JPS6256473A - Novel 1,4-dihydropyridine derivative and salt thereof, production thereof and agent, acting on cardiovascular system and containing said compound as active constituent - Google Patents

Abstract

NEW MATERIAL:A 1,4-dihydropyridine derivative expressed by formula I (either one of R1 and R2 is H, and the other is nitro; R<3> is alkoxycarbonyl R<4> is alkoxycarbonyl, alkoxycarbonyl having nitrogen atom-containing heterocylclic ring or alkoxycarbonyl or alkyl having phosphorus atom-containing substituent group, R<5> and R<6> are alkyl or alkyl having phosphorus atom-containing substituent group, provided that R<3> and R<4> do not mean alkoxycarbonyl at the same time except when R<6> means alkyl having phosphorus-atom containing substituent group) and a salt thereof. EXAMPLE:3-Dimethylphosphonylmethyl 5-methyl 1,4-dihydro-2,6-dimethyl-4-(2- nitrophenyl)-3,5-pyridinecarboxylate. USE:Useful as an agent for cardiovascular systems having slight cardiotonic action and great lasting property. PREPARATION:Compounds expressed by formulas II, III and IV are reacted to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to novel high-dihydropyridine derivatives and salts thereof, processes for producing them, and circulatory system active agents containing these compounds as active ingredients.

(Prior Art) It has been known for some time that 1,4-dihydropyridine derivatives have a calcium antagonistic effect and are useful as active ingredients of cardiovascular system agents, that is, therapeutic agents for cardiovascular diseases. Ta. In particular, 1,4-dihyro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-bilimicumcargonic acid dimethyl ester (generic name, nifedipine) has a coronary vasodilatory effect and a blood pressure lowering effect. It is known as a useful compound with various effects (W, Vater et al.
Arzneim, -Forscb.

(Drug Res, ) Vol. 22, p. 1, 1972].

(Problems to be Solved by the Invention) Although the above-mentioned nifedipine has the advantage of having a strong pharmacological effect, it also has a problem in that it has high hair properties.

Furthermore, known 1,4-dihydropyridine derivatives generally have a problem in that they have a cardiac contraction inhibitory effect as a side effect.

Therefore, the present invention provides a compound that is excellent in coronary vasodilatory effect and blood pressure lowering effect, has low toxicity, does not exhibit cardiac systolic depressant effect, but rather has mild cardiotonic effect, and thereby The purpose of this invention is to solve the above-mentioned problems of high-dihydropyridine calcium antagonists.

(Means for solving the problem) According to the present invention, the above problem is solved by the formula (wherein one of R and R means hydrogen, the other means a nitro group, and R means an alkoxycarbonyl group, R means an alkoxycarbonyl group, an alkoxycarbonyl group having a nitrogen-containing heterocycle, an alkoxycarzanyl group having a phosphorus-containing substituent, or an alkylaminocarbonyl group having a phosphorus-containing substituent, and R and 1°C are means an alkyl group or an alkyl group having a phosphorus-containing substituent; provided, however, that both R3 and R4 do not mean an alkoxycarbonyl group, unless R means an alkyl group having a phosphorus-containing substituent) The above object of the present invention is achieved by the novel 1,4-dihydropyridine derivative and its salt shown in .

In the above compounds according to the invention, substituents R3 and R4
The alkoxycarbonyl group is a methoxycarbonyl group,
Ethoxycarvinyl group, cycloglobylmethyloxycarbonyl group, etc., and alkoxycarbonyl group having a nitrogen-containing heterocycle include pyrrolitinon-7a-ylmethyloxycarbonyl group, 2-(pyrrolitidin-7a-yl)ethyloxycarbonyl group, etc. ? An alkoxycarbonyl group having a phosphorus-containing substituent is a group having 1 to 4 carbon atoms.
A phosphonylmethyloxycargenyl group having the above alkyl group as an ester moiety, (2-phosphonylethyl)
Oxycarbonyl group, (3-phosphonylpropyl)oxycarbonyl group, etc., phosphinoylmethyloxycarbonyl group having an alkyl group having 1 to 4 carbon atoms, (2-
phosphinoylethyl)oxycarbonyl a,, (3-
phosphinoylglobyl)oxycarbonyl a, etc., and an alkylaminocarbonyl group having a phosphorus-containing substituent means a phosphonylmethylaminocarbonyl group having an alkyl group having 1 to 4 carbon atoms as an ester moiety; (2
-phosphonylethyl)aminocarbonyl group, (3-phosphonylpropyl)aminocarbonyl group, etc., and carbon number 1-4
Phosphinoylmethylaminocarzenyl group having an alkyl group up to, (2-phosphinoylethyl)aminocal d? nyl group, (3-phosphinoylglobyl)-aminocarbonyl group, etc., and the alkyl group of substituents R5 and R6 means a methyl group, ethyl group, etc., and an alkyl group having a phosphorus atom substituent. The group refers to a phosphonylmethyl group having an alkyl group having up to 1 to 4 carbon atoms as an ester moiety, a 2-
It means phosphonylethyl M, 3-phosphonylethyl group, etc., phos-2-ynoylmethyl group, 2-phosphinoylethyl group, 3-phosphinoylpropyl group, etc. having an alkyl group having 1 to 4 carbon atoms.

According to the method of the present invention, the compound represented by the above formula I can be produced according to any of the following routes. The blending molar ratio of the raw material compounds in route 1 is Z: o,
tt: o, s to 1: 1,5: about 1,5, and routes 2 to 4 about 1:1,5.

The reaction can be carried out without solvent or in methanol, ethanol,
In the presence of alcohols such as inglopanol and butanol, aromatic hydrocarbons such as benzene and toluene, aprotic polar interrogators such as dimethylformamide, or water,
The temperature is about 150°C.

Separation of the target compound from the reaction mixture can be carried out by operations such as concentration, extraction, column chromatography, and recrystallization.

Root l (■) (111) (IV) (R1 in the formula
, R2, R3 and R6 have the above-mentioned meanings, and R4' is an alkoxycarboxylic group having a nitrogen-containing heterocyclic ring, an alkoxycarbonyl group having a phosphorus-containing substituent, or an alkylamino group having a phosphorus-containing substituent. Cal? R5' means an alkyl group) The aldehyde of the formula (1), which is the starting compound in this route, can be one that is well known per se;
Angyal r Org, Reactions
It can be synthesized according to the method disclosed in J Vol. The other starting compounds, the enaminoesters of 2.
, C., Coper J., Am., Cham., So.
e, J Vol. 67, p. 1017 (1945). Furthermore, the ester of the formula (1), which is another raw material compound, is also well known per se or, for example, Oren-01ov Law
esson et al. Org, Syn, J Volume V, No. 15
5 (1973), etc., according to the method disclosed therein.

Route 2 ■ m (y) (In the formula, R1, R2, R3, R4', 85' and R6 have the above-mentioned meanings) The benzylidene of formula V, which is the raw material compound in this route, may be known per se. , for example, G,
Jonas r Org, Reactions J
It can also be synthesized by dehydration condensation reaction of compound (1) in JIC and I according to the method disclosed in Vol. 15, p. 204 (1962).

As the ammonium salt, ammonium acetate, ammonium carbonate, ammonium hydrogen carbonate, etc. can be used.

Route 3 (I-b) (wherein R, R, R, R and R6 have the above meanings, R
4" means δ-R8-R7, R means an alkyl group having a nitrogen-containing heterocycle or an alkyl group having a phosphorus-containing substituent, R8 means O or S) Raw materials in this route The calgenic acid compound of formula (1) can be known per se or can be synthesized.

In this route, the starting compound (■) is prepared in a halodanized hydrocarbon such as methylene chloride or chloroform, an aromatic hydrocarbon such as benzene or toluene, an ether such as diethyl ether or tetrahydrofuran, or an aprotic polar solvent such as trimethylformamide. , in the presence of equimolar amounts of triethylamine, pyridine, etc., with an equimolar amount of thionyl chloride, phosphorus pentachloride, or chloroethyl chloride, and then further reacted with an equimolar amount of the compound shown in the stratification. The target compound of formula 1-b can be obtained by reacting equimolar amounts of dicyclohexylcarbodiimide in the above solvent and in the presence of a catalytic amount of N,N-dimethylaminopyridine to obtain the compound of formula i- Compound b can be synthesized in one step.

Even in this route, the target compound can be separated from the reaction mixture by sieving, extraction, column chromatography, recrystallization, etc.

Route 4 (In the formula, R1, R2, R3, R4', R5' and R6 have the above-mentioned meanings)
It can also be one synthesized by reacting compounds (1) and (2). Regarding this route, please also refer to routes 1 and 2.

Route 5 α) (In the formula, R1, R2, R5, R4', R5' and R6 have the above-mentioned meanings) The starting compound in this route, the noketoester of the formula For example, G.
Jones r Org, Reactlons J
It was synthesized by reacting compound V used in Route 2 with ■ using potassium fluoride, cesium fluoride, etc. as a catalyst, according to the disclosure of Vol. 15, p. 204 (1967), etc. You can also do that.

(Effects of the Invention) The novel 1,4-dihydropyridine derivative according to the present invention has coronary vasodilatory action, antihypertensive action, and inotropic action, and has low toxicity, so it is an active ingredient of a drug for treating angina pectoris and hypertension. It has an effect that is said to be useful as a.

(Dosage form and dosage when used as a drug) The drug according to the present invention can be orally administered in the form of tablets, capsules, granules, etc. in a conventional manner, and the dosage depends on the type of active ingredient. Generally speaking, 5 to 5 servings per day is appropriate for adults.

(Production Examples, etc.) Next, production examples of compounds according to the present invention, pharmacological test examples, and formulation examples of drugs according to the present invention will be specifically explained.

Production Example 1 1,4-dihydro-2,6-dimethyl-4-(:1-nitrophenyl)-3,S-pyridinedicarganic acid 3-
Dimethylphosphonylmethyl 5-methyl ester acetoacetic acid dimethylphosphonylmethyl ester z4. o
i (1oy mmol), 0-nitrobenzaldehyde 1 s, sl (s 9.s mmol), and 3-aminocrotonic acid methyl ester 10.6j9 (tt 9.3 mmol) were reacted at 70-75°C for 24 hours. Then, the reaction mixture is subjected to silica glu column chromatography (developing solvent: chloroform/methanol) to obtain 25.0 g of a yellow oily substance (yield ex, e%). This oil is dissolved in chloroform and ethyl ether is added to crystallize the desired compound.

Melting point: 167-169℃ Elemental analysis (C49H25N20.P): Calculation: N5.1
0 C50, 23N6.16 actual measurement; N5.16 C4
9,93N6.1332B0, 3220, 1700
, 1350, 1200, 1020M102O vector (EI/DI) m/z:454 <M+)
, 4s2.4sv <>-speak) traced spectrum (
coct3) δppm: 2.31 (3H*S)
2.34 (3H1s) J, 54 (J H
#s) 3.6 J -3-J 7
(,6H1m)3.95-4.83(2H,m) 5
．． 70(JH,S)y,o2-v,yx(sH,m) Production Example 2 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-S,S-pyridinedicarboxylic acid 3-diethylphosphonylmethyl 5-)f ester acetoacetic acid diethylphosphonylmethyl ester 5.30
1 (21 mmol) and 0-nitropesidaldehyde 3
．． 2011C (21 mmol) and 3-aminocrotonic acid methyl ester 2.5011 (21 mmol) are reacted and treated in the same manner as in Production Example 1 to obtain the desired compound e,oo9C (yield: 59.2%).

Melting point: 170-173C Elemental analysis (C2, N2.N2o, P): Calculation: Hs,
C4csx, zs N5.81 actual measurement: N5.75
C51,92N5.74! Rs(kutle(νKB')
) cm-':ax 32g0. 3220. 1700. 1530. 1
350. 1200.

1010, 980 Mass spectrum k (EI/DI) m/z:
4sr (M+), 4g5 (pace peak), zgvNM
R spectrum (CDC1,) δppm: 1,20
-1,48 (6H, m) 2.31 (3k1, S”)2
．． 37C3H,s') 3.57C3H,m
) s, sv, t, 5v (exx*m) s, ys (z
r(,m)7.00-7.83(5H,m') Production Example 3 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-hy+) Jinjikargan 23-
[2-(dibutylphosphonyl)ethyl]5-methylesteracetoacetic acid 2-(zig, tylphosphonyl)ethyl ester 37.1fi (111 mmol) and 0-nitrobenzaldehyde 17.41! (113 mmol) and 3-
When 13.29 (111 mmol) of aminocrotonic acid methyl ester is reacted in the same manner as in Production Example 1 and subjected to silica gel column chromatography (developing medium: chloroform/methanol), the desired compound as an oily substance is obtained as 11, 6)! (yield: 18.3%).

Thin layer chromatography (Silica Dull Grate "Merck 5715 J"): Rf: 0.46 (ethyl acetate, Uv254) IR
Spectrum (ν) cm.

3280, 3230, 1710, 1690, 1
530, 1350.

1190, 1010 101O spectrum (EI/IH) m/z:
55,? (M+), sss, xev (pacebeak) NMR spectrum (CDCt3) δppm
:o,ys-x,4s()6H,m) 2.33(
6H, s) 3.55 (3H, s) 3.80-
4.23 (4H, rw) 5.74CIH, s)
7.03-7.70 (5H, m) Production Example 4 1,4-dihydro-2,6-dimethyl-4-(S-nitrophenyl)-3,s-pyridinedicarboxylic acid 3-cycloglobylmethyl 5-diethylphosphonyl methyl ester α-acetyl-3-nitrocinnamate cyclopropyl methyl ester 14.0 g (48.4 mmol) and acetoacetic acid diethylphosphonyl methyl ester 12.3 g C4
8.8 mmol) was added to 110 rIil of ethanol and stirred, and 3.25 t (48,8 mmol) of 28% ammonia water was added to 110 rIil of ethanol.
8 mmol) was added dropwise and then refluxed for 7 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: chloroform/methanol) to obtain xz, 11i (yield 47.8%) as an oily substance.
)can get. This oily substance crystallizes when dissolved in methanol and left to stand.

Melting point: ies, 5-N69. s℃ elemental analysis (C24H5, N209P・1/zH20)
: Calculation: H6,07C54,24N5.27 Actual measurement:
H6,06C54,22N5.28rR spectrum (V
KB') cm-':ax 3270, 3200, 30B0, 1
690, 1490, 1190.

1100, 1010 101O spectrum (EI/DI) m/z: 5
22 (M+), 505 (M+-17, pacebeak) infant spectrum (cocz3) δppm: o, os-
x, 4y (zni, m) 2.41 (eH, s)
3, gy-4,5v (sH, m), 5.22 (IH,
8') 7.23-IJ, 27(5H, m') Production Example 5 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl) -S,S-pyridinedicarboxylic acid 3- Dimethylphosphinoylmethyl 5-methyl ester acetoacetic acid dimethylphosphinoyl methyl ester 1 Otsu 311C9), 1 mmol), 0-nitrobenzaldehyde 13.711 (9), 3 mmol), and 3-aminocrotonic acid methyl ester 10.7ji(9), 0 mmol) and treated in the same manner as in Production Example 1 to obtain 27.5fi of the desired compound (yield: 7L, 5%).

Melting point: 175-179℃ Elemental analysis (CH+H25N207P-1/2 H20)
: Calculation: H5,6I C52,90N6.49 Actual measurement:
H5,85C52,93N6.39IR spectrum (v
"')cIN-': 32110, 3200, 1
700, 1530, 1200Mass spectrum (
EJ/DI') m/z: 4,? J(M+)
, 4os (pacebeak) m spectrum (cocz
,) δppm: 1,33-1,67 (6H, m)2.
32 (6H, s) 3.57 (3H, 8) 3.
93-4.92 (2H, m)5, g8CIH, *)
7, os-s, ov (sa, m) Production Example 6 1,4-dihydro-2,6-nomethyl-3-dimethylphosphinoylmethylaminocarbonyl-4-(2-nitrophenyl)-5-+:' IJ zincaldenic acid methyl ester 1,4-dihydro-2,6 was added to a mixed solvent of 120 nl of methylene chloride and some N,N-dimethylformamide.
-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-3-pyridinecarboxylic acid5. ool(I
s, o mmol) and dimethylphosphinoylmethylamine 1,7011<15.9 mmol) and dicyclohexylcalgediimide 3.281 (16,9 mmol)
and N,N-dimethylaminopyridine 1oolng
(0,879 mmol) was added, stirred at 25°C for 4 hours, and then evaporated. After concentrating the P solution under reduced pressure, water was added to collect the precipitated solid, which was washed with water. , 3.201 crude crystals of the desired compound (yield: 50.6 cm) were obtained.

Purification is carried out by recrystallization from methanol.

Melting point: 157-16)°C Elemental analysis (C1, H24Ns06P): Calculation; N5.7
4 C54, J6 N9.97 actual measurement: N5.66
C53,78N9.96IR Suiktor(y"'
) cWl-': 3400, 3200, 1670
, 1510 , 1350 , 1225 .

1140, 935 Mass spectrum (FA/DI) m/z
:421 (M+) 1404 (base peak), 267
Traction spectrum (D20) δppm: 1,36 (6H, d, J=13.2H8')2.
20(3H,s') 2.28(3H,
s) 3.5x (3H, s) 3.70-
3.97 (2H, m) 5.50 (IH, a)
5.1J7 (IH, wide S) y, 5s-s, oo(
4H, m) Production Example °7 1,4-dihydro-2,6-dimethyl-4-(x-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-pyrrolitidin-7a-ylmethyl 5-methyl ester and its Fumarate 1,4-di-and-draw 2,6-dimethyl-5-methoxycarbonyl-4-(Z-nitrophenyl)-3-pyridinecarboxylic acid6. eol (x9.y mmol) and pyrrolitidin-7a-yl methyl ester 3.0011 (21
. %)
is obtained.

The fumarate salt is obtained by dissolving this oil in acetone, adding an equimolar amount of fumaric acid, distilling off the solvent under reduced pressure, and recrystallizing the resulting solid from methanol.

Melting point: 164-167℃ Elemental analysis (C28H33N30..N20): Calculation:
Hs, 9s C57,04N7.13 actual measurement; ■6.
06 C51,31N7.06IRX < ri) /
l/(v”')cm-': ax 3470, 3260, 31g0, 2950, 2
520, 16B0.

1510, 1420, 1200, 1020, 7
70Massx Vector (EI/DI) m/z
:455 (M), 124. 110 (pace peak) NMR spectrum (pMso-d6) δppm
:1,25-2.12(8H,rn) 2.23(
3H, s) 2.29 (3H, 8') 2.65
-4.01 (9H, m') 5.60 (IH-→
6.58 (2H, s) 7.25-7.87 (4H, m)
9.17 (IH, wide 8) Production example 8 2-diethylphosphonylmethyl-1,4-dihydro-6
-Methyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester 4-diethylphosphonylacetoacetic acid methyl ester 19
．． 0fl (75.3 mmol), 0-nitrobenzaldehyde 11,4fi (75.4 mmol), and 3-aminocrotonic acid methyl ester 8.951 (76.4 mmol) were reacted in the same manner as in Production Example 1. The desired compound can be converted into 8. OE (yield 22.0%) is obtained.

Melting point: 160-164℃ Elemental analysis (C2, H27N209P・1/2H20):
Calculation: N5.74 C6), 32N5.70 actual measurement:
N5.72 C51,59N5.66IRsu-<ri),Q/(yKB')tM-':ax 3300, 3230, 3100, 3000, 1
700, 1650.

1530, 1360, 1210, 1090, 1
050, 970Mass Spect k (FI/DI
) m/z: 482 (M+), 465 (pace beak), 36ONMR, <-<cuttle (CDC13) δpp
m: 1, θ8-1,43(6H,m) 2.33(
3H, n') 3.50-4.27 (1211, m')
5.76 (IH, s) y, o4-v, ys (sH,
m) Using 10 to 15ktj as experimental animals, the test compound was dissolved in 50% ethanol and injected through the brachiocephalic vein, blood flow, blood pressure, and heart rate were measured.The rate of change in these was investigated.The results are as follows. It was as shown in Table 1-3.

Blood flow was measured by attaching an electromagnetic blood flow meter glove to the left coronary artery rotator and aortic origin, blood pressure was measured via a pressure transducer inserted through a cannula from the left femoral artery, and heart rate was measured by inserting a cannula into the left femoral artery. The number was measured by triggering the R wave on the electrocardiogram.

The results shown in these tables show that the compound according to the invention has a more potent and long-lasting effect when compared with the reference drug diltiazem, and that nifedipine has a higher effect when compared with the reference drug nife-zopine. It can be seen that the compounds according to the invention have a cardiotonic effect, albeit a mild one, whereas they show a tendency towards cardiac depression.

Table 1 Table 2 Table 3 Pharmacology test example 2 (acute toxicity) Body! The test compound was orally administered to 1B-209 DD mice (5 mice per group) for 72 hours after administration.

It can be seen from this table that the acute toxicity of the compounds according to the invention is low.

Table 4 Formulation Example 1 (Tablets) The various ingredients are blended according to the following formulation, kneaded and tableted in a conventional manner.

Compound of Production Example 1 10 (In9>Gelatin 8 Cornstarch
55 Microcrystalline cellulose 2
5 Magnesium Stearate 2 Total 100 da/tablet Formulation Example 2 (Capsules) The various ingredients are blended according to the following formulation and loaded into hard gelatin capsules by a conventional method to prepare capsules.

Compound 10 (IR9) Lactose of Production Example 2
30 Corn starch 104 Polyvinylpyrrolidone 2 Magnesium stearate
4 Total 150 da/capsule

Claims (27)

[Claims] (1) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, one of R^1 and R^2 means hydrogen, the other means a nitro group, and R^3 means an alkoxycarbonyl group. R^4 means an alkoxycarbonyl group, an alkoxycarbonyl group having a nitrogen-containing heterocycle, an alkoxycarbonyl group having a phosphorus-containing substituent, or an alkylaminocarbonyl group having a phosphorus-containing substituent, and R^5 and R
^6 means an alkyl group or an alkyl group having a phosphorus-containing substituent, provided that R^3 and R^4 are both alkoxy, except when R^6 means an alkyl group having a phosphorus-containing substituent. A novel 1,4-dihydropyridine derivative and a salt thereof, represented by (not meaning a carbonyl group). (2) The method according to claim 1, wherein R^4 represents an alkoxycarbonyl group having a phosphorus-containing substituent or an alkylaminocarbonyl group having a phosphorus-containing substituent. Derivatives and their salts. (3) The derivative and salt thereof according to claim 1, wherein R^4 is an alkoxycarbonyl group having a pyrrolitidinyl group. (4) R^4 means an alkoxycarbonyl group, R^
The derivative and its salt according to claim 1, wherein 5 represents an alkyl group, and R^6 represents an alkyl group having a phosphorus-containing substituent. (5) 1,4-dihydro-2,6-dimethyl-4-(2
-nitrophenyl)-3,5-pyridinedicarboxylic acid 3
-dimethylphosphonylmethyl 5-methyl ester. (6) 1,4-dihydro-2,6-dimethyl-4-(2
-nitrophenyl)-3,5-pyridinedicarboxylic acid 3
-diethylphosphonylmethyl 5-methyl ester. (7) 1,4-dihydro-2,6-dimethyl-4-(2
-nitrophenyl)-3,5-pyridinedicarboxylic acid 3
The derivative according to claim 1 or 2, which is -[2-(dibutylphosphonyl)ethyl]5-methyl ester. (8) 1,4-dihydro-2,6-dimethyl-4-(3
-nitrophenyl)-3,5-pyridinedicarboxylic acid 3
-cyclopropylmethyl 5-diethylphosphonyl methyl ester
Or the derivative according to item 2. (9) 1,4-dihydro-2,6-dimethyl-4-(2
-nitrophenyl)-3,5-pyridinedicarboxylic acid 3
-dimethylbosphinoylmethyl 5-methyl ester. (10) 1,4-dihydro-2,6-dimethyl-3-dimethylbosphinoylmethylaminocarbonyl-4-(
Claim 1, characterized in that it is 2-nitrophenyl)-5-pyridinecarboxylic acid methyl ester.
Or the derivative according to item 2. (11) 1,4-dihydro-2,6-dimethyl-4-(
Claim 1 or 3, characterized in that it is 3-pyrrolitidin-7a-ylmethyl 5-methyl ester of 2-nitrophenyl)-3,5-pyridinedicarboxylic acid.
Derivatives described in Section. (12) 2-diethylphosphonylmethyl-1,4-dihydro-6-methyl-4-(2-nitrophenyl)-3,
The derivative according to claim 1 or 4, which is 5-pyridinedicarboxylic acid dimethyl ester. (13) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, one of R^1 and R^2 means hydrogen and the other means a nitro group) A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R^3 means an alkoxycarbonyl group, R^
5' means an alkyl group) and the compound represented by the formula ▲ Numerical formula, chemical formula, table, etc. means an alkoxycarbonyl group having a phosphorus atom substituent or an alkylaminocarbonyl group having a phosphorus atom substituent, R^6 means an alkyl group or an alkyl group having a phosphorus atom substituent) There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼( I -a) (in the formula, R^1, R^2, (R^3, R^4', R^5' and R^6 have the above meanings) A method for producing a novel 1,4-dihydropyridine derivative and its salt. (14) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, one of R^1 and R^2 means hydrogen, the other means a nitro group, and R^3 means an alkoxycarbonyl group. (R^5' means an alkyl group) and the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) means a carbonyl group, an alkoxycarbonyl group having a phosphorus-containing substituent, or an alkylaminocarbonyl group having a phosphorus-containing substituent, R^6 means an alkyl group or an alkyl group having a phosphorus-containing substituent) There are formulas, chemical formulas, tables, etc. that are characterized by reacting the compound shown in the formula in the presence of ammonia or its salt, and then converting the resulting compound into a salt as necessary. ) (wherein R^1, R^2, R^3, R^4', R^5' and R^6 have the above-mentioned meanings) and a novel 1,4-dihydropyridine derivative represented by The method of making the salt. (15) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, one of R^1 and R^2 means hydrogen, the other means a nitro group, and R^3 means an alkoxycarbonyl group. and R^5 and R^6 mean an alkyl group or an alkyl group having a phosphorus-containing substituent) and a compound represented by the formula R^7-R^8H (VII) (in the formula R^7 means an alkyl group having a nitrogen-containing heterocycle or an alkyl group having a phosphorus-containing substituent, and R^8
means O or NH) There are formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by dehydration condensation with the compound shown by , and then converting the resulting compound into a salt as necessary. b) (In the formula, R^1, R^2, R^3, R^5 and R^6 have the above meanings, and R^4'' means ▲There are mathematical formulas, chemical formulas, tables, etc.▼ , R^7 and R^8 have the above-mentioned meanings). (16) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, one of R^1 and R^2 means hydrogen, the other means a nitro group, and R^3 means an alkoxycarbonyl group. R^4 means an alkoxycarbonyl group, an alkoxycarbonyl group having a nitrogen-containing heterocycle, an alkoxycarbonyl group having a phosphorus-containing substituent, or an alkylaminocarbonyl group having a phosphorus-containing substituent, and R^5 and R
^6 means an alkyl group or an alkyl group having a phosphorus-containing substituent, provided that R^3 and R^4 are both alkoxy, except when R^6 means an alkyl group having a phosphorus-containing substituent. 1. A circulatory system active agent characterized by containing at least one of the novel 1,4-dihydropyridine derivatives and salts thereof represented by the formula (without meaning a carbonyl group) as an active ingredient. (17) At least one 1,4-dihydropyridine derivative and its salt, in which R^4 represents an alkoxycarbonyl group having a phosphorus-containing substituent or an alkylaminocarbonyl group having a phosphorus-containing substituent, as an active ingredient The circulatory system acting agent according to claim 16, characterized in that: (18) Claim 16, characterized in that the active ingredient is at least one 1,4-dihydropyridine derivative and its salt, in which R^4 represents an alkoxycarbonyl group having a pyrrolitidinyl group. The circulatory system active agent described in . (19) R^4 means an alkoxycarbonyl group, R
^5 means an alkyl group, and R^6 means an alkyl group having a phosphorus-containing substituent, the active ingredient being at least one kind of 1,4-dihydropyridine derivative and its salt. The circulatory system active agent according to claim 16. (20) The active ingredient is 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-dimethylphosphonylmethyl 5-methyl ester. Claim 16
or the circulatory system acting agent according to item 17. (21) The active ingredient is 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-diethylphosphonylmethyl 5-methyl ester. Claim 16
or the circulatory system acting agent according to item 17. (22) The active ingredient is 3-[2-(dibutylphosphonyl)ethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate]
The circulatory system active agent according to claim 16 or 17, which is a 5-methyl ester. (23) The active ingredient is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-cyclopropylmethyl 5-diethylphosphonylmethyl ester. A circulatory system acting agent according to claim 16 or 17, characterized by: (24) The active ingredient is 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-dimethylphosphinoylmethyl 5-methyl ester. The circulatory system acting agent according to claim 16 or 17. (25) The active ingredient is 1,4-dihydro-2,6-dimethyl-3-dimethylphosphinoylmethylaminocarbonyl-4-(2-nitrophenyl)-5-pyridinecarboxylic acid methyl ester. The circulatory system acting agent according to claim 16 or 17. (26) The active ingredient is 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-pyrrolitidin-7a-ylmethyl 5-methyl ester. The circulatory system acting agent according to claim 16 or 18. (27) The active ingredient is 2-diethylphosphonylmethyl-1
, 4-dihydro-6-methyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester, Claim 16 or 1
The circulatory system acting agent according to item 9.