JPS60246376A - N-substituted-3,4-dihydropyrimidine derivative, its preparation and remedy for circulatory disease - Google Patents

Abstract

NEW MATERIAL:The N-substituted-3,4-dihydropyrimidine derivative of formula I [R is phenyl or nitrophenyl; R<1> is arylalkoxy, alkoxy, cycloalkyl, or -O-(CH2)n-Z (Z is alkoxy, cycloalkyl or halogen-substituted alkyl; n is 1-3); R<2> is methyl or ethyl]. EXAMPLE:5-Ethoxycarbonyl-2,6-dimethyl-4-( 2'-nitrophenyl )-3-N-octyloxycarbonyl- 3,4-dihydropyrimidine. USE:A remedy for circulatory diseases such as hypotensor, agent for improving cerebral circulation and metabolism, antistenocardia, etc. It has prolonged drug action and strong vasodilating activity. PREPARATION:The compound of formula I can be prepared e.g. by reacting the tautomer of formula II or formula III with the compound of formula IV (X is halogen) in the presence of a base, and if necessary, treating with an acid suitable for pharmaceutical use.

Description

Detailed Description of the Invention Object of the Invention a) Industrial Field of Application The present invention relates to the general formula (1) 1: where R represents a phenyl group or a nitrophenyl group, R1 represents an arylalkoxy group, and has 6 to 100 carbon atoms. Represents a straight-chain or branched alkoxy group, a straight-chain or branched chain having 1 to 4 carbon atoms or a cyclic alkyl group having 3 to 6 carbon atoms, or a group -O-(CH2)n-Z, where Km is an alkoxy group having 1 to 6 carbon atoms,
Represents a cyclic alkyl group having 6 or 4 carbon atoms or a halogen-substituted alkyl group having 1 to 6 carbon atoms, where n is 1 to 6
N-substituted 6,4-dihydropyrimidine derivatives having the following integer and R2 represents a methyl group or an ethyl group ft), acid addition salts thereof suitable as pharmaceuticals, methods for their production, and circulatory system diseases using them as active ingredients. Regarding therapeutic agents.

The Nlf-converted 6,4-dihydropyrimidine derivative represented by the above general formula +1+ has a long duration and strong vasodilatory effect, so it is used as a circulating agent for antihypertensive drugs, cerebral circulation and metabolism improving drugs, antianginal drugs, etc. It is used as a therapeutic agent for certain diseases.

b) Conventional technology In recent years, calcium antagonists (Ca + antagonists) have been attracting attention as a new type of therapeutic drug for cardiovascular disorders, and they have a wide range of medicinal effects, including hypertension, angina pectoris, cerebral circulation and metabolic insufficiency,
Not only is it effective for arrhythmia and is currently used in these treatments, but it has also recently been found to be effective in preventing arteriosclerosis and enhancing the effects of anticancer drugs, and its indications are increasing.

Currently known calcium antagonists include Nifedipine 7 and Nicardipine (N
1cardipine), verapamil (Verapa
mil), diltiazem
and so on.

On the other hand, there has not been much research on dihydropyrimidine derivatives to date, and only a few studies have been conducted on dihydropyrimidine derivatives.
h.

E,F,J,Org,Chem,, 27, (40
90 (1962).

Na5ipuri, D., et al.5ynthesis 10
73 (1982).

Kashima+ C, etrahedron:
I, etters 209 (1983) and Japanese Patent Publication No. 5
9-75572<Beyer A, G,) and the like. The reason for this is thought to be the instability and tautomerism of the dihydropyrimidine derivative.

C) Problems to be Solved by the Invention The above-mentioned known calcium antagonists have room for improvement in properties such as duration of action, organ selectivity, stability against light, heat, etc., and side effects. conducted extensive research to create a calcium channel blocker with improved properties. As a result, N- expressed by the above general formula (1)
It has been discovered that substituted-6,4-dihydropyrimidine derivatives have excellent sustainability and stability, and have a strong vasodilatory effect,
The invention has been completed.

Structure of the Invention a) Means for Solving the Problems According to the present invention, there are provided N-substituted 6,4-dihydropyrimidine derivatives represented by the general formula (1), acid addition salts thereof, and methods for producing them. .

(In the formula, R represents a phenyl group or a nitrophenyl group, W represents an arylalkoxy group, a straight chain or branched alkoxy group having 6 to 10 carbon atoms, a straight chain or branched chain having 1 to 4 carbon atoms) or a cyclic alkyl group having 3 to 6 carbon atoms or a group -O-(CH2)n-2!, where O is an alkoxy group having 1 to 6 carbon atoms,
Represents a cyclic alkyl group having 6 and 4 carbon atoms or a non-rogen-substituted alkyl group having 1 to 6 carbon atoms, represents an integer from nLl to O, and R2 represents a methyl group or an ethyl group) General formula (2) and ( Dihydropyrimidine derivatives, which are tautomers represented by two 121 (in the formula, R and R2 are the same as defined above), also have a vasodilatory effect, but are even more chemically stable. For the purpose of enhancing the effect and enhancing the effect, the general formula (
A compound represented by 11 was synthesized.

The manufacturing process of the N-substituted 6,4-dihydropyrimidine derivative represented by the general formula (1) is as follows, for example.

(1) 6-methyl-dihydropyrimidine (2) and (
First, an α,β-unsaturated nibonyl compound R2 represented by the general formula (3) is a methyl group or an ethyl group, and R is a phenyl group or a nitrophenyl group) is converted into an acetate compound of 1 or more equivalents. Tetrahydropyrimidine derivative (4) is obtained by reacting with amidine in a suitable alcohol.

When using a salt such as acetamidine hydrochloride, it is preferable to prepare the free amine with an alkali metal alkoxide in advance. The alcohol used is preferably an alcohol having an alkyl group represented by substituent R2.

The tetrahydropyrimidine derivative (4) thus obtained can be purified as a hydrochloride or converted into dihydropyrimidine derivatives represented by general formulas (2) and (2) without purification.

K, which yields compounds (2) and (29) from compound (4), is dehydrated by heat treatment with an acid such as p-ph luenesulfonic acid or benzenesulfonic acid to obtain a dihydropyrimidine derivative: alumina, Mix with at least 5 times the weight of an inorganic substance such as silica gel or molecular sieve, preferably about 10 times the weight, and heat at 120° to 200°C.
Methods include heating for 5 minutes to 1 hour and extracting with an organic solvent; dissolving in phosphorus oxychloride and heating under reflux for dehydration.

Dihydropyrimidine derivatives are obtained in 40-70% yields when treated with acids, 20-50% yields when treated with inorganics, and 50% yields when further treated with phosphorus oxychloride. Furthermore, the dehydration conditions can be changed using acids such as camphor-10-sulfonic acid, Lewis acids such as boron trifluoride fist ether complex, and dihydropyrimidine 1E4.
4 bodies (2) and (29) are obtained.

The obtained compound can be purified by general purification methods such as layered chromatography, ion exchange chromatography, partition chromatography, and distillation. Also, hydrochloric acid? It can also be purified by crystallization and recrystallization as a salt of an inorganic acid such as #, acid, phosphoric acid, or an organic acid such as oxalic acid, tartaric acid, phosphoric acid, or maleic acid.

(Two (in the formula, R2 is a methyl group or an ethyl group, R is a phenyl group,
The compound represented by the general formulas (2) and (2) obtained in Production +++ is dissolved in an organic solvent such as a chlorine-based, aromatic hydrocarbon-based, or ether-based solvent, and a base such as a trichloride is added. In the presence of alkylamine, sodium hydride, potassium hydride, triethylamine, the general formula % formula % (in the formula, group, a linear or branched chain having 1 to 4 carbon atoms or a cyclic alkyl group having 6 to 6 carbon atoms, or a group -O-<CH2)I, -Z, where KZ is a group having 1 to 6 carbon atoms. alkoxy group,
a cyclic alkyl group having 6 or 4 carbon atoms or a substituted alkyl group having 1 to 6 carbon atoms, where n is 1.2 or 6), such as chloroalkyl carbonate, acylnotameride or chloro The Nff1-substituted 6,4-dihydropyridine derivative, which is the compound of the present invention, can be obtained by reacting with dialkyl carbonate which is equivalent to carbonic acid.

Or, the compound represented by (2) and (2') is made into two metal salts with sodium hydride, potassium hydride, alkyl lithium or lithium hydride and then reacted with the above formula % formula % It can also be obtained by k.

NIi conversion 6.4- which can be synthesized in this way
The Na substituent at the 6-position of the dihydropyrimidine derivative (1) is, for example, n-propoxy group, impropoxy group, n-butoxy group, 5ec-butoxy group, t-butoxy group, imbutoxy group, n-pentyloxy group, methylbutoxy group. group, ethylpropoxy group, n-hexyloxy group, methylpentyloxy group, ethylbutoxy group, n-hebutyloxy group,
Methylhexyloxy group, ethylpentyloxy group, n
-Octyloxy group, methylhebutyloxy group, ethylhexyloxy group, n-nonyloxy group, methyloctyloxy group, ethylhebutyloxy group, n-decanyloxy group, methylnonyloxy group, ethyloctyloxy group, cyclopropylmethyloxy group , cyclopropylethyloxy group, cyclopropylpropyloxy group, trichloroethoxy group, trichloropropoxy group, benzyloxy group, aromatic ring-substituted benzyloxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group,
Dichloroethoxy group, ethoxypropoxy group, methyl group, ethyl group, propyl group, zusoprobyl group, cyclopropyl group, n-butyl group, 5ec-butyl group, isobutyl group, t-butyl group, pentyl group, methylbutyl group, hexyl group group, methylpentyl group, heptyl group, methylbexyl group, octyl group, methylhebutyl group, nonyl group, methylnonyl group, methyloctyl group, decanyl group, cyclopropyl group, cyclobutyl group, and the like.

The compound represented by the general formula (1), which is the compound of the present invention, can be purified by general adsorption column chromatography, ion exchange chromatography, recrystallization, etc. after the above-mentioned reaction, or by hydrochloric acid, sulfuric acid, etc. It can be purified using recrystallization, adsorption chromatography, or ion exchange chromatography by treating with an inorganic acid such as phosphoric acid, or an organic acid such as sulfuric acid, phosphoric acid, or malic acid.

fb1 action The thus obtained compound (1) of the present invention exhibited long-lasting, strong vasodilatory action, and antihypertensive action in vasodilatory action according to the Langendorff method or in pharmacological tests under severe anesthesia.

That is, the compound of the present invention exhibits an excellent coronary vasodilator effect in guinea pigs, and in dogs, it causes an extremely excellent increase in vertebral artery blood flow, a decrease in vertebral artery vascular resistance, and a decrease in systemic blood pressure. Therefore, the present compounds are useful in the treatment of coronary artery defects, cerebral circulation improvement, and hypertension.

The compound (1) of the present invention can be used alone or together with other compositions.
, for example, tablets, troches, pills, granules, powders,
It can be used in the form of capsules, ampoules, suppositories, etc. Other compositions include, for example, starch, dextrin, sucrose, lactose, silicic acid, carboxymethylcellulose, cellulose, gelatin, polyvinylpyrrolidone, glycerin, agar, calcium carbonate, sodium bicarbonate, paraffin, cetyl alcohol, stearate, Examples include kaolin, bentonite, talc, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, and propylene glycol.

For parenteral administration using injection pressure, the water-soluble salt of the present compound is dissolved in sterile distilled water or sterile physiological saline and sealed in an ampoule to prepare an injection preparation.

If necessary, stabilizers and/or buffer substances may be included.

The daily dosage for a light dose of the compound of the present invention (11) is suitably 5r+y to 50011 g per day for an adult. Naturally, the dosage should be adjusted as appropriate depending on the condition at the time of administration.

lcl Examples Reference examples and examples of the present invention are shown below. Temperatures are Serra's unless otherwise specified.

115-ethoxycarbonyl-2,6-cymethyl-4
-Phenyl-dihydropyrimidine 5-ethoxycarbonyl-6-hydroxy 2゜6-dimethyl-4-phenyl-1,4,5,6-titrahydropyrimidine 625~ in anhydrous benzene 5d L, paratoluenesulfonic acid 472~ and reflux for 1.5 hours. Most of the benzene is distilled off, diluted with a saturated aqueous solution of potassium carbonate, and extracted with chloroform. After drying the organic layer over anhydrous potassium carbonate, the solvent was distilled off under reduced pressure to obtain residue 572. The product was subjected to column chromatography on alumina (Aiko Junyaku) and eluted with a 1:1 mixed solvent of chloroform and benzene, then chloroform to obtain the title compound 698.

This compound was dissolved in ethanol and treated with saturated hydrochloric acid solution in ether to give the title dihydropyrimidine hydrochloride.

Properties: Colorless crystals Melting point: 156-157° (Recrystallization solvent: ether/hexane) IR spectrum (chloroform, my-”): 3
440,1695'H-NMR spectrum (DMSO-
d6. Chu-): 1.08 (3H, t, J=7Hz)
+ 1.86 (3H, s).

2.20 (!IH, s), 3+, 95 (2H, q, J=
7Hz).

5.33 (IH, s), 7.15-7.30 (5H, m
) Physical properties of hydrochloride Melting point: 209-211° (Recrystallization solvent: ethanol/ether) Elemental analysis (j@H(Working N(@Calculated value 61.12 6.50 9.50 Actual value 61
．． 14 6.50 9.34 (molecular formula Cl5H1
, ClN2O□] Example 1 5-ethoxycarbonyl-2+ 6- dimethyl-4-
(2'-ditrophenyl)-3-N-octyloxycarbonyl-3,4-dihydropyrimidine hydrogenation) I
172 da (4.3 mmol) of suspension of Jum in 60 oil
5-ethoxycarbonyl-2゜6-dimethyl-4-
(2'-nitrophenyl)-dihydropyrimidine 1.0
g (3.3 mmol) of anhydrous tetrahydrofuran 53 m
/solution [added in portions at 0° C., then 98 Jll (5Q in IJ mole) of n-octyl chloroformate were added. The reaction solution was stirred at room temperature for 45 minutes, concentrated under reduced pressure using an AK vacuum cleaner, water was added, and further extracted with chloroform.

The organic layer was washed with saturated brine, dried over magnesium sulfate, and then evaporated under reduced pressure to obtain a residue.

This residue was purified using silica gel column chromatography (elution solvent: chloroform) to give 1.52 (yield: 99
The title compound of Section 2) was obtained.

Example 2 5-ethoxycarbonyl-2,6-dimethyl-4- (
2'-nitrophenyl)-3-N-(2,2゜2-to11 chloroethoxycarbonyl)-i4-dihydropyrimidine5-ethoxycarbonyl-2,6-dimethyl-4-(
2'-nitrophenyl)-cyhydrohirimicin 1.01
Dissolve 2-triethylamine (14,5 mmol) in 20 ml of formal and stir at room temperature.
0.9d (6.54 mmol) of 2.2.2-trichloroethoxychloroformate was added. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: methylene chloride) to give 0.71. The title compound was obtained in a yield of 45 cm.

Example 6 6-N-cyclopropylmethoxycarbonyl-2,6-
Suspension of dimethyl-5-ethoxycarbonyl-4-(2'-nitrophenyl)-3,4-dihydropyrimidine sodium hydride in 50% oil 408 da(8,5
cyclopropylcarbinol 612~(
A solution of 41111 (8.5 mmol) in anhydrous tetrahydrofuran was added and stirred for 10 minutes at room temperature.

Trichloromethyl chloroformate (
30.5+n/(4.2 mmol) of phosgene dimer was slowly added to the mixture, and the mixture was further stirred at room temperature for 25 minutes.

On the other hand, a suspension of sodium hydride in 504 oil 45”&(
0.94 mmol) was suspended in 5 ml of anhydrous tetrahydrofuran, and 5-ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-dihydropyrimidine 259# (0.85 mmol of tetrahydrofuran ( 5d) The solution was stirred.
Stir for a minute. To this solution was added the reaction mixture of sodium hydride, cyclopropyl carbinol and trichloromethyl chloroformate at 0°C.

After 15 minutes, saturated brine was added and extracted with chloroform. The organic residue was dried over anhydrous magnesium sulfate and concentrated. The submerged residue was subjected to thin layer chromatography using silica gel (developing solvent: chloroform:acetone = 15:
1. Elution solvent chloroform: methanol = ID
: 1) to obtain the title compound 122 days (yield: 66%).

Examples 4-11 Following the method of Example 1, each product 2 was obtained from the appropriate reactants.

The yield, physical properties, etc. of the products of Examples 1 to 11 are shown in Table 1 below.

Example 12 5-ethoxycarbonyl-2,6-dimethyl-4- (
2'-nitrophenyl)-3-probionyl-6,4-
Dihydropyrimidine 5-ethoxycarbonyl-2,6-dimethyl-4-(2
'-nitrophenyl) -dihydropyrimidine 1.00
．． 9 (3.30 mmol) was dissolved in chloroform of 151R1, triethylamine 2d (14.3 smol) was added thereto while stirring at room temperature, and then globionyl chloride (0.4014.32 mmol) was added dropwise. After stirring at room temperature for 40 minutes, it was condensed under reduced pressure, and the resulting residue was purified by silica gel column chromatography, and then recrystallized from benzene/hexane to obtain the title compound of 0.69.9 (yield: 58). Ta.

Example 16 5-Ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-6-acetyl- in the same manner as Example 12, but using acetyl chloride instead of globionyl chloride. 6,4-dihydropyrimidine was obtained, Example 14 6-cyclopropionyl-5-ethoxycarbonyl-4
-(2'-nitrophenyl)-2,6-cymethyl-6.
0.2 g (5 mmol) of a suspension of 4-dihydropyrimidine sodium hydride in 60 M oil was suspended in iQ ml of anhydrous tetrahydrofuran,
Add to this solution a solution of 113.3 mmol of 5-ethoxycarbonyl-2,6-dimethyl-4-(2'-nitrophenyl)-dihydropyrimidine in anhydrous tetrahydrofuran.
1 omt> was added at 0° C. and then stirred at room temperature for 5 minutes. Add 10ml of anhydrous tetrahydrofuran to this solution! Dissolved cycloglovir chloride 1.1.9 (1
0.5 mmol) and stirred for 1 hour.

Chloroform was added to the reaction solution, and the mixture was washed with a 2% aqueous sodium hydroxide solution and further washed with saturated brine. The organic layer was dried and condensed, and the resulting residue was subjected to silica gel column chromatography (solvent: chloroform) to obtain crystals. Then, it was recrystallized from an ether solvent to obtain 0.703 g (yield 57%) of the Mukuro compound as pale yellow prism crystals.

The yield, physical properties, etc. of the products of Examples 12 to 14 are shown in Table 2 below.
It was shown to.

Example 15 The pharmacological effect (ED3o) of the compounds of the present invention on vertebral artery vascular resistance in anesthetized dogs was tested.

Test method Mixed male and female dogs (7 to 14 years old) were treated with thiobental sodium (
After induction anesthesia with 35IA9/kg (intraperitoneal administration), the animals were anesthetized with urethane (400~/kl?, intravenous administration) and α-chloralose (60~/kg, intravenous administration), and the test was conducted under artificial respiration. I did it. The left vertebral artery was exposed through a thoracic interstitial incision, a blood flow measuring probe was attached to its origin, and an electromagnetic blood flow meter (MF-27, Nihon Kohden Co., Ltd.) was used.
Blood flow was measured at

At the same time, the systemic blood pressure (mean blood pressure) is obtained from the right femoral artery, the electrocardiogram is obtained from lead ①, the heart rate is obtained by driving the tachometer with the R wave of the electrocardiogram, and the output of the mean blood pressure value and the mean vertebral artery blood flow is multiplied and divided. Unit CEO-601G, Nihon Kohden (
Polygraph CRM-600. Japan light! Co., Ltd. recorded simultaneously above.

All drugs were injected through a cannula previously inserted into the femoral artery.

ED3o (IR9Ag) by intravenous injection as shown in Table 3.
) got the value. The compound numbers in the table correspond to the example numbers above.

Table 6 Effects of the Invention The compound of the present invention represented by the general formula (1) has a strong vasodilatory effect and has a long duration of action, so it can be administered less frequently than Ca' antagonists currently in practical use. I'll try it.

Therefore, we believe that the treatment of circulatory system diseases that require a long treatment period can be greatly simplified.

Procedural amendments May L7, 1985 Manabu Shiga, Commissioner of the Patent Office2, Name of the invention: N-substituted 6,4-dihydropyrimidine derivatives, their manufacturing process and therapeutic agents for circulatory system diseases6, Person making the amendment and Relationship of Patent Applicant Address Name (190) Suntory Ltd. 4, Agent] The contents of the amendment in column 6 of the [Detailed Description of the Invention] of the specification are amended as follows.

Negative line Before correction After correction 9 4 (40904090 16 lower 5 groups R1 of group / 28 6 44 64 34 4.9.1i ”+9/to 91r9/to 9 or more -
1-

Claims (1)

[Scope of Claims] (In the formula, R represents a phenyl group or a nitrophenyl group, and R1 is a aryl alkoxy group, a linear or branched alkoxy group having 6 to 10 carbon atoms, or a linear or branched alkoxy group having 1 to 10 carbon atoms. 4 linear or branched or cyclic alkyl group having 6 to 2 carbon atoms, or group -0-(CH2)n-Z'
Y, where Z represents a lower alkoxy group having 1 to 2 carbon atoms, a cyclic alkyl group having 6 or 4 carbon atoms, or a halogen-substituted alkyl group having 1 to 6 carbon atoms, and n is an integer from 1 to 6; , R2 represents a methyl group or an ethyl group, and a pharmaceutically suitable acid addition salt thereof. (2) R1 is n-propoxy group, n-butoxy group, isobutoxy group, 5ec-butoxy group, t-butoxy group,
n-pentyloxy group, methylbutoxy group, hexyloxy group, methylpentyloxy group, ethylbutoxy group,
heptyloxy group, methylhexyloxy group, ethylpentyloxy group, octyloxy group, methylhebutyloxy group, ethylhebutyloxy group, nonyloxy group, methyloctyloxy group, ethylhebutyloxy group, decanyloxy group, methylnonyloxy group, The scope of claims that is an ethyl octyloxy group, a cyclopropylmethoxy group, a cyclopropylethoxy group, a cyclopropylpropoxy group, a methoxyethoxy group, an ethoxyethoxy group, an ethoxypropoxy group, a trichloroethoxy group, a dichloroethoxy group, or a benzyloxy group Compound according to item 1. (31R' is a methyl group, an ethyl group, a propyl group, a butyl group, a 5ee-butyl group, a t-butyl group, an inpropyl group, an isobutyl group, a cyclopropyl group, or a cyclobutyl group) Compound. (4) General formula C, where R is a phenyl group or a nitrophenyl group,
R2 is represented by a methyl group or an ethyl group) (in the formula, Straight chain or branched chain or 6 carbon atoms
to 6 cyclic alkyl group, or group -0-(CH2). -2, where KZ is an alkoxy group having 1 to 6 carbon atoms,
(represents a cyclic alkyl group having 6 or 4 carbon atoms or a -.rogen-substituted alkyl group having 1 to 6 carbon atoms, and n represents an integer of 1 to 6). The general formula (in the formula R
+ R1 and R2 represent the same meanings as above j) A method for producing an N-substituted 6,4-dihydropyrimidine derivative and a pharmaceutically suitable acid addition salt thereof. (5) General formula (wherein R is a phenyl group or a nitrophenyl group,
R2 represents a methyl group or an ethyl group, and Y represents an alkali metal. 100 represents a linear or branched alkoxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a cyclic alkyl group having 6 to 6 carbon atoms, or a group -0-(CH□)n-Z , where 2 is an alkoxy group having carbons a1 to 6,
Represents a cyclic alkyl group having 6 or 4 carbon atoms or a halogen-substituted alkyl group having 1 to 6 carbon atoms, where n is 1 to 6
(representing an integer number of Method for producing acid addition salts. (6) General formula (in the formula, R represents a phenyl group or a nitrophenyl group, R1 is an arylalkoxy group, a straight chain or branched alkoxy group having 6 to 10 carbon atoms, a straight chain having 1 to 4 carbon atoms) represents a branched or cyclic alkyl group having 6 to 6 carbon atoms or a group -0-(CH2)n-Z, where 2 is an alkoxy group having 1 to 6 carbon atoms;
a cyclic alkyl group having 6 or 4 carbon atoms or a -.rogen-substituted alkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 6, and R2 represents a methyl group or an ethyl group j) 2 N-substituted A therapeutic agent for circulatory system diseases comprising a 6,4-dihydropyrimidine derivative or a pharmaceutically suitable acid addition salt thereof as an active ingredient.