

C, 71.74; H 7.24;

Pr and m in. p 36. A mixture of para-cyanobenzaldehyde, (4,4-dimethylbenzhydryl) -1-piperazinyl) ethyl acetoacetate and ethyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, as a result of which the desired (4 , 4-dimethylbenzhydryl) -1-piperazinyl ethyl ethyl ethyl-4- (4-cyanophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylate as a light yellow powdery substance with m.p. 93-96 C (with sintering). The yield of this product is 61.9% of the theoretically possible.

IR spectrum (dispersion in liquid paraffin), 3330, 2220, 1685.

PMR spectrum (in deuterium chloroform), 8: 1.15 (MN, triplet,

2.24 (6H, singlet, 9-CH,); 2.29 (6H, singlet, C-CH); 4.03 (2H, quadruplet, ,,); 4.11 (1H, singlet,: jN-CHO; 4.13 (2H, triplet,, -COOCHj CH -); 5.01 (1H, singlet, C (4) -H); 5.77 (1H, broad singlet, NH).

Calculated,%; C, 74.02; H 7.01; N 8.86.

С, Н „Н404

Found,%: C 74.07; H 7.22; N 9.06 ..

II p. 37. The mixture of m-nitrobenzaldehyde, 3- (4-benegryl-1-riperazinyl) -propyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to example 1, as a result which gives the desired 3- (4-benzhydryl. 1-piperazinyl) propyl-methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as oils. Then this product is treated with a methanol solution of hydrogen chloride. Recrystallization of the isolated hydrochloric acid salt from methanol gives the desired dihydrochloride as a light yellow crystalline product with mp. 168-173 S.

read in the form of a light yellow crystalline product with so pl. 168-17

tricheskogo product with so pl.

The product yield of 34.3%.

Calculated,%: C, 61.19; H 6.13;

N 7.93

 2HC1. 1 / 2HgO Found%: C 61.09; H 6.07; 7.93.

N

0

five

Example 38. A mixture of m-chlorobenzaldehyde, 3- (4-benzhydryl-1-piperazinyl) propyl acetoacetate and methyl g3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a desired 3- ( 4-benzhydryl-1-piperazinyl) propyl-methyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxyllate as an oil. Then this product is treated with a solution of hydrogen chloride in methanol, the separated hydrochloric acid salt is recrystallized from methanol, and the target dihydride is finally obtained. RochLoride of the title compound as a colorless crystalline substance; mp. 169-172 C. The yield is about 45.6%.

Calculated,%: C, 62.93; H 6.16; N 6.12.

21 С H4oClN, 04-2S1

Found,%: C 62.89; H 6.36; N 6.07.

II p and mepera 39. A mixture of furfural, 3- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrone donate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a result the desired 3- (4-benzhydryl-1-piperaeinyl) ethylmethyl-4-2-furh1) -2,6-dimethyl-1,4-dihydropyrndYan-3,5-dicarboxylate in the form of a light yellow powder with mp 71-77 C (with sintering). The yield of this product is 33.4%,

IR spectrum of the dispersion of the product in vaseline oil, crt: 3310, 1700, 1685.

PMR spectrum (in deuterium chloroform), 8: 2.30 (6H, singlet, (2nd, triplet, J 6, -ffl-CHj NC); 3.62 (OG, singlet, AXIS,); 5.16 ( 1H, singlet,); 5.77 (broad singlet, NH).

Vych sleno,%: C 71.33; H 6.71;

one

N 7.56.

C ,, Hj, N, 05

Found,%: C 71.02; L 6,69; N 7,64.30

P and Measure 40. A mixture of 5-methyl-2-thiofenkareldehyde, (4,4-dimethyl-1-benzhydryl) -1-piperaziyyl ethyl acetoacetate, and methyl-3-acetoscrotonate is heated in nsopropyl alcohol 35 under the conditions anal, (“ In Example 1, as a result, (4,4-dimethylbenzhydryl) -1 hyperazine 12-methyl-ethyl-2,6-dimesh-1-4 (5-methylP and me 42) are obtained. (4 -fluorophenyl) -1-piperazinsh1 of ethyl acetoacetate and methyl 3-aninocrotonate is heated in isopropyl alcohol under conditions similar to example 1, resulting in (4-phorhenshen1) -1-piperazinyl of ethyl methyl-4- (3- chlorf enyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicar-bauxalate as a light yellow powdery substance with mp 44-49 ° C (sintering). The yield of the specified product is 34 ,one%.

The IR spectrum of the product dispersion in va- (lava oil, cm: 3430, 1700, 16B5.

PMR spectrum (in deuterium chloroform), 8: (ZN, singlet, (: -CH,); 2.34 (ZN, singlet, C-SI,); 3.63 (ZN,

2-thienyl) -1,4-dihydropyridia-3,5-di-40 singlet, -COOCH); 4.18 (2H, triplet,

, -СООСН СНг-); 4.99 (Ш, singlet, С ,, - Н); (1H, singlet, W).

Calculated,%: C 64.26; H 6.14; 7.75.

CjvH, vClFN, 04

Found% j C 63.96; H 5.94; 7.48,

carboxylate in the form of a light powdered substance with so pl. 82-85 ° C (with sintering). The yield of the specified product 25-, 8%.

The JK-spectrum of the product dispersion in Vaselinov oil, 3330, 1690.

1 CR spectrum (B deuterochloroform), S: 1.22 (3N, triplet, -CH-SS), 2-, 24 (6H, singlet, f-CH,); 2.28 (6H, singlet, C-CH,); 2.30 (3N, sinlet, C-CH,)} (1H, singlet, N-CHC); 5.20 (W, singlet, С {, у – Н); 5.75 (1H, broad singlet, NH).

Calculated,%: C, 70.79; H 7.23; N 6.69.

C, 7H, N304S

Found,%: C 70.76; H 7.30; N 6.5 |,

N

45

 I

PRI me R 43. A mixture of 2,3-dichlorobenzaldehyde, 2-G4- (4-fluorophenyl) -1-50-t.

piperazinyl | etch1 acetoacetate and methyl 3-aminocrotonate are heated in isopropyl alcohol under conditions similar to example 1, resulting in (4-fluorophenyl) -1-pipera-3HKHJi-methyl-methyl-4- (2,3-dichlorophenyl) -2, 6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylate in the form of colorless prismatic Jc-crystals with so pl. 146to

15

5832422

EXAMPLE 41. A mixture of metatone-benzaldehyde, (4-fluorophenyl) -1-piperaeinyl ethyl acetoacetate and ethyl 3-aminocrotonate is heated in isopropyl alcohol under conditions similar to libix example 1, resulting in a 2- 4- (4-fluorophenyl) -1-piperazinyl ethyl-2,6-dimethp-4- (3-nitrophenyl) -1,2-dihydropyridine-3, 5-dicarboxylate as a yellow crystalline substance having .pl. 129-131, (after recrystallization from a mixture of ethyl acetate - hexane). The yield of 45.3%.

Calculated,%: C 63.03; H 6.02; N 10.14.

.

Found% C 62,95; H 6.10; N 10.10.

PRI me R 42. A mixture of m-chlorobenzaldehyde, (4-fluorophenyl) -1-piperazins 1 of ethyl acetoacetate and methyl 3-3-aninocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a Get (4 Thorrhens1) -1-piperazinyl ethyl methyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxalate as a light yellow powdery substance with mp . 44-49 C. (with sintering). The yield of this product is 34.1%.

The IR spectrum of the product dispersion in va- (lava oil, cm: 3430, 1700, 16B5.

PMR spectrum (in deuterium chloroform), 8: (ZN, singlet, (: -CH,); 2.34 (ZN, singlet, C-SI,); 3.63 (ZN,

singlet, -COOCH); 4.18 (2H, triplet,

PRI me R 43. A mixture of 2,3-dichlorobenzaldehyde, 2-G4- (4-fluorophenyl) -1- -t.

piperazinyl | etch1 acetoacetate and methyl 3-aminocrotonate are heated in isopropyl alcohol under conditions similar to example 1, resulting in (4-fluorophenyl) -1-pipera-3HKHJi-methyl-methyl-4- (2,3-dichlorophenyl) -2, 6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylate in the form of colorless prismatic Jc-crystals with so pl. 14623

 (after recrystallization from a mixture of ethyl acetate - diethyl ether). The yield of the specified product FOR, 9%.

Calculated,%; C, 59.79; H 5.38; N 7.47.

C, 8 ".FC1, N, 04

Found,%: C 59.84; H 5.40; N 7.16.

EXAMPLE 44. A mixture of m-nitrobenzaldehyde, (2-chlorophenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isoproyl alcohol c. conditions analogous to example 1, resulting in (2-chloro-phenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5 - dicarboxylate as a yellow crystalline product with m.p. 153-154 C (after recrystallization from a mixture of diethyl ether - hexane). The product yield of 46.5%.

Vychnseno,%: C 60,59; H 5.63; N 10.09.

С „Н„ СЩОб

Found,%: C 60.47; H 5.84; N 9.91.

PRI me R 45. A mixture of meta-nitrobenzaldehyde, (4-chlorofensh1) -1N

N

(after recrystallization from a mixture of diethyl ether - hexane}. The yield of the product is 29.2% of theory.

Calculated,%: C 58.09; H 5.22; 7.26.

Cj8H, oCl, N, 04

Found,%: C 58.23; H 5.25; 6.87.

EXAMPLE 47. A mixture of m-tri-10 fluoromethylbenzaldehyde (3-chlorophenyl) -1-piperazinyl-ethyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in 15 results ( 3-. Chlorophenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-trifluoromethylphenyl) -1,4 dihydropyridine-3,5-dicarboxylate as a colorless crystalline substance 20 (prism-shaped crystals) having a mp. 141-143 C (after recrystallization from a mixture of diethyl ether - hexane). The product yield of 44.6%.

Calculated,%: C 60.26j H 5.41; 25 N 7.27.

C ,, H ,, C1F, N, 04 Found,%: C 60.13; H 5.51; N 6.95.

Example 48. Ortho-chlorine blend35

piperazinyl ethyl acetoacetate and methyl azobenzaldehyde, (3-chlorofenk) -1 piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate are heated in isopropyl alcohol under conditions similar to the example. 1, resulting in a target (3-chlorophenyl) -1-piperazinyl ethyl methyl-4- (2-chlorophenyl) -2,6-dimethyl-1, 4-digndroPyridine-3,5-dicarboxylate as a colorless crystalline substances (crystals in the form of prisms) with so pl. 130-132 C (after recrystallization from a mixture of diisopropyl ether - hexai). The output of the specified product is 24.1%.

W 1 number% 1 C 61,77; H 5.74; 7.72.

3-aminocrotonate is heated in isopropane. alcohol under the conditions similar to Example 1, resulting in 2- 4- (4-chlorophenyl) -1-piperazinylZ eth1-methyl-2,6-dimethyl-4- (3-nitrophenyl) -1 , 4-dihndropyridine-3, 5-dicarboxylate in the form of a yellow crystalline product, having so pl. 141.5-143 s (after recrystallization from ethyl acetate-hexane) 40 Yield 55.7%.

Calculated,%: C 60.59; H 5.63; N 10.09.

CjgH ,, ClN40s

Found,%: C 60.52; H 5.74; N 9.83.

EXAMPLE 46 A mixture of 2,3-dichlorobenzaldehyde, 2-C4- (3-chlorophenyl) -1-piperazinyl ethyl acetoacetate, and methyl45

N

N

CjjH ,, CljN, 04

Found,%: C 62.06; H 5.74; 7,69. EXAMPLE 49 A mixture of meta-chloro-3-aminocrotonate is heated in isopro-benzaldehyde, 2-L4- (2-chlorophenyl) -1-alcohol, under conditions similar to example 1, resulting in the desired (3-chlorophenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-1-datrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as a colorless crystalline substance (prism-shaped crystals) with m.p. 140-143 С

1238324

24

N

N

(after recrystallization from a mixture of diethyl ether - hexane}. The yield of the product is 29.2% of theory.

Calculated,%: C 58.09; H 5.22; 7.26.

Cj8H, oCl, N, 04

Found,%: C 58.23; H 5.25; 6.87.

EXAMPLE 47. A mixture of m-trifluoromethylbenzaldehyde (3-chlorophenyl) -1-piperazinyl-ethyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a resultant (3 . Chlorophenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-4- (3-trifluoromethylphenyl) -1,4 dihydropyridine-3,5-dicarboxylate as a colorless crystalline substance (crystals in the form of prisms), having .pl. 141-143 C (after recrystallization from a mixture of diethyl ether - hexane). The product yield of 44.6%.

Calculated,%: C 60.26j H 5.41; N 7.27.

C ,, H ,, C1F, N, 04 Found,%: C 60.13; H 5.51; N 6.95.

Example 48. A mixture of ortho-chlorine benzaldehyde, (3-chlorofencle) -135

40

45

N

CjjH ,, CljN, 04

Found,%: C 62.06; H 5.74; 7,69. PRI me R 49. The mixture of meta-chlorine

piperazinyl) ethyl acetoacetate and methyl α-aminocrotonate are heated in isopropyl alcohol in wapa x, analogous to example 1, as a result of which the target (2-chlorophenyl) -1-piperazinyl ethyl methyl-4- (3-chlorophenyl) -2 is obtained , 6-dimethyl-1,4-dihydroshfidin-3,5-dicarboxylate as colorless25

a crystalline substance (prism-shaped crystals) having a melting point of 1b1.5 to 1b3 C (after recrystallization. From a mixture of diisopropyl ether to hexane). The yield of this product is 52.6.% Of theory.

Calculated,%: C, 61.77; And 5.7D; N 7.72.

,, 04

Found,%: C 61.86; H 5.73; N 7.58.

EXAMPLE 50 A mixture of m-chlorobenzaldehyde, (4-chlorophenyl) -1-piperazyl ethyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in a target (4-Chlorophenyl) -1-piperazinylZ ethyl methyl-4- (3-chlorophenyl) -2,6-dimethyl-1,4-digdropyridine-3,5-dicarboxylate as a colorless crystalline substance with mp. 127-131 0 (after recrystallization from a mixture of diisopropyl ether - hex1258324

dicarboxylate in the form of a colorless crystalline substance with 15t-l53 ° C (after recrystallization from a mixture of diisopropyl ether, 5 san). The product yield is 48.6%.

Calculated: C 66.47; H N 8.02.

C ,,,

ten

15

Found,%: C, 66.47; H 6 N 7.79.

Example 53. A mixture of benzaldehyde, 2- (4-phenyl-1-nyl) ethyl acetoacetate and methynocrotonate with heated acyl ester under conditions similar to Example 1, resulting in the target methyl 2- (4-phenyl zinyl) ethyl 2,6-dimethyl-4- (3 Q nyl) -1,4-dihydropyridine-3, 5 xylate in the form of a yellow crystalline color, ymeckceg 113-118 C (after perekrist from a mixture of diisopropyl

san). The yield of the indicated product is 47.5% .25 The yield of the product is 51.2%.

Calculated,%: C 64.60; And N 10.76,

Calculated,%: C, 61.77; H 5.74; N 7.72.

,

Found,%: C 61.81; H 5.93; N 7.73.

PRI imper 51. A mixture of m-cytobenzaldehyde, (2-methylphenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, in the resultant methyl -2- 4- (2-methylphenyl) -1-piperazinyl ztil-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5- dicarboxylate as a colorless crystalline substance with mp . 156-157 ° C (after recrystallization from a mixture of diisopropyl ether - hexane). The product yield is 72.1%.

Calculated,%: C 65.15; H 6.41; N 10.48.

Cj, H ,, N “0,

Found,%: C 64.98; H 6.40; N 10.27.

Example 52. A mixture of m-chlorobenzaldehyde, (2-methylphenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in iso-propyl alcohol under conditions similar to example 1, resulting in methyl 2-4 - (2-methylphenyl) -1-piperazinyl z-4- (3-chlorophenyl) -2,6-dimethyl-1,4-dihydropyridine-3, 5-

26

dicarboxylate as a colorless crystalline substance with a mp. 15t-l53 ° C (after recrystallization from a mixture of diisopropyl ether - hexane). The product yield is 48.6%.

Calculated: C 66.47; H 6.54; N 8.02.

C ,,,

Found,%: C, 66.47; H 6.55; N 7.79.

Example 53. A mixture of meta-nitro-benzaldehyde, 2- (4-phenyl-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated up under diisopropyl ether under conditions analogous to example 1, resulting in get the target methyl 2- (4-phenyl-1-piperazinyl) ethyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3, 5-dicarboxylate in the form of a crystalline substance yellow color, i.me. 113-118 C (after recrystallization from a mixture of diisopropyl ether - hex25. The yield of the product is 51.2%.

Calculated,%: C 64.60; And 6.20; N 10.76,

C, gH ,, N, Ofi

0

five

0

Found,%: C 64.41; H 6.16; N 10.58.

EXAMPLE 54 A mixture of meta-chlorobenzaldehyde, 2- (4-phenyl-1-piperazinyl) ethyl acetoacetate, and metst-3-ayinocrotonate is heated in isopropyl alcohol under conditions similar to example t , resulting in a target methyl-2- (4-phenyl-1-piperazinyl) ethnl-4- (3-chlorophenyl) -2,6-dimethyl- 1, 4-dihydropyridine-3, 5-dicarboxylate in the form colorless crystalline substance with so pl. 147-148, (after recrystallization from a mixture of diisopropyl ether - hexane). The product yield of 44.2%.

Calculated,%: C 65.94; H 6.32; N 8.24. .

C, jH ,, ClN, 04

Found,%: C 65.86; H 6.25; N 8.17.

Example 55. A mixture of meta-nitro-benzaldehyde, (4-methoxyfennl) -1-pinperazinyl} ethyl acetoacetate and methyl 3-aminocrotonate is heated in isogrothyl alcohol under conditions similar to example t, resulting in a resultant (4 -methoxyphenyl) -1-piperazinyl ethyl-methyl-2,6-di-methyl-4- (3-nitrophenyl) - 1,4-dihydropyridine-3, 5-dicarboxylate as yellow

27.

of crystalline (prism-shaped crystals) substances with so pl. 1b9-171 with (after recrystallization from diisopropyl ether). The yield of the obtained product is 62.1%.

Calculated,%: C 63.26; H 6.22; N 10.18.

C2, H ,, N, 0,

Found,%: C 63.10; H 6.28; N 10.16.

Example 56. A mixture of m-chlorobenzaldehyde, (4-methoxyphenyl) J-piperazinyl ethyl acetoacetate and me-yl-3-aminocrotonate is heated in iso-propyl alcohol under conditions similar to example 1, resulting in a target (4-labels - syphenyl) -1-piperazinyl ztil-methyl-4- (3-chlorophenyl) -2,6-dnmethyl-1,4-dihydropyridine-3,5-dicarboxylate in the form of a colorless crystalline substance (prism-shaped crystals) m.p. 163.5-164, C (after recrystallization from diisopropyl ether). The product yield of 50.9%.

Calculated,%: C 64.50; H 6.35; N 7.78.

substances yellow so pl. 155-157 С

C2, H44ClN, Oy

Found,%: C 64.31; And 6.28; N 7.78.

Example 57. A mixture of meta-nitro-benzaldehyde, 2- 4- (3-chloro-4-methylphenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under the conditions of a similar example. 1, whereby (3-chloro-4-methyl-phenyl) -1-piperazinyl-Cr-1-methyl-2,6 dimethylg-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate is obtained in the form of a crystalline color, having

(after recrystallization from a mixture of diethyl ether - hexane). The output of the product is 54.8%.

Calculated,%: C 61.21; H 5.85; N 9.85.

С „Н„ СЩОб

Found.%: C 61.35; H 5.87; N 9.78.

Example 6 p 58. A mixture of m-nitrobenzaldehyde, (2,3-dichlorophenyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in target (2,3-di-chlorophenyl) -1-piperazinyl ztil-methyl128,832,428 is obtained

2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate in the form of a yellow crystalline substance with t.pcs. 189-190 ° C. The yield of product 5 is 75.7%.

Calculated,%: C 57.05; H 5.13;

five

0

five

0

five

five

N 9.50.

C ,, H ,, C1

N406

Found,%: C 56.99; H 5.12; o N 9.47.

Example 59. A mixture of meta-nitro-benzaldehyde, 2- 4- (2,5-dichlog of e-nyl) -1-piperazinyl ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under conditions analogous to example 1, resulting in target (2,5-dichlorophenyl) -1-piperazinyl-ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate is obtained as a crystalline substance yellow, having so pl. 170-172 C (after recrystallization from a mixture of diisopropyl ether - hexane). The yield of the obtained product is 54.9%.

Calculated,%: C 57.05; H 5.13; 9.50.

Found,%: C 56.88; H 5.14; 9.17.

EXAMPLE 60 A mixture of 2,1,3-benzoxadiazole-4-carbaldehyde, 2- (4-benzhydrnl-1-piperazinyl) ethyl acetoacetate and methyl 3-aminocrotonate is heated in isopropyl alcohol under the conditions analogous to example 1, resulting in a product that is then treated with a methanol solution of hydrogen chloride. As a result, the target 2- (4-benzhydryl-1-piperazinyl) ethyl-meT11n-4- (2, 1,3-benzoxa-diazol-4-yl) -2, b-dimethyl-1,4 -digdropyridine-3,5-dicarboxylate as a light yellow crystalline product with mp. 192-198 ° C. The product yield is 45.0%.

N

N

Calculated,%: C 60.96; H 5.85; N10.16.

С „Н, уНуО, 2НС1-1 / 2HiO

Found,% C 60,89; H 5.55; N 10.09.

EXAMPLE 61 The hydrochloric acid monohydrate prepared in Example 1 is dissolved in methanol and the solution is concentrated by careful evaporation in vacuo. Recrystallization from ethyl acetate gives a waterless dihydrogen.

2- (4-benzhydryl-1-piperazined) ethyl-methyl-2,6-dimethyl-4 (3-nitrophenyl) -, 4-dihydropyridine-3, 5-dicarboxylate rochloride, having . 174-180 ° C (204-206.5 ° C, with decomposition, when measuring the melting point in a sealed capillary).

Calculated,%: C, 61.49; H 5.90; N 8.20.

C, 5Н4вН О 2НС1

Found,%: C 61.50; H 5.81; N 8.32.

Example 62. The free base obtained in Example 9 was dissolved in a small amount of methanol and a small excess of a solution of hydrogen chloride in methanol was added to the resulting solution, after which the reaction solution was concentrated in vacuo. The residue obtained by evaporation is recrystallized from ethanol-diethyl ether. As a result, 2–4- (4,4-dimethylbenz1258324) hydrochloride dihydrochloride are obtained.

thirty

A 15% solution of ammonia in ethanol (15 ml) was added to the residue (15 ml), after which the reaction mixture was left in the refrigerator for two days. The solvent and ammonia are then distilled off and the residue is taken up in crude (crude) 2- (4-benz hydro-1-piperazinyl) ethyl-3-amino-crotonate as an oil.

The second stage. Oil received

to in the previous step and methyl 2- (3 nitrobenzylidene) acetoacetate (1.97 g is dissolved in isopropyl alcohol (30 ml) and the solution is refluxed for 10 hours. Then

J5 the solvent was distilled off and the residue was purified by silica gel column chromatography. The product thus obtained is converted into the corresponding dihydrochloride by the method

20 as described in Example 1, resulting in the desired 2- (4-benzhydryl-1-piperazinyl) ethyl-methyl-2,6-di methyl-4- (3-nitrophenyl) -1,4-dihydropyridine 3,5-dicarboxylate dihydrochlori

hydryl) -1 piperaenzine ethyl methyl-2,6-25 monohydrate (0.83 g, 15% of theory)

40

dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate as a light yellow crystalline substance with mp. 182-183 p.

Calculated,%: C, 62.44; H 6.23; N 7.87.

With „2NS1

Found,%: C 62.31; H6.19; N 7.90.

Example 6 The free base obtained in Example 17 is dissolved in a small amount of methanol and an excess of methanol solution of hydrogen chloride is added to it, after which the reaction mixture is evaporated in vacuo. The resulting crystalline precipitate is separated from the mother liquor by filtration and recrystallized from methanol. As a result, the desired (3-chlorophenyl) -1-piperazinyl ethyl methyl-2,6-dimethyl-D- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate hydrochloride is obtained in the form of a yellow crystalline product with m.p. 192-196 ° C.

Calculated,%: C 56.86; H 5.45; N 9.47; C1 11.99.

CyjH ,, ClN Og-HCl

Found,%: C 56.79; H 5.48; N 9.67; C1 11.85.

PRI me R 64. First Stage, To a solution of 2- (4-benzhydryl-1-piperazinyl) ethyl acetoacetate (3.0 g in eta50

55

in the form of a crystalline product having so pl. 1b4-1b9 ° C.

The IR and PMR spectra of this compound are identical to the corresponding spectra of the dihydrochloride monohydrate obtained in Example 1.

An example of the preparation of dosage forms.

For use as an anti hypertensive (antihypertensive) drug, the compounds may be used (in the form of the following dosage forms and formulations.

A. Tablets, g:

(t) 2- (4-Weizgidril1-piperazinyl) ethylmethyl-2, 6-methyl-4 (3-nitrophenyl) -1,4 dihydr6pyridin-3, 5 dicarboxylate dihydrochloride monohydrate 5

(2) Lactose95

(3) Cornstarch29

(4) Magnesium stearate 1 Total130 g

dl 1000 tab islets.

All of the indicated amounts of the components (1) and (2) are mixed with 17 g of corn starch (3) and the mixture is granulated with a paste prepared from 7 g of corn starch (3)

thirty

A 15% ammonia / ethanol solution (15 ml) was added to the residue (15 ml), after which the reaction mixture was left in the refrigerator for two days. The solvent and ammonia are then distilled off and the residue is crude (crude) 2- (4-benzhydryl-1-piperazinyl) ethyl-3-amino-crotonate as an oil.

The second stage. Oil received

in the previous step, methyl 2- (3-nitrobenzylidene) acetoacetate (1.97 g) is dissolved in isopropyl alcohol (30 ml) and the solution is refluxed for 10 hours. Then

the solvent is distilled off and the residue is purified by silica gel column chromatography. The product thus obtained is converted into the corresponding dihydrochloride by the method.

described in example 1, resulting in a target 2- (4-benzhydryl-1-piperazinyl) ethyl methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine -3,5-dicarboxylate dihydrochloride

0

0

in the form of a crystalline product having so pl. 1b4-1b9 ° C.

The IR and PMR spectra of this compound are identical to the corresponding spectra of the dihydrochloride monohydrate obtained in Example 1.

An example of the preparation of dosage forms.

For use as antihypertensive (antihypertensive) drugs, the proposed compounds (1) can be used in the form of the following dosage forms and formulations.

A. Tablets, g:

(t) 2- (4-Weizgidril1-piperazinyl) ethylmethyl-2, 6-methyl-4 (3-nitrophenyl) -1,4 dihydr6pyridin-3, 5 dicarboxylate dihydrochloride monohydrate 5

(2) Lactose95

(3) Cornstarch29

(4) Magnesium stearate 1 Total130 g

for 1000 tablets.

All of the indicated components of tone (1) and (2) are mixed with 17 g of corn starch (3) and the mixture is granulated with a paste prepared from 7 g of corn starch (3).

31

Then, 5 g of corn starch (3) and the entire specified amount of component (4) are added, after which the whole mixture is directly compressed on a compression-tabletting machine. The result is 1000 tablets with a diameter of 7 mm, each containing 5 mg of the compound ( I) B. Capsules, g:

(O (4-4 -Difluorobenzhydryl) -1-piperazinyl-egyl-methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxy xylate dihydrochloride

(2) Lactose140

(3) Microcrystalline cellulose70

(4) Magnesium Stearate 5

In total, 220 g of the mixture are obtained to prepare 100 capsules.

All of the indicated amount of the listed components are mixed and thoroughly mixed to obtain a homogeneous composition of the mixture, which is filled with 1003 gelatin capsules (Japanese Pharmacopoeia IX). Capsules are obtained, each containing 5 mg of the active ingredient (G). Reference Example 1. The first stage, to a mixture of 1-piperazine ethanol (11.4 g), powdered potassium carbonate (24.3 g) and N, N-dimethyl forms and (too ml) is added dropwise with stirring and benzhydryl bromide (21, 7 g). The reaction mixture is stirred at room temperature for 2 hours, then diluted with water and extracted with dithyl ether, the ether layer is washed in a separating 40 ml funnel with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then the solvent is distilled off and the residue is purified by a column.

h

chromatography on silica gel; using a solvent mixture of hexane-ethyl acetate (2: 1) as a solvent. After evaporation of the precipitate in the residue, 21.9 g (84.2% of theory) are obtained.

4-benzhydryl-1-piperazine ethanol in vi

de butter. IR spectrum of the obtained compound (in film) 3380. PMR spectrum (in chloroform), 8: 2.46 (UN, broad singlet); 3.57. (2H, triplet,, 5); 4.20 (1H, singlet); 7.03-7.45 (12H, multiplet).

In the same way, the following compounds were obtained:

58324

32

- 40

4- (4,4 -Difluorobenzhydryl) -1-piperazine ethanol: oil, IR spectrum (in film) 3380. 1 H NMR spectrum (in deutero-chloroform), S: 2.2-2.7 (IQH, multiple-5 plet) J 3.54 (2H, triplet); 4.18 (1H, singlet); 6.8-7.4 (8H, multiplet).

4- (4,4-Dichlorobenzhydryl) -1-piperazine ethanol: oil, IR spectrum (film) of 3400 cm. HMR spectrum (in deutero-chloroform), 6: 2.2-2.6 (UN, multiplet); 2.82 (1H, singlet, -OH); 3.53 (2H, triplet,); 4.14 (1H,; singlet); 7.23 (8H, singlet). -. 15 4- (4,4-Dimethoxybenzhydryl) -1-piperazine ethanol: oil. IR spectrum of undiluted substance 3330. PMR spectrum (in deuterium chloroform), 8: 2.3-2.7 (UN, multiplet); 3.15 (1H, 20 broad singlet, -OH); 3.55 (2H, triplet,); 3.74 (6H, singlet); 4.14 (1H, singlet); 6.78 (4H, doublet); 7.27 (4H, doublet).

4- (4,4-Dimethylbenzhydryl-1-pipet-25-razineethanol: oil, IR spectrum of undiluted compound (film) 3400 cm. PMR spectrum (in deuterochloroform): 2.24 (6H, singlet); 2, 2-2.7 (YUN, multiplet); 3.54 (2I, 30 triplet, 4.21 (1H, singlet), 6.9-7.3 (8H, multiplet).

The second stage. Diketene (, 1 g) is added to 4-benzhydrcl-1-piperazine ethanol (18.1 g) and the mixture is heated h with stirring at a temperature of 70-80 ° C for t, 5 h. The product thus obtained is purified by column chromatography on silica gel using hexane-ethyl acetate (3: 2) as a solvent mixture. The result is 2- (4-benzhydryl-1-piperazinyl) et chacetoacetate as an oil. The output of 17.1 g (73.6% of theory). IR spectrum undiluted

muptiplet).

compounds (in film), cm: 1730, 1715. PMR spectrum (deuterochloroform), 5: 2.22 (3N, singlet); 2.43 (YUN, broad singlet); 3.39 (2H, singlet); 4.18 (1H, singlet); 4.20 (2H, triplet,); 6.64-7.73 (UN,

The following compounds were also prepared according to the described procedure:

(4,4-D fluorobenzhydryl) -1-piperazinyl ethyl acetoacetate: oil, IR spectrum (in film), cm: 1740, 1715. GOSR spectrum (in deuterochloroform), S: 2.25 (ZN, singlet); 2.2-2.7

(YUN, multiplet); 3.40 (2H, singlet); 4.18 (1H, singlet) 4.25 (2H, triplet); 6.8-7.5 8H, multiplet).

, 4-Dichlorobenzgndryl) -1-piperazinyl} ethyl acetoacetate: oil, IR spectrum. Undiluted compound, 1740, 1715, PMR spectrum

Arabica and injected animals orally. A dosage of 10 mg / kg was used for all compounds. Animals of the control group 5 were given only one 5% gum arabic solution. Blood pressure measurements were taken 1.5.8 and 24 hours after administration of each test compound.

The antihypertensive effect (blood pressure after medication, i.e. after administration of the test drug, minus the blood pressure measured before the medication) is suggested.

(in deuterium chloroform), 8: 2.23 (KN,

Singlet); 2.3-2.8 (YUN, multiplet);

3.42 (2H, singlet); 4.17 (1H, siglet); 4.23 (2H, triplet,); 7.28

(8H, singlet).

(4,4-Dimethoxybenzhydryl) 1-piperazinyl ethyl acetoacetate oil, 15 my compounds illustrated

The IR spectrum of the undiluted compound, in Table. one,

 1740, 1715. PMR spectrum (in action), as shown in Table 1,

- chloroform), S: 2.23 (Zy, sii- it follows that the proposed compounds

glet); 2.3-2.8 (YUN, multiplet) | not inferior (equivalent in their

20), and in most cases, the well-known dihydropyridine derivatives (nifedipine and nicardipine) are significantly higher in intensity of antihypertensive dehiscence and are significantly greater;

3.40 (2H, singlet); 3.73 (6H, singlet); 4.13 (tH, singlet); 4.24 (2H, triplet,); 6.77 (4H, doublet); 7.3t (4H, doublet),

(4,4-Dimethylbenzylhydryl) -1-piperazinyl ztylacetoacetate: oil, IR spectrum of undiluted compound, cm: 1740, 1715. PMR spectrum (in deuterium chloroform): 2.23 (3N, synlet); 2.25 (6H. Singlet); 2.3-2.8 (UN, multipet); 3.40 (2H, singlet); 4.12 (1H, singlet); 4.23 (2H, triplet,); 7.03 (4H, doublet); 7.27 (4H, doublet).

Below are the results of pharmacological tests of the proposed compounds and their fields, illustrating the usefulness of the compounds of formula (I), and test data for acute toxicity

thirty

35

the duration (duration) of the hypotensive effect in comparison with the aforementioned known 1,4-dihydropyridine derivatives.

2. E1 |) effect of increasing renal (renal) blood flow (the effect of improved blood circulation in the kidneys).

Male rats aged 10-1 weeks with spontaneously developing hypertension were grouped by 3-6 animals in a group and anesthetized with pentobarbital. After laparotomy (laparotomy - operative open

1. Antihypertensive effect of the cavity through the abdominal wall)

An automatic electromagnetic probe (Narco) flow meter was connected to the left renal artery; it was designed to measure blood flow in this artery.

(test procedure).

. For this series of tests, male rats and 10-11 weeks of age with spontaneously developing hypertension were used (45 Ria animals, with the help of which

divided into groups of 3-6 rats in each). To determine blood pressure (initial blood pressure was about 200 mm of mercury — the column for the upper systolic blood pressure), an automatic Tonometer — a device for measuring blood pressure — was used by the firm Ueda Chemical Co. Ltd. (USM-105R), the systolic blood pressure in the caudal (tail) artery of each rat was measured.

Each test compound was suspended in a 5% gum- solution.

50

55

recorded on a recorder-polygraph (manufactured by Sanei Sokki K, K.). Renal blood flow and its intensity. Before the administration of the tested drugs (before medication), the blood flow in the experimental animals was at the level of about 6.5 ml per minute.

V,

Each test compound was dissolved in polyethylene glycol with a molecular weight of 400 (PER-400), as a result of which a basic (secret) solution was obtained. This main growth

Arabica and injected animals orally. A dosage of 10 mg / kg was used for all compounds. Animals of the control group were given only one 5% gum arabic solution. Blood pressure measurements were taken 1.5.8 and 24 hours after administration of each test compound.

The antihypertensive effect (blood pressure after medication, i.e. after administration of the test drug, minus the blood pressure measured before the medication) suggests

0

five

the duration (duration) of the hypotensive effect in comparison with the aforementioned known 1,4-dihydropyridine derivatives.

2. E1 |) effect of increasing renal (renal) blood flow (the effect of improved blood circulation in the kidneys).

Male rats aged 10-1 weeks with spontaneously developing hypertension were grouped by 3-6 animals in a group and anesthetized with pentobarbital. After laparotomy (laparotomy - operative open

recorded on a polygraph recorder (manufactured by Sanei Sokki K, K.). Renal blood flow and its intensity. Prior to the administration of the test drugs (before medication), the renal blood flow in experimental animals was at the level of about 6.5 ml per minute.

V,

Each test compound was dissolved in polyethylene glycol with a molecular weight of 400 (PER-400), resulting in the preparation of a stock solution. This basic solution was diluted fivefold with physiological saline and the resulting diluted solution was administered intravenously to experimental rats in an amount of 0.5 ml / kg body weight. The injected dose for all test compounds was 0.01 mg / kg. Changes in the renal blood flow after medication were recorded for 40 minutes.

The effect of the proposed compounds on renapny (renal) blood flow is shown in Table. 2. The indicator characterizing the change in the renal blood flow as a result of the administration of the test compounds (as a result of the medicinal cycle) was calculated by the formula: (Renal blood The renal blood flow after blood flow before the medication - medication)

  X100 (%)

Renal blood flow before medication

Test compound for example

The change in blood pressure, mm Hg, after

1 hour after drug administration

group one gum + 2

-89

-99

-thirty

-59

-96

-96 -88

-85

-34 -38

3. Acute toxicity (method of determination).

2- (4-Benzhydryl-1-piperazinyl) -stil-methyl-2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride was suspended in 5% solution of gum arabic and was administered orally to males and females of Wistar rats of 5 weeks of age (who had a body weight in the range of 105-139 g). Animals were divided into several groups of 4-8 rats in each group. The drug was administered to animals in doses of 62.4, 125, 500 and 1000 mg / kg of chese, after which each animal that received its dose was under observation for 7 days.

Test data for acute toxicity are presented in table. 3,

Table 1

The duration of anti-hypertonic effect, h

5 hours after drug administration

-2

-91 101 -33 -79 -98 -98 -57 -87 -31 -18

ABOUT

24 8-24 8-24

24

24

24 8-24

24 8-24 5-8

37

1258324

38

. Continuation of table 1

39

, 05 (compared with the control group), 1))

1258324

40 Continuation of table. I

TEA

SC, 00 (l.SOO (1yz

H

N0:

OS

rVcOO-fCH2), - N CHj N CHj

/ SNZ

CH:

effect of increased blood flow in the kidney blood vessels

2.4 10.4 4.5 5.7 6.9 4.2

Table 2

3.4 12.8 6.0 9.7 6.8 2.9

41

Test compound for example

Changes in renal blood flow as a result of medication,%,

after

t min after medicine

18

22

23 31 37

Nifedipine

Nicardipine.

 P «: 0.05 (in comparison with the control group of animals).

T a b l and c a 3

Rat Ostra toxicity, LD, mg / kg

i 250: .500 (survived) 9 250 LW (, 500 (died)

Compiled by V.Gorin Editor M.Petrova Tehred I.Hodanich Corrector V.But ha

Order 5043/60 Circulation. 379 Subscription VNIIPI State Committee of the USSR

for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5

Production and printing company, Uzhgorod, Projecto st., 4

1258324

42 Continuation of table 2

20 min after copper casting

Sh40 min after medication

5.0 9.6

10.9 1.8

11.3 2.2 0.3

Claims (4)

G. The method of obtaining derivatives of dihydropyridine General formula where K, and - the same or different and each of them is alkyl, cycloalkyl or alkoxyalkyl; K and K. are the same or different. and each of them is hydrogen, halogen, nitro, trifluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl, or alkylthio; - hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; X is oxygen or sulfur, a vinyl group, an aometin group, or a group of the formula ) (Ii) A is an alkylene group; Ag - aryl or pyridyl Group; w - an integer of 1-3; η is a simple integer 0 - 2, wherein the compound of the general formula / COOH-g (IV) where K, and K ₂ have the indicated meanings, act with ammonia, the resulting product is reacted with a compound of the general formula (V) and with a compound of the general formula "Βυ,., 1258324 A 3 γ'ΟΟΟ-Α-ΝθΝ-ΚΗΙη-ΑΡ. 0 ^ B ₃ ^(CH ^ B ₆ < ^νι > 1258324 where _{r p} , Α, ηι and η ^K 5 " TO*. K ₅ , have the indicated meanings. 2. The method of obtaining derivatives of dihydropyridine General formula act ammonia, the resulting product is subjected to interaction with the compound of the General formula -AH ^) * HCH) _n -Ag ".-F‘ is clear (V) 1) Yu I® and with a compound of the general formula where, Κ * and are the same or different and each of them is · alkyl, cycloalkyl or alkoxyalkyl; K ₄ and E _? - the same or different and each of them is · hydrogen, halogen, nitro, trifluoromethyl group, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl group or alkyl tyrgroup; K ₆ is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; X is oxygen or sulfur, a vinyl group, an azomethine group, or a group of the formula soya ₂ Ο ^ Ηι where K ,, K ₄ , (Iv) E. and X have the indicated meanings. 3. The method of obtaining dihydropyridine derivatives of the general formula. where E ,, E _g and K. K ₄ and K ₅ Yb Ne ₍₁₎ and;, O (W or (AND ABOUT A is an alkylene group; Ar is an aryl or pyridyl group; t is an integer of 1-3; η is a simple integer 0-2, characterized in that on. the connection of the general formula < ^С °° -А-О- <СН) p-Ar e, the same _o or different and each of them is alkyl, cycloalkyl or alkoxyalkyl; they are the same or different and each of them is hydrogen, halogen, nitro, trfluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl or alkyl thio; hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; oxygen or sulfur, a vinyl group, an azomethine group, or a group of the formula where K ,, K ₄ , A, type have the indicated meanings. ϊΛ op TSE (IR (Vi) A is an alkylene group; Ag - aryl or pyridyl Group; ’ Y - an integer of 1-3; η is a simple integer 0-2, characterized in that. on the compound of the general formula 1258324 £ O ^ -Wa СОО-А-т / ~) l- (СН) [, - Ar (Vi) where 1C, K ₆ , A, shchi η have the specified values, they act with ammonia, the product formed during this process is treated with a compound obtained by reacting a compound of the general formula £ is clear (V) with a compound of the general formula SOOVg K _in - hydrogen, alkyl, cycloalkyl, aralkyl, aryl or pyridyl; X is oxygen or sulfur, a vinylen group, an azomethine group, or a group of the formula (I) or (IG) A is an alkylene group; Ar is an aryl or pyrpidyl group; ha is an integer of 1-3; η is a simple integer 0-2, wherein the compound of the general formula soov, (Iv) Βΐ Ό ^ Βι ^(Ιν) where K ₄ , K _g , K ₄ , 1C and X have the indicated values. 4. The method of obtaining derivatives of cihydropyridine General formula (СН) _П -АГ Й6 (Г) where and K _g have the indicated meanings, act with ammonia, the product thus formed is treated with a compound obtained by reacting a compound of the general formula is clear (V) where K ,, K _g and K, are the same or different. and each of them is alkyl, cycloalkyl or alkoxyalkyl; K ₄ and K ₅ are the same or different and each of them is hydrogen, halogen, nitro, trifluoromethyl, alkyl, cycloalkyl, alkoxy, cyano, alkoxycarbonyl, or alkylthio; with a compound of the general formula where K ,, K ₄ , X, A, ha and η have the indicated values. 1258324 2