FI58772C - PROCEDURE FOR THE FRAMSTATION OF HYDROGEN-RELEASE 2,6-DIMETHYL-4-SUBSTITUTES-PHENYL-1,4-DIHYDROPYRIDINE-3-CARBOXYLSYRA-AMINOALKYLESTRAR - Google Patents

Description

ΓβΊ m) iCONVENT PUBLICATION c QO Ί O

m <11> utlAcgnincsskrift oo7 / l C / 45 »Patent granted 10 04 1901” Patent meddelat ^ (51) Kv.lk?/lnt.CI.3 C 07 D 211/90 FINLAND — FIN LAND pi) PitMttihikiMii-PitiMweiwiiii ι + ι + 6 / τ1 * (12) H »k * ml * pUvi Ansekninpdtg 15-02.7 ^

vr, / (23) Alkupthfi — GHtl | h * ttd »| 15-02.7U

(41) Tullut | ulktMk * t - Bllvlt offuntllg 21.08.7U

Patents registered by the Patent Office (44) Date of issue of the filing date. -

Patent · och registrerttyrelaen 'AmMcm utlagd och mi ^ krHtun pubikund 31-12.80 (32) (33) (31) Pyydttty utuolkeu * —Bujlrd prlorlwt 20.02.73 03.03.73, 20.0U.73, 11.05.73, 17.05.73, 2U.07.73, 29.11.73, 29.11.73 Japan-Japan (JP) 20U23 / 73, 25566/73, UU821 / 73, 52307/73, 5U939 / 73, 83276/73, 13U069 / 73, 13U070 / 73 (71 ) Yamanouchi Pharmaceutical Co., Ltd., no. 5-1, Nihonbashi-Honcho 2-chome, Chuo-ku, Tokyo, Japan-Japan (JP) (72) Masuo Murakami, Tokyo, Kozo Takahashi, Tokyo, Masaru Ivanami, Kanagawa, Masaharu Fujimoto, Tokyo, Tadao Shibanuma, Saitama , Ryutaro Kawai, Sai-tama, Toichi Takenaka, Tokyo, Japan-Japan (JP) (7U) Leitzinger Oy (5U) Method for the preparation of cerebrovascular dilators 2,6-dimethyl-U-sub-substituted — phenyl-1, U— dihydropyridine-3-carboxylic acid-amino & alkyl esters - For the preparation of phenylhydroxy-2,6-dimethyl-U-substituents-phenyl-1,1'-dihydropyridine-3-carboxylic acid amino-alkyl esters

The present invention relates generally to a process for the preparation of novel 1,4-dihydropyridine derivatives and, more particularly, to a process for the preparation of 2,6-di-lower alkyl-4-substituted phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester derivatives, having the general formula r6, ^ r3 R5 OC ^ X ^ COOAN · ^ 111 TT \ r4 CH3 ^ N- ^ Ch3 R is a hydrogen atom or a lower alkyl group; 3 R is a phenyl group or a benzyl group which may be substituted by a p-Cl, n-CH, O or p-CH 1 group;

4 0 J

R is a hydrogen atom or a lower alkyl group; 58772 A is a lower alkylene group; R 5 is a lower alkyl group, a lower alkoxy group which may be substituted with a lower alkoxy group, or

6 '' R

R is a nitro group or a trifluoromethyl group.

The compounds of this invention have excellent cerebral vascular dilartor activity.

As derivatives of 1,4-dihydropyridine-3,5-dicarboxylic acid, 4-nitro-substituted diethyl esters of phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid have long been known, for example Chem. Ber., 20, 1338-1343 (1887) and J. Am. Chem. Soc. , 71, 4003-4007 (1949). Other examples are the alkoxyalkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acid described in U.S. Patents 3,485,847 and 3,511,847 and German Patent 1,813,436; 2,013,431 and 2,018,738.

Of these known compounds, methyl 4- (2, -nitrophenyl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid is known to have a compound having coronary vasodilatory activity and spasmolytic activity (see U.S. Patent 3,485, 847; known as "Nifedipine" (name approved by The British Pharmacopoea Commission). It is also known that 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -3,5-nyridine dicarboxylic acid diethyl ester has antihypertensive activity (see U.S. Patent 3,511,847). However, it is not known that these known compounds have cerebrovascular activity.

As a result of various studies on 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives, the researchers have found that the compound of formula I has musculotropic spasmolytic activity, and in particular excellent cerebrovascular activity, and low toxicity. The compound of this invention is therefore particularly suitable for the treatment of cerebrovascular obstruction.

In addition, the nitrogen-substituted alkyl ester of 1,4-dihydropyridine-3,5-dicarboxylic acid of this invention has not been known, and it is unexpected that such novel compounds have the activities described above.

3,58772

The compounds of the invention of the general formula I are prepared by the following methods: A) The benzaldehyde derivative of the formula II Q-r6

CHO

wherein is as defined in general formula I, the acetoacetic acid aminoalkyl ester of formula III R3 /

CH, -COCH- ~ COO-A-N. III

J ^ R

3 4 wherein R, R and A have the same meaning as in general formula I, and an enamine derivative of general formula IV

CH - C = CH-COR5 IV

NH-R

Wherein R and R are as defined in general formula I, are reacted in substantially equal molar ratios in a solvent-free state or in a solvent such as ethanol, isonronanol, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, etc. The reaction can be promoted by heating the reaction system. In addition, an enamine derivative of formula IV can be prepared by reacting a 3-diketone compound of formula V.

ch3-coch2-cor5 V

Wherein R is as defined in general formula I, to react with an amine of formula XVI

R-NH2 XVI

where R is as defined in general formula I, and by separating the products before use, but of course the following method can be used. The compound of formula V is reacted with a substantially equal molar amount or excess of an amine of formula XVI in a reaction vessel, preferably in the presence of an organic solvent such as ethanol, to form a compound of formula IV, followed by a compound of formula II and a compound of formula III. compound to a reaction mixture containing an uninsulated

V

4,58772 of a compound of formula IV, wherein the reaction proceeds further.

B). A compound of general formula II, an enamine compound of general formula VI

X R

CH -, - C = CH-COOA-N. VI

3 I ^ R4

NH-R

3 4 wherein R, R, R and A have the same meaning as in general formula I, and the compound of general formula V is reacted under similar conditions as in method A). As in Method A), a compound of general formula III can be further reacted with an amine of general formula XVI to give a compound of general formula VI, after which a compound of general formula VI and a compound of general formula V are added to the reaction mixture without isolation.

C). A compound of formula VIII ^ β 6 -CH = C-COR 5 (3ΠΠ) COCH 3 5 6 wherein R and R are as defined in general formula I is reacted with a compound of general formula VI.

D). The compound of formula VIII is first prepared by a method similar to that of method C) and the product is reacted with a compound of formula III and an amine of formula XVI.

E). A compound of formula II, a compound of formula IV and a compound of general formula IX

CH3-COCH2COOA-X IX

wherein X represents a halogen atom and A represents the same as in general formula I, is reacted to give a compound of formula X 5 5 8772 T m

R5 OC 'sJkv ^ COOA-X

CH ^ N ^ CHA

R

Wherein R, R, R, A and X have the same meaning as above, and then the compound is reacted with an amine of formula XI R3 /

HN, XI

R 4 3 4 wherein R and R are as defined above, or alternatively a compound of formula II, a compound of formula V and a compound of formula XII

CH o-C = CHCOO-A-X XII

NH-R

wherein R, A and X are as defined above, are reacted to give a compound of formula X, and then the product is reacted with a compound of formula XI.

The desired products prepared by said various methods can be isolated and purified by a conventional chemical procedure such as extraction, column chromatography, recrystallization, and the like.

If desired, the compounds of general formula I can be converted into therapeutically non-toxic salts, for example mineral acid salts, for example hydrochlorides, sulphates, phosphates, etc., or salts of organic acids, such as acetates, fumarates, maleates, tartrates, etc.

For humans, a suitable dose of a compound of this invention is 0.1 to 0.5 mg administered intravenously and 5 to 10 mg orally at a single time. Two to three administrations a day is appropriate.

The following table shows the results of the cerebral vasodilatory activity of the following compounds.

6,58772

Method: Adult mixed breed dogs were anesthetized with sodium pentabarbital (30 mg / kg, i.v.) and ventilated. Vertebral blood flow was measured with an electromagnetic flowmeter (Nihon Target Co., Ltd. MF-5) placed around the vessel. LD, -0 was measured using mice. The results are shown in the following table.

^ VNO2 / r3 r5 ° CvJL-C0 ° -A-N * HCl

jf T

CH3 ^ pCH3 H

__Sample ___ Vertebraa- LD_q r5 A r3 r4 ii «aamar1 '' ______ (mg / kq iv) 1, V '' _ CH30- -CH2CH2- ^^ - CH2- CH3- 0.0003-0.01 20.7 CH O- "2 5,? 11" 11 15

CH

^ W n It II II II

tl II

M C2H5 ~ "n 12" -CH ~ CHOCH0- "CH.-" M 10 e /./ · yssv ^ C2H5 ° "-CH2CH2- CH3 °" 4a "CH2" m "" 10 "" Cl-Q "ch2 "" "" 12 CH3 ~ "" 0.001-0.01 40

Cl ^ ^ ~ ^ 2— "" "4 5

Nifedipine 0.001-0.01 5.6 7 58772

The following pharmacological data indicate the ethyl ester of a compound of the invention, 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-6- (N-benzyl-N-methylamino) -5-methyl ester hydrochloride (hereinafter referred to as Compound A), cerebral vasodilatory activity, spasmolytic activity and acute toxicity compared to papaverine and nifedipine.

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

Methods: Adult mixed breed dogs were anesthetized with sodium pentobarbital (30 mg / kg, i.v.) and ventilated. Vertebral blood flow was measured with an electromagnetic flowmeter (Nihon Target Co., Ltd. MF-5) placed around the vessel. Femoral artery blood pressure was measured using a pressure transducer (Nihon Target Co., Ltd. MPU-0.5) and heart rate with a cardiotachometer (Nihon Target Co., Ltd. RT-2). All drugs were administered intravenously.

Results: The following table shows the effects of Compound A, panaverine, and nifedipine on vertebral blood flow, mean blood pressure, and heart rate in anesthetized dogs.

Drug Dose Animal Vertebra- Mean- Cardiac (mg / kg, ten linen blood volume- i.v.) volume flow pressure speed (A% ± SE) (AmmHgiSE) (beats / min.iSE)

Papaverine 0.1 8 22 ± 3.4 - 9 ± 1.1 8 + 1.5 0.3 8 6 7 ± 7.1 -21 ± 2.8 22 ± 3.5 1.0 8 124 + 13, 8 -32 ± 3.5 44 ± 4.8

Nifedipine 0.001 5 47 ± 13.5 -10 ± 1.6 10 ± 3.5 0.003 4 104 ± 25.8 -24 + 5.9 18 ± 3.2 0.01 6 135 + 28.8 -39 ± 3 , 2 17 ± 4.0

Compound A 0.0003 8 27 ± 4.4 1 + 0.6 4 ± 1.3 0.001 8 61 ± 9.5 7 ± 1.5 12 ± 2.2 0.003 8 132 ± 13.8 14 ± 2.2 18 ± 2.0 0.01 8,200 + 27.3 29 ± 3.0 25 ± 5.3 8 58772 2. Direct effect on cerebral and femoral arteries:

In order to elucidate the selective effect of drugs on the vasculature, their direct effect on the cerebral (vertebral artery) and peripheral (femoral artery) mattress was studied by the constant volume perfusion method.

Method: Adult mixed breed dogs were anesthetized with sodium pentobarbital (30 mg / kg, i.v.) and ventilated. Heparin (1000 y / kg, i.v.) was used as anticoagulant. The perfusion methods for each artery were as follows: 1) In the case of a vertebral artery, arterial blood derived from the left common carotid artery was collected with a Tygon tube and drained into the right vertebral artery using a Sigma motor pump (Mippleport N.Y., T-8). 2) In the case of a perforated artery, arterial blood derived from the proximal femoral artery was drained into the distal peritoneal artery using a Sigma motor pump. Vascular reactions were expressed as changes in perfusion pressure when measured with a pressure transducer (Nihon Kohden Co., Ltd. MPU-0.5). All drugs were administered using a microinjector (Jinta Terumo, NSN-100) into a rubber tube connected to an arterial cannula. A dose-response curve was determined for each drug to obtain a 50% effective dose (ED, -q) for each drug when the maximum responses to papaverine at doses of 3000 μg i.a. was reported as a 100% reaction.

Results: The following table shows the effects of intravenous papaverine, nifedipine and Compound A on the vertebral and femoral arteries.

Table Drug Animal Vasodilation Selectivity ratio amount ED50 ^ 9 ± SE femoral artery ED50 /

Vertebral Artery of the femoral vertebral artery Timo Timon ED ^ q

Papaverine 4 72.8 ± 8.71 48.8 ± 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 58772 3. Spasmolytic activity:

R

Methods: Isolated guinea pig ileum was suspended in Tyrodes solution using a Magnus device and muscle movements were recorded with an isotonic lever on a chymograph. Barium chloride, acetylcholine and histamine were used as the area of action. 50% inhibition of the active substance

Results: Table

Active ingredient Concentra- Spasmolytic activity (g / ml ± S.E)

thio (g / ml) Papaverine Nifedipine Compound A

BaCl2 2x10 ”4 (7.2 ± 0.2) x10 ~ 6 (3.3 + 0.2) x10 ~ 9 (1.9 ± 0.4) x10_9

Acetylcholine 10 7 (l, l ± 0, l) xl0 9 (1,6 + I, l) xl0 8 (5,2ίΐ, 0) χ10 9

Histamine 10-7 (7.0 + 1.9) x10 ~ 6 (5.5 ± 0.9) x10_8 (1.8 + 0.2) x10 ~ 9 4. Acute toxicity:

The acute intravenous toxicity of Compound A and nifedipine was compared using ICR male mice and mixed breed dogs.

Table Sample LD50 (m9 / k9 'i.v.)

Mice Dogs

Compound A 20.7 6.1

Nifedipine 5.6 1.5

From the above results, it appears that the compounds of this invention have potential spasmolytic activity, potential and selective cerebral vasodilatory activity and low toxicity.

The compounds are therefore useful in the treatment of sudden seizures due to cerebrovascular obstruction and apoplexic and postapoplectic conditions caused by cerebrovascular diseases, both by injection and by long-term oral administration.

10 58772 H. Cerebrovascular dilating effect

The following is a comparison of the vasodilatory effect of the compounds prepared according to the invention in Finnish patent application 1193/73 and according to the invention.

X

* b ° c.JL c °° ra "ch.

Λ B J

..... -........- - · - Duration of effect Rä Rn - X * 2 »g / Kg i-v.

Papaverin 1 f 27.0 suom. pending Applications. 1193/73 compounds. and -CH2CH2N-H -OCHj Qf 2 1 ++ 46.7

Xch3 T

-CH, CH_N — CH, 1 1 10 ’53.0.

2 2 \ 3 <»3 ** CH2CH2N - CH3 1 ·. 33.0 '\ c2h5 -CH2CH2N ^ C2H5 · · · .39.5

Nc2H5 -CBjCHjY] · · 1 · 33.0 "CH2CH2CH2N- ch3" 12.5 -CH-CH-N-CH 1 1 70.0 XCH3 CH3 • “0CH3 '" 10- f + 53.0 »~ OC_Hc 1" 37.0 2 5 1. -OCH-CH, tM1 37.0 11 58772

Finnish Pat. Compounds according to 1193/73 ** CH-CH ~ N — CH, -OCH-CH, ¢ 5 ^ 2 10 +++ 42.0 2 * v - £ c (ch3) 3 "++ 50.0 i • -OCHoCH-CH- * "" ". -------------- -.....: ........ * \ · ......... .λ .. ..... ....

“3 ......... .CH, · - <x {c» 3 * * C2 »5 -OCHjCHjOCHjCHjCHj * * * 23.5 -OC2H5 O If 25.3 ..... 48 · 1.

• · ^ Y <X: H3 · ++ 28.0 Χ ° * Η3 • -och3 O "f S3 * 4

Or ^ 1 10 H- 18.0 j £ ci Q i f 43.1 'ί ^ -ΝΟ. 10 ♦ + 20 · 5 * ¢ ^ 2 · · 53.0 'i®2 "Q 0.3 + 76.6 - ^ HCH2N-CH3" Q, m 10 ff 10.3 ch3 χη3 2 "CH2CH2,, vCH3 -CH3 Qr ^ V * + 85.0 ^ 3 9 * 1 * «♦ ^: rtton -CH2CH2N ~ CH3 -OCHj (Π) · 0.3 · 25.0 ^ 3.

·% 12,58772

Compounds of the invention -CH 2 CH 2 N -H-OCH 2 (Qf 30 444 16.0

T

-CH-CH-H — CH- ·. 200 4444 20.7

? XCH 1-Q

-CH2CH2Nv "C2H5 -OCH-CH3" 1 1 1. 13.5 \ η ^ © «3 -CB2CH2N-CH3 · 7 · 4 N« 2 - ^ "CB3 -CH-CH-N-CH--OC-H. 1 "1 0.6 N · ^ © -OCHj -CH, CH, N — CH, -OCB, 1 1 1 1 · 1 2 2 \ cb2-0-ci -CH2CH2CH2N-CH3 -OC ^ -CH3" "9.7 \ h2 -® ch3 -CR2Cn2U-CH2 -OCHj 1 1 "16.5 ^ 2" 1® -CH2CH2N-CH3 -OCHj (pLCp 30 444 23.7

Nch2- © 2 · (φΓ ° 13 1 1 16.0 • t £ - „o2 200 1tt + '• -CH2CHjH-CH3 -OfCBj 1¾ · 0.6 CHj- © CH3. 1 ^ fCH3 100 444 40.7 -CH5CH9N — CH- · · 1 50.0 2'c4 © -.ci 1 1 Papaverin 1..

* 2 · f: 5-10 min. 14: 10-20 min. 444: 20-30 min. 4 + 44 · 30-50 min.

i3 5 87 72

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 in an oil bath. Treatment of the product as in Example 2 below gave 2.5 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester 3-3 - (n-benzyl-n-methylamino) ethyl ester hydrochloride.

Elemental analysis for C28H34N34N3O6 (+): C (%) H (%) N (%) Cl (%)

Calculated: 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 N-benzyl-N-methylaminoethyl ester of acetoacetic acid, 2.3 g of methyl ester of β-aminocrotonic acid and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100 ° C in an oil bath. The reaction mixture was chromatographed on a silica gel column (diameter 4 cm, height 25 cm) and then eluted with a 20: 1 mixture of chloroform and acetone. The eluent containing the desired product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone, and the pH of the solution was adjusted to 1-2 with an ethanolic 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 3-5- (N-benzyl-N -methylamine-amino) ethyl ester hydrochloride. The product thus obtained was crystallized from a gun-Toni-ether mixture.

Melting point: 136-140 ° C (decomposes)

Elemental analysis for C26H30N3C6Cl2: C (%) H (%) N (%) Cl (%)

Calculated: 60.52 5.86 8.14 6.87

Found: 60.25 5.87 7.88 6.67

Example 3 58772 a) 82 g of crude m-nitrobenzaldehyde, 135 g of crude acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and 63 g of crude 3-aminocrotonic acid methyl ester were dissolved in 340 ml of isorpopyl alcohol under reflux for stirring for 6 hours. . After the reaction, 580 ml of methylene chloride was added to the reaction mixture. The solution was washed with a hydrochloric acid solution containing 92 ml of concentrated hydrochloric acid and 320 ml of water, then with 240 ml of water and then with a brine solution containing 40 ml of concentrated hydrochloric acid and 240 ml of water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off.

To the residue thus obtained was added 1500 ml of ethyl acetate, and the solution was stirred overnight at room temperature. The precipitate thus formed was collected and washed with ethyl acetate. Thus, 200 g of crystals were obtained.

b) -130 g of the crystals thus obtained 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 of the suspension was separated and washed twice with 360 ml of water, then once with a hydrochloric acid solution containing 22 ml of concentrated hydrochloric acid and 360 ml of water, and then 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-freezing to give 93 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester 3-8- (N-benzyl Β-type crystals of -N-methylamino) ethyl ester hydrochloride with a melting point of 168-170 ° C.

b) -2,100 g of crystals obtained in the same manner as in step a) were suspended in 700 ml of methylene chloride, and 340 ml of water were added to the suspension, followed by stirring for 30 minutes. The organic layer of the suspension was separated and washed twice with 270 ml of water and once with a hydrochloric acid solution containing 16 ml of concentrated hydrochloric acid and 270 ml of water, followed by drying over anhydrous sodium sulfate. The solvent was distilled off, and the caramel-like residue thus obtained was dissolved in 500 ml of acetone. The solution was allowed to stand overnight at room temperature. The precipitate thus formed was collected and washed with acetone to give 70 g of α-type crystals of the product, 58772, melting point 179-181 ° C.

2.0 g of the crystals thus obtained were dissolved in 6 ml of methanol, and the solution was concentrated under 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 thus obtained 1.5 g of the desired product, m.p. 168-170 ° C.

Example 4

A mixture of 4.2 g of β- (N-methyl-N-phenylamino) ethyl ester of acetoacetic acid, 2.05 g of methyl ester of β-aminocrotonic acid and 2.68 g of m-nitrobenzaldehyde was stirred for 5 hours at 100 ° C in an oil bath. The reaction mixture was chromatographed on a silica gel column (diameter 4 cm, height 25 cm) and eluted with a 20: 1 mixture of chloroform and acetone (v / v). The eluent was checked by thin layer chromatography. The eluent containing the desired product was collected and concentrated under reduced pressure, whereupon the desired product crystallized. 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'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester-3- 6- (n-methyl-n-phenyl) aminoetyyliesteriä.

Melting point: 135-138 ° C

Elemental analysis for C25H27N3Cl: C (%) H (%) N (%)

Calculated: 64.50 5.85 9.03

Found: 64.48 5.81 8.95

Example 5 4.4 ml of β- (N-Benzyl-N-methylamino) ethyl ester, 2.6 g of β-aminocrotonic acid isopropyl ester and 2.7 g of o-nitrobenzaldehyde were dissolved in 3 ml of isopropanol. The solution thus prepared was heated at 80 ° C for 5 hours. The reaction mixture was dissolved in 50 ml of chloroform, and the solution was washed with 20 ml of 10% hydrochloric acid, 20 ml of water, 30 ml of 10% aqueous sodium hydroxide solution, and 20 ml of water. The formed chloroform layer was separated, dried over anhydrous magnesium sulfate. Chloroform was distilled off under reduced pressure. The resulting residue was dissolved in a small amount of chloroform, and the resulting solution was chromatographed on a silica gel column (diameter 3 cm, height 30 cm). The product was eluted with a 20: 1 mixture of chloroform and acetone (v / v). The eluent was checked by thin layer chromatography. The eluent containing the desired product was collected and concentrated under reduced pressure to give 2.2 g of 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester-3-6 n-benzyl-n-methyl-amino) ethyl ester. The product was dissolved in acetone and the solution was neutralized 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 (decomposes)

Elemental analysis for C 28 H 34 N 3 O 6 Cl; C (%) H (%) N (%) Cl (%)

Calculated: 61.82 6.30 7.72 6.52

Found: 61.63 6.25 7.65 6.73

Example 6 In 5 ml of isopropanol were dissolved 5.0 g of acetoacetic acid γ- (N-Benzyl-N-methylamino) propyl ester, 2.7 g of β-aminocrotonic acid isopropyl ester and 2.9 g of m-nitrobenzaldehyde. The solution was heated at 80 ° C for 5 hours.

Treatment of the reaction mixture thus obtained as in Example 5 gave 3.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester-3-γ- (n-benzyl-n-me-methylamino) propyl. The hydrochloride of this compound had a melting point of 166-169 ° C (decomposes).

Elemental analysis C ^ gH ^ gN ^ OgCl: C (%) H (%) N (%) Cl (*)

Calculated: 62.41 6.50 7.53 6.35

Found: 62.35 6.39 7.41 6.55 i7 58772

Example 7 4.0 g of acetoacetic acid β- (N-Benzyl-N-methylamino) ethyl ester, 2.1 g of β-aminocrotonic acid ethyl ester, 2.4 g of m-nitrobenzaldehyde were dissolved in 3 ml of isopropanol. The solution was then heated at 80 ° C for 5 hours.

Treatment of the product obtained as in Example 5 gave 1.5 g of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-ethyl ester-3-3- (n-benzyl-n-methylamino) -ethyl ester. The results of the elemental analysis of the product hydrochloride are shown below:

Elemental analysis C 1 -C 10 H 2 N 2 O 2 Cl: C (%) H (%) N (%) Cl (%)

Calculated: 61.19 6.09 7.93 6.69

Found: 61.43 6.33 7.66 6.59

Example 8 No isopropyl alcohol was dissolved in 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. The resulting solution was stirred for 6 hours at 85 ° C.

The reaction mixture was cooled, dissolved in 10 ml of chloroform, and the solution was washed once with excess dilute hydrochloric acid and then three times with 7 ml of water. The formed chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform was distilled off. The residue was stirred with 15 ml of ethyl acetate and stirred, whereupon the product crystallized. The product was separated, dried and recrystallized from acetone to give 2.4 g of crystalline 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester. -β- (N-benzyl-N-methylamino) ethyl ester hydrochloride. Melting point: 128-132 ° C (decomposes)

Elemental analysis for C 29 H 28 N 2 O 9 Cl, 1 H CH 2 COCH 2: C (%) H (%) N (%) Cl (%)

Calculated: 60.60 6.10 7.71 6.50

Found: 60.61 6.14 7.46 6.71

Example 9 18,58772 In 20 ml of isopropyl alcohol were dissolved 5.0 g of g-aminocrotonic acid g-dimethylaminoethyl ester, 7.2 g of acetoacetic acid (N-benzyl-N-methylamino) ethyl ester and 4.3 g of m-nitrobenzaldehyde. 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 50 ml of water. All extracts were combined and the solution was made alkaline with dilute aqueous sodium hydroxide solution, after which the product was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography using ethyl acetate as an eluent. The desired fractions were collected. The mixture was concentrated, acidified with hydrochloric ethanol, and then the solvent was distilled off. 4.0 g of a crystalline powder of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-g- (N-benzyl) were obtained. N-methylamino) ethyl ester-5- (β-Ν, Ν-dimethylamino) ethyl ester.

Elemental analysis for C 29 H 39 N 4 O 6 Cl 2: C (%) H (%) N (%) Cl (%)

Calculated: 57.14 6.28 9.18 11.63

Found: 57.02 6.56 8.93 11.83

Example 10 To 12 ml of isopropyl alcohol was dissolved 4.0 g of 8- (N-benzyl-N-methylamino) ethyl ester of acetoacetic acid, 1.22 g of m-nitrobenzaldehyde and 1.3 ml of ammonia water. The resulting solution was stirred for 6 hours at 85 ° C. Treatment of the resulting reaction mixture as in Example 9 gave 3.0 g of a crystalline powder which was 2,6-dimethyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bi s / g- ( N-benzyl-N-methylamino) ethyl / ester hydrochloride a.

Elemental analysis ^ 35 ^ 2 ^ ^ 6 ^ 2: C (%) H (%) N (%) Cl (%)

Calculated: 61.31 6.17 8.17 10.34

Found: 61.06 6.20 7.95 10.22 i9 58772

Example 11 2.2 g of acetoacetic acid β-chloroethyl ester, 6.6 g of m-nitrobenzaldehyde and 5.2 g of β-aminocrotonic acid ethyl ester were dissolved in 7 ml of isopropanol. The solution was heated at 80 ° C for 4 hours. The reaction mixture was cooled, the formed crystals were collected by filtration and recrystallized from methanol to give 3.5 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid. -3-8-chloroethyl ester-5-ethyl ester.

Melting point: 164-165 ° C.

Elemental analysis ^ Ig ^ i ^ OgCl: C (%) H (%) N (%) Cl (%)

Calculated: 55.76 5.16 6.85 8.69

Found: 55.55 5.00 6.58 8.83

Example 12 (a) In 5 ml of isopropanol were dissolved 3.0 g of 8-chloroethyl acetoacetate, 3.3 g of m-nitrobenzaldehyde and 2.3 g of methyl 8-aminocrotonate. The solution was heated at 80 ° C for 4 hours.

The resulting reaction mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of ethyl acetate, and the solution was chromatographed on a silica gel column (diameter 3.3 cm, height 20 cm). The product was eluted with ethyl acetate. The eluates 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-β-chloro. ethyl ester 5-methyl ester.

Melting point 130-131 ° C.

Elemental analysis for C 18 H 19 N 2 O 6 Cl 2: C (%) H (%) N (%) Cl (%)

Calculated: 54.76 4.85 7.10 8.95

Found: 54.43 4.74 6.91 9.18 (b) 2.0 g of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyride was dissolved in 6 ml of toluene. .ini-3,5-dicarboxylic acid 3-8-chloro ethyl ester-5-methyl ester and 1.3 g of N-methylbenzylamine. A solution of Form -205 8772 was refluxed under heating for 5 hours. . After the reaction, 30 ml of chloroform and 10 ml of water were mixed with the reaction mixture. The resulting organic layer was separated and washed with 10 ml of 10% hydrochloric acid and then with water. The obtained organic solvent solution 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 give 2,6-dimethyl-4- (31-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β- (N-benzylic acid). N-methylamino) ethyl ester-5-methyl ester hydrochloride crystallized. The amount of product obtained was 1.6 g. The product was recrystallized from methanol-acetone.

Melting point 180-181 ° C.

Elemental analysis for C 26 H 30 N 3 O 6 Cl: 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'-nitrophenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid 3-8-chloroethyl ester-5-methyl ester, 1.2 g of benzylamine and the solution were refluxed for 3 hours. After the reaction, 30 ml of chloroform and 10 ml of water were mixed with the reaction mixture. The formed organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was chromatographed on a silica gel column (diameter 4 cm, height 25 cm) and the product was eluted with a 10: 1 (v / v) mixture of benzene and acetone. The eluate containing the desired product was checked by thin-layer chromatography, collected and concentrated under reduced pressure to give 0.8 g of a crystalline powder of 2,6-dimethyl.-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid. -3-8- (N-benzylamino) ethyl ester-5-methyl ester.

Elemental analysis for C 25 H 27 N 3 O 6: C (%) H (%) N (%)

Calculated: 64.50 5.85 9.03

Found: 64.41 5.72 8.85 2i 5 8772

The hydrochloride of the product was prepared by treating it with alcoholic hydrochloric acid. The hydrochloride had a melting point of 128-130 ° C (decomposes)

Example 13 (a) In 10 ml of isopropanol were dissolved 3.32 g of acetoacetic acid β-chloroethyl ester, 3.0 g of m-nitrobenzaldehyde and 2.86 g of β-aminocrotonic acid isopropyl ester. The solution was refluxed for 5 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel. The product was eluted using a 10: 1 mixture of chloroform and acetone (v / v). The eluates containing the desired product were collected, the solvent was distilled off from the solution, and the formed crystals were recrystallized from a mixture of chloroform and ether. 2,6 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β-chloroethyl ester-5-isopropyl ester were obtained. Melting point: 140-145 ° C.

Elemental analysis for C 20 H 25 N 2 O 6 Cl 2: C (%) H (%) N (%) Cl (%)

Calculated: 56.81 5.48 6.62 8.38

Found: 56.52 5.22 6.46 8.63 (b) In 6 ml of toluene was dissolved 2.0 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-hydropyridine-3, 5-Dicarboxylic acid 3-6-chloroethyl ester-5-isopropyl ester and 1.4 g of N-ethylbenzylamine. The solution was refluxed for 5 hours. After the reaction, 30 ml of chloroform and 10 ml of water were mixed with the reaction mixture. The formed organic layer was separated, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column (diameter 4 cm, height 25 cm). The product was eluted using a 10: 1 mixture of benzene and acetone (v / v), and the eluates containing the desired product were collected and concentrated in vacuo. The resulting residue was dissolved in ethanol and acidified with an ethanolic solution of hydrochloric acid. The solution was concentrated under reduced pressure. The product obtained by crystallization from a mixture of chloroform and ether gave 1.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-6- (N-benzyl-N- ethyl-amino) ethyl ester 5-isopropyl ester hydrochloride.

Melting point: 132-135 ° C.

22 5 8 7 7 2

Elemental analysis for C 29 H 36 N 3 O 6 Cl 2: C (%) H (%) N (%) Cl (%)

Calculated: 62.41 6.50 7.53 6.35

Found: 62.30 6.38 7.49 6.41

Example 14

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

After the reaction, the reaction mixture was chromatographed on a silica gel column (diameter 4 cm, height 25 cm). The product was eluted with a 20: 1 mixture of chloroform and acetone, (v / v), and the eluates containing the desired product were checked by thin layer chromatography, collected and concentrated to give 2,6-dimethyl-4- (31-nitrophenyl) -1 , 4-dihydropyridine-3,5-dicarboxylic acid-5-isorpopyyliesteri-3-g- (n-methyl-Np-methyl-benzylamino) -ethyl ester.

The product was dissolved in acetone and the pH of the resulting solution was adjusted to 1-2 with ethanolic solution saturated with hydrogen chloride. The solution was concentrated. The resulting residue was dissolved in a small amount of acetone, and 4 g of powdered 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-isopropyl ester-3-β- ( n-methyl-Np-methylbenzylamino) etyy1ies-ester-hydrochloride.

Elemental analysis ^ 29 ^ 36 ^ 3 ^ 6 ^ ^ C (%) H (%) N (%) Cl (%)

Calculated: 62.41 6.50 7.53 6.35

Found: 62.61 6.69 7.23 6.35

Example 15

A mixture of 5.0 g of acetoacetic acid β- (N-methyl-N-p-methoxy-benzylamino) ethyl ester, 2.4 g of β-aminocrotonic acid ethyl ester and 2.4 g of m-nitrobenzaldehyde was treated for 5 hours at 85 ° C. Subsequent work-up of the reaction mixture as in Example 14, 23,58772, gave 4.1 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-5-ethyl ester-3- Q- (N-methyl-Np-methoxybenzylamino) ethyl ester.

The NMR spectrum of this product corresponded to its chemical structure. Elemental analysis C (%) H (%) N (%)

calculated; 64.23 6.35 8.03

Found: 64.01 6.41 7.85

Example 16

A mixture of 1.5 g of m-nitrobenzaldehyde, 2.8 g of acetoacetic acid β- (N-methyl-Np-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 from the reaction mixture under reduced pressure, the residue was chromatographed on a silica gel column, and the product was eluted with a 10: 1 mixture of benzene and acetone (v / v). The eluates containing the desired product were collected and the solvent was distilled off. The resulting residue was dissolved in ethanol, and the solution was acidified with 1 N hydrochloric acid in ethanol. Ethanol was removed under reduced pressure. The resulting residue was dissolved in a small amount of acetone and ether was added until the solution became cloudy. The solution was allowed to stand at 0 ° C to give 2.8 g of pale yellow needle-like crystals of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-ethyl ester. 3-8 (n-methyl-Np-chlorobenzylamino) -etyyliesterihydrokloridia.

Melting point: 135-139 ° C (decomposes)

Elemental analysis ^ 7 ^ ^ 3 ^ 6 ^ 2 5 C (%) H (%) N (%) Cl (%)

Calculated: 57.45 5.54 7.44 12.56

Found: 57.10 5.62 7.35 12.77

Example 17 To 20 ml of isopropyl alcohol was dissolved 7.0 g of acetoacetic acid B- (N-methyl-Np-methoxybenzylamino) ethyl ester, 2.0 g of m-nitro-24 5 8 7 7 2 benzaldehyde and 2.2 ml of 28% ammonia water. . The solution was stirred for 6 hours at 85 ° C. The reaction mixture was dissolved in ethyl acetate and extracted once with excess dilute hydrochloric acid and then three times with water. The extracts were combined and basified with dilute aqueous sodium hydroxide solution. The product was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was chromatographed on a silica gel column and the product was eluted with ethyl acetate to purify it. Fractions of the desired product were collected and concentrated. The residue was acidified with 1N ethanolic hydrochloric acid solution, and the solvent was distilled off under reduced pressure to give 5.0 g of crystalline powdered 2,6-dimethyl-4- (31-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid bis. / 3- / n-methyl-Np-me-toksibentsyyliamino) ethyl / ester dihydrochloride.

Elemental analysis for C37H46N4®8 <"^ 2: C (%) H (%) N (%) Cl (%)

Calculated: 59.60 6.22 7.51 9.51

Found: 59.55 6.03 7.79 9.69

Example 18 1.6 g of o-trifluoromethyl-benzaldehyde, 1.6 g of O-aminocrotonic acid β- (N-benzyl-N-ethylamino) ethyl ester and 0.9 g of acetoacetic acid propoxyethyl ester were dissolved in 3 ml of isopropyl alcohol. The solution was stirred for 14 hours at 85 ° C. The reaction mixture was concentrated, the residue was dissolved in a small amount of a 20: 1 mixture of chloroform and acetone (v / v), and the solution was chromatographed on a silica gel column (diameter 3.5 cm, height 20 cm). The product was eluted with a 20: 1 (v / v) mixture of chloroform and acetone and the eluates containing the desired product were checked by thin layer chromatography, collected and concentrated to give 0.6 g of 4- (2-trifluoromethylphenyl) -2,6-dimethyl-1,4 dihydropyridine-3,5-dicarboxylic acid A-3-β- (n-benzyl-n-ethylamino) ethyl-5-B-propok sietyyliesteriä.

Elemental analysis for C 32 H 39 N 2 O 5 F 3: C (%) H (%) N (%)

Calculated: 65.23 6.68 4.76

Found: 65.37 6.89 4.82 25 58772

Example 19 To 3 ml of isopropyl alcohol was dissolved 1.07 g of 3- (N-methyl-N-p-methylbenzylamino) ethyl ester of acetoacetic acid, 0.466 g of methyl ester of 3-aminocrotonic acid, and 0.705 g of m-trifluoromethylbenzaldehyde. The solution was refluxed for 6 hours. The reaction mixture was concentrated, chromatographed on a silica gel column (diameter 4 cm, height 15 cm) and the eluates containing the desired product were collected and concentrated. The obtained residue was dissolved in acetone, and the pH of the solution was adjusted to 1-2 with an ethanolic solution saturated with hydrogen chloride. The solution was concentrated. Crystallization of the residue formed with acetone gave 0.8 g of 2,6-dimethyl-4- (3'-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 5-methyl ester 3-3- (N-methyl- Np-methyl-benzylamino) ethyl ester hydrochloride. Elemental analysis for C 28 H 32 N 2 O 4 F 3 Cl 2: C (%) H (%) N (%) Cl (%)

Calculated: 60.81 5.83 5.07 6.41

Found: 61.11 6.01 5.35 6.67

Example 20

A mixture of 1 g of acetylacetone, 0.75 ml of concentrated ammonia rock, 1.5 g of m-nitrobenzaldehyde, 2.5 g of 3- (N-benzyl-N-methylamino) ethyl ester of acetoacetic acid and 5 ml of ethanol was heated for 4 hours. 90 ° C. After the solvent was distilled off from the reaction mixture under reduced pressure, the residue was dissolved in 10 ml of ethyl acetate, and the product was extracted with 2N hydrochloric acid solution. The extract was neutralized with sodium carbonate and the product was extracted with ethyl acetate. The solvent was distilled off from the extract under reduced pressure, and the resulting residue was dissolved in 3 ml of ethanol. The solution was acidified with 2N ethanolic hydrogen chloride solution, ethyl acetate was added to the solution until cloudy, and the solution was allowed to stand for 20 hours at 0 ° C.

5-Acetyl-2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid 3 '(N-benzyl-N-methylamino) ethyl ester hydrochloride was obtained as 1.4 g of yellow needles. crystals.

Melting point: 154-157 ° C (decomposes)

Elemental analysis for C 26 H 30 N 3 O 5 Cl: C (%) H (%) N (%) Cl (%)

Calculated: 62.46 6.05 8.40 7.09

Found: 62.75 6.21 8.22 6.99 26 58772

Example 21 To 1 g of acetylacetone were added 0.75 ml of concentrated ammonia water and 5 ml of ethanol. The mixture was stirred for 30 minutes at room temperature to form crystals. To the product were added 1.5 g of m-nitrobenzaldehyde and 2.8 g of acetoacetic acid B- (N-p-chlorobenzyl-N-methyl) ethyl ester. The mixture was heated at 95 ° C for 4 hours. 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 10: 1 mixture (by volume) of benzene and acetone, the eluates were collected and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol and the solution was acidified with 2N ethanolic hydrogen chloride solution. Ethyl acetate was added to the solution until cloudy. The solution was allowed to stand for three days at 0 ° C to give 1.2 g of 5-acetyl-2,6-dimethyl-4- (3'-nitrotenyl) -1,4-dihydropyridine-3-carboxylic acid-8 · - ( Np-chloro-benzyl-N-methylamino) ethyl ester hydrochloride as yellow needle-like crystals.

Melting point: 145-150 ° C (decomposes)

Elemental analysis for C 26 H 29 N 3 O 5 Cl: C (%) H (%) N (%) Cl (%)

Calculated: 58.43 5.47 7.88 13.27

Found: 58.65 5.59 7.68 13.10

Example 22 5.0 g of β-aminocrotonic acid N-Benzyl-N-methylaminoethyl ester, 3.1 g of m-nitrobenzaldehyde and 2.0 g of acetylacetone were dissolved in 15 ml of isopropanol. The solution was stirred for 4 hours at 85 ° C. The reaction mixture was dissolved in 40% ethyl acetate and the product was extracted with excess dilute aqueous hydrochloric acid and three more times with 40 ml of water. The aqueous extracts were combined and 10 g of sodium chloride was dissolved in the extract. The resulting oily substance was extracted four times with 50 ml of chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The residue was dissolved in acetone, and acetone was added to the solution to give 5.0 g of 5-acetyl-2,6-dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3-carboxylic acid-3- (N -benzyl-N-methylamino) ethyl ester hydrochloride as yellow needle-like crystals.

27 o 58772

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

Example 23 2.9 g of 2-amino-2-penten-4-one, 4.41 g of m-nitrobenzaldehyde and 7.7 g of 8- (N-benzyl-N-methylamino) ethyl ester of acetoacetic acid were dissolved in 20 ml of isopropyl alcohol. The solution was refluxed for 6 hours. To the reaction mixture was added 70 ml of ethyl acetate, and the pH of the solution was adjusted to 1-2 with 2 N hydrochloric acid. The formed aqueous layer was separated. The resulting ethyl acetate layer was extracted twice with water. The aqueous layers were combined and saturated with sodium chloride. The product was extracted twice with chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate and concentrated. When a small amount of ethanol was added to the concentrate, crystals formed which were collected by filtration and crystallized from ethanol to give 7 g of 5-acetyl-2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid - and - (N-benzyl-N-methylamino) -ethyl ester hydrochloride.

Melting point: 147-152 ° C (decomposes)

Elemental analysis for C 26 H 30 N 3 O 5 Cl.C 2 H, -OH: C (%) H (%) N (%) Cl (%)

Calculated: 61.77 6.62 7.67 6.79

Found: 61.59 6.65 7.70 6.49

Example 24 To 3 ml of isopropanol was dissolved 1.18 g of N-benzyl-N-methylaminoethyl ester of acetoacetic acid, 0.48 g of 2-amino-2-penten-4-one, and 0.83 g of trifluoromethylbenzaldehyde. The solution was refluxed for 6 hours.

The reaction mixture was concentrated and the residue was chromatographed on a silica gel column (diameter 4 cm, height 15 cm). The product was eluted with a 22: 1 mixture of chloroform and acetone (v / v), and the eluates containing the desired product were checked by thin layer chromatography, collected and concentrated. The resulting residue was dissolved in acetone, and the pH of the solution was adjusted to 1-2 with an ethanolic solution saturated with hydrogen chloride. The solution was concentrated. The formed crystals were recrystallized from acetone to give 1.3 g of 5-acetyl-2,6-dimethyl-4- (3'-trifluoromethylphenyl) -1,4-dihydropyridine-3-carboxylic acid β- (N-benzyl-N- methylamino) ethyl ester hydrochloride 28,58772.

Melting point: 168-169 ° C (decomposes)

Elemental analysis ^ 7 ^ 301 ^ ^ 5 ^^ C (%) H (%) N (%) Cl (%)

Calculated: 62.01 5.78 5.36 6.79

Found: 62.30 5.90 5.33 6.95

Example 25

A mixture of 1.0 g of ό-trifluoromethylbenzaldehyde, 1.6 g of acetoacetic acid β- (N-benzyl-N-methylamino) ethyl ester and 700 μl of β-aminocrotonic acid methyl ester was stirred for 6 hours at 110-120 ° C. The reaction mixture was dissolved in a small amount of a 20: 1 mixture of chloroform and acetone (v / v); The solution was treated on a silica gel column (diameter 3.5 cm, height 20 cm) and the product was eluted with a 20: 1 mixture of chloroform and acetone (v / v). The eluates containing the desired product were checked by thin layer chromatography, collected and concentrated. The residue was dissolved in a small amount of acetone and the solution was acidified with an ethanolic solution saturated with hydrogen chloride. The solution was concentrated. The resulting residue was treated with a mixture of acetone and ether and crystallized to give 0.7 g of 2,6-dimethyl-4- (o-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β- (N-benzyl). -N-methylamino) ethyl ester 5-me-ester-hydrochloride.

Melting point: 182-192 ° C.

Elemental analysis C 2 H 3 N 2 O 2 F 3 Cl: C (%) H (%) N (%) Cl (%)

Calculated: 60.17 5.61 5.20 6.58

Found: 59.93 5.86 5.48 6.90

Example 26 To 3 ml of isopropyl alcohol were dissolved 1.18 g of acetoacetic acid (R, N-benzyl-N-methylamino) ethyl ester, 0.55 g of β-aminocrotonic acid methyl ester and 0.3 g of m-trifluoromethylbenzaldehyde. The solution was refluxed for 6 hours. The reaction mixture was concentrated and the residue was chromatographed on a silica gel column (diameter 4 cm, height 15 cm). The product was then eluted with a 20: 1 (v / v) mixture of chloroform and acetone and the eluates containing the desired product were checked by thin layer chromatography, collected and concentrated.

29 5 8772

The resulting residue was dissolved in acetone, and the pH of the solution was adjusted to 1-2 with an ethanolic solution saturated with hydrogen chloride. The solution was concentrated. Crystallization of the residue thus formed and using ethyl acetate gave 1.3 g of 2,6-dimethyl-4- (m-trifluoromethylphenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-β- (N-benzyl-N- methylamino) ethyl ester 5-methyl ester hydrochloride.

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

Elemental analysis Co-, Ho.N »0 .F-.C1: 27 30 2 4 3 C (%) H (%) N (%) Cl (%)

Calculated: 60.17 5.61 5.20 6.58

Found: 60.47 5.63 5.49 6.71

Example 27 1.07 g of 8- (N-benzyl-N-methylamino) propyl ester of acetoacetic acid, 0.52 g of ethyl 8-aminocrotonic acid and 0.71 g of m-trifluoromethylbenzaldehyde were dissolved in 3 ml of isopropyl alcohol. The solution was refluxed for 6 hours.

The reaction mixture was chromatographed on a silica gel column according to Example 26, 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-dihydropyridine-3.5 -dicarboxylic acid-3- 8- (N-benzyl-N-methylamino) propyl ester-5-ethyl ester. Elemental analysis for C 29 H 33 N 2 O 4 F 3: C (%) H (%) N (%)

Calculated: 65.55 6.27 5.28

Found: 65.45 6.40 5.40

Example 28

A mixture of 1.5 g of 2- (31-nitrobenzylidene) acetoacetic acid 8- (N-benzyl-N-methylamino) ethyl ester, 0.452 g of β-aminocrotonic acid methyl ester and 7 ml of isopropyl alcohol was refluxed with stirring for 6 hours. After cooling, 30 ml of chloroform was added to the reaction mixture, followed by 10 ml of 2N aqueous hydrochloric acid solution. The mixture was shaken in a separatory funnel, washed twice with water, and the formed chloroform layer was separated. The resulting chloroform layer was concentrated. To the resulting residue was added 7 ml of ethyl acetate, and the mixture was allowed to stand overnight to give 1.4 g of crystals of 58772 g. The crystals were dissolved in methanol, and after distilling off the solvent, 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 3-8- (N-benzyl-N-methylamino) ethyl ester-5-methyl tert-hydrochloride a.

Melting point: 180-181 ° C Elemental analysis ^ 26 ^ 30 ^ 3 ^ 6 ^: C (%) H (%) N (%) Cl (%)

Calculated: 60.52 5.86 8.14 6.87

Found: 60.76 5.72 8.04 7.00

Example 29

A mixture of 1.1 g of 2- (3'-nitrobenzylidene) acetoacetic acid 8- (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 refluxed. 5 hours with stirring. After distilling off the solvent, the reaction mixture was treated in the same manner as in Example 28 to give 0.33 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3 8- (n-benzyl-n-methylamino) -etvyliesteri-5-methyl ester hydrochloride.

The IR spectrum of the product was consistent with the IR spectrum of the product obtained in Example 28.

Example 30

A mixture of 2.49 g of 2- (3'-nitrobenzylidene) acetoacetic acid methyl ester, 2.48 g of β-aminocrotonic acid 8- (N-benzyl-N-methylamino) ethyl ester and 8 ml of isopropyl alcohol was refluxed with stirring for 8 hours. After cooling, 100 ml of chloroform was stirred in the reaction mixture to dissolve the product. The solution was washed with 2N aqueous hydrochloric acid solution to give a pH of 1-2 of the formed aqueous layer.

The chloroform solution was washed twice with water, and the resulting chloroform layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was mixed with 20 ml of ethyl acetate to give 3.3 g of crystals. The crystals were dissolved in methanol, and then the solvent was distilled off to obtain a sticky substance. Crystallization of this material from acetone gave 2 g of 2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-8- (N-benzyl). -N-methylamino) ethyl ester 5-methyl ester hydrochloride.

The IR spectrum of the product was consistent with the IR spectrum of the product obtained in Example 28.

Example 31

A mixture of 2.49 g of 2- (3'-nitrobenzylidene) acetoacetic acid methyl ester, 2.49 g of acetoacetic acid 8- (N-benzyl-N-methylaminoethyl ester), 1.18 ml of ammonia water and 10 ml of ethanol was refluxed. After stirring for 6 hours, the reaction mixture was concentrated, the residue was chromatographed on a silica gel column and the desired portions were eluted with a 10: 1 mixture of chloroform and acetone (v / v), and the collected portions were dissolved in chloroform and washed with 2N hydrochloric acid to pH 1-2.

The solution was washed twice with water, and the formed chloroform layer was separated, dried over anhydrous sodium sulfate and concentrated. When ethyl acetate was added to the resulting residue, 1.1 g of crystals formed. The crystals were collected and dissolved in methanol. When the solvent was distilled off from the solution, a sticky substance was obtained. Crystallization of this material in acetone gave 0.7 g of 2,6-dimethyl-4- (3'-nitro-phenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-8- (N-benzyl-N-methylamino). ) ethyl ester-5-methyl ester hydrochloride.

The IR spectrum of this product was consistent with the IR spectrum of the compound obtained in Example 28.

Example 32 In 7 ml of pyridine were dissolved 675 mg of methylamine hydrochloride, 2.43 g of acetoacetic acid 8- (N-benzylmethylamino) ethyl ester, 1.17 g of acetoacetic acid methyl ester and 1.51 g of m-nitrobenzaldehyde. The mixture was heated at 90 ° C for 3 hours. The reaction mixture was cooled, and 30 ml of chloroform was added. Washed successively with 10 ml of water, 10 ml of 2% acetic acid, 10 ml of 3% sodium trioxide and 10 ml of water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated.

32 5 8772

The residue obtained was dissolved in a small amount of an 8: 1 mixture of benzene and acetone (v / v) and chromatographed on a silica gel column (diameter 4 cm, height 25 cm). The eluate was checked by thin layer chromatography and the eluates containing the desired product were collected and the combined eluates were concentrated. The resulting oily substance was dissolved in a small amount of acetone, acidified with ethanolic hydrochloric acid to give 1.1 g of 1,2,6-trimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid. 3-8- (N-benzyl-N-methylamino) ethyl ester-5-methyl ester hydrochloride. Elemental analysis C ^ H ^^ OgCl C (%) H (%) N (%) Cl (%)

Calculated: 61.19 6.08 7.93 6.69

Found: 61.03 6.12 7.72 6.81

Example 33 675 mg of methylamine hydrochloride, 2.48 g of m-nitrobenzylideneacetoacetic acid methyl ester and 2.49 g of acetoacetic acid 6- (N-benzyl-N-methylamino) ethyl ester were dissolved in 7 ml of pyridine. The mixture was heated at 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 3-6- (N- benzyl-n-methylamino) ethyl ester 5-methyl ester hydrochloride. The IR spectrum of the product was identical to that of the product of Example 31.

Claims (5)

33 58772 A process for preparing a cerebrovascular vasodilator 2,6-dimethyl-4-substituted-phenyl-1,4-dihydropyridine-3-carboxylic acid aminoalkyl ester having the formula iTX-R6, / r3 rS ocOL.cooan ^ XX R wherein R is a hydrogen atom or a lower alkyl group; 3 R is a phenyl group or a benzyl group which may be substituted by a p-Cl, p-CH 2 O or p-CH 2 group; is a hydrogen atom or a lower alkyl group; A is a lower alkylene group; R ~ * is a lower alkyl group, a lower alkoxy group which may be substituted by a lower alkoxy group, or a _O_R_R group (wherein A, 34, R and R have the same meaning as above) and is a nitro group or a trifluoromethyl group, characterized in that a) a benzaldehyde derivative of the formula Q- * 6 CHO wherein R is as defined above is reacted with an acetoacetic acid aminoalkyl ester of the formula ch9-co-ch9cooa-n & 0 * 'R wherein R1, R2 and A have the same meaning as above, and with an enamine of the formula CH., -C = CH-COR5 and NH-R wherein e R and R have the same meaning as above, wherein said enamine is prepared by reacting a compound of the formula 34 58772 CH3-CO- CH2-COR5 in which FT is as defined above, to react with a compound of formula R-NH2 in which R is as defined above, or b) a benzaldehyde derivative of the formula in which CHO R1 is as defined above is reacted with β-aminocrotonic acid. an aminoalkyl ester having a k aava is ^ * 3 CH-3-C-CH-COOAN. 3 i \ NH-R where 3 4. R, R, R and A are as defined above, and a β-diketone of the formula ch3-co-ch2cor5 wherein R is as defined above is reacted, wherein said β-aminocrotonic acid aminoalkyl ester is prepared by reacting a compound the formula is - / R CH 2 -COCH 2 COOAN, 1 * ^ R 4 wherein 34 R, R and A are as defined above, and a compound of the formula r-nh 2 wherein R is as defined above, to react, or c) ketone of formula R6 CH = C-COY COCH3 wherein 3 5. K 3 4 5 Y represents a group R or is -O-A-N. (wherein R, R, R and A "R" are as defined above) and R 1 is as defined above, to react with an enamine of formula 35 58772 CH-JC = CH-CO-Z JI NH-R where 3 5 ^ ™ Z represents a group R when the above-mentioned Y is -OAN ^ 4 ^ R3 5 or a group -OAN when the aforementioned Y represents a group R 3 4 5 ^ (where R, R, R and A have the same meaning as above) and R means the same as above, or d) a styryl ketone of the formula R 6 O-CH-C-COY wherein COCH 3 R 1 and Y are as defined above is reacted with a β-dictonone of the formula ch 3 -coch 2 -coz where R ° and Y are as defined above, and with an amine of formula r-nh2 wherein R is as defined above, or e) a benzaldehyde derivative of formula (J5- * 6 wherein CHO R ° is as defined above) is reacted with an enamine of the formula CH - C = CHCOR5 NH-R wherein R and R5 are as defined above, and with an acetoacetic acid haloalkyl ester to which the formula is CH3-CO-CH2COOA-X wherein X is a halogen atom and A is as defined above to give 2,6-dimethyl-4-substituted phenyl-3-carboxylic acid 58772 36 haloalkyl ester and then reacting the product thus obtained with an amine of the formula -R 3 NH "R 4 wherein 3 · 4 R and R are as defined above. 58772 For the preparation of phenylhydrous 2,6-dimethyl-A-substituents phenyl-1,4-dihydropyridine-3-carboxylic aminoaminoalkyl ester, 0-R6 R3 R5OC1 ^ COOAN ^ X <ch3 I CH3 J R3 is a hydrogen atom or an alkyl group; R is an phenyl group or a benzyl group which may be substituted by a p-Cl-, p-CH-O- or p-CH group; R * is not an atom or an alkyl group; A hydrogen is an alkyl group; RJ is an alkyl group, an alkoxy group, which may be substituted with an alkoxy group, or an R 3 4 -O-A-N 2 group (wherein A, RJ and R are as defined); R and R 1 are nitro groups or trifluoromethyl groups, but a) a benzaldehyde derivative having the formula Q-R 6 CHO is the word R is used as a compound, having the form acetoacetyl amino amino alkyl ester, the formula being R CH -CO -CH „-COOA — N ^ 3 3 4 där R och R rhh A betyder satuna som tidigare, och en mostin, vars formula CH -OCH-COR5 NH-R där R och betyder word som somidigare, varvid enaminen har framställts genom The compound of formula R3 NH2, the formula R is NH3, the formula R is NH2, the formula R is NH2, the formula R is NH2, the formula R is NH2, or R) is 9 - ** CHO is R, but the same is selected from the group consisting of B-aminocrotonylaminoalkyl ester, and the formula is R3 X CH-OCH-COOAN 3. \ k NH-R R 3 When R, R, R and A are selected from the group consisting of β-diketone, the same formula as ch3-co-ch2-cor5 to which R ^ betyder is selected from the group consisting of β-aminocrotonsyrra-aminoalkyl esters and framställts genome att l & ta en förening, vars formel är R3 CH -COCH -COOAN 3 3 \ B <. 3 1 *. . ... for R, R and A is a compound of the same formula as och and forenmg, the formula is R-nh2 for R is the same as the formula, a reagent, or c) a styrene ketone, the formula is R6 - CH = C-COY coch3 R3 3 ä 5 aär Y betyder grupp R '* eller är -OAN. (wherein R, R, R5 and A are the same as ^ R in each case) and R is the same as the same as in the same case, For the most important reagent, the formula is CH-OCH-CO-Z 3 · NH-R