JPS6081173A - Dihydropyrimidine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A dihydropyrimidine derivative which is tautomers expressed by formulas I and II (R<1> is lower alkyl; R<2> is phenyl, substituted phenyl, furyl or thienyl) and an acid addition salt thereof. EXAMPLE:5-Alkoxycarbonyl-2,6-dimethyl-4-phenyl-dihydropyrimidine. USE:A safe agent, having vasodilator action, and effective for treating a wide variety of cardiovascular diseases, e.g. hypertension, angina pectoris, arrhythmia, etc. and having selectivity for blood vessels. PREPARATION:A tetrahydropyrimidinol derivative expressed by formula III is treated with a dehydrating agent selected from the group consisting of phosphorus oxychloride, alumina, silica gel and acids and if desired an acid suitable to a medicine to afford the compounds expressed by formulas I and II. For example, a method of heat treatment is carried out in case and acid, e.g. p-toluenesulfonic acid, is used as the dehydrating agent.

Description

Detailed Description of the Invention (α) Technical Field The present invention relates to compounds of the general formula (1) and (1 (in the formula, R1 is a lower alkyl group, R is a phenyl group,
The present invention relates to dihydropyrimidine derivatives which are tautomers represented by substituted phenyl, furyl, and chenyl groups, acid salts suitable as pharmaceuticals, and methods for producing the same.

The dihydropyrimidine/derivatives represented by the above general formulas (1) and (1) disrupt the vasodilatory action and are expected to be effective compounds for the treatment of a wide range of cardiovascular disorders such as hypertension, angina pectoris, and arrhythmia. .

(b) Background Art In recent years, calcium antagonists (Ca+ antagonists) have attracted attention as a new type of therapeutic drug for cardiovascular disorders, and they have a wide range of medicinal effects and are effective against hypertension, angina pectoris, arrhythmia, etc. Not only is it currently used in these treatments;
Further indications are on the rise.

Currently known calcium channel blockers include nifedipine (N1fedipirLt) and nicardipine (N1c
ardsine), Verapamil (Verapamil)
), diltiazem, etc., but there is a strong desire for a new calcium antagonist that has a long duration of action, is selective to blood vessels, is safe, and has few side effects.

(C) Disclosure of the Invention As a result of planning and research into the development of the calcium antagonist system, which has become increasingly important in recent years, the present inventors found that the general formula (1
) and (1) have discovered that dihydropyrimidine/derivatives represented by one have an excellent vasodilatory effect and have completed the present invention.

That is, according to the present invention, there are provided dihydropyrimidine derivatives which are tautomers represented by the general formulas (1) and (1), salts of dihydropyrimidine Bk4, and methods for producing them.

Until now, there has not been much research on dihydropyrimidine derivatives [E3i1verssmith, E, F.
J.

Ory, Clrtm, 27.4090 (1962
), NapsuUγt.

D. et al. F3ynthesis 1073 (1982),
Kazhima, C.

raTttrahetron Letter,? 209
(1933)). The reason for this is thought to be the instability and tautomerism of the dihydropyrimidine derivative. Furthermore, since this dihydropyrimidine/derivative can be converted to pyrimidine by oxidation, it is useful as a general method for producing pyrimidine derivatives.

According to Vhiz et al., dihydropyrimidine takes the (A) form in X-ray crystallography, has tautomerism between (A) and (c) in the solution state, and states that (the Q form is unstable).

(Gl (5) (B) [Weis, A, H,, Tgtrahtdron
Letters, 449 (1982)) These dihydropyrimidine derivatives (1) and (one manufacturing process is, for example, as follows).

First, a Cχ, β-unsaturated carbonyl compound FI3 represented by the general formula (2) (wherein R1 is a lower alkyl group, R is phenyl 4,
(represents a substituted phenyl group, furyl group, or chenyl group)
A tetrahydropyrimidine derivative (3
) is 14) done.

When using a salt such as acetamidine hydrochloride, it is preferable to prepare the free amine with an alkali metal alkoxide in advance. Also, alcohols having an alkyl group as shown in alcohol 9ffl11 are preferred.

Tetrahydropyrimidine derivative (3) thus obtained
can be purified by general purification methods such as recrystallization, adsorption chromatography, ion exchange chromatography, and partition chromatography.

This tetrahydropyrimidine conductor (3) can be converted into the dihydropyrimidine compound of the present invention into the 6L form (1) and (1) by a unique method.

Example: Method for obtaining dihydropyrimidine derivative a by dehydration by heat treatment with an acid such as Eva, p-toluenesulfonic acid or benzenesulfonic acid: 10 times the weight of an inorganic substance such as alumina, silica gel or molecular sheep. Methods include mixing with the above, heating at 1200 to 200 C for 15 minutes to 1 hour, and extracting with an organic solvent; and methods of dissolving in phosphorus oxychloride and heating for 1 vif:L dehydration.

Dihydropyrimidine U4 in 40-70% yield when treated with acid, 20-50% yield when treated with inorganic and about 50% yield when further treated with phosphorus oxychloride.
The body can be obtained. Furthermore, the dehydration conditions can also be changed using acids such as can-7ar-10-sulfonic acid and Lewis acids such as boron trifluoride ether complex.
SJ bodies (11 and (1) are obtained.

The obtained compound of the present invention is subjected to adsorption chromatography, ion exchange chromatography, partition chromatography,
It can be purified using common pod manufacturing methods such as distillation. Also, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, tartaric acid, succinic acid
, maleic acid 7.1: It can be crystallized as a salt of any organic acid and purified by recrystallization.

General synthesis method 1, synthesis of tetrahydropyrimidine NH 29 compound (3) Dissolve the α,β-unsaturated carbonyl compound represented by the general formula (2) in alcohol, and separately add 1.1 molar equivalent of acetamidine hydrochloride to this solution. and 1.0 molar equivalent of sodium alcoholade. After stirring at room temperature for 1 hour, the mixture was concentrated, the residue was diluted with chloroform, washed six times with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the tetrahydropyrimidine derivative (3).

2. Synthesis of dihydropyrimidine derivative (1) and (1) 2-1.1-) Luenesulfonic acid The synthesized tetrahydropyrimidine derivative used and 1 to 2 molar equivalents of 7)-) Luenesulfonic acid were mixed in benzene for 1 hour. Heat to reflux,
After cooling, add chloroform and wash twice with potassium carbonate water bath and once with water. The organic layer is dried over anhydrous magnesium sulfate and then concentrated to obtain dihydropyrimidine U4 bodies (1) and (1) using the purification method described above. Alternatively, after condensation of the daughter, dissolve in alcohol and add hydrochloric acid gas saturated ether to crystallize as a hydrochloride. ) and (one salt can be obtained.

2-2 Synthesis using alumina Mix tetrahydropyrimidine and 10 times the amount of alumina powder (Wako Tsumugi Co., Ltd.) at 120-200C.
The dihydropyrimidine derivatives (11 and (1
get one.

2-3. The dihydropyrimidines ii'i and (1) are prepared by carrying out exactly the same way as in Synthesis 2-2 using silica gel.

2-4. Synthesis using phosphorus oxychloride Tetrahydropyrimidine is dissolved in an appropriate amount of phosphorus oxychloride, heated under reflux for 60 minutes, and then A-sized phosphorus oxychloride is distilled off under reduced pressure. The residue is 2-1. The dihydropyrimidine/derivatives (1) and (1) are obtained in exactly the same manner as above.

Dihydropyrimidine derivatives (1) and (one for example 1,5-alkoxycarbonyl-2,6-dimethyl-4-phenyl-dihydropyrimidine 2,5-fluoroxycarbonyl-2,6 -cymethyl-4
-(2-nitrophenyl)-dihydropyrimidine 3.5
-Alkoxycarbonyl-2,6-dimethyl-4-(3
-nitrophenyl)-dihydropyrimidine 4,5-alkoxycarbonyl-2,6-cy) thyl-4=(4-nitrophenyl)-dihydropyrimidine 5,5-alkoxycarbonyl-2,6-dimethyl-4-(2- Chlorphenyl)-dihydropyrimidine 6.5-Alkoxycarbonyl-2,6-dimethyl-4-(3-chlorphenyl)-dihydropyrimidine 7, 5-Alkoxycarbonyl-2,6-cy)thyl-4-(4-di) 0runenil)-
Dihydropyrimicine 8.5-alkoxyluponyl 2
．． 6-dimethyl-4-(2-fluorophenyl)-dihydropyrimidine 9,5-alkoxycarbonyl-2,6
-Simethyl-4-(3-fluorophenyl)-dihydropyrimidine 10.5-alkoxycarbonyl-2.6-
dimethyl-4-(4-fluorophenyl)-dihydropyridine 11.5-fluoroxycarbonyl-2.6-dimethyl-4-(2-7"romphenyl)-dihydropyrimicine 12.5-alkoxyluponyl-2.6-dimethyl-4 -(3-7'romphenyl)-dihydropyrimicine 13,5-alkoxycarbonyl-2,6-dimethyl-4-(4-7'romphenyl)-dihydropyrimicine 14,5-alkoxycarbonyl-2,6-dimethyl-f Ru-4-(2-cyanophenyl)-dihydropyrimidine 15
, 5-alkoxycarbonyl-2,6-cymethyl-4-
(6-cyanophenyl)-dihydropyrimidine 16.5
-Fluroxycarbonyl-2,<5''))f-4-
(4-cyanophenyl)-dihydropyrimidine 17.5
-alkoxycarbonyl-2,6-dimethyl-4-(2
-methylthiophenyl)-dihydropyrimidine 18,5
-Alkoxycarbonyl-2,6-dimethyl-4-(3
-methylthiophenyl)-dihydropyrimidine 19,5
-Alkoxycarbonyl-2,6-dimethyl-4-(4
-methylthiophenyl)-dihydropyrimidine 20.5
-Fluoro dicarbonyl-2,6-)methyl-4-(2
-methylphenyl)-dihydropyrimicine 21, 5-alkoxycarbonyl-2,6-dimethyl-4-(6-methylphenyl)-dihydropyrimidine 22, 5-alkoxycarbonyl-2,6-dimethyl-4-(4-methylphenyl )-dihydropyrimidine 23,5-alkoxycarbonyl-2,6-)methyl-4-(2-methoxyphenyl)-dihydropyrimidine 24.5-alkoxycarbonyl-2,6-dimethyl-4-(3-methoxyphenyl)- Dihydropyrimidine 25,5-Alkoxycarbonyl-2,6-dimethyl-4-(4-methoxyphenyl)-dihydropyrimidine )-Dihydropyrimicine27.5-Alkoxycarbonyl-2.6-cyme7-4-(6,4-dimethoxyphenyl)-dihydropyrimidine28.5-Fluroxycarbonyl-2.6-dimethyl-4-(2 ,3
, 4-toIJ me)xyphenyl)-dihydropyrimidine 29.5-alkoxycarbonyl-2,6-dimethyl-4-<2.6-dichlorophenyl)-dihydrohyrimidine, 5-alkoxycarbonyl-2,6- dimethyl-4-(2,5-dichlorophenyl)-dihydropyrimidine 31,5-alkoxycarbonyl-2,6-dimethyl-4-(2,4-dichlorophenyl)-dihydropyrimicine 32.5-alkoxycarbonyl 2,6-cymethyl-4-(2-)! Jy fluoromethylphenyl)-dihydropyrimicine 33.5-alkoxycarbonyl-2,6-dimethyl-4 = (5-) IJ fluoromethylphenyl)-dihydropyrimicine 34.5-alkoxycarbonyl-2,6-dimethyl-4 -(4-)Lifluoromethylphenyl)-dihydropyrimidine 35.5-alkoxycarbonyl-2,6-)methyl-
4-(2-ethylphenyl)-dihydropyrimicine 36
, 5-alkoxycarbonyl-2,6-cymethyl-4-
(6-ethylphenyl)-dihydropyrimicine 37,5
-Alkoxycarbonyl-2,6-dimethyl-4-(4
-ethylphenyl)-dihydropyrimidine 38.5-alkoxycarbonyl-2,6-dimethyl-4-(2-ethoxyphenyl)-dihydropyrimidine 39,5-alkoxycarbonyl-2,6-dimethyl-4-(6-ethoxyphenyl) -dihydropyrimidine 40.5-Alkoxycarbonyl-2,6-dimethyl-4-(4-ethoxyphenyl)-dihydropyrimidine 41,5-alkoxycarbonyl-2,6-dimethyl-4-(2-chloro-
5-Nitrophenyl)-dihydropyrimicine 42, 5-alkoxycarbonyl-2,6-dimethyl-4-(2-nitro-5-chlorophenyl)-dihydropyrimicine 43, 5-alkoxycarbonyl-2,6-dimethyl-4 -(2-furyl)-dihydropyrimidine 44.5-Alkoxycarbonyl-2,6-dimethyl-4-(3-furyl)-dihydropyrimidine 45.5-Alkoxycarbonyl-2,6-dimethyl-4-(2-thenyl) -dihydropyrimidine, 5-alkoxycarbonyl-2,6-dimethy-4-(3-thenyl)-dihydropyrimidine, and the like. In Exemplary Compounds 1 to 46, alkoxy means methoxy, ethoxy,
It means lower alkoxy such as propoxy, isopropoxy, butoxy, 5yec-butoxy, t-butoxy and the like.

For example, if globionamidine, butyramidine, etc. are used instead of acetamidine or a salt thereof and reacted with an α,β-unsaturated nylbonyl compound, a tetrahydropyrimidine derivative having an ethyl group or a propyl group at the 2-position ( 3
) can be obtained. This tetrahydropyrimidine derivative (3
It will be obvious to those skilled in the art that dihydropyrimidine derivatives (1) and (1) can be obtained by the dehydration operation described above.

The synthesis leading to the above-mentioned compounds of the present invention is summarized by the following process diagram.

(2) (3) (In the above reaction formula, R1 and H2 have the same meaning as nF2 above) The dihydropyrimidine derivative of the present invention exists as a mixture of tautomers represented by the above formula (1) and (1). In this Specification 1, the dihydropyrimidine derivative refers to a mixture of tautomers represented by formulas (1) and (1).

An example of producing the tetrahydropyrimidinone derivative (3) for producing the compound of the present invention will be shown.

Representative Production Example 1.5-Ethoxycarbonyl-6-hydroxy-4-phenyl-2,6-dimethyl-1.4,5.6-dutrahydrobyrimidine/benzaldehyde 10.6L ethyl acetoacetate f-) 1
Dissolve 4.3g in 50m6 of benzene to obtain 11n piperidine.
The mixture was heated under reflux for 15 hours. The solvent and base were distilled off under reduced pressure to obtain a residue 21.8.9 (quantitative).

Meanwhile, add 1 JJ of acetamidine salt to 6 Qml of absolute ethanol.
Dissolve n1.15Ji' and add sodium ethylene at room temperature)
Add 0.839 and stir for 50 minutes to prepare an acetamidine solution.

The remaining 1fi2.669 obtained earlier was mixed with 60% ethanol and water.
7d, this was added to the acetamidine solution and further stirred at room temperature for 1 hour. Ethanol was distilled off under reduced pressure at 30C or lower, saturated brine was added, and chloroform extraction was performed. After removing the solvent, a yellow foamy substance *6. I got s1g.

The obtained title compound was dissolved in ethanol, and 6 liquids (excess) of ether saturated with hydrochloric acid gas were added to obtain hydrochloride crystals.

Physical properties of the title compound: yellow foamy substance IT R spectrum (RIOO form Hcrn') *
3460 *3100~3500,1700.1650
i”JMR Subek) Le (CDG13*δ): 0.90
(3H, t, J==7Hz), 1.49 (3H, J),
2.01 (3H,,r).

2.55 (IH, d, J = 12Hz), 3.91 (2H
.

q, J=7H2), 4.74(IH, d, J=12Hz
).

7, 17-7.40 (5H, m) High-resolution mass spectrum Actual measurement value 276.1471 meters q
- value 276.1471 (C15II2oN203) Melting point of hydrochloride = 177-178° (recrystallization solvent: ethanol, ether, hexane) Below is a list of the physical properties of the tetrahydropyrimidine derivative (3) obtained according to Production Example 1. Shown. There are also examples in which the compounds of the present invention were synthesized without isolation of this compound.

Dihydropyrimidine 9 of the present invention (1) and 1
The following tests were conducted on the coronary vasodilator effect of lily.

1) Actual test method Weight: 400-500.9 C) L/-(Hartl
ey) type guinea pigs were bludgeoned to death, and the hearts were rapidly removed using the Langendorff surface flow method (J, Pharmacol, M
9 in accordance with methods 2°143 (1979))
Krebs-Jlense was kept at 37C by aerating 5%02+5%CO2 mixed gas.
leit) solution at a constant flow rate (6 m).

Blood flow pressure was measured with a pressure transducer.

To prepare the sample, 1 m of the test compound was dissolved in 11 nl of a mixture of dimethyl sulfoxide and physiological saline (1:9), and then diluted to a predetermined concentration using physiological saline. 1 ml of stiffness bath solution Q was administered directly into the coronary artery through a rubber tube connected to the aortic cannula, and the ED as shown in Table 2 was obtained.
,. (μg/heart) was obtained. The compound numbers in the table correspond to the example numbers below.

2) Pharmacological activity test results The pharmacological activity test results for dihydropyrimidine derivatives (1) and (1) are shown in the table below.

Table 2 Example 1゜5-Ethoxycarbonyl-2,6-dimethyl-4-phenyl-dihydropyrimidine Production row 1
Dissolve 5 mA'Ki of anhydrous Hensen, add 472 m9 of para-toluenesulfonic acid, and reflux for 1.5 hours. Most of the benzene was distilled off, diluted with potassium carbonate saturated water bath solution 'C,
Extract with chloroform. After drying the organic layer over anhydrous potassium carbonate, the solvent was distilled off under reduced pressure to obtain 5721v of residue. The residue was subjected to alumina (Wako Tsumugi) column chromatography, eluted with a 1:1 mixture of chloroform and benzene, and then eluted with chloroform to obtain the title compound 698 (yield: 68%).

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

The yield was calculated based on the starting material benzaldehyde.

Melting point: 156-157° (recrystallization solvent: ether/hexane) IR spectrum (reoform, cm''): 3
440,1695”H-NMR spectrum #(DMSO-
c16. δppm>: 1.08 (!IH, t, J=
7Hz), 1.86 (3H, J), 2.20 (3H, y
), 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) = + calculated value 61.12. 6.50 9.5
0 夾6 (S1 shift 61.14 6.52 9.34 (as molecular formula C□5H19Cli''J202) Example 2゜5-ethoxycarbonyl-2,6-dimethyl-4-C6
-nitrophenyl)-cyhydrohirimicin 5-ethoxycarbonyl-6-hydroxy-2゜6-simethyl-4-
150 mg of (6-nitrophenyl)-1.4,5.6-titrahydrobyrimidine was dissolved in 14 m of phosphorus oxychloride and heated under reflux for 60 minutes.

After phosphorus oxychloride was distilled off under reduced pressure, a saturated aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous potassium carbonate, the solvent was distilled off to obtain α compound 72 rv (yield 54%).

The yield was calculated based on the raw material 6-nitrobenzaldehyde.

Physical properties IR spectrum (chloroform, crn''): 344
0.16901H-NMR spectrum (CDCr13.
δppm): 1.18 (3H, t.

J=7H2), 2.05 (3H,-5'),
2.37 (3H, I).

4.09 (2H, q, J=7Hz), 5.67
(1■-1,s).

7.40-8.20 (4H, m) Physical properties of hydrochloride Melting point: 223-226° (Recrystallization solvent: methanol
Ether) Elemental analysis: C) I N Calculated value 55.02 5.34 12.57 Actual value 5
3.12 5.28 12.24 (However, molecular formula C05
H18C4N304) Example 6゜5-t-butoxycarbonyl-2,6-cymethyl-4-
(3-Chlorphenyl)-dihydropyrimidine 5-t-
butoxycarbonyl-2,6-cymethyl-4-(3-1
Mix a small amount of chloroborum with 10 g of calalumina powder (Wako Tsumugi Co., Ltd.) and carefully mix the chloroborum under reduced pressure. Distilled away. The alumina powder on which the compound was evenly adsorbed was heated under argon for 120 minutes.
0 for 30 minutes. After cooling, the mixture was eluted with chloroform to obtain 310m9 of the title compound (yield 62%).

The hydrochloride salt was prepared as in Example 1.

This compound cannot be obtained by the method of Example 1 using 7)-) toluenesulfonic acid.

The yield was calculated based on the raw material 6'-chlorobenzaldehyde.

Properties: Oily substance engineering R spectrum (chloroform + C11L J:342
0.1690”H-NMR spectrum (CDCI13+
δppm): 1.27 (9H.

ε), 1.78(3H, scoop, 2.1<5(3H,,s'
).

5.32 (I H,!), 7.08-7.20
(4H, m) High-resolution mass spectrum calculated value 320.1289 Actual value 320.1279 (Molecular formula C17H2, ClN2O2) In Examples 4 to 17, the reaction conditions and dihydropyrimidine derivative (1) and (1
I got one. Table 6 shows the yield, physical properties, and instrumental analysis of the obtained product.

The yield was calculated from the raw material aldehyde.

Industrial Application Field The dihydropyrimidine derivative of the present invention has a vasodilatory effect as described above. It is useful as a therapeutic agent for a wide range of circulatory system diseases because it has a coronary vasodilating effect. For this reason, we are confident that it will be frequently used in the medical field as a safe drug for the treatment of circulatory system diseases, which are increasing considerably in modern society.

Patent Applicant: Zantry Co., Ltd. (4 others) Procedure: Masa Ura, Director of the Japan Patent Office, Aio Wakasugi, 1, Indication of the case: 1982 Patent H No. 191600, 6, Person making the amendment Relationship to the case Patent applicant address name (190) Suntory Ltd. 4, Column 6 of [Detailed description of the invention] of the agent's specification, contents description of the glaze surface X1lllνl as below.
OP line 1 怀正: ffl i stroke j, after FE.''
2. Procedural amendments 1. Indication of the case Patent Application No. 191600 of 1982 2. Title of the invention, Dihydropidine derivatives and their manufacturing method 6. Person making the amendment Relationship with the case Patent applicant address name (190 ) San I Riichi Co., Ltd. 4, Agent 6, contents of the amendment as shown in the attached sheet (attached sheet)
Market.

"(1) Dihydropi 1) which is a tautomer represented by the general formula (wherein R1 is a lower alkyl group and R2 is a phenyl group, substituted phenyl group, furyl group, or chenyl group) 492430 bodies-
1, 3 and f! which is suitable as a medicine. (J salted.

(2) R2 caffeyl group, nitrophenyl group, chlorophenyl group, bromphenyl group, fluorophenyl group, trifluoromethylphenyl group, lower alkylthiophenyl group, dichlorophenyl group, lower alkylphenyl group,
Claims f! Dihydropyrimidine derivatives of item 1 and 1&.

13) A tetrahydropyrimidinol derivative having the general formula (wherein R1 is a lower alkyl group and R2 is a phenyl group, a substituted phenyl group, a furyl group, or a chenyl group) is converted into phosphorus oxychloride, Ryolumina, or silisonogel. , and a dehydrating agent selected from the group consisting of acids, if desired with a pharmaceutically suitable l'1%.

Claims (3)

[Claims] (1) Dihydropyrimidine derivatives which are tautomers represented by the general formula (wherein R1 is a lower alkyl group and R2 is a phenyl group, substituted phenyl group, furyl group, or chenyl group) and acid derivatives suitable for pharmaceutical use. Add salt. (2) l'("caffeyl group, nitrophenyl group, chlorphenyl group, bromphenyl group, fluorophenyl group, trifluoromethylphenylx, lower alkylthiophenyl group, dichlorophenyl group, lower alkylphenyl group, lower alkoxyphenyl The dihydropyrimidine derivative according to claim 1, which is a cyanophenyl group. (3) Tetrahydropyrimidinol derivatives having the general formula (wherein R1 is a lower alkyl group, and R2 is represented by a phenyl group, a substituted phenyl group, a furyl group, or a chenyl group) are combined with phosphorus oxychloride, alumina, silica gel, and a tautomer represented by the general formula (wherein R1 and R2 have the same meanings as above), treated with a dehydrating agent selected from the group consisting of A method for producing a dihydropyrimidine derivative and a pharmaceutically suitable acid addition salt.