JPS60255778A - 2-substituted dihydropyrimidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:Tautomeric isomers of 2-substituted dihydropyrimidine derivative of formula I and II [R<1> is lower alkyl; R<2> is phenyl; R<3> is phenyl, amino, lower alkylamino, di-lower-alkylamino; R<4> is methyl, chloro (where in case that R<3> is phenyl, R<4> is not methyl)] and its acid adduct. EXAMPLE:6-Chloro-2-dimethylamino-5-ethoxycarbonyl-4- ( 3'-nitrophenyl )-dihydropyrimidine. USE:It is used as a remedy for stenocardia, hypertension, arrhythmia, because it has coronary vasodilative action. Especially, it has high stability. PREPARATION:A tetrahydropyrimidinol derivative of formula III is treated with a dehydrating agent selected from the group consisting of phosphorus oxychloride, alumina, silica gel and acids to give a compound of formula I or II.

Description

DETAILED DESCRIPTION OF THE INVENTION Object of the Invention The present invention provides general formulas (1) and (1') (1) (1') [wherein R1 represents a lower alkyl group and R2 is a phenyl L-substituted phenyl group, R represents a phenyl group, a substituted phenyl group, an amine group, or a di-lower alkylamino group, and R4 represents a methyl group or a chloro group (provided that when R is a phenyl group or a substituted phenyl group, R4 is not a methyl group). The present invention relates to a 2-substituted dihydropyrimidine derivative represented by a tautomer, a pharmaceutically suitable acid salt thereof, and a method for producing the same.

The compounds represented by the above general formulas (1) and (1') have a coronary vasodilatory effect and are therefore effective in the treatment of a wide range of conditions such as angina pectoris, hypertension, arrhythmia, and cerebral circulation disorders.

In recent years, calculum antagonists (Ca+F antagonists) have been in the spotlight as a new type of therapeutic drug for cardiovascular disorders.They have a wide range of medicinal effects, are effective for hypertension, angina pectoris, arrhythmia, etc., and are currently being used to treat these conditions. Not only is it being used more and more, but its indications are also increasing.

Currently known calculum antagonists include nifedipine and nicardipine.
rdipine), Verapamil (Verapamil)
), diltiazem, etc.

Until now, not much research has been done on dihydropyrimidine derivatives (Si 1versnith, E, F.
, J. Org.

Chem, 27.4090 (1962), Na5i
puri.

D. et al. Synthesis 1073 (1982),
Kashima, C.

Tetrahedron Let+1era, 20
9 (1983) and JP-A-59-73572].

A possible reason is the instability of dihydropyrimidine derivatives. It is also thought that the reason is that it is difficult to give a single resultant because it is a tautomer. According to Weis et al. [Wθis.

A, H, etrahedron L6tiers,
449 [(1982)] dihydropyrimidine has tautomerism in X-ray crystal analysis (-form and in solution state, form (A)), and states that (Q-form is unstable).

(E) (A) (Q The above-mentioned known calcium antagonists have potential for improvement in properties such as duration of action, organ selectivity, stability against light and heat, and side effects. We conducted extensive research to create dihydropyrimidine derivatives with improved properties, especially stability.As a result, we obtained the general formula (
It has been found that the 2-substituted dihydropyrimidine derivative represented by 1) or (1') has excellent stability.

Structure of the Invention (a) Means for Solving the Problems The compounds represented by the general formulas (1) and (1') of the present invention can be produced as follows.

(a) Synthesis method 1 General formula (in the formula, R1 represents a lower alkyl group, R2 is a phenyl group or a substituted phenyl group, and 1 (3' represents an amine group, a lower alkylamino group, or a di-lower alkylamino group) A general method for producing a compound in which R represents a methyl group.

First, an α,β-unsaturated carbonyl compound H3 represented by the general formula (2) (in the formula, R% and R2 represent the same meanings as above) is converted to 1 equivalent or more of guanidine N-monosubstituted lower alkyl/7nidine. Alternatively, the tetrahydropyrimidine derivative (3) can be obtained by reacting it with N-disubstituted lower abenzene guanidine in a suitable alcohol.

When using a salt such as guanidine hydrochloride, it is preferable to first convert it into a free amine with an alkali metal alkoxide 9. The alcohol used is preferably an alcohol having an alkyl group represented by substituent R1.

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 derivative (3) can be converted into a dihydropyrimidine derivative (3) which is a compound of the present invention by various methods.
1a) and (1a').

Example i, p -) Method to obtain a dihydropyrimidine derivative by dehydration by heat treatment with an acid such as luenesulfonic acid or benzenesulfonic acid; Methods include mixing, heating at 100 DEG C. to 200 DEG C., preferably 120 DEG C., for 20 minutes to 120 DEG C., and extracting with an organic solvent; and a method of dissolving in phosphorous chloride and heating under reflux for dehydration. Furthermore, the dehydration conditions include acids such as 7!7777-10-sulfonic acid,
Dihydropyrimidine derivatives (la) and (
la') is obtained.

The obtained compound of the present invention can be purified by a general purification method such as adsorption τ comatogelatography, ion exchange chromatography, partition chromatography, or distillation. 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 7-euric acid, tartaric acid, succinic acid, or maleic acid.

(b) Synthesis method 2 General formula % Formula % (1) (In the formula, R1 is a lower alkyl group, R2 is a phenyl group or a substituted phenyl group, and R3 is a phenyl group, a substituted phenyl group, an amino group, a mono-lower alkylamino group, or -i method for preparing a target compound (representing a di-lower alkylamino group).

(In the formula, R and R have the same meanings as above) By heat treatment in a system solvent, the general formula (5
) (R1, R2 and R3 have the same meanings as above) is obtained. -: When using a salt such as benzamidine hydrochloride instead of nzamidine etc., lithium ethoxyde, sodium ethoxyde, potassium ethoxide, sodium methoxyde, tokiku r1, lithium methoxyde, sodium propoquid, potassium propoquid 9, potassium - A 5,6-sihydro-4-bilimibin compound represented by the general formula (5) can be obtained by heat treatment in an alcoholic solvent in the presence of an alkali metal alcoholade such as ↑-butoxide. The thus obtained 5,6-dihydro-4-pyrimidone (5) can be easily purified by general purification methods such as distillation, recrystallization, adsorption chromatography, partition chromatography, gel filtration, methods utilizing solubility and acidic obscurity. Can be isolated and purified.

This 5,6-hydro-4-pyrimidone (5) is obtained by heating and refluxing with excess oxy-7 chloride for 20 to 30 minutes. 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 oil by extraction with an organic solvent, or the crude product can be isolated as a pure crystal or oil. 7. Pure dihydropyrimidines (1) and (11) can be obtained by common methods such as adsorption chromatography such as silica gel column chromatography, partition chromatography, gel filtration chromatography, recrystallization, and distillation.

Q):) Hydropyrimidines form salts with inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as citric acid and succinic acid.

(b) Action The dihydropyrimidine derivatives (1) and (1') of the present invention
The following tests were conducted on the coronary vasodilator effect of

1) Experimental method Hartley weighing 400-500#
After killing the guinea pig, the heart was immediately removed and subjected to Langendorff perfusion method (J, Pharmacol, Metho).
ds2.

143 (1979)), 95%02+5%co
The tube was perfused with a constant flow rate (6-7 minutes) of Krebs-Hensleit solution kept at 37''C through aeration of a gas mixture of 2 and 3.

Perfusion pressure was measured with a pressure transducer.

To prepare the sample, test compound 1 is mixed with dimethylsulfochloride 7
After dissolving in a mixture 1d of r and physiological saline (1:9), the solution was diluted to a predetermined concentration using physiological saline. This solution 0.
1- was administered directly into the coronary artery through a rubber tube connected to the aortic cannula, and the ribs as shown in the table below were administered. (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 of dihydropyrid S dine derivatives (1) and (1') are shown in the table below.

Thus, it is clear that the compound (1) or (1') of the present invention has a strong vasodilatory effect.

(C) Examples The present invention will be explained in more detail with reference to Examples below, but it goes without saying that the present invention is not limited to these examples.

Example 1 6-chloro-2-dimethylamino-5-ethquincarbonyl-4-(3'-nitrophenyl)-dihydropyrimidine 2-N-dimethylamino-5-ethquincarbonyl-6
-(3'-nitrophenyl)-5,6-cyhydropyrimidin-4-one 271~ was dissolved in phosphorus oxychloride 10- and refluxed during addition.

After phosphorus oxychloride was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous potassium carbonate solution, dried, and then the solvent was distilled off. Purify the residue using silica gel thin layer chromatography (developing solvent chloroform:acetone-1:1)
t, the title compound 189■ (yield 66%) was obtained.

Properties: Pale yellow crystal Melting point = 135-137° (recrystallization solvent acetone ether) Example 2 5-ethquincarbonyl-6-methyl-2-phenyl-
4-(2'-ditrophenyl)dihydropyrimidine (3.0 g of benzamidine hydrochloride and sodium ethylene) 1
Dissolve 3g in 7511+1j ethanol to obtain 2-nitroindylidene diethylmalone) 5. An ethanol solution of OF (75 tA') was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, saturated brine was added to the residue, and the mixture was extracted with chloroform. Evaporation of the solvent yielded 7.7 g of oil.

This oily substance 6.7y and para-toluenesulfonic acid 6.7y
g was added, dissolved in 150 g of benzene, and heated under reflux to dehydrate. After the reaction was completed, water was added to the reaction solution, and the aqueous layer was made alkaline by adding an aqueous potassium carbonate solution, and then extracted with chloroform. After distilling off the solvent at 35'C or below, the obtained extraction residue was purified by silica gel column chromatography using 2% methanol/chloroform as a developing solvent.2. ．． 8
g crystals were obtained (total yield 47%).

Example 3 2-amino-5-ethquinecarbonyl-6-methyl-(
2'-nitrophenylhydrohyrimidine guanidine α hydrochloride 28g and potassium-1-butyrate 0
．． 26g of t-butanol IQ+4! Ethyl 2- in solution
7 Cetyl-3-(2'-nitrophenyl)-2-pQ
+=! ! / : L-t0.55' t-butanol 1
0d solution was added and stirred at room temperature for 1 hour.

The solvent was distilled off without strong heating, chloroform was added to the residue, and the mixture was filtered using a glass filter.

It was concentrated to obtain a residue of 484 cm.

This residue 4841r#9 was dissolved in a small amount of methylene chloride, 5.0 g of alumina powder (Wako Tsumugi Co., Ltd., alumina for column chromatography, 300 ml) was added, and the solvent was carefully distilled off. 1 of this dried albas powder
After heating at 20°C, methanol:chloroform-3=
7 to obtain 125 da crystals (total yield 20%).

Properties: pale yellow crystal Melting point = 196-198° (recrystallization solvent ether chloroform) Physical data of Examples 1-3 and Examples 4-7 are shown below.

Examples 4-7 were synthesized by the same method as Examples 1-3.

The compound represented by the general formula (5) can be synthesized as shown in the following production example.

Production Example 1 2-amino-5-ethquincarbonyl-6-(2'-chlorophenyl)-5,6-u hydrohyrimidin-4-one guanidine hydrochloride 2.23 & sodium ethyl) Z2
An ethanol (75117) solution of 2-chlorobenzylidene diethyl malo $ - OOg was added to a solution of 9 g of ethanol (751L6), and the mixture was heated under reflux for 2 hours.

The crystallized compound was collected using a glass filter, washed with water three times, and dried under reduced pressure. This crude crystal was recrystallized from methanol, acetone, and chloroform to give 4.38 g (yield 70%).
A pale yellow crystal of was obtained.

Properties: Pale yellow crystal Melting point: 169-172° IR: 1720
゜1690.167O NMR spectrum (DMSO-db, δ): 1.08
(3H.

t, J-7Hz), 3.51 (LH, d, J-7Hz)
, 4.01 (2H, Qy J-7Hz), 5.22
(LH, a, J -7Hz), 7.30-7.50
(4H, m) High resolution mass 7 is Cx3H14
Calculated value as CeN303: 295.0724 Actual value: 295.0761 Production example 2 2-dimethylamino-5-ethquincarbonyl-6-(
3'-nitrophenyl)-5,6-cyhydropyrimidin-4-one 3-
A solution of 891 ml of ditropendylidene diethyl malonate in 10 ml of ethanol was added, and the mixture was heated under reflux for 2 hours. The precipitated compound was collected using a glass filter, washed with water three times, dried under reduced pressure, and recrystallized from methanol.

Crystals of 9371119 (yield 92%) were obtained.

Note: Colorless crystal melting point: 211-213° IR spectrum (Nujol, α-1): 1740.1
645NMR Sue! :ri)k(cDCe3:QD3oI
), 1: L a): 1.20 (3H, t, J"7H
z), 3.12 (6H, s), 3.52 (LH, d.

J-7Hz), 4.15 (2H,q, J-7Hz),
5.12 (IH.

d, J-7Hz), 7.55-8.25 (4H, m
) High resolution mass quictor: Cs sHt 8N40
Calculated value as 5: 334.1275 Actual value: 334.1275 Production example 3 2-phenyl-5-ethoxycarbonyl-6-(3/-
Nitrophenyl)-5,6-cyhydrohyrimidine-4-
1.6g of nzamidine hydrochloride and sodium ethylene)
A solution of 3-nitroincylidene diethyl malo, I-)L5#17) ethanol 25WLt was added to a 0.68.9% ethanol 25WLt mixture, and the mixture was heated under reflux for 3 hours.

Ethanol was distilled off under reduced pressure, and the residue was dissolved in chloroform and washed with saturated brine. After drying the chloroform layer and distilling off the solvent, pale yellow crystals zOg were obtained. This was recrystallized from ethyl acetate/hexane to obtain the title compound 154.9 (yield 85%)
I got it.

Properties: Pale yellow crystal Melting point: 178.5-180° Engineering R spectrum (CHce3, cy+-”): 3400
,1740°1720.1655, NMRx-! ! I Tor (CDCIs, a): 1.1
7 (3H, t, J, 71 (z), 3.58 (IH, a,
J=12Hz), 4.16 (2H.

qs J-7Hz), 5.37 (LH, a, J-12H
z), 7.4 to 8.3 (9Hz m) High-resolution mass coverage: Calculated value as C19H17N305: 367.1168 Actual value: 367.1164 The following Production Examples 4 to 3 were obtained in the same manner as Production Examples 1 to 3. Figure 7 shows the physical data of compound No. 7.

Claims (8)

[Claims] (1) General formula [In the formula, R1 represents a lower alkyl group, R2 represents a phenyl group or a substituted phenyl group, R3 represents a phenyl group, a substituted phenyl group, an amino group, a mono-lower alkylamino group, or a di-lower alkylamino group; R4 represents a methyl group or a chloro group (provided that when R3 is a phenyl group or a substituted phenyl group, R4 is not a methyl group)] and its pharmaceutically suitable acid addition. salt. (2) Claim 1, wherein R' is a methyl group, an ethyl group, a propyl group, a phthyl group, an R2caffeinyl group, a nitrophenyl group, a methylthiophenyl group, a dribliomethylphenyl group, or a halogenophenyl group. compound. (3) R3 is a phenyl group, substituted phenyl group, amine group, methylamine group, ethylamino group, dimethylamino group, diethylamino group, methylethylamino group, propylamino group or diisopropylamino group, and R4 is a chloro group A compound according to claim 1. (4) Claims in which R3 is an amine group, methylamine group, ethylamino group, dimethylamino group, diethylamino group, methylethylamino group, propylamino group, or diisozolopylamino group, and R is a methyl group A compound according to item 1. (5) General formula [In the formula, R1 is a lower alkyl group, R2 is a phenyl group or a substituted phenyl group, and R is an amine group, a mono-lower alkylamino group, or a di-lower alkylamino group]
A tetrahydropyrimidinol derivative having the general formula (in which R1 , R2 and R3 have the same meanings as defined above), and a method for producing a pharmaceutically suitable acid addition salt thereof. (6) Enones having the general formula (in the formula, R1 is a lower alkyl group and R2 is a phenyl or substituted phenyl group) are combined with guar herring, N-lower alkylguanidine, N-dilower alkylguanidine, or these. Hydrochloride is cyclized in the presence of a metal alcoholade, resulting in a general formula (wherein R1 and R2 represent the same meanings as above, R3
' is represented by an amino group, a lower alkylamino group or a di-lower alkylamino group), and then treated with a dehydrating agent selected from the group consisting of phosphorus oxychloride, alumina, silica gel and acid. , a tautomer dihydropyrimidine derivative represented by the general formula (wherein R1, R2 and R3' have the same meanings as above), which is characterized by being dehydrated and, if desired, treated with a pharmaceutically suitable acid. and a method for producing its pharmaceutically suitable acid salts. (7) General formula (in the formula, R1 is a lower alkyl group, R2 is a phenyl group or a substituted phenyl group, and R is a phenyl group, a substituted phenyl group, an amino group, a lower alkylamino group, or a di-lower alkylamino group). The dihydropyrimidine derivative having the general formula (in which R1, A method for producing a dihydropyrimidine derivative which is a tautomer represented by (R2 and R3 have the same meanings as above) and a pharmaceutically suitable acid U salt thereof. (8) A 2-alcoquine carbonylproinic acid ester derivative having the general formula (wherein R1 is a lower alkyl group and R2 is a 7-enyl group or a substituted phenyl group) is used as a benzamidine, an aromatic ring-substituted benzamidine, A general formula consisting of cyclizing N-di-lower alkylguanidine, guanidine or a hydrochloride thereof in the presence of a metal alcoholade (wherein R1 and R2 represent the same meanings as above, R3
(represented by a phenyl group, substituted phenyl group, amine group or di-lower alkylamino group), and then heat treated with a chloride selected from the group consisting of phosphorus oxychloride and phosphorus pentachloride. , dihydropyrimidine derivatives which are tautomers represented by the general formula (wherein R1, R2 and R3 have the same meanings as above) and pharmaceuticals thereof, which are treated with an acid suitable for pharmaceutical use if desired. A method for producing acid salts suitable as