JPS6143171A - Novel n-substituted 3,4-dihydropyrimidine derivative and remedy for disease in cardiovascular system - Google Patents

Abstract

NEW MATERIAL:An N-substituted 3,4-dihydropyrimidine derivative expressed for formula I [X<1>, X<2> and X<3> are H, nitro, cyano, halogen, trifluoromethyl, methyltio or lower alkoxyl; R<1> is 1-13C straight chain or branched chain alkyl, formula II (n is 1 or 2; A is cycloproply, etc.), etc,; R<2> is 3-12C straight chain or branched chain alkyl, 4-7C alkenyl, formula III (l is 1, 2 or 3; D is cyclopropyl, etc.), etc., provided that R<2> is formula III when R<1> is 1-13C alkyl or formula II, and D is group other than cycloproply, etc.] and a salt thereof. EXAMPLE:5-(n-Buthyloxycarbonyl)-4-( 2'-chlorophenyl )-3-( 2''-ethylhexyloxycarbonyl)-2,6-dimethyl-3,4-dihydropyrimidine. USE:A teating agent for coronary vasodilation, amelioration of cerebral circulation and hypertension. PREPARATION:A compound expressed by formula IV is reacted with a compound expressed by formula V (X is halogen) in the presence of a base to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of Application The present invention relates to the general formula (1) [wherein x1, I2 and I3 are the same or different and represent a hydrogen atom, a nitro group, a cyano group, a halogen atom, a trifluoro Represents a methyl group, methylthio group or lower alkoxy group: R1 is a linear or branched alkyl group having i-13 carbon atoms, or a group -(c)I2)nA (in the formula, n is 1 or 2) , A is a cyclopropyl group,
(represents a cyclomethyl group or cyclohytyl group), a straight-chain or branched alkenyl group having 4 to 12 carbon atoms, a straight-chain or branched alkynyl group having 5 to 8 carbon atoms, or a group -(CH2) m- B (in the formula, m represents an integer of 1 to 8, B represents a phenyl group or a substituted phenyl group); R2 has 3 carbon atoms;
~12 straight-chain or branched alkyl groups, with 4 or more carbon atoms
A linear or branched alkenyl group of 7, or a group -(CH2)rD (in the formula, 4 represents 1.2 or 3, D represents a cyclopropyl group, a cyclobutyl group, or a cyclo represents a methyl group) However, when R1 is a linear or branched alkyl group having 2 to 13 carbon atoms, or a group -(OH2)n-A, and A is a cyclopropyl group or a cyclobutyl group, R2 is a group. A novel N-substituted 3,4-dihyropyrimidine derivative having (CI(z)l-D in which D is a group other than a cyclozolopyl group or a cyclobutyl group) and a pharmaceutically suitable acid addition salt thereof; The present invention relates to a therapeutic agent for circulatory system diseases containing these as active ingredients.

The novel dihyropi'J midine derivative represented by the above general formula (1) has a strong vasodilatory effect and is therefore a therapeutic agent for circulatory system diseases such as an antihypertensive drug, a drug for improving cerebral circulation and metabolism, and an antianginal drug. It is used as a.

Background of the Invention In recent years, calcium antagonists (Ca+ antagonists) have been attracting attention as a new type of therapeutic drug for cardiovascular disorders, and 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 channel blockers include nianidipine (Ni fedipine) and nicardipine (Ni fedipine).
cardipine), Vera, e-mil (Verapam)
Examples include diltiazem with il.

To date, not much research has been done on dihibiropyrimidine derivatives, with only a few studies being carried out by Silversmith, E.

F, J, Org, Chem, 27. (4090(
1962) - Nasipuri, Do et al. 5ynth
esis 1073 (1982).

Kashima, C+et al. Tetrahedron L
etters 209 (1983), and JP-A-59
-73572 (Bayer A, G,) and the like. The reason for this is thought to be the instability and tautomerism of the dihuman 90-pyrimidine derivative.

Since the above-mentioned known calcium antagonists have room for improvement in properties such as duration of action, organ selectivity, stability against light and heat, and side effects, the present inventors have developed a calcium antagonist with improved properties. We conducted extensive research to create this. As a result, N expressed by the above general formula (1)
-substituted-3,4-dihydropyrimidine fatty conductor is persistent,
They discovered that it has excellent stability and a strong vasodilation effect, and completed the present invention.

Means for Solving the Problem According to the present invention, the new N represented by the general formula (1)
Fif-converted 3,4-dihuman 90-pyrimidine derivatives and acid addition salts thereof are provided.

[In the formula, X1, x2 and X3 are the same or different and represent a hydrogen atom, a nitro group, a cyano group, a halogen atom, a trifluoromethyl group, a methylthio group or a lower alkoxy group; R1 is a C1-C13 group; A straight-chain or branched alkyl group, or a group -(CH2)n-A (wherein n represents 1 or 2, A is a cyclopropyl group,
(cyclobutyl group or cyclo represents an ethyl group), a straight-chain or branched lead alkenyl group having 4 to 12 carbon atoms, a straight-chain or branched alkynyl group having 5 to 8 carbon atoms, or a group -(CH2) m-B (in the formula, m represents an integer of 0 to 8, B represents a phenyl group or a substituted phenyl group); R2 has 3 carbon atoms;
~12 linear or branched chain alkyl group, carbon number 4~
7 represents a straight-chain or branched alkenyl group or group -(CHz)j-D (in the formula, 1 represents 1.2 or 3, and D represents a cyclointhyl group, a cyclobutyl group, or a cyclointhyl group), but , provided that R1 is a linear or branched alkyl group having 1 to 13 carbon atoms or a group -(CHz)n-A, and A
When R represents a cyclopropyl group or a cyclobutyl group, R
2 is a group -(CHz)j-D, where D is a group other than a cyclopropyl group or a cyclobutyl group] General formulas (2) and (2') (2) (2') (Formula Middle xi,
x2, x3 and R2 are the same as defined above. ), the tautomer dihydrohy'J anticonductor has also been found to have a vasodilatory effect;
A compound represented by the general formula <1) was synthesized for the purpose of making it chemically stable and enhancing its action.

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

(1) General formulas (2) and (2') XI X2
XI X2 [in the formula x1, X2
and Branched alkyl group, linear or branched alkenyl group having 4 to 7 carbon atoms, or group -(GH2)g-D (in the formula, l represents 1.2 or 3, and D is a cyclopropylene group) , represents a cyclodityl group or a cyclopentyl group)
] The tautomer represented by can be obtained by the following method. That is, R20H (in the formula, R2 represents the same meaning as above) and 1 equivalent of diketene are heated at 100 to 200°C, preferably 120°C, for 0 minutes, provided that when R2 contains a nitrogen atom, 0°C Alternatively, the reaction proceeds at room temperature to obtain a β-, ketoester represented by the general formula (3).

(In the formula, R2 has the same meaning as above) or by treating R20H with diketene in the presence of 1 equivalent of a base such as trialkylamine at room temperature or 0°C, or by reacting it with diketene in the presence of sodium hydride or potassium hydride. A compound of general formula (3) can also be obtained.

A benzylidene compound (4) is obtained by adding an aromatic ring-substituted or unsubstituted benzua A/dehyde to this β-ketoester (3) and subjecting it to dehydration condensation.

(In the formula, x1, x2, X3 and R2 have the same meanings as above) This -:ndylidene (4) is condensed using acetamidine or acetamidine hydrochloride to give a tetrahydropyrimidine compound (5).

The above condensation reaction is carried out in the presence of a base for synthesizing this tetrahuman tetrapyrimidine (5). The base used here is preferably a metal alkoxide or metal Hytri-P, and the solvent is alcohol, ether, or dimethylformamide. The pyrimidine (5) may be treated with an acid such as p-)luenesulfonic acid, boron trifluoride, camphorsulfonic acid, etc., heated, heated, or silica gel.
Compounds represented by formulas (2) and (2') can be obtained by heating alumina or molecules.

The obtained compound can be produced by general purification methods such as adsorption chromatography, ion exchange chromatography, partition chromatography, filtration, distillation, and recrystallization;
. It can also be purified by crystallization and recrystallization as a salt of an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or an organic acid such as oxalic acid, tartaric acid, succinic acid, or maleic acid.

(II) Production of novel N-substituted 3,4-dihydropyrimidine visiting conductor (1) The above general formula (2) and (
The compound represented by 2') is dissolved in a chlorine-based, aromatic hydrocarbon-based, or needle-based organic heating medium, and in the presence of a base such as trialkylamine, sodium hydride, potassium hydride, or triethylamine, the compound represented by formula (6)% Formula % (6) [In the formula, X represents a halogen atom; R has 1 to 13 carbon atoms
straight-chain or branched alkyl group, group -(CH2)
n-A (in the formula, n is l or 2 missing, A is a cyclopropyl group,
cyclomethyl group or cyclopentyl group), linear or branched alkenyl group having 4 to 12 carbon atoms, linear or branched alkynyl group having 5 to 80 carbon atoms, group -(CH2)m-B (in the formula, m represents an integer of 1 to 8, B represents a phenyl group or a substituted phenyl group); R2 has 3 carbon atoms;
~12 linear or branched chain alkyl group, carbon number 4~
A linear or branched alkenyl group of 7, or a group -(CHz)g-D (in the formula, I represents 1.2 or 3, and D represents a cyclopropyl group, a cyclomethyl group, or a cyclocinthyl group) The novel N-substituted 3,4-dihydropyrimidine derivative (1), which is a compound of the present invention, can be obtained by reacting with the compound shown below.

Alternatively, the compound (1) of the present invention can be obtained by combining the compounds represented by (2) and (2') with sodium hydride, potassium hydride,
Alkyl lithium or lithium hydride (2) and (2
It can also be obtained by forming a metal salt of `) and then reacting it with a compound of general formula (6).

Novel N substitutions 3,4 that can be synthesized in this way
- The 3-position N substituent of dihydropyrimidine derivative (1) is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, formula -methyl group, t-butyl group, pentyl group, methyldityl group, ethylpropyl group group, hexyl group, methyl is a methyl group, ethylmethyl group, dimethylnonyl group, heptyl group, methylhexyl group, ethylpentyl group, dimethyl is a methyl group, octyl2, methylheptyl group, ethylhexyl group, dimethylhexyl group, nonyl group, methyloctyl group, ethylheptyl group, dimethylhebutyl group, decanyl group, methylnonyl group, ethyloctyl group, dimethylofnal group, undecanyl group, methyldecanyl group, nonyl group, dimethylnonyl group, dodecanoyl group.

Tridecanoyl group, cyclopropylmethyl group, cyclozolobyl ethyl group, cyclozolobyl zorobyl group, cycloditylethyl group, cycloditylethyl group, cyclopentylmethyl group, cyclopentylethyl group, 2-ffnyl group,
2- is enthenyl group, 3-hexenyl group, 3-heptenyl group, 4-octenyl group, 3-methyl-2-octenyl group, geranyl group, 2-decenyl group, 3.7-cymethyl-2
-decenyl M, 3-ethyl-7-methyl-2-decenyl group, ar-yethyl-2-7'cenyl group, 4-antynyl group, 2-hexynyl group, 2-hebutynyl group, 6-methyl f
-2-hebutynyl group, 3-hebutynyl group, 4-ethoxycarbonylphenyl group, 4-propoxycarbonylphenyl group, 3,4-dichlorophenyl group, 3,4-dinitrophenyl group, 4-nitrophenyl L 3 -Nitrophenyl &, 4-chlorophenyl group, 3-chlorophenyl group, 4-bromophenyl L4-methoxyphenyl group-3
, 4-dimethoxyphenyl group, 4-ethoxyphenyl group, phenyl group, 4'-methoxycarbonylphenylmethyl L4'-ethoxycarbonylphenylmethyl &, 2'
-nitrophenylmethyl L3'-nitrophenylmethyl! , 4'-ditrophenylmethyl group, a'-vt-ruphenylmethyl group, 4/-chlorophenylmethyl group, 3/
, 4/ -dichlorophenylmethyl group, 4'-bromophenylmethyl group, 3'-methoxyphenylmethyl group, 4
'-Methoxyphenylmethyl group, 3',4/-dimethoxyphenylmethyl group, 4'-7'lopoxycarbonylphenylmethyl group, benzyl group, phenethyl group, 3'-methoxyphenyl group, 4' -methoxyphenylethyl group, 3',4'-dimethoxyphenylethyl group, 3
'-Methoxycarbonylphenylethyl group, 4'-ethoxycarbonylphenylethyl group, 4'-methoxycarbonylphenylethyl group, 3',4'-dimethoxycarbonylphenylethyl group, 3'chlorophenylethyl group, 4'-chloro Phenylethyl group, 3'l 4'-'
) Chlorophenylethyl M, 4/-10muffenylethyl, S, 3', 4'-dinomphenylethyl group, 3'
-nitrophenylethyl group, 4'-nitrophenylethyl group s 3'p 4'-E'nitrophenylethyl group, phenylfurohyl group, 3'-methoxyphenylpropyl group, 4'-methoxyphenylpropyl group 3 /, 4
/-dimethoxyphenylpropyl group, 3'-methoxycarbonylphenylzorobyl group, 4'-methoxycarbonylphenylfurobyl L4'-ethoxycarbonylphenylpropyl group, 3'-chlorophenylpropyl group, 4'
-Chlorphenylpropyl as s'y c-dichlorophenylpropyl &, 4'-, / romphenylpropyl group, 3'-nitrophenylpropyl group, 4'-nitrophenylpropyl &, 3', 4'- Dinitrophenylpropyl group, phenylzutyl i, 4'-meth)qui7phenylbutyl group, 3'-ethoxyphenylbutyl group, 3'
, 4'-dimethoxyphenylbutyl group, 4'-chlorophenylethyl L 3', 4'-dichlorophenylethyl group, 4'-methoxycarbonylphenylmethyl group, 4'
-nitrophenylbutyl i, 3', 4'-9=)0 phenylbutyl group, phenylpentyl group, 4'-methoxyphenylintyl group, 4'-ethoxyphenyl 47f group, 3', 4'-1 methoxy Phenyl R-thyl group, 4'
-Chlorphenylpentyl group, 3', 4'-dichlorophenyl methyl M, 4'-ditrophenyl inthyl group, 3', 4'-cinitrophenyl/thyl group, phenylhexyl group, 4'- Methoxyphenylhexyl group, 4'-methoxycarynyl phenylhexyl &, 4'
-Chlorphenylhexyl group, 3', 4'-dichlorophenylhexyl group, 4'-nitrophenylhexyl group, 3/, 4/-9 nitrophenylhexyl group, phenylheptyl group, 3'-methoxyphenylheptyl group base, 4
'-Chlorphenylheptyl group sa', 4' -y
Chlorphenylheptyl 8. 4'-nitrophenylhebutyl group, phenyloctyl group, 4'-methoxyphenyloctyl group, 4'-chlorophenyloctyl &, 3'
, 4'-dichlorophenyloctyl group, 4'-nitrophenyloctyl group, 3/, 4/-dinitrophenyloctyl group, and the like. Regarding the substituent R2 of the 5-position ester group, propyl group, inpropyl group, butyl group, isobutyl group, 5ec-butyl group, t-butyl group,
is a methyl group, 3-methylbutyl group, 2-methylbutyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-ethyl7'tyl group, heptyl group, 5-methylhexyl group, 4-methyl Hexyl group, 3-ethylpentyl group, octyl group, 6-methylheptyl group, 4-ethylhexyl group, 3,3-dimethylhexyl group, 2-butenyl &, 3-, 'thenyl group, 3-pentenyl group, 3-
Mef-2--1 tenyl M, 2--' phthynyl group, 2-
Hexenyl group, 3-hexenyl &, 4-methyl-3-hex-1! =/'4.3- mef-2-hexenyl group,
2-heftynyl group, 3-methyl-2-hexenyl group, 5
-Methyl-4-hexenyl group, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclo-4-ethylmethyl group, cyclo-ethyl group, '/
Examples include clopentylzolopyl group.

The compound represented by the general formula (1) of the present invention can be purified by general adsorption column chromatography, ion exchange chromatography, recrystallization, etc. after the above-mentioned reaction, or can be purified by hydrochloric acid, sulfuric acid, phosphoric acid, etc. Inorganic acids such as oxalic acid, succinic acid, phosphorus! It can be purified using recrystallization, adsorption chromatography, and ion exchange chromatography after treatment with organic acids such as acids.

Effect The compound (1) of the present invention thus obtained exhibited a long-lasting, strong vasodilatory effect, and antihypertensive effect in a vasodilatory effect according to the Langendor 7 method or in a pharmacological test using anesthetized dogs.

That is, the compound of the present invention exhibits an excellent coronary vasodilator effect in guinea pigs, and produces an excellent increase in vertebral artery blood flow, decrease in vertebral artery vascular resistance, and decrease in systemic blood pressure in dogs. Therefore, this compound is useful for coronary vasodilation, improving cerebral circulation, and treating hypertension.

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

For parenteral administration by injection, the water-soluble salt of this compound is dissolved in sterile distilled water or sterile physiological saline and sealed in an ampoule to form an injectable preparation.

If necessary, a stabilizer and/or a buffer substance may be included.

The appropriate daily dosage for oral administration of the compound (1) of the present invention is 5 my to 500 mg per day for adults.

Naturally, the dosage should be increased or decreased as appropriate depending on the condition at the time of administration.

EXAMPLES The present invention will be explained in more detail with reference to Examples and Production Examples, but it goes without saying that the present invention is not limited to the scope of the Examples.

Furthermore, the compounds of the present invention shown in Examples easily form salts when dissolved in a suitable solvent, such as an ether or alcohol solvent, and treated with a solution of the above-mentioned inorganic or organic acid at room temperature.

In addition, unless otherwise specified, temperatures are Mr. Serra's.

Example 1 5-(n-butyloxycarbonyl)-4-(2'-chlorophenyl)-3-(2"-ethylhexyloxycarbonyl)-2,6-cymethyl-3.4-:)hydropyrimidinetetrahydronerane 50% sodium hydride rf in 51nl
A solution of 1.4 g of 5-(n-butyloxycarbonyl)-4-(2'-chlorophenyl)-2,6-dimethyl-dihydropyrimidine dissolved in 10 d of tetrahydrone was added to a suspension of 1 g of y fake at room temperature. After 20 minutes, a solution of 2-ethylhexylchloroformate 117'' dissolved in 5d of tetrahydrofuran was added dropwise, and after another 30 minutes, the reaction solution was diluted with ice water and extracted three times with ether.
After washing twice with water, it was dried over anhydrous magnesium sulfate and the solvent was removed to leave a 2-y residue.

This was subjected to silica gel column chromatography (Si02
50. ! i'), and 147 g of the title compound (yield 71
%) was obtained.

Example 2 3-(2-hebutynyloxycarbonyl)-2,6-
cymethyl-5-(3-methyl-2-guthynyloxycarbonyl)-4-(3,4,5-)rimethoxyphenyl)
-a, 4-:) hydropyrimidine tetrahydrofuran (THF) 5-a6-cymethyl-5-(3-methyl-2-guthynyloxycarbonyl)-
Add triethylamine 015d to a solution of 200 μl of 4-(3,4,5-)rimethoxyphenyl)-dihydropyrimidine, then add 2-heptyn-1-ol o,isg and trichloromethylchloroformate to a separate container. )Q,
Solution KN,N of 1 ml dissolved in 4 ml of THF
-diethylaniline Q, 25m/! -1THF 2ml
2-hebutynyl chloroformate, which had been prepared by adding dropwise a solution dissolved in water under cooling with water, was added dropwise to THF5+ILIV. After stirring for 1 hour under vacuum, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel 2 (JaO1fB solvent: benzene: ethyl acetate -9 = 1) to give the title compound Sound 18711+
y (yield 69%) was obtained.

Example 3 5-inpropyloxycarbonyl-2,6-dimether-4-1-ditrophenyl)-3-(4-n-propyloxycarbonylphenyloxycarponyl)-3,4
-dihydropyrimidine trichloromethyl chloroformate 0.12 ml (1
,00 mmol) (tetrahydro7uyTHF)2w
A solution of rlK dissolved in Il'17p-human 90xybenzoic acid n-propyl 250 mol (1,39 mmol) was added to THF.
After adding the solution dissolved in water, add N, N while stirring with water cooling.
- A solution of 0.2511 d (1.57 mmol) of diethylaniline in TI (F 5me) was added dropwise. This was stirred at room temperature for 1.5 hours. Separately, 30 g of sodium hydride α washed with hexane (6.25 mmol) was suspended in THF 5- and 5-inpropyloxycarbonyl-2,,6-dimethyl-4-
A solution of 200 μm (0.63 mmol) of (2-nitrophenyl)-1,4-dihydropyrimidine dissolved in 5 WL of THF was added dropwise. After stirring for 40 minutes at room temperature, the above reaction mixture was added. After stirring at room temperature for 30 minutes, ice water was added to the reaction mixture, and the mixture was extracted three times with ether. The organic layer was washed twice with water, dried over magnesium sulfate (dehydrating agent), and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (30 g of silica gel, eluent: ethyl acetate - 9:l) to obtain the title compound 117W (yield: 3).
5%).

The physicochemical properties of the product in Example 11-3 are shown in Table 1. Furthermore, Examples 1 to 3
Examples 4 to 26 were carried out according to the method of . The physicochemical properties of the obtained product are also shown in Table 1.

11 Examples 27 The pharmacological effects (ED3.,') of the compounds of the present invention on vertebral artery vascular resistance in anesthetized dogs were tested.

Test Moaning Method: A dog (7 to 14 kg) was induced to undergo induction anesthesia with sodium thiointal (35; nQ/kg, intraperitoneal administration).

Urethane (4001u'?/'9, intravenous administration) and α-chloralose (60mf)/9, intravenous administration)
The animals were anesthetized and tested under artificial respiration. chest i −
The left radial artery was exposed through an intercostal incision, a blood flow measuring probe was attached to its origin, and an electromagnetic blood flow meter [MF-27
, Nihon Kohden Co., Ltd.] to measure blood flow.

Ushida and Udai III at the same time! ! Measure the systemic blood pressure (mean blood pressure) from the artery, the 1st cardiac diagram in lead 11, and the electrocardiogram P.
A multiplication/division unit (EO
-601G, Nihonko tE+', Co., Ltd.] to determine the vascular resistance value, and all parameters were measured using a polygraph [Rivl-600, Nihonko rb', C stock].
Recorded simultaneously above.

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

ED3o (μflA) by intravenous injection Cζ as shown in the following table.
9) Obtained the value. The compound numbers in Table 2 correspond to the previous 5e persimmon example numbers.

Table 2 Dihydropyridine derivatives represented by general formula (2) or (2') were produced using 1 diketene in the same manner as in Production Example 1. Table 3 shows the yield, properties, and physical properties of the products.

Production Example 1゜J7j acid acetamidine 13.9 fI: dimethylformamide'' In a solution dissolved in 100 rJ, under stirring, t
- 12g of pudquin potassium in dimethylformamide 5Q
The solution in mJ was added at 0°C. Then, n-butyl 2-acetyl-3-(orton 0) phenyl-2-
28g of propenoate in 50ml of dimethylformamide
After 30 minutes, 40 g of nogradolene sulfonic acid hydrate was added to the reaction mixture, and 100
Heated at ~120°C for 2 hours. The reaction solution was made alkaline with caustic soda and extracted four times with ether 200d, and the organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to 31.6 Ft silica gel column chromatography (S102500 F/ ) and purified with 3
From the methanol-chloroform eluate in Section 10, the title compound 24I was obtained in completely crystalline form (yield 75%).

The physicochemical properties of the product are shown in Table 3. Production Examples 2 to 12t were carried out in the same manner as Production Example 1.

Effects of the Invention The compound of the present invention has a strong vasodilatory effect and its duration is long, so it is particularly effective against coronary vasodilation, improving cerebral circulation, and hypertension.

Since the treatment can be performed with a small dose and a small number of administrations, the treatment can be continued safely and easily.

Patent applicant: Suntory Ltd. (5 other people)

Claims (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Represents a methyl group, methylthio group, or lower alkoxy group; R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms, or a group -(CH_2)_n-A (in the formula, n is 1 or 2 , A is a cyclopropyl group,
cyclobutyl group or cyclopentyl group), a linear or branched alkenyl group having 4 to 12 carbon atoms, a linear or branched alkynyl group having 5 to 8 carbon atoms, or a group -(CH_2)_m -B (in the formula, m represents an integer of 0 to 8, B represents a phenyl group or a substituted phenyl group); R^2 is a linear or branched alkyl group having 3 to 12 carbon atoms, Carbon number 4
-7 linear or branched alkenyl group, or group -(CH_2)_l-D (in the formula, l represents 1, 2 or 3, and D represents a cyclopropyl group, a cyclomethyl group or a cyclopentyl group) However, when R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms or a group -(CH_2)_n-A and A represents a cyclopropyl group or a cyclobutyl group, R^ A novel N-substituted 3,4-dihydropyrimidine derivative having a group -(CH_2)_l-D in which D is a group other than a cyclopropyl group or a cyclomethyl group] and its pharmaceutically suitable acid addition salt. (2) R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms, or a group -(CH_2)_m-B (in the formula, m represents an integer of 0 to 8, and B is a phenyl group) or a substituted phenyl group). (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Represents a methyl group, methylthio group, or lower alkoxy table; R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms, or a group -(CH_2)_n-A (in the formula, n is 1 or 2 , A is a cyclopropyl group,
cyclobutyl group or cyclopentyl group), a linear or branched alkenyl group having 4 to 12 carbon atoms, a linear or branched alkynyl group having 5 to 8 carbon atoms, or a group -(CH_2)_m -B (in the formula, m represents an integer of 0 to 8, B represents a phenyl group or a substituted phenyl group); R^2 is a linear or branched alkyl group having 3 to 12 carbon atoms, Carbon number 4
-7 linear or branched alkenyl group, or group -(CH_2)_l-D (in the formula, l represents 1, 2 or 3, and D represents a cyclopropyl group, cyclobutyl group or cyclopentyl group) However, when R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms or a group -(CH_2)_n-A and A represents a cyclopropyl group or a cyclobutyl group, R^ 2 is a group -(CH_2)_l-D, and D is a group other than a cyclopropyl group or a cyclobutyl group], or a pharmaceutically suitable acid addition thereof A therapeutic agent for circulatory system diseases containing salt as an active ingredient. (4) R^1 is a linear or branched alkyl group having 1 to 13 carbon atoms or a group -(CH_2)_m-B (in the formula, m is 0
4. The therapeutic agent for circulatory system diseases according to claim 3, wherein B is a phenyl group or a substituted phenyl group.