JPH0524150B2 - - Google Patents

Description

Detailed Description of the Invention (a) Technical Field The present invention relates to the general formula (1) [Formula] and [Formula] (wherein R ¹ represents a lower alkyl group, R ² represents a phenyl group, a substituted phenyl group, a furyl group, The present invention relates to dihydropyrimidine derivatives which are tautomers of a thienyl group, a thienyl group, a pharmaceutically suitable acid addition salt thereof, and a method for producing the same. The dihydropyrimidine derivatives represented by the above general formulas (1) and (1)' have strong vasodilatory effects and are expected to be effective compounds in the treatment of a wide range of circulatory disorders such as hypertension, angina pectoris, and arrhythmia. It is something that will be done. (b) Background technology Calcium antagonists (Ca ⁺⁺ antagonists), which have recently attracted attention as a new type of therapeutic drug for cardiovascular disorders, have a wide range of medicinal effects and are effective for hypertension, angina pectoris, arrhythmia, etc. Not only are they currently being used for these treatments, but the indications are increasing. Currently known calcium channel blockers include verapamil, nifedipine, nicardipine, and diltiazem, but they have a long duration of action, are selective to blood vessels, and are safe. There is a strong desire for new calcium antagonists with fewer side effects. (c) Disclosure of the Invention The present inventors planned the development of a new calcium antagonist and as a result of intensive research, the above general formula (1) and
The inventors discovered that the dihydropyrimidine derivative represented by (1)' has an excellent vasodilatory effect and completed the present invention. That is, according to the present invention, the general formula (1) and
Dihydropyrimidine derivatives which are tautomers represented by (1)' and methods for producing them are provided,
Furthermore, as a manufacturing method, general formula (2) (In the formula, R ¹ is a lower alkyl group, and R ² is a phenyl group, substituted phenyl group, furyl group or thienyl group). A method is provided comprising heat treatment with a reagent such as phosphorous chloride. Although the reaction may be carried out in an inert organic solvent, it is preferable to carry out the reaction with only the reagent. The raw material of the present invention, 5,6-dihydro-4-pyrimidone represented by general formula (2), can be prepared by a method known in the literature [CFHAllen et al. Org.Syn.Coll.Vol. 3 , 377
(1955)]. First, malonic acid dialkyl ester and an equivalent amount of aldehyde are heated in the presence of a base such as piperidine, methylpiperidine, or trialkylamine in a solvent, preferably an aromatic hydrocarbon, an ether, or a halogenated hydrocarbon. Formula (3) (In the formula, R ¹ is a lower alkyl group, and R ² represents a phenyl group, a substituted phenyl group, a furyl group or a thienyl group.) A 2-alkoxycarbonylpropenoic acid ester is obtained. This ester
(3) can be easily purified as a crystal or oily substance by general distillation, recrystallization, column chromatography, or thin layer chromatography. The aldehydes used here include benzaldehyde, nitrobenzaldehyde, trifluoromethylbenzaldehyde, chlorobenzaldehyde, bromobenzaldehyde, fluorobenzaldehyde, cyanobenzaldehyde, methoxybenzaldehyde, ethoxybenzaldehyde, tolualdehyde, ethylbenzaldehyde,
Examples include aryl aldehydes such as methoxybenzaldehyde, dichlorobenzaldehyde, chloronitrobenzaldehyde, dinitrobenzaldehyde, dimethoxybenzaldehyde, trimethoxybenzaldehyde, and methylthiobenzaldehyde, and heterocyclic aldehydes such as furfuralthiophenecarboxaldehyde. The thus synthesized 2-alkoxycarbonylpropenoic acid ester (3) has R ¹ as a methyl group, ethyl group, propyl group, or butyl group; R ² as a phenyl group, 2-, 3-, and 4-nitrophenyl group. , 2-, 3- and 4-trifluoromethylphenyl groups, 2-, 3- and 4-chlorophenyl groups, 2-, 3- and 4-bromophenyl groups,
4-cyanophenyl group, anisoyl group, 3- and 4-methylphenyl group, tolyl group, 2-ethylphenyl group, 2-, 3- and 4-methoxyphenyl group, 2- and 3-ethoxyphenyl group, 2
-,3- and 4-fluorophenyl groups, 2,
6,2,5- and 2,4-dichlorophenyl groups, 2-chloro-5-nitrophenyl groups, 2-chloro-4-nitrophenyl groups, 5-chloro-2-
Aryl groups such as nitrophenyl group, 3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, and 2-furyl group, 2-thienyl group, 3-furyl group, 3-thienyl group, etc. It has a heterocyclic ring. Next, the propenoic acid ester (3) and an equivalent amount of acetamidine or acetamidine salt are added to lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium methoxide, lithium methoxide, sodium propoxide, potassium propoxide. , 5,6- represented by the general formula (2) by heat treatment in an alcoholic solvent in the presence of an alkali metal alcoholate such as potassium butoxide.
Dihydro-4-pyrimidones are obtained. 5,6-dihydro-4-pyrimidone (2) thus obtained
can be easily isolated and purified by common purification methods such as distillation, recrystallization, adsorption chromatography, partition chromatography, gel filtration, and methods utilizing solubility and acidity. As a final step, the compound of the present invention, general formula (1)
The tautomer dihydropyrimidines represented by (1)′ and 5,6
- dihydro-4-pyrimidone by heating with an excess of a compound selected from the group consisting of phosphorus oxychloride and phosphorus pentachloride. After terminating the reaction by decomposing the reagents by adding water or removing them by distillation, the residue may be isolated as pure crystals or an oil by extraction with an organic solvent, or the crude product can be isolated as a pure crystal or oil. Pure dihydropyrimidines (1) and (1)' can be obtained by common methods such as adsorption chromatography such as silica gel column chromatography, partition chromatography, gel permeation chromatography, recrystallization, and distillation. . These dihydropyrimidines also form salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as oxalic acid and succinic acid. Dihydropyrimidines that can be synthesized in this way are, for example, 1 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-phenyl-dihydropyrimidine (alkoxy here refers to methoxy and ethoxy) 2 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-nitrophenyl)-dihydropyrimidine (alkoxy here refers to methoxy, ethoxy, propoxy) 3 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3-nitrophenyl)-dihydropyrimidine (alkoxy here refers to methoxy, ethoxy, isopropoxy, and pryloxy) 4 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(4-nitrophenyl)-dihydropyrimidine (alkoxy here refers to methoxy, ethoxy, propoxy) 5 Alkoxycarbonyl-6-chloro-2-methyl-4-(2-trifluoromethylphenyl )
-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-trifluoromethylphenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-trifluoromethylphenyl)-dihydropyrimidine (alkoxy here means methoxy or ethoxy) 6 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3-chlorophenyl)-dihydropyrimidine (alkoxy here means methoxy, ethoxy, isoprokoxy) 7 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-chlorophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-chlorophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-chlorophenyl)-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 8 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-promophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-bromophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-promophenyl)-dihydropyrimidine (alkoxy here means methoxy, ethoxy, and bopoxy) 9 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3-cyanophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-cyanophenyl)-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 10 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-methoxyphenyl)-dihydropyrimidine (alkoxy here means methoxy, ethoxy, propoxy, butoxy) 11 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-methylthiophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-methylthiophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-methylthiophenyl)-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, propoxy, butoxy) 12 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-methylphenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-methylphenyl)-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 13 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-ethylphenyl)-dihydropyrimidine (alkoxy here means methoxy, ethoxy, or bopoxy) 14 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-ethoxyphenyl)-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 15 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-fluorophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(3-fluorophenyl)-dihydropyrimidine 5-alkoxycarbonyl-6-chloro-2-
Methyl-4-(4-fluorophenyl)-dihydropyrimidine (alkoxy here means methoxy or ethoxy) 16 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-furyl)-dihydropyrimidine (alkoxy here means methoxy or ethoxy) 17 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-thienyl)-dihydropyrimidine (alkoxy here means methoxy,
18 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3-furyl)-dihydropyrimidine (alkoxy here means methoxy or ethoxy) 19 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3-thienyl)-dihydropyrimidine (alkoxy here means methoxy or ethoxy) 20 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2,6-diclophenyl)-dihydropyrimidine (alkoxy here means methoxy, ethoxy, or bopoxy) 21 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-chloro-5-nitrophenyl)-1,4-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 22 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(2-nitro-5-chlorophenyl)-1,4-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, or bopoxy) 23 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3,-dimethoxyphenyl)-
1,4-dihydropyrimidine (alkoxy here means methoxy, ethoxy, and bopoxy) 28 5-alkoxycarbonyl-6-chloro-2
-Methyl-4-(3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine (alkoxy herein means methoxy, ethoxy, and isobropoxy) acetamidine. Or, instead of the salt thereof, for example, propionamidine, butyramidine, etc.
- When reacted with alkoxycarbonylpropenoic acid ester (3) in the presence of a base, 5,6-dihydro-4-pyrimidone (2) having an ethyl group and a propyl group at the 2-position is obtained, and further phosphorus oxychloride is obtained. It is clear to those skilled in the art that by treating (2) with phosphorus pentachloride, 1,4-dihydropyrimidine (1) having an ethyl group or a propyl group in place of methyl at the 2-position of the general formula can be obtained. Will. The synthesis leading to the compounds of the invention described above is summarized by the following flow diagram. [Formula] and [Formula] R ¹ : Lower alkyl group R ² : Phenyl group, substituted phenyl group, furyl group,
Thieryl group The dihydropyrimidine derivative of the present invention has the above formula (1)
It exists as a mixture of tautomers represented by (1)′ and (1)′. In this specification, the term dihydropyrimidine derivative refers to a mixture of tautomers represented by formulas (1) and (1)'. The following tests were conducted on the coronary vasodilator effect of the dihydropyrimidine derivative of the present invention. (1) Experimental method The hearts of Hartley guinea pigs weighing 400 to 500 g were removed immediately after being killed by Langendorff perfusion method (J.Pharmacol.Methods).
2, 143 (1979)), 95% O ₂ + 5% CO ₂
The mixed gas was aerated and a Krebs-Henseleit solution kept at 37° C. was flowed at a constant flow rate (6 ml/min). Perfusion pressure was measured with a pressure transducer. To prepare the sample, 1 mg of the test compound was dissolved in 1 ml of a mixture of dimethyl sulfoxide and physiological saline (1:9), and then diluted with physiological saline to a predetermined concentration. 0.1 ml of this solution was directly administered into the coronary artery through a rubber tube connected to the aortic cannula, and the ED50 (μg/heart) as shown in Table 1 was obtained.
I got it. The compound numbers in the table correspond to the example numbers below. [Table] As is clear from Table 1, compound number 7,
Compounds 10, 15, 21, 22 and 23 showed very strong coronary vasodilator activity. Since these compounds exhibit sufficient efficacy in very small doses, side effects of these compounds can be suppressed to a negligible level. (d) Examples Production examples of intermediate (2) for producing the compound of the present invention and Examples of the compound of the present invention are shown below. Production example 1 5-ethoxycarbonyl-2-methyl-6-phenyl-5,6-dihydro-4-pyrimidone 0.5 g of benzylidene diethyl malonate and 0.19 g of acetamidine hydrochloride were added to 20 g of absolute ethanol.
0.27 g of dissolved sodium ethylate was added to the solution and heated under reflux for 1 hour. The obtained crystals were recrystallized using an acetone-hexane mixed solvent. Colorless bowl-shaped crystals 0.45g (yield 87%) Melting point: 129-131° Infrared absorption spectrum (in chloroform, cm ^-1 ) 3400, 1740, 1720, 1680 ¹ H-NMR spectrum (CDl _3.8ppm ) 1.12 ( 3H, t, J = 7Hz), 2.07 (3H, d, J = 2
Hz), 3.46 (1H, d, J = 12Hz), 4.08 (2H, q,
J=7Hz, 5.00 (1H, dd, J=2, 12Hz), 7.27
(5H, S), 9.45 (1H, br, S) Mass spectrum (m/z): 260 (M ⁺ ) A product (2) having the physical properties listed in the table was obtained. [Table] [Table] [Table] In the purification method, (A) represents purification by silica gel column chromatography. Unless otherwise specified, infrared absorption spectra are values in chloroform. Example 1 5-ethoxycarbonyl-6-chloro-2-methyl-4-phenyl-1,4-dihydropyrimidine (1) and 5-ethoxycarbonyl-6-chloro-2-methyl-4-phenyl-1,2 -Dihydropyrimidine 10 ml of phosphorus oxychloride was added to 200 mg (0.77 mmol) of 5-ethoxycarbonyl-2-methyl-6-phenyl-5,6-dihydro-4-pyrimidine (melting point: 129-131°) and heated under reflux for 20 minutes. did. Excess phosphorus oxychloride was removed under reduced pressure, and chloroform was added to the resulting residue. A saturated aqueous potassium carbonate solution was then added under ice cooling, and after separating the chloroform layer, the aqueous solution was further extracted with chloroform. After chloroform was distilled off, the obtained oily substance was purified using silica gel column chromatography, and then recrystallized from a mixture of ether and acetone. The yield, physical properties, and instrumental analysis data of the obtained product are shown in the table below. Examples 2 to 26 also followed the method of Example 1, using the starting compounds and reaction conditions listed in the table below to obtain the respective corresponding products. [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] [Table] *Data from high-resolution mass spectra **Data as hydrochloride Compounds of the present invention A pharmaceutically suitable acid addition salt of was prepared as follows. Production of acid addition salts 1 g of dihydropyrimidine derivative is dissolved in 100 ml of an alcohol-based organic solvent, and an excess amount of an inorganic acid such as hydrochloric acid, perchloric acid, or formic acid, or an organic acid such as oxalic acid, tartaric acid, or maleic acid is added. In this case, it is better to dissolve the acid in a suitable organic solvent. Also, if dihydropyrimidine derivatives are soluble, they can be used in ethers, chlorinated hydrocarbons, etc. instead of alcoholic solvents.
It may be dissolved in an acetone solvent. After adding these excess acids, if the acid addition salt separates as crystals, it is passed. If not, the acid addition salt is obtained by evaporating the solvent, concentrating, and recrystallizing. (e) Industrial Applicability The dihydropyrimidine derivative of the present invention has a strong vasodilatory effect, particularly an important coronary dilator effect, as described above, and is therefore useful as a therapeutic agent for a wide range of cardiovascular diseases. Moreover, the desired therapeutic effect can be achieved with an extremely small dose, minimizing side effects.For this reason, in the medical field, it has become a safe and powerful drug for the treatment of cardiovascular diseases, which are increasing in number in modern society. I am sure that it will be used frequently.

Claims (1)

[Scope of Claims] 1 Tautomers represented by the general formula [Formula] and [Formula] (wherein R ¹ is a lower alkyl group, and R ² is a phenyl group, substituted phenyl group, furyl group, or thienyl group) dihydropyrimidine derivatives and their pharmaceutically suitable acid addition salts. 2 R ² is a nitrophenyl group, trifluoromethylphenyl group, bromophenyl group, chlorophenyl group, chlornitrophenyl group, lower alkylthiophenyl group, fluorophenyl group, mono, di,
The dihydropyrimidine derivative according to claim 1, which is a trimethoxyphenyl group, lower alkyl phenyl group, dichlorophenyl group or cyanophenyl group, and a pharmaceutically suitable acid addition salt thereof. 3 General formula (In the formula, R ¹ is a lower alkyl group, R ² is a phenyl group,
A 5,6-dihydro-4-pyrimidone derivative having a substituted phenyl group, furyl group or thienyl group is heat treated with a chloride selected from the group consisting of phosphorus oxychloride and phosphorus pentachloride to form a pharmaceutically suitable compound, if desired. Dihydropyrimidine derivatives which are tautomers represented by the general formulas [Formula] and [Formula] (wherein R ¹ and R ² have the same meanings as above) and which are suitable as pharmaceuticals by treatment with an acid. A method for producing acid addition salts.