JPS60252471A - Novel n-substituted 3,4-dihydropyrimidine derivative, its preparation, and remedy for disease of circulatory system - Google Patents

Abstract

NEW MATERIAL:An N-substituted 3,4-dihydropyrimidine derivative shown by the formula I [R is phenyl, nitrophenyl, etc.; R<1> is saturated hydrocarbon, group shown by the formula II (R<3> is cyclopropyl, etc.; n is 1, or 2), or group shown by the formula III (R<4> is methyl, etc.; m is 2-4), etc.; R<2> is group shown by the formula IV (R<5> is cyclopropyl, etc.; h is 1-3), group shown by the formula V(R<6> and R<7> are phenyl, methyl, benzyl, etc.; i is 2-4), etc.], and its acid addition salt suitable as a drug. EXAMPLE:2,6-Dimethyl-3-ethoxycarboxyl-5-( 2-N-methyl-N-benzyl )aminoethoxycarbonyl-4-(2-nitrophenyl)-3,4-dihydropyrimidine. USE:A remedy for diseases of circulatory system, a hypotensor, an improver for cerebral circulation metabolism, an agent for alleviating angina pectroris, etc. PREPARATION:A tautomer shown by the formula VI or formula VII is reacted with a compound shown by the formula VIII (X is halogen) in the presence of a base, to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Object of the Invention (α) Industrial Application Field 1 The present invention relates to the general formula (1) C, in which R represents a phenyl group, a nitrophenyl group, a chlorophenyl group, or a zlomophenyl group; R1 is a carbon Number 1
11 linear or branched saturated hydrocarbon groups from
or a group -(OH2)nR3 (wherein R3 represents a cyclopropyl group or a cyclobutyl group, and R is 1 or 2), or a group -(CH2)nL□H4 (wherein R is a methyl group or an ethyl group) and m represents 2 to 4) or a group (where ! represents 6 to 6); R2 is a group -(OH2)-R5 (here, ! represents 1, 2 or 6); , R5 represents a cyclopropyl group or a cyclobutyl group), or a group 6 (where t represents 2, 6 or 4, and R6 represents an isopropyl group), or a group -(OH2), -0
-R8 (here) represents 1 or 2, R8 is a methyl group,
The present invention relates to novel N-substituted 6,4-dihydropyrimidine derivatives having the following formula (representing an ethyl group or a phenyl group), acid addition salts thereof suitable as pharmaceuticals, methods for producing these, and therapeutic agents for circulatory system diseases.

The novel dihydropyrimidine derivative represented by the above general formula (1) has a strong vasodilatory effect, so it can be used as an antihypertensive drug.
It is used as a drug for treating circulatory system disorders, such as a cerebral circulation and metabolism improving drug and an antianginal drug.

(b) Conventional technology In recent years, calcium antagonists (GcL"+ antagonists), which have been in the spotlight as a new type of therapeutic drug for cardiovascular disorders, have a wide range of medicinal effects, including hypertension, angina pectoris, cerebral circulation and metabolism. It is effective in treating cardiac insufficiency, arrhythmia, etc., and is currently being used to treat these diseases.Recently, it has been found to be effective in preventing arteriosclerosis and enhancing the action of anticancer drugs, so the number of indications for it is increasing. be.

Currently known calcium channel blockers include nifedipine (N1fedipine) and dicalcin 2 (kJi).
cardipine), Bella, (MiA/ (Vtrap
ami L) and diltiazem (DiltiαzgJ).

Until now, there has not been much research on p-pyrimidine derivatives, and only Silvgrsrnith, Silvgrsrnith,
E.

F, J, Org, Ghem,, 27. (40
90 (1962).

Na5iptLri, D, et al. E3ynthtsis
1073 (1982).

Kashima, C. et al.
Lgtterz 2Q 9 (1983), and JP-A-5
9-73572 (Bayer 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 Since there is room for improvement in properties such as organ selectivity, stability against light, heat, etc., and side effects, the present inventors have developed a calcium antagonist with improved these properties. Create a drug (
I have done extensive research. As a result, it was discovered that the N-substituted-6,4-dihydropyrimidine derivative represented by the general formula (1) has excellent sustainability and stability, and has a strong vasodilatory effect, and the present invention was completed.

Structure of the Invention According to the present invention, the novel N represented by the general formula (1)
Substituted 3,4-dihydropyrimidine derivatives and R in the formula C
is a phenyl group, a ditronenyl group, p.

] If R is a straight chain having 1 to 11 carbon atoms, (is a branched saturated hydrocarbon group, or a group -(CH2), R3 is a cyclopropyl group or a cyclobutyl group, and R is a 1 or 2), or the group -(C:R2).-〇-R' (where R4 represents a methyl group or an ethyl group, and the door is 2
to 4), or a group (where l represents 6 to 6); R2 is a group -(CH2)h-R5 (where 4 represents 1, 2 or 6, R5 is a cyclopropyl group); or a cyclobutyl group), (where t represents 2, 6 or 4, R6 and R7 are the same or different, and each phenyl group represents an inpropyl group), or a group -(OH2), -〇- R8 (herein) represents 1 or 2, and R8 represents a methyl group, ethyl group or phenyl group] General formula (2) and (2 f2) (2 (in the formula, R and R2 are Dihydropyrimidine derivatives, which are tautomers represented by formula(
A compound represented by 1) was synthesized.

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

(1) General formulas (2) and (21 (2 [in the formula, R represents a phenyl group, nitrophenyl group, chlorophenyl group, or bromophenyl group; R2 is a group -(OH2)h-R5 (here den represents 1, 2 or 3, R5 represents a cyclopropyl group or a cyclobutyl group), or a group (wherein 2 represents 2, 6 or 4, R6 and yR7
are the same or different, each represents a phenyl group, represents an isopropyl group), or the group -(CH2), -〇-R8 (herein) represents 1 or 2, and R8 represents a methyl group, an ethyl group, or a phenyl 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 200C, preferably 120C, for 60 to 60 minutes. However, if R2 contains a nitrogen atom, the reaction proceeds at OC or at room temperature. A β-ketoester represented by general formula (3) is obtained.

(In the formula, R2 has the same meaning as above) or by treating ROH with diketene in the presence of a white amount of a base such as trialkylamine at room temperature or OC, or by reacting with diketene in the presence of sodium hydride or potassium hydride. However, the compound of general formula (3) is also restricted.

A benzylidene compound (4) is obtained by adding aromatic ring-substituted or unsubstituted benzaldehyde to the β-ketoester (3) and carrying out dehydration condensation.

(In the formula, R2 represents the same meaning as above, and R represents a phenyl group, nitrophenyl group, chlorophenyl group, or bromophenyl group) This benzylidene (4) is condensed using acetamidine or acetamidine hydrochloride to form a tetrahydropyrimidine It is referred to as compound (5).

In synthesizing tetrahydropyrimidine (5), the base is preferably a metal alkoxide or metal hydride, and the solvent is preferably alcohol-based, ether-based, or dimethylformamide 9.

By heating this pyrimidine (5) in the presence of an acid catalyst such as P-toluenesulfonic acid, boron trisulfide, or phosphoric acid, or by heating it with silica gel, alumina or molecular sieves, the general formula (2) can be obtained. and (2
A compound represented by is obtained.

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

(11) Production of novel N-substituted 3.4-:) hydropyrimidine derivatives (2) and (2) obtained in (1)
A compound represented by formula (6) is dissolved in a chlorine-based, aromatic hydrocarbon-based, or ether-based organic solvent in the presence of a base such as triplekylamine, sodium hydride, potassium hydride, or triethylamine. 6) [In the formula, cyclomethyl group, R is 1 or 2), or the group -(CH2)77L-o-R4 (where R4 is a methyl group or an ethyl group, and the door is 2
to 4) or a group (where l represents 6 to 6)] to form a novel N-substituted 6 which is a compound of the present invention.
, 4-dihydropyrimidine derivative (1) is obtained.

Alternatively, the compound (1) of the present invention can be prepared by combining the compound represented by (2) and (2) with sodium hydride, potassium hydride, alkyllithium or lithium hydride (2) and (2'
) and then reacting it with a compound of general formula (6).

Novel N substitutions 6,4 that can be synthesized in this way
-The N substituent at the 6-position of the dihydropyrimidine derivative (1) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a methyl group, an inbutyl group, a 5ec-butyl group, a t-butyl group, an inthyl group, a methylmethyl group, an ethyl group. Propyl group, hexyl group, methylpentyl group, ethylbutyl group, dimethylbutyl group, heptyl group, methylbexyl group, ethylinchyl group, dimethylpentyl group, octyl group, methylhebutyl group, ethylhexyl group, dimethylbexyl group, nonyl group , methyloctyl group, ethylheptyl group, dimethylheptyl group, decanyl group, methylnonyl group, ethyloctyl group, dimethyloctyl group, untecanyl group, methyldecanyl group, ethylnonyl group, dimethylnonyl group, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclonotylmethyl group, cyclomethylethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, ethoxyethyl group, ethoxypropyl group, ethoxybutyl group, propoxyethyl group, propoxypropyl group, Examples include propoxybutyl group, phenylpropyl group, phenylbutyl group, phenyl intyl group, phenylhexyl at, r)::.

In addition, for the substituent of the 5-position ester group, H, cyclopropylmethyl group, cyclopropylethyl group, cyclonotylmethyl group, cyclomethylethyl group, methylphenylaminoethyl group, ethylphenylaminoethyl group, methylphenylaminopropyl group , methylphenylaminomethyl group, ethylphenylaminobutyl group, diphenylaminoethyl group, dimethylaminoethyl group, dimethylaminopropyl group, methylbenzylaminoethyl group, ethylbenzylaminoethyl group, methylbenzylaminopropyl group,
Ethylbenzylaminopropyl group, Methylbenzylaminopropyl group, Methylphenethylaminoethyl group, Methylmethoxycarbonylaminoethyl group, Ethylmethoxycarbonylaminoethyl group, Methylmethoxycarbonylaminopropyl group, Methyl A/ethoxycarbonylaminoethyl group , ethylethoxycarbonylaminoethyl group, methylisopropylaminoethyl group, diisopropylaminoethyl group, methoxymethyl group, ethoxymethyl group, phenoxymethyl group, ethoxymethyl group, ethoxyethyl group, phenoxyethyl group, and the like.

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. It can be purified using inorganic acids such as oxalic acid, cono-phosphoric acid, malic acid, etc., followed by recrystallization, adsorption chromatography, and ion exchange chromatography.

(A) Effect The compound (1) of the present invention thus obtained showed 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 can treat coronary artery defects, improve cerebral circulation,
Useful in the treatment of 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, 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, Merck, calcium stearate, magnesium stearate, polyethylene glycol, water, ethanol, isopropyl alcohol, and propylene glycol.

For parenteral administration by injection, the water-soluble salt of the present compound is dissolved in sterile distilled water or sterile physiological saline and sealed in ampoules to prepare 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 to 500 cm per day for adults. Naturally, the dosage should be increased or decreased as appropriate depending on the condition at the time of administration.

(C) Examples The present invention will be explained in more detail by 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 2,6-dimethyl-6-ethoxycarbonyl-5-(
2-N-methyl-N-benzyl)amine ethoxycarbonyl-4-(2-nitrophenyl)-3゜4-dihydropyrimidine (7) 2-(N-methyl-N-benzyl)aminoethanolbenzyl bromide 4 .7d (39.5 mmol) in DC
To a solution of 2.961 (695 mmol) of 2-methylaminoethanol in triethylamine (157 m),
Stirred at room temperature for 8 hours. Water was added to the reaction solution, extracted with chloroform, and the organic layer was dried (magnesium sulfate). Distill the solvent under reduced pressure, 5.38. ! 2 of 9' (yield 86 cm)
-(N-methyl-N-indyl)aminoethanol was obtained.

0.47 g (6.06 mmol) of diketene was added to 1.0 ml of 2-(N-methyl-N-benzyl)aminoethanol cooled in OC. F (6.06 mmol) was carefully added with stirring. The reaction was completed instantaneously, with a yield of 100% of 2-(N-
Methyl-N-benzyl)aminoethyl acetoacetate was obtained.

0-Nitrobenzaldehyde 86019 (5.7 mmol), 2-(N-methyl-N-benzyl)aminoethyl acetoacetate) t4. F (6 mmol) 41 itl
! of benzene, piperidine 0.061R1 (0
, 57 mmol) and Dean Stark (Dga
The mixture was heated and dehydrated for 15 hours using a 5-tark device.

The solvent and base were distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 1.74 g (yield: 80 cm).
The title compound was obtained.

) 2,6-dimethyl-5-2-N-methyl-N-
benzyl)aminoethoxycarbonyl]-4-(2-nitrophenyl)-dihydropyrimidi-t-butanol 40
m1K acetamidine hydrochloride (3.0131.8 mmol) was added and at room temperature 6.56 g o) t-butoxypotassium (31.8 mmol) was added. 2' with DC to this
-Nitrobenzylidene-2-(N-methyl-N-benzyl)amine ethyl acetoacetate 9.33.9 (24
, 4 mmol) of t-Tsukunol 5Qmj bath solution was added. After stirring for 30 minutes, saturated brine was added and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue 9.4 Ii. This residue 1.08.9 was dissolved in a small amount of chloroform, 10F 300 mesh alumina powder (Wako Junkei Co., Ltd.) was added, mixed uniformly, and the solvent was distilled off.

This alumina powder was heated for 120 tl for 30 minutes and then eluted with a 5:4 mixed solvent of chloroform and methanol. The obtained crude product was subjected to alumina column chromatography (elution solvent: chloroform) to obtain 0.35 g (37 g) of hydroxide.

OC
Under argon flow 2.6-Simethyl-5-(2-(N-methyl-N-benzyl)]]aminoethoxycarbonyl-4-2-nitrophenyl)-dihydropyrimidine 498
# (1,18 mmol) of anhydrous tetrahydrofuran I
Mi solution was added, and after 5 minutes, the reaction mixture was brought to room temperature and further stirred for 5 minutes.

To this reaction solution was added 167μjIL of ethyl chloroformate (
1,77 mmol) was added. Then, saturated brine was added and extracted with chloroform. After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel thin layer chromatography (developing solvent: chloroform:acetone='+:1) to obtain the title compound 228# (yield: 69cm).

Example 2 2,6--,>methyl-6-ethoxycarbonyl-5-
Cyclopropylmethoxycarbonyl-4-(2-nitrophenyl)-3,4-cyhto90pyrimidine (7) cyclopropylmethylacetoacetate (α) cyclopropylcarbinol 13.2Ii (179 mmol) of triethylamine 18.11179 mmol ) solution, add OC
Then, 14,711 J (179 mmol) of diketene was slowly added. Stir for 10 min at OC, 30 min at room temperature,
After diluting with an aqueous dihydrochloric acid solution and extracting with chloroform, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 24 g of oily cyclopropylmethylacetoacetate was obtained.
I got it.

(b) Cyclopropyl carbinol 1.0113.9
1.09 WLl (13.9 mmol) of diketene was added to the mixture and heated at 120 tons for 2 hours. Cyclopropyl methyl acetoacetate was obtained quantitatively.

(a) 2-Nitrophenylbenzylidenecyclopropylmethylacetoacetate cyclopropylmethylacetoacetate 8.2# (52
, 6 mmol) and orthonitrobenzaldehyde 6.6
1C (45.8 mmol) was dissolved in 55 m of benzene, and 0.44111 J (4.38 mmol) of biridine was added. Dgan-stark
) for 15 hours to dehydrate. After distilling off the solvent and base under reduced pressure, the residue was purified by silica gel column chromatography to obtain 6.11 (49'%) of the title compound.

To acetamidine hydrochloride 46,F (1"5.5 mmol) in t-pyrimidine t-butanol 121R1 was added potassium butoxy (1.73115.5 mmol) with stirring at room temperature. After 5 minutes, Toacetate 3 to 2-nitrophenylbenzylidenecyclopropylmethy87- at ~10C
．． A t-methanol 24-solution of 44111.9 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours, diluted with saturated brine, and extracted with chloroform. The solvent was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a residue 3.18% F.

This was dissolved in 33 ml of benzene, 3.48 g (18.33 mmol) of para-toluenesulfonic acid was added, and the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform as the developing solvent:
880 m9 (yield: 29 methanol) of the title compound (methanol=10:1) was obtained.

47 m9 (0.98 m) of sodium hydride suspended in 50% oil
millimoles) of OC in 1 dM suspension of anhydrous tetrahydrofuran.
A solution of 270 m9 (0.82 rn, moll) of 2,6-dimethyl-5-cyclopropylmethoxycarbonyl-4-(2-nitrophenyl)-dihydropyrimidine in 4 d of anhydrous tetrahydrone was added thereto, followed by stirring at room temperature for 5 minutes. Ethyl tetraroforme) 102 μ7 (1,3
2 mmol) and stirred at room temperature for 30 minutes. The reaction solution was diluted with saturated brine, extracted with chloroform, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was purified using silica gel thin layer chromatography to obtain the title compound of 196 cm (yield: 60 cm) (developing solvent: chloroform:acetone = io:i, i output medium: chloroform:methanol = 4:1). Ta.

Example 6 1. diketene in 5 ml of anhydrous dioxane. ? of sodium hydride (5
5-cyclopropylmethoxycarbonyl-2,6 prepared in Example 2, suspended in 0% oil, 20.8 mmol → dissolved in 10 ml of anhydrous dioxane.
-Simethyl-1-(S'-nitrophenyl:)-3,4
0.50.9 (1.52 mmol) of -dihydropyrimidine was added at room temperature and stirred for a further 60 minutes.

To this reaction mixture was added 0.60 IC (1.68 mmol) of ruhebutyl chloroformate dissolved in 5M dioxane.
was added dropwise and stirred at room temperature for 60 minutes. Then, cold water was added to the DC and extracted with ether.

The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a crude product (0.68%). This crude product was subjected to silica gel column chromatography to obtain the title compound with a yield of 400 to 56 cm (eluent: benzene).

The yield (H) of the products of Examples 1 to B and each physical and chemical data are shown in Table 1 below.

Example 4t('I-17) Following the method of Example 1, each product was obtained from the appropriate reactants. Data for these products are also shown in Table 1.

Example 18 The pharmacological effect (ED3o) of the compounds of the invention on vertebral artery vascular resistance in anesthetized dogs was tested.

Test method Male and female mixed dogs (7 to 14) t Sodium thiobental (
35~/lψ, intraperitoneal administration) after induction anesthesia.

Urethane (400 Iv/intravenous administration) and α-
The test was performed under anesthesia with chloralose (60In9/J, intravenous administration) and one artificial respiration. 9. Perform thoracic incision.9. The left vertebral artery was exposed, a blood flow measuring probe was attached to its origin, and the blood flow was measured using an electromagnetic blood flow meter (My'-27, Nihon Kohden Co., Ltd.).

At the same time, the systemic blood pressure (mean blood pressure) t from the right femoral artery, the electrocardiogram t from lead ①, and the heart rate by driving a tachometer using the R wave of the electrocardiogram, and the output of the mean blood pressure value and the mean peristaltic artery blood flow. Multiplication/division unit [EO-601G, Nihon Kohden (
Vascular resistance values r were continuously measured and simultaneously recorded on a polygraph [RM-soo-Nihon Kohden Co., Ltd.] for all parameters.

Yakuchi injected Kanyuleev, which had been inserted into the femoral artery.

ED3o (μg #> values by intravenous injection as shown in the following figure were obtained. Compound number 1 in Table 2 corresponds to the example number described above.

Production Examples 1 to 7 A dihydropyridine brocade conductor represented by general formula (2) or (2') was prepared in the same manner as in Examples 1 (a) and 2 (7).

Produced using diketene. The yield, properties and physical data of the product are all shown in Table 3.

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.

Compared to the Ca ox antagonist mulberry, which is currently in practical use, it requires fewer administrations. Therefore, we are confident that the treatment of circulatory system diseases, which require a long treatment period kW, can be greatly simplified.

Patent applicant: Suntory Ltd. Agent: Patent attorney Kyozo Yuasa (5 other people) Handbook Supplementary Book May λ/day, 1985 Mr. Manabu Shiga, Commissioner of the Patent Office 2. Name of the invention 6. Person who makes corrections Relationship to the incident: Patent applicant address Name (19o) - Zantry Co., Ltd. 4. Agent 6. Contents of amendment The specification is amended as follows.

Page Line Before correction After correction 13 12 (40904090 229 groups R1 of group 3686,976,87 ro6 10 brS brs 66 14 5E (8H ro71 (2 sh) S 8 ro7 1ro 17ro5 1720 38 5 C21H26C21H25 38 86 ,61126,92 38133,1i15 Ro, 85 42 9 Metquinethyl 2-methoxyethyl 42 11 7e/xyethyl 2-phenoxyel thyl

Claims (5)

[Claims] (1) General formula [wherein R represents a phenyl group, nitrophenyl group, chlorophenyl group or bromophenyl group; R1 has 1 carbon number
11 linear or branched saturated hydrocarbon groups from
or the group -(OH2)n-R'' (where R3 represents a cyclopropyl group or cyclobutyl group and R is 1 or 2), or the group -(CH2), -0-R' (where R4 is Represents a methyl group or an ethyl group, m is 2
to 4), or a group (where l represents 6 to 6); R2 is a group -(OH2)h-R5 (herein represents 1, 2 or 3, R5 is a cyclopropyl group); or cyclomethyl group) -1 or group 6 / -(OH,), -N's, 7 (where the number represents 2, 6 or 4, R6 and R7
are the same or different, each represents a phenyl group, an isopropyl group), or a group -(OH2), -゛-R8 (where) ゛ represents 1 or 2, and R represents a methyl group, an ethyl group, or a phenyl group. Novel N-substituted 6,4-dihydropyrimidine derivatives having the following formula and pharmaceutically suitable acid addition salts thereof. (2) R" is a methyl group, an ethyl group, a propyl group, a methylpropyl group, a methyl group, a pentyl group, a hexyl group,
Claims that are a methylbexyl group, an ethylhexyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group, a cyclopropylmethyl group, a cyclopropylethyl group, a methoxyethyl group, an ethoxyethyl group, a methoxypropyl group, or a phenyl group. A compound according to item 1. (3) Claim 1, wherein R2 is a cyclopropylmethyl group, a cyclopropylethyl group, a methoxyethyl group, an ethoxyethyl group, a phenoxyethyl group, a methylbenzylaminoethyl group, or a methylethoxycarbonylaminoethyl group. Compound. (4) General formula (wherein R represents a phenyl group, nitrophenyl group, tetrarophenyl group or bromophenyl group; R2 is a group -(OH2)h-R5 (where h represents 1, 2 or 6) , R5 represents a cyclopropyl group or a cyclobutyl group), or a group (where i represents 2, 6 or 4, R6 and R7
are the same or different and each represents a phenyl group, methyl group, ethyl group, benzyl group, phenethyl group, methoxycarbonyl group, ethoxycarbonyl group or isopropyl group), or a group -(CH2)j-0-R8 (where) represents 1 or 2, and R8 represents a methyl group, ethyl group, or phenyl group)] In the presence of a base, the tautomer represented by is a linear or branched saturated hydrocarbon group having 1 to 11 carbon atoms, or a group -(CH2)rL-R3 (where R3 represents a cyclopropyl group or a cyclobutyl group, and L is 1 or 2). ), or the group -(OH2)rrL-0-R' (where R4 represents a methyl group or an ethyl group, etc.
to 4) or a group (wherein l represents 6 to 6), and optionally further treated with a pharmaceutically suitable acid. R, R” and R
2 has the same meaning as above) Novel N substitution 6,4
- A method for producing dihydropyrimidine derivatives and pharmaceutically suitable acid addition salts thereof. (5) General formula (wherein R represents a phenyl group, nitrophenyl group, chlorophenyl group or bromophenyl group; R2 is a group -(OH2)7.-R5 (here, h represents 1, 2 or 6, R represents a cyclopropyl group or a cyclobutyl group), (where t is 2
, 6 or 4, R and R7 are the same or different, each phenyl group and isopropyl group),
or the group -(OH2), -〇-R8 (wherein) represents 1 or 2, R represents a methyl group, ethyl group or phenyl group); Y represents an alkali metal] The mutant is represented by the general formula % [wherein X represents a halogen atom; R1 is a linear or branched saturated hydrocarbon group having 1 to 11 carbon atoms, or a group -(OH2)rL-R3 (wherein R3 represents a cyclopropyl group or a cyclomethyl group, and ru is 1 or 2), or the group -(CH2)m-0-R4 (wherein R4 represents a methyl group or an ethyl group, and m is 2
to 4) or a group (where l represents 6 to 6), and optionally further treated with a pharmaceutically suitable acid. R,, R1 and R2 have the same meanings as above) 6,
Process O for producing 4-dihydropyrimidine derivatives and pharmaceutically suitable acid addition salts thereof [wherein R represents a phenyl group, nitrophenyl group, chlorophenyl group or bromophenyl group; R1 has 1 carbon number
11 linear or branched saturated hydrocarbon groups from
or the group -(OH2)rL-R3 (wherein R3 represents a cyclopropyl group or a cyclonotyl group and R is 1 or 2), or the group -(OH2), -0-R4 (wherein R4 is Represents a methyl group or an ethyl group, m is 2
to 4), or a group (where l represents 3 to 6); R2 is a group -(aH2)h-R'' (where h represents 1, 2 or 6 and R5 represents a cyclopropyl group or a cyclomethyl group), or a group 6 (where t represents 2, 6 or 4); R and R7 are the same or different, each represents a phenyl group and an isopropyl group), or the group -(OH2)・-〇-R8 (herein) represents 1 or 2, R8 is a methyl group, an ethyl group or a phenyl group) or a pharmaceutically suitable acid addition salt thereof as an active ingredient.