JPS61143359A - Novel dihydropyridine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A dihydropyridine dervatice of formula I (R<1> is phenyl, phenoxymethyl; R<2>, R<3>, R<4> are lower alkyl; A is alkylene which may be interrupted with O atoms, formula: Y<1>-NHCO-Y<2>; Y<1> is single bond, alkylene which may be interrupted with O atoms; Y<2> is alkylene) and its salt. EXAMPLE:Diethyl 2-[(2-hydroxy-3-phenoxypropylamino) methyl]-6-methyl-4-(m- nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate hydrochloride. USE:Since it has actions of Ca antagonism, beta-blocking and endogenous stimulation of sympathetic nerves, it is used as a preventive or remedy for ischemic cardiopathy, circulatory diseases. Additionally, it is used as an improver for central nerve functions. PREPARATION:The reaction of an amine of formula II with an epoxide of formula III gives the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention is directed to calcium (Ca”) antagonism and sympathetic
The present invention relates to novel dihydropyridine derivatives and salts thereof that also have receptor blocking action, and methods for producing them.

(Prior art) Conventionally, dihydropyridine derivatives are calcium (Ca″)
It has been established that the antagonist is highly useful as a prophylactic and therapeutic drug for ischemic heart disease9, such as angina pectoris, myocardial infarction, and other cardiovascular diseases, such as hypertension. It has also been established that sympathetic beta receptor blockers are useful in similar areas.

However, the modes of action of the nine drugs are completely different.

In other words, beta-blockers mainly affect heart rate.

Calcium antagonists reduce cardiac output, cardiac work, and myocardial oxygen consumption, whereas calcium antagonists mainly cause a decrease in left ventricular load due to increased coronary flow and vasodilation, and prevent coronary artery spasm. do.

Recently, there have been many reports that the combination of these two drugs with different mechanisms of action has clinically superior antianginal effects than the administration of each drug alone [
Ba5san+ M,, Weiler-Ravel
L D, and 5 halev+ 0. ; Add
tive antianginal effect
f verapamil in patients r
Eceiving propranolol; B
r.

Med, J., 284.1067 (1982) Ko. In addition, in the treatment of hypertension, when a calcium channel blocker is used in combination with a beta-blocker, the beta-blocker suppresses side effects such as increased heart rate and increased renin secretion caused by calcium channel blockers, so it is a good anti-hypertensive drug. Adrenergic b, which is clinically recognized to have hypertensive effects.
locked; Am, Heart J, t 9
6* 218 (1978)].

(Problems to be Solved by the Invention) Given this clinical background, it is easy to infer that compounds that share calcium antagonistic and β-blocking effects will be highly useful in the treatment of ischemic heart disease and hypertension. be done.

However, to date, there has been no report on the successful synthesis of a single compound that shares both calcium antagonistic and β-blocking effects.

Follow? The object of the present invention is to provide a compound having both calcium antagonistic and β-blocking effects, and a method for producing the same.

(Means for Solving the Problems) The present inventors synthesized various new compounds, and as a result of their intensive search for compounds that have both calcium antagonistic action and β-blocking action, they were found to be represented by the following general formula (I). The present invention was completed by discovering that a synthetic compound or a salt thereof has both of the above-mentioned effects.

(The symbols in the formula have the following meanings.

R'=phenyl group or phenoxymethyl group.

R2, R3 and R: the same or different lower alkyl groups.

A: An alkylene group which may be interrupted by an oxygen atom, or a group represented by the formula -Y'-NHCO-Y'-.

YI: Alkylene group optionally interrupted by a single bond or an oxygen atom.

Y! : Alkylene group) In the definition of the general formula in this specification, "lower" means a straight or branched carbon chain having 1 to 5 carbon atoms, unless otherwise specified.

Therefore, the lower alkyl group is a methyl group.

Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 1ee-butyl group, t@rt -
Butyl group, pentyl (amyl) group, isopentyl group
Examples include tart-hentyl group, neopentyl group, l-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, and 1-ethylpropyl group.

In addition, the alkylene group which may be interrupted by an oxygen atom includes a straight chain or branched alkylene group having 1 to 6 carbon atoms, and a straight chain or branched alkylene group having 2 to 6 carbon atoms. and a divalent group of an ether type alkylene chain into which an oxygen atom is introduced so as to interrupt it at an arbitrary position.

For example, the alkylene group represented by A, Y' or Y2 is:
Methylene group, ethylene group, methylmethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, epentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3 -methyltetramethylene group, 4-methyltetramethylene group,
Examples include hexamethylene group.

In addition, as an alkylene group having 2 to 6 carbon atoms interrupted by an oxygen atom, 2-oxapropane-1,3
-diyl group (-CH20CH,-).

2-oxabutane-1,4-diyl group, 3-oxabutane-1,4-diyl group, 3-methyl-2-oxapropane-1,3-diyl group, 2-oxapentane-1,5-
Diyl group, 3-oxapentane-1,5-diyl group, 4
-Oxapentane-1,5-diyl group, 2-oxahexane-1,6-diyl group, 3-oxahexane-1,6
-diyl group.

4-oxahexane-1,6-diyl group, 5-oxahexane-1,6-diyl group, 2-oxaheptane-1,
Examples include 7-diyl group.

The compound of the present invention represented by general formula (I) forms a salt.

The present invention also includes pharmacologically acceptable salts of compound (I), such salts as hydrochloric acid, hydrobromic acid, and hydroiodic acid.

Mineral acids such as sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid.

Oxalic acid, citric acid, succinic acid, fumaric acid.

Examples include acid addition salts with organic acids such as maleic acid, malic acid, tartaric acid, methanesulfonic acid, and ethanesulfonic acid.

Compound (I) and its salts provided by the present invention can be produced by two different methods.

Typical manufacturing methods are illustrated below.

(Symbols in the reaction formula, R1, R, Rj, R' and A
has the above-mentioned meaning) The compound (I) of the present invention can be produced by reacting an amine represented by the general formula (I[) with an epoxy compound represented by the general formula (m).

Although the reaction proceeds without a solvent, it is preferably carried out in an organic solvent that does not participate in the reaction. Examples of organic solvents that do not participate in the reaction are methanol and ethanol.

Alcohols such as impropatol, ether, tetrahydrofuran, ethyl acetate, dimethylformamide, etc. are suitable.

Compounds (n) and (III) are used in the reaction in approximately equal moles, or in a slightly excess mole of one of them. The reaction temperature is usually advantageously set at room temperature to elevated temperature. The reaction time is appropriately set in consideration of various reaction conditions.

Second production method (in the reaction formula, Rs, Bt, Ra, R4 and A have the same meanings as above, Xl is a halogen atom or an amino group, X2 is an amino group when XI is a halogen atom,
When l is an amino group, it means a halogen atom. ) The compound (I) of the present invention can also be produced by reacting a halide or amine represented by the general formula (rv) with an amine or halide represented by the general formula (V).

Here, the halogen atoms include iodine atom, bromine atom,
Examples include chlorine atoms.

The reaction is carried out without solvent or with benzene or toluene.

In an organic solvent that does not participate in the reaction, such as xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, ethanol, etc., compound (V) is used in equimolar to slightly excess molar relative to compound σ).

It is advantageous to carry out the reaction at room temperature or at elevated temperature, or under heating under reflux.

During this reaction, pyridine, picoline, N, N-L k
V'g＼ Addition of secondary or tertiary bases such as dimethylaniline, N-methyl-91F, trimethylamine, triethylamine, dimethylamine, etc. or inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, etc. can accelerate the reaction. It may be advantageous to proceed smoothly.

Furthermore, in order to suppress side reactions, it is also possible to adopt a method in which a protecting group is introduced into the amino group of the compound (C) or (V), the reaction is caused, and the protecting group is removed after the reaction. Such protecting groups include toluenesulfonyl group, acetyl group, and hunacylsulfonyl group.

Examples include trifluoromethanesulfonyl group and bisbenzenesulfonyl group. Removal of the protecting group can be easily accomplished by conventional hydrolysis.

Third production method fl (I&) (In the reaction formula, R1, B2. BS and R4 have the same meanings as above, and have the following meanings.

A1: A single bond, an alkylene group into which an oxygen atom having one less carbon number than A above may be introduced, or a group represented by the formula -Y''-NHCO-ys-.

Y3: A single bond or an alkyref group having one less carbon number than Y2.

However, A, Yl and have the meaning of the description) general formula (
The compound of the present invention represented by It) is prepared by reacting the aldehyde represented by the general formula (B) with the amine represented by the general formula (■) to form a Schiff base.2Then, the compound is reduced under reaction conditions that do not reduce the nitro group. Manufactured by

The first reaction proceeds even in the absence of a solvent, but it is usually carried out between compound (Vl) and compound (VI
) using the equivalent molar to excess molar amount of the compound (■),
It is carried out at room temperature or under heating, or under heating under reflux. Depending on the reaction conditions, potassium hydroxide may be added or Dean-Stark (Dean-8tark) may be added.
It may be suitable to use plastic wrap to remove the water that forms.

In the reduction reaction, the reaction can be carried out by adding a reducing agent to the reaction solution containing the thick base, without isolating the thick base produced in the first-stage reaction.

Furthermore, in order to produce the compound (I&) of the present invention by selectively reducing only the imino group of the Schiff base without reducing the nitro group, it is advantageous to use hydrogenation as a reducing agent.

The reduction reaction is carried out in alcohols such as methanol and ethanol, organic solvents such as acetic acid, water, or a mixed solvent of these.
It is usually carried out at room temperature or under heating.

During the reaction, it may be advantageous to keep the reaction liquid neutral or basic in order to allow the reaction to proceed smoothly.
Methylamine, ethylamine, propylamine, dimethylamine as needed.

Potassium hydroxide, sodium acetate, etc. are added to react.

The compound of the present invention thus produced by 51C is isolated and purified as a free substance or as a salt thereof. Isolation and purification can be carried out by ordinary chemical operations such as extraction, crystallization, recrystallization, and various chromatography. It is done by applying.

Note that the starting material compound (n) has the formula -Yl-NHCO-r
The compound represented by - is an amine compound represented by the general formula (2) (wherein R1, R2, R3, R4 and yl have the above meanings) and an amine compound represented by the general formula OX) (wherein R1, R2, R3, R4 and yl have the above meanings) ) is reacted with a phthalimide-substituted alkanoic acid or its reactive derivative at the carboxy group to produce a ryomido compound by amidation using a conventional method.

It is then produced by hydrolysis to eliminate phthalic acid residues.

In addition, in the starting compound (III), A is of the formula -Y' -NH
A compound represented by a group represented by CO-r- and in which Xi is a halogen atom is an amine compound represented by the general formula (Vjl) and a compound represented by the general formula x'-y''-co- (wherein X3 is a halogen atom). It can be easily produced by amidation in a conventional manner, such as by reacting an atom with x4 (x4 means a halogen atom that is the same as xi or more reactive than X3).

(Effects of the Invention) The compound CI) and its salts provided by the present invention have both calcium (Ca') antagonistic action and sympathetic β receptor blocking action, as well as endogenous sympathomimetic action (ISA). It is useful as a preventive and therapeutic agent for ischemic heart diseases such as angina pectoris and myocardial infarction, as well as cardiovascular diseases such as hypertension and arrhythmia, with few side effects.

In addition to their circulatory effects, the two compounds of the present invention also have cerebrovascular curvature-improving effects and central function-improving effects, and are useful as cerebrovascular curvature-improving agents and central function-improving agents.

These pharmacological effects of the compound of the present invention were confirmed by the test method shown below, and the blood pressure lowering effect and coronary flow increasing effect by intravenous administration were 0.001.
~0.3■/kg, and 1 to 300μg/kgt β for intravenous administration for coronary vasodilatory effect by intracoronary administration.
The receptor blocking effect was effective within the range of 0.1 to 3 nw/kg, and reductions in cardiac work and myocardial oxygen consumption were observed.

It was also confirmed that the two compounds of the present invention have longer durations of antihypertensive action and coronary vasodilator action than known dihydropyridine compounds.

(1) Effect on the heart and vascular system The dog is anesthetized by intravenously injecting 30 rr@/kg of pendoparbital, and the dog's chest is opened under 2 artificial respirations. The test compound was administered through the femoral vein, and a known dihydropyridine compound was used as a control to determine blood pressure, heart rate, left ventricular pressure, left ventricular maximum systolic velocity,
Pulmonary artery pressure, central venous pressure, cardiac output, and coronary blood flow were measured.

(2) Coronary vasodilator effect Dogs were anesthetized by intravenously injecting 301 Qg/kg of Betbalpital, 1 artificial vet-F-, 2 sauces, 5 aliments, 1 faction, 7
Perfusion is carried out through an extracorporeal circuit created in the circumflex artery of Eg. The test compound was administered intraarterially via the extracorporeal circuit.

It was determined by an electromagnetic flowmeter installed in the extracorporeal circuit.

(3) Measuring method of β-receptor blocking effect by Tachikawa and Mononaka et al. [Pharmaceutical Journal, 93(12)
, 1573 (1973)].

8 kg of reserpine was administered intraperitoneally to male Wistar rats, and 18 hours later, 55 m of pentocurbital was administered.
The patient was anesthetized by intraperitoneally administering 1 g/kg, and the cervical vagus nerve was excised. The number of beats was determined.

ED was calculated from the rate of suppression of tachycardia by 0.1 μg/kg of impreterenol by silent injection, and the effect was evaluated using propranolol as a control.

One or two compounds represented by general formula (I) or salts thereof
Preparations containing more than 1 species as active ingredients.

Two tablets, powders, fine granules, granules, capsules, pills, liquids, injections, layers, ointments, and patches are prepared using commonly used pharmaceutical carriers, excipients, and other additives. It is prepared as a drug and administered orally (including sublingually) or parenterally.

The clinical dosage of the compound of the present invention is appropriately determined taking into consideration the patient's symptoms, body weight, age, gender, etc., and is usually 1 to 2001 t1g per adult when administered intravenously.
Administer in one dose or in divided doses.

(Example) EXAMPLES The present invention will be explained in further detail with reference to Examples below.

Example 1゜H diethyl 2-dimethyl-6-methyl-4-(m-
nitrotunyl) -1,4-dihydropyridine-3,
2 g of 5-dicarboxylate and 0.75 g of glycidylphenyl ether are dissolved in 50 ml of methanol and left at room temperature for 2 days. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform-methanol (98:2 v/v). The obtained crude crystals were treated with an ethanolic solution of hydrogen chloride and recrystallized from ethanol to give diethyl 2-[(2-hydroxy-3-phenoxypropyl-termino)methylco-6-methyl-4-(m-nitrophenyl). -1,4-dihydropyridine-3,5-dicarboxylate hydrochloride 1
．． Obtain 7g. This compound has the following physical properties.

(i) Melting point 180-183C (++) Elemental analysis value (CtsHssNsOs・l-
as lCl)C(chronic)H(chronic'N(19
Calculated value 58.38 5.95 7.29 Actual value 58.34 6.03 7°21 (110 Nuclear magnetic resonance spectrum (CDCl3) (free compound) δ: 1.20 (6H, t) 2.42 (3H ,s) 2.6-3.1 (8H9m) 5.10 (IH,s) Example 2゜diethyl 2-formyl-6-methyl-4-(m-nitrotunyl)-1,4-dihydropyricin- 1.5 g of 3,5-dicarboxylate and 0.53 g of β-hydroxyph, netylamine were dissolved in methanol 30a+jK,
Heat to reflux for 1 hour. After cooling 2. Cool the reaction mixture to 0-5C and add 0.22 g of sodium borohydride little by little. 6. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, water was added to the residue, and diluted with ethyl acetate. Extract. After washing the extract with water and drying, the solvent is distilled off. The obtained crude crystals were recrystallized from isopropyl alcohol to give diethyl 2-[(2-hydroxy-2-7-dylethylamino)methyl]-6-methyl-4-(m-nitro7-nyl)-1. , 4-dihydropyridine-3,5-dicarboxylate was obtained.

This was treated with a hydrogen chloride ethanol solution to give a hydrochloride of 1.3
get g. This compound has secondary physical properties.

(1) Melting point 181-184t:'(11)
Elemental analysis value (Ct))lss N3o,・HCZ) C(@a(I N(n) Calculated value 59.39 5.91 7.70 Actual value 59.20 5.99 7.40 (110 Nuclear magnetic resonance Spectrum (CDC6,) (free compound) δ: 1.20 (6H, t) 2.22 (3H, s) 2.8-3.0 (2H, m) 4.88 (IH, t) 5.10 (IH,s) Example 3 Diethyl 2-aminomethyl-6-methyl-4-(m-
(nitrophenyl)-1,4-dihydropyridine-3,5
-dicarboxylate o, s g and pyridy y0.24
Dissolve 1K of 30ml of dry benzene, and add 0.38g of 3-chloropropionic acid chloride to 511ml of dry benzene under water cooling.
The solution in It is added dropwise. The reaction solution was left at room temperature overnight, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give diethyl 2-[(3-chloropropionamide)methylco-6-methyl-4-(m-nitrophenyl )-1,4-dihydropyridine-3,5-dicarboxylate is obtained. This was used in the next reaction without purification.

υH diethyl 2-[(3-chloropropionamido)methyl]-6-methyl-4-(m-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylate 0
．． 8 g and 0.56 g of 2-hydroxy-3-phenoxyglopylamine were dissolved in 301 ml of methanol and left overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform-tutanol (95:5 v/v). The obtained crude crystals were treated with a hydrogen chloride ethanol solution and recrystallized from ethanol to give diethyl 2-[[3-(2-hydroxy-3-phenoxyglopylamin)propionamidocomethyl]-6-methyl. 0.3 g of -4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride was obtained. This compound has secondary physical properties.

(1) Melting point 70-73℃ (11) Elemental analysis value (Cst Has N40@-IC
(as l) C (%) H (%) N [Yes]) Calculated value 57.54 6.07 8.66 Actual value
57.25 6.09 8.49 (iii)
Nuclear magnetic resonance spectrum (CDCI) (free compound) J: 1.12 (3H, t) 1.30 (3H, t) 2.32 (3H, s) 4.44 (21, d) 5.10 ( IH,s) diethyl 2-aminomethyl-6-methyl-4-(m-
Nitrophenyl)-1,4-dihydropyridine-3,5
- 6.5 g of dicarboxylate and 3.1 g of triethylamine are dissolved in 40 tal of methylene chloride, and after cooling with water, a solution of 3.7 g of phthalimidobutanoic acid chloride dissolved in 15 III t of methylene chloride is added dropwise over 30 minutes. The reaction solution was left at room temperature overnight.

After washing with water, drying with anhydrous sodium sulfur and distilling off the solvent under reduced pressure.
9 g of amorphous powder of diethyl 6-methyl-2-[(3-phthalimidobutyramide)methylco-4-(m-nitrophenyl)-1,4-cyhydrohyricin-3.5-dicarboxylate was obtained.

Nuclear magnetic resonance spectrum (CDC13) J: 1.22 (3H, t) 1.28 (3H, t) 2.32 (3H, s) 3.72 (2H, t) 4.44 (2H, d) 5 .04 (IH,s) Diethyl 6-methyl-2-[(3-phthalimidobutyramide)methylco4-(m-nitrophenyl)-1
, 9 g of 4-dihydropyridine-3,5-dicarboxylate and 2.3 mt of hydrazine monohydrate are dissolved in 140 ml of ethanol and heated under reflux for 30 minutes.

The precipitated crystals are removed from the furnace while hot, and the solvent of the P solution is distilled off under reduced pressure. Water was added to the residue and extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sulfuric acid), the solvent was distilled off and an amorphous powder of diethyl 2-[(4-7minoptylamido)methyl]-6-methyl-4-(m-nitrophenyl)- 7.4 g of 1,4-dihydropyridine-3,5-dicarboxylate are obtained.

Nuclear magnetic resonance spectrum (CDCIs) δ: 1.22
(3H, t) 2.36 (3H, s ) 2.76 (2H, t ) 4.26 (2H, d) 5.08 (IH, 5) υh diethyl 2-[(4-aminobutyramido)methyl ]
-6-methyl-4-(m-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylate 4.3
g and 1.4 g of glycidylphenyl ether were dissolved in 45 ml of methanol and left at room temperature for 2 days. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel column chromatography and chloroform-methanol (9:
IV/V) and diethyl 2-[[3-(2-hydroxy-3-phenoxypropylamide)butyramido]methyl]-6-methyl-4-(m-nitrophenyl).
1.5 g of -1,4-dihydropyridine-3,5-dicarboxylate was obtained as an amorphous powder. This compound has the following physical properties.

(1) Elemental analysis value (Cst H40N40s and shite) C
(I) Hc%) N [Yes]) Calculated value 61.53 6.45 8.97 Actual value 61.16 6.52 8.89 (11) Nuclear magnetic resonance spectrum (CDCIm) δ: 2.16
(3H, t) 1.6:l'-1,98 (2H, m) 3.32 (3H, s) 4.42 (2H, d) 5.02 (IH, s) Examples 5-6 Implementation The following compound was obtained by processing in the same manner as in Example 1.

Example 5 Sui・MCI Diethyl 2-[[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]methyl]-6-methyl-4-(m-nitrophenyl)-1,4-dihydropyridine- 3,5-dicarboxylate hydrochloride Physicochemical properties (1) Melting point 128-130°C (i+) Elemental analysis value (CS. H3? N3 os.
n (%) N (%) Calculated value 58.11 6.18 6.78 Actual value 58.03 6.23 6.750ii)
Nuclear magnetic resonance spectrum (DMSO-d6) δ: 1.1
4 (6H,t) 2.38 (3H,s) 4.70 (2H,d) 5.02 (I H,s ) Example 6 Diethyl 2-[3-(2-hydroxy-3-phenoxypropylamino) )propyl]-6-methyl-4-(m
-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylate oxalate Physicochemical properties (1) Shape Amorphous powder (11) Elemental analysis value (C5oHsyNsOs ・(CO
OH) 1) C (%) H (%) Nc%) Calculated value 58.44 5.98 6.39 Actual value 58.13 6.12 6.330iD Nuclear magnetic resonance spectrum (CDC1s) (free compound) δ : 2.18 (6H, t) 1.64-2.0 (2H, m) 2.30 (3H, s) 5.04 (IH, s) Example 7 Processed in the same manner as Example 3, and the following The compound was obtained.

Diethyl 2-[3-(2-hydroxy-3-phenoxypropylamino)propionamide]-6-methyl-
4-(m-nitrophenyl)-1゜4-dihydropyridine-3,5-dicarboxylate hydrochloride Physical and chemical properties (1) Melting point 159-161°C (11) Elemental analysis value (CS. H8, N40゜(as HCI) C (%) II (%) N) Calculated value 56.92 5.89 8.85 Actual value 56.69 6,00 8.84011) Nuclear magnetic resonance spectrum (CDCI, ) (free compound) a : 1.24 (3H,t) 2.38 (3H,a) 2.48-2.74 (2H,m) 2.80-3.14 (4H,m) 3.92-4.24 (7H , m) 5.06 (IH, s) Examples 8 to 11 The following compounds were obtained in the same manner as in Example 4.

Example 8 Diethyl 2-[3-[3-(2-hydroxy-3-phenoxypropylamino)propionamido]brovle]-6-methyl-4-(m-nitrophenyl]-1,4
-Dihydropyridine-3,5-dicarboxylate hydrochloride Physicochemical properties (1) Shape Amorphous powder (11) Elemental analysis value (as Cs5H4tN<Ch・HCI) C (%) H (%) N (%) Calculated value 58.71 6.42 8.30 Actual value 5
8.53 6.57 8.25 (11) Nuclear magnetic resonance' spectrum (CDCI3) (free compound) δ: 1.10 (3H,t) i, 22 (3H,t ) 2.34 (3H,s ) 5.04 (11,s) Example 9 h Diethyl 2-[5-[3-(2-hydroxy-3-phenoxypropylamine)propionamido]pentyl]-6-methyl-4-(m-nitrophenyl )-1,4
-Dihydropyridine-3,5-dicarboxylate Physical and chemical properties (1) Shape Amorphous powder (11) Elemental analysis value (as C35H46H40i1)
C (%) Hc%) NG) Calculated value 63.05 6.95 8.40 Actual value 62,76 6.99 8.47011) Nuclear magnetic resonance spectrum (CDC13) δ: 1.12 (3H,
t) 1.12 (3H, t) 2.98 (3H, s) 5.10 (IH, a) Example 10 Suh ・MCI Diethyl 2-[[2-[3-(2-hydroxy-3-
phenoxypropylamine)propionamido]ethoxy]methyl]-6-methyl-4=(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride Physicochemical properties (1) Shape Amorphous Powder (11) Elemental analysis value (Cps HHH40+.・HCI
cc%) HC%) C) Calculated value 57.35 6.27 8.11 Actual value 57.15 6.13 8.13011) Nuclear magnetic resonance spectrum (CDCb) J: 1.20 (6
H,t) 2.44 (3H,II) 4.76 (2H,8) 5.10 (IH,8) Example 11 Dimethyl 2-[[6-(2-hydroxy-3-phenoxypropylamine)hexane amido]methyl]-6-
Methyl-4-(m-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride Physicochemical properties (1) Shape Amorphous powder (11) Elemental analysis value (as C32H40H409・HCl) C) H) N (%) Calculated value 58.13 6.25 8.47 Actual value 57.87 6.11 8.39011) Nuclear magnetic resonance spectrum (CDC5) (free compound) δ: 2.34 (6H, a ) 3.64 (3H, s) 4.40 (2H, d) 5.04 (IH, s)

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. R^1: Phenyl group or phenoxymethyl group, R^2, R^3 and R^4: The same or different lower alkyl groups, A: an alkylene group which may be interrupted by an oxygen atom, or a group represented by the formula -Y^1-NHCO-Y^2-, Y^1: a single bond or an oxygen atom An alkylene group which may be interrupted by (Y^2: alkylene group) or a salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Symbols in the formula have the following meanings. R^2, R^3 and R^4: Same or different lower alkyl group, A: An alkylene group which may be interrupted by an oxygen atom, or a group represented by the formula -Y^1-NHCO-Y^2, Y^1: a single bond, or an alkylene group which may be interrupted by an oxygen atom, Y ^2: Alkylene group) Reacting an amine represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 means a phenyl group or phenoxymethyl group) Reacting with an epoxy compound represented by the general formula Dihydropyridine represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Symbols R^1, R^2, R^3, R^4 and A in the formula have the same meanings as above) Derivative manufacturing method (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Symbols in the formula have the following meanings. R^2, R^3 and R^4: Same or different lower alkyl group, A: An alkylene group which may be interrupted by an oxygen atom, or a group represented by the formula -Y^1-NHCO-Y^2-, Y^1: a single bond, or an alkylene group which may be interrupted by an oxygen atom, Y^2: alkylene group X^1: halogen atom or amino group , X^2 means an amino group when X^1 is a halogen atom, and a halogen atom when X^1 is an amino group). General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Symbols R^1, R^2, R^3, R^4 and A in the formula have the same meanings as above) Method for producing dihydropyridine derivatives