JPS62267272A - Novel dihydropyrimidine compound and its salt, production thereof and agent for circulatory system containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:A dihydropyrimidine compound characterized by the mesomeric types expressed by formulas I and II (R<1> and R<2> are same or different and H, halogen, alkyl, halogenoalkyl, nitro or cyano; R<3> and R<4> are same or different and H or alkyl; R<5> is halogen, alkyl or nitro or aralkyl which may be substituted by halogenoalkyl) or an equilibrium substance between the two types. EXAMPLE:Methyl 6-methyl-4-(2-nitrophenyl)-2-(2-phenylethylthio)-dihydropy-rimidine- 5-carboxylate. USE:Useful as an agent for circulatory systems and having improved calcium antagonistic action, excellent safety and long duration of action with hardly any side effect. PREPARATION:A ylidene-beta-keto ester expressed by formula III is reacted with an isothiourea expressed by formula IV to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides novel dihydropyrimidine compounds and salts thereof,
The present invention relates to a method for producing these and a circulatory system active agent containing the compound as an active ingredient.

(Prior art) Calcium antagonists (Ca"+ antagonists) act on the circulatory system and are therefore effective as antihypertensive agents, vasodilators, angina treatment agents, arrhythmia treatment agents, and brain treatment agents. The one currently known is nifedipine (Nlf@di
pins), nicardipine (N1cardipins)
), soltiazem (Diltiazem), etc.

(Problems to be Solved by the Invention and Objectives of the Invention) Calcium antagonists are not only used for the above-mentioned therapeutic purposes, but their indications are increasing, and therefore, they have selectivity to blood vessels in specific locations. There is a strong desire for the emergence of a new calcium antagonist that has fewer side effects, is superior in safety, and has a longer action time.

Therefore, the main object of the present invention is to provide an effective calcium antagonist to replace conventional nifedipine and the like.

(Means and effects for solving the problems) As a result of extensive research, the present inventors have discovered the general formula (in both formulas, R and R are the same or different, hydrogen, halogeno, alkyl group, halogenoalkyl R3 and R4 are the same or different and mean hydrogen or an alkyl group, R can be substituted with halogeno, alkyl group, nitro group or halogenoalkyl group The present invention is based on the discovery that novel dihydropyrimidine compounds and salts thereof, which are mesomely-type (meaning an aralkyl group) or an equilibrium between these two types, have excellent calcium antagonistic effects. I was able to complete it.

In the compounds represented by the above general formulas I and Im,
Examples of halogens include fluorine, chlorine, bromine, and iodine. Alkyl groups can be linear, branched or cyclic alkyl groups, examples of linear alkyl groups include alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, n- Examples of branched alkyl groups include isozolobyl, isobutyl, l-butyl, t-butyl, isopentyl, etc. Examples of the cyclic alkyl group include cyclobutyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the halogenoalkyl group include trifluoromethyl and dichloromethyl. Examples of the aralkyl group include phenylmethyl and phenylethyl.

The salts of the compounds represented by general formulas I and Im are acid addition salts, and are non-toxic salts for use as medicines. Examples of salt-forming acids include hydrochloric acid, hydrobromic acid, etc. Examples include mineral acids such as hydrohalodic acid, sulfuric acid, and phosphoric acid, and organic acids such as maleic acid, fumaric acid, tartaric acid, succinic acid, and lactic acid.

According to the method of the present invention, the compounds represented by the general formulas (1) and (la) and their salts are: or B) react the aldehyde represented by the general formula (in which R and R have the above-mentioned meanings) with the isothiourea represented by the above general formula (1) and the general formula %. () (in which R and R have the above meanings)
- It can be obtained by reacting with ketocargenic acid and then converting the resulting product into a salt if necessary.

The above methods and B can be carried out, if necessary, in the presence of an inert organic solvent as a diluent, in which case the solvent may be methanol, ethanol, isozolo.9
Alcohols such as alcohol, ethers such as diethyl ether, tetrahydrofuran, and dioxane, carbonized frozen confections such as benzene and toluene, halodanized hydrocarbons such as chloroform, and DMFA, DM80, birinone, and HM.
Examples include PA. Furthermore, methods A and B above
This can also be carried out by adding an acid or a base if necessary.

The reaction temperature when carrying out the above method A or B't varies depending on the type of raw material compound, the presence or absence of a solvent, etc.
Generally, the temperature is 20 to 150°C, and when the reaction is carried out in the presence of a solvent, it is preferable to carry out the reaction at the boiling point of the solvent.

Depending on the selection of the starting materials, the compounds according to the invention may exist as stereoisomers in mirror image (enantiomer) or non-mirror image (norastereomer) form; mer mixture.

Racemates, as well as diastereomers, can be resolved into stereochemically stereotypical components using known methods (e.g., E. L. Eliel, "5tsreo").
eh@m1mtry of Carbon Co
mpounds '1962 McGraw Hl
(published by 11 companies).

Incidentally, among the starting materials used in the above method A, ylidene-β-ketoester of formula (1) can be produced by a known method (for example, G@Jones “Org, R
eactlons” Volume XV, pages 204 et seq., 196
7 years).

■ Among the starting materials used in the above method B, the growing β-ketocarboxylic acid ester is known per se or can be produced by a known method.
-11 Deki (e.g. ” M@thod@n de
rOrganlseh*n Ch@ml@' No.■/4
Volume fM 230g or less, 1968 and Y, Olkaw
a etc.” Je Org, Chem, 'Volume 43 No. 2
082-11978), the aldehydes of Bunmu W are known per se or can be produced by known methods (T. D. Harris et al.'' J. Org.
*Chem,” Vol. 4144, No. 146 g, 197
9 years and M, Mardln%” J, Org
*Chem, 'Vol. 31, p. 615, 1966 and "Ja Am* Chem, Soc,'/No. 28
Volume 2543, 1956).

In addition, isothiourea (2), which is a common raw material used in the above methods A and B, is also known per se, but can be produced by a known method (Z, J, Ve
jd@lek etc”Chsm, Li5ty’42nd
Volume No. 49, 1958 and S, Siegel @
” J, Am.

Chem, Soc, 'Volume 75 No. 4s2S@, 1
953].

(Dosage form and administration when used as a medicine) The compound according to the present invention and its salt can be formulated as an active ingredient and administered for the improvement of circulatory system diseases. There are no restrictions on dosage form when formulating, so tablets, pills, hard capsules, soft capsules, powders, granules,
It can be made into solid preparations such as suppositories, or liquid preparations such as bath solutions, suspensions, and emulsions. In the case of solid preparations, conventional excipients such as starch, lactose, glucose, g12 calcium, magnesium stearate, gum arabic, etc. can be used, and if necessary, lubricants, binders,
A disintegrant, a coating agent, a coloring agent, etc. can be used. In the case of a liquid preparation, it may contain stabilizers, bath dissolution aids, suspending agents, emulsifiers, buffers, preservatives, and the like.

The dosage of the compound according to the present invention or its salt should be determined taking into account factors such as its type and dosage form, the type and severity of the disease, and the age and condition of the patient, but in general it is recommended for adults. About 0. J~sooomci/day, preferably J~5ooortw;)7 days.

(Effects of the Invention) The compounds and salts thereof according to the present invention are excellent in calcium antagonistic activity, and therefore can be used as active ingredients for preventive and therapeutic agents for cardiovascular diseases.

On the other hand, according to the method of the present invention, desired compounds and their salts can be obtained easily and in good yields under mild conditions using compounds known per se or compounds that can be easily derived therefrom as raw materials.

(IA! Examples, etc.) Next, the present invention will be explained in relation to production examples and pharmacological test examples.

Production example J 6-methyl-4-(3-nitrophenyl)-2-(2-
Phenylethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester 2-(J-nitrophenyl)methylene-3-oxobutyric acid methyl ester 15.0fiC6
0.2 mmol] and 18.811 (72.0 mmol) of 2-phenylethylinthiuronium bromide were suspended in 360 ml of benzene, and while stirring at room temperature, triethylamine v, tyllc (72.0 mmol) was added. The mixture was stirred and refluxed for 17 hours. The solvent was then distilled off under reduced pressure, and the resulting residue was subjected to silica dull column chromatography (CH2Cl2: Et20 = 2:
1) If purified in step 1), the desired product 17.8 will be obtained as a yellow oil.
g is obtained (yield: 71.8).

Hydrochloride melting point: 168-175°C (decomposition) Mass quictor (m/z): EI/1)I: 39'l (M''-14), 30
7 (pace beak) CI/1)■; 412 [(M+
1) 4″, pace beak] NMR: x, vector (DM
SO-d6) δppm: 2.5y (JH
, me C6-OH,)z, or -4,57(4HI
J -CH2CH2-)s-70(3He a,
C00CH3)5-96 usIr 1.
ca-n) 1.05-'1.50C5H, m, 5
-C-C-C6H,)7.60-s,5o(4H,m
, -C6H4NO□)9.00-14.00(Il■
, ), N”H) IR spectrum (νIna Riwa.

2750.1715 Elemental analysis (C2, H2, N304S-) (C2): Calculation: H4,95, C56,31, H9,31j actual measurement;
H4, lj9. C55,93,H9,46 Free Base Mass Spectrum (In/z) EI/1) I: 4 J J (M”), 307
(pace beak) CI/'I)I: 4 J j
(: CM+1)", pace peak) Production example 2 6-methyl-4-(3-nitrophenyl)-2-(1-
Two noastereomers of phenylethylthio)-nohydropyrimizone-5-cal+Ie acid methyl ester (
Compounds 2α and 2β) 2l- 2-(3-nitrophenyl)methylene-3-oxobutyric acid methyl ester 30.011 (120 mmol) and 1-
Phenylethylinthiuronium bromide 37! , 51
(144 mmol) was suspended in (Nzene 550d) and stirred at room temperature, and triethylamine 14-51
Cz (44 mmol) was added and refluxed for 18 hours with stirring. The solvent was then distilled off under reduced pressure, and the resulting residue was subjected to silica dull column chromatography (Et20:C
If purified with H2CH2=1:1), the first flux,
One diastereomer (2α) is 15.71
The other diastereomer (2β) was obtained as a second fraction (yield: 31.7%), and the other diastereomer (2β) was obtained (yield: 40.4%).

Melting point: xsv-1ss°C (decomposition) Mama spectrum (m/z): EI/bI: 4 J J (M”), J 85
(H-xe-ri) CI/1) I: 412 [(
M+1)”, base peak] NMR spectrum (DMS
O-d6) δppm: Ha44 (3H, d,
J=7. □Hz, 5-C-CH,)2.55
(,9H, Hatake C6-CH5) 3.68
C3H,I, C00CH,)5-95
Ul(, l, C4-H)5-95 (
J Heq ) J=7-OHz e S -CH
CH3) y, zv (sH, m, 8-C-
C6H3) 7.70-8.50 (4H, m, c6tt
4No2) 10.00-13.00CN1. b, N
”H) IR spectrum (ν) information.

ax 2800.1725 Elemental analysis (C2, H22N, 04S-HCt): Calculation; H4,! ? 5. csrt, sl, H9, 3B actual measurement; H4JIF# cse, 1s, No, sy2α
Free base Ma as spectrum (IV/z): IEI/DI
: 4 J J (M”, base peak) CI/
I)I: 4Jff [(M+J)", pacebeak) Melting point: 1s4-1ss°C (decomposition) Mass spectrum (mHz): EI/1)I; 4J1 (M"), 185
(Pace Beak) CI Power I: 412 [(W1+
1)”, Pace Beak) NMRX-1! Kutle (0M8
0-d6) 899m: 1.60 (,9H,
d, J=7.0Hz, S-C-CH,)2.
50 (,9H,1,C6-Cf(,)3.6
6 C3H-1, C00CH3) 5.82
(IHs q, J=7.0f(z, 5-CI
(-CH,)5-84 (IHs I!,
C4-H)6-85-8-54(9H+ mt Ar
-JH) 10.0 -13.0 (JHt b, N'
″H) IR spectrum (ν111&X) c1n11
2800.1225.1700.1530.1350,
Elemental analysis (C2, H22N304S Salary HC!t): Calculation: H4,95, C56,31, H9,3B Actual measurement: H
4,97,C56,20,H9,44Mass spectrum (mHz): II/l)I: 411 (M+, pace beak)
CI/DI; 412 [CM +1)'', pace peak] IR spectrum (νmax) @ 1700.1640.1530.1345.1115 Production example 3 6-Methyl-4-(2-nitrophenyl)-2-(phenyl Methylthio)-dihydropyrimidine-5-carzeneic acid methyl ester 2-(2-nitrophenyl)methylene-3-oxobutyric acid methyl ester 1'1.41 (70.0 mmol) and phenylmethylthiuronium chloride 15.6y (
77.0 mmol] was suspended in 300 d of benzene,
To this was added 7.79 g (77.0 mmol) of triethylamine, and the mixture was refluxed for 18 hours while stirring.

Next, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica dull ram chromatography (ca2ct2:n-
By teaing with hexane (J:J), the desired product 20.311 is obtained as a pale yellow oil (yield: 73.θ)
.

Hydrochloride melting point: 14o-14s°C Mass spectrum (rrL/x): El/1)I
: 397 (M”), 91 (Pace Beak) CI
/DI; 398 [(M+1)+, pace beak) N
MR spectrum CDMSO-d 6) 899m:2.
50 (,9H,s, C6-0H3)3.5
3 C3H,g, C00CE(3)4.3
0-5.35C2H,m, CH2-Ph)6.37
(JH,l,C4-H)1-10-8-2
0 (9Hs @, Ar-H) 7.00-9.50 (I
HI b, N”H) IR spectrum (νm, x) LM
.

2750, 1705 Elemental analysis CC2oH4,N,04S-HCl): Calculation; H4,65# css, se, H9,6B actual measurement;
H4,69, C55,41, H9,74 Production Example 4 6-Methyl-4-(2-nitrophenyl)-2-(2-
Phenylethylthio)-dihydrobyrimidine-5-carboxylic acid methyl ester 2-(2-nitrophenyl)methylene-3-oxobutyric acid methyl ester 17.49 (7
0.0 mmol) and phenylethylinthiuronium bromide 20.126-1 (77.0 mmol) were suspended in 300 d of benzene, and refluxed for 19 hours while adding triethylamine (7.79177.0 mmol). I let it happen. The solvent was then distilled off under reduced pressure, and the resulting residue was subjected to silica dull column chromatography (CH2Cl2:n-hexane=
1:1~CH2Cl2 alone), the target product is J8. as a pale yellow oil. J# obtained (yield 62.8
4) Hydrochloride Melting point: 1eo-1g2℃ MI-spectrum (m/s): EI/I)I: 41 J(M”), 105 (Pace peak) CI/1)I: 412 [CM+1
)”, Pacebeak) NMR spectrum (DM80-
d4) δppln: 2.00-4.10 (4H, m
e C) I, -CH, -Ph)2.52 (jH
, l, C6-Cl5)3-63 <3He l
, C00CHs)6-38 (JfLme
C4-H)7.33 (5H,lI, -〇-
C-06H5) 1.53-11.23 (4H, m, C
6H4-N02) 6.00-11.00 (IIl, b
, N"H)!R spectrum (νKB') Fl: ax 2650, 1225 element cumulative analysis (C2, H2, N, 04B-HCl): calculation; Ha, 9s, cse, so, H9, ss actual measurement:
114.93. C56, 04, H9, 50 Methods for finding drug efficacy pharmacology test examples, etc.
The calcium antagonistic effect of the compound according to the present invention was investigated by the Magnus method according to 1977).

Specifically, a New Sealant White female rabbit (weighing approximately 2.5 kl1) was killed by air embolization, and the descending thoracic aorta was immediately removed, and the rabbit was 5 cm wide and 25 cm long.
A complete spiral specimen of trm was prepared, and this specimen was suspended in a Magnus device, and its isometric tension changes were recorded on a recorder.

That is, the Krebs-Hensleit temperature was kept at 37±1°C through aeration of Co2 mixed gas.
After the resting tension (1g load) of the specimen stabilized in the solution, KCL (30mM) was added to reduce the Ca in the specimen.
The specimen was caused to contract by the action of (in this case,
Cm inherent in the specimen is consumed). The above Kr/bs became Ca-free in this way.
- Ca 2.5 and 5. Or
Add rM and record the contraction width of the specimen. Next, the test compound was added into the above solution, the contraction width of the specimen was recorded, and the contraction width recorded before the addition of the test compound was set as 100, and the relative value of the contraction width recorded after the addition of the test compound was calculated. Seeking,
The contraction inhibition rate and END5o value were calculated.

The results were as shown in the table below. In addition, all the compounds according to the production examples described as test compounds are hydrochlorides.

Claims (11)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I ) and General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) (In both formulas, R^1 and R^2 are the same or mutually exclusive. Unlike hydrogen,
It means halogen, alkyl group, halogenoalkyl group, nitro group or cyano group, R^3 and R^4 are the same or different and mean hydrogen or alkyl group, R^5 means halogen, alkyl group, nitro group or an aralkyl group which can be substituted with a halogenoalkyl group), or an equilibrium between these two types, and novel dihydropyrimidine compounds thereof. salt. (2) R^1 and R^2 are different and each means a hydrogen or nitro group, R^3 and R^4 both mean an alkyl group, and R^5 means an aralkyl group A novel dihydropyrimidine compound and a salt thereof according to claim 1, characterized in that: (3) 6-methyl-4-(2-nitrophenyl)-2-
(2-phenylethylthio)-dihydropyrimidine-5
- carboxylic acid methyl ester,
A novel dihydropyrimidine compound and a salt thereof according to claim 1 or 2. (4) 6-methyl-4-(3-nitrophenyl)-2-
(1-phenylethylthio)-dihydropyrimidine-5
- carboxylic acid methyl ester,
A novel dihydropyrimidine compound and a salt thereof according to claim 1 or 2. (5) 6-methyl-4-(2-nitrophenyl)-2-
The novel dihydropyrimidine compound and its salt according to claim 1 or 2, which is (phenylmethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester. (6) 6-methyl-4-(2-nitrophenyl)-2-
(2-phenylethylthio)-dihydropyrimidine-5
- carboxylic acid methyl ester,
A novel dihydropyrimidine compound and a salt thereof according to claim 1 or 2. (7) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^1 and R^2 are the same or different, hydrogen, halogen, alkyl group, halogenoalkyl group, nitro group, or cyano group (where R^3 and R^4 are the same or different and mean hydrogen or an alkyl group) and the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^5 means an aralkyl group that can be substituted with a halogen, an alkyl group, a nitro group, or a halogenoalkyl group.) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I ) and General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) (In both formulas, R^1, R^2, R^3, R^4 and R^5 have the above-mentioned meanings) A novel dihydropyrimidine compound and its salt which is a mesomeric type or an equilibrium between these two types. Manufacturing method. (8) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (In the formula, R^1 and R^2 are the same or different, hydrogen, halogen, alkyl group, halogenoalkyl group, nitro group, or cyano group (Means) ) The aldehyde represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, R^5 is substituted with a halogen, alkyl group, nitro group, or halogenoalkyl group) isothiourea represented by the general formula R^4COCH_2COOR^3 (V) (wherein R^3 and R^4 are the same or different and mean hydrogen or an alkyl group) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) and general formula ▲ Mathematical formula, chemical formula , tables, etc. ▼ (I a) (In both formulas, R^1, R^2, R^3, R^4 and R^5 have the above meanings) or these A method for producing a novel dihydropyrimidine compound which is an equilibrium between two types and a salt thereof. (9) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I ) and General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) (In both formulas, R^1 and R^2 are the same or Unlike hydrogen,
It means halogen, alkyl group, halogenoalkyl group, nitro group or cyano group, R^3 and R^4 are the same or different and mean hydrogen or alkyl group, R^5 means halogen, alkyl group, nitro group or an aralkyl group which can be substituted with a halogenoalkyl group) or an equilibrium between these two types. A circulatory system active agent characterized by containing it as an ingredient. (10) A dihydropyrimidine in which R^1 and R^2 are different and each represents a hydrogen or nitro group, R^3 and R^4 both represent an alkyl group, and R^4 represents an aralkyl group. The circulatory system active agent according to claim 9, which contains a compound as an active ingredient. (11) The active ingredient is a) 6-methyl-4-(3-nitrophenyl)-2-(
2-phenylethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester, b) 6-methyl-4-(3-nitrophenyl)-2-(
1-phenylethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester, c) 6-methyl-4-(2-nitrophenyl)-2-(
phenylmethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester, d) 6-methyl-4-(2-nitrophenyl)-2-(
2-phenylethylthio)-dihydropyrimidine-5-carboxylic acid methyl ester, e) at least one compound selected from salts thereof, according to claim 9 or 10. Circulatory system agent.