JPS60202883A - Pyrimidone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1>, R<3> are H, 1-6C alkyl, l is 1-6; m is 2, 3; R<3> is formula II and III (n is 0-4; X is single bond, O, S; R<4>, R<5> are H, halogen, 1-5C alkyl; R<6> is H, halogen)] or its salt. EXAMPLE:2-[ 2-[[ 2-[( Diaminomethylene )amino]-4-thiazolyl]methyl ]thio]ethyl]- 5-[3-[4-(p-fluorophenyl)-1-piperazino]propyl]-6-methyl-4(1H)-pyrimidone. USE:Remedy for gastropathies. PREPARATION:The reaction of a compound of formula IV or its salt such as 3-[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propion amidine hydrochloride with a compound of formula V such as ethylalpha-[3-[4-(p-fluorophenyl)-1- piperazino]propyl]acetoacetate gives the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel IJ midone compounds represented by the following general formula (Il) and acid addition salts thereof useful as therapeutic agents for gastric diseases, and methods for producing them.

3 [The symbols in the formula have the following meanings.

R1; hydrogen atom or lower alkyl group 1; integer from 1 to 6 m; 2 or 3 The group shown in

Rs: hydrogen atom or lower alkyl group.

n; an integer of 0 or 1 to 4;

Or the two together become a lower alkyre. dioxy group.

R6; hydrogen atom or halogen atom. The same applies hereinafter] In the definition of the group in the general formula ill above and the general formula below, "lower"
The term means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, examples of lower alkyl groups include methyl and ethyl groups.

Propyl group, inglovir group, butyl group, inbutyl group, 5ec-butyl group, tert-butyl group, pentyl group (
amyl) group, impentyl group, neopentyl group, ter
t-pentyl group, etc., lower alkoxy groups include methoxy group, ethoxy group, propoquine group, impropoquine group,
Butoxy group etc. are lower alkylenedioxy groups,
Examples include methylenedioxy group, ethyl/dioxy group, trimethylenedioxy group, and the like.

Well, examples of halogen atoms include fluorine atoms, chlorine atoms, and bromine atoms.

The compound of the present invention represented by the general formula (Il) forms an acid addition salt. The present invention also includes pharmaceutically acceptable acid addition salts of the compound (II), and specific examples of such acid addition salts include Hydrochloric acid.

Mineral acids such as hydrobromic, sulfuric, nitric, and phosphoric acids.

Examples include salts with organic acids such as maleic acid, fumaric acid, and picric acid.

Further, the two compounds of the present invention CII exist as IH and 3H tautomers, or as hydroxy tautomers. The present invention includes all of these isomers.

The pyrimidone compound of the present invention and its acid addition salt have an antagonistic effect on histamine H1 and H2 receptors, and are also observed to have a gastric mucosal protective (side-blocking) effect. Useful as a therapeutic agent.

The two compounds of the present invention also include those that have excellent long-lasting medicinal effects.

The compound of the present invention can be prepared using the 5 hay rat 4 hr method (Sh
ay et al., Gastroenterology, Volume 5, Nos. 43-6.
1 page.

(1945), it has been confirmed that gastric acid secretion is effectively suppressed at doses of 30 mg/kg or less.

I cut it. Gastroenterology
77, p. 433 (1979), gastric mucosal damage in rats was
It has been confirmed that it can be suppressed at less than g/kg.

A preparation containing a compound represented by the general formula (Il) or an acid addition salt thereof as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier, excipient, etc.

Administration may be either oral or parenteral. The dosage is determined depending on the individual case, taking into account the symptoms, the age and gender of the recipient, but it is usually 50 doses per day for adults.
~600 mg, administered once or in 2 to 4 divided doses.

Compounds fIl and acid addition salts of the invention may be prepared by a variety of methods. The present invention also includes methods for producing these compounds. Typical methods are illustrated below.

First manufacturing method or its acid addition salt (m) 3 (1) or its acid addition salt (In the reaction formula, R7 means a lower alkyl group.

The same applies hereinafter) The compound CI+ of the present invention or its acid addition salt has the general formula (II
It can be produced by reacting an amidine derivative represented by () or an acid addition salt thereof with an acylacetate derivative represented by general formula (III), and carrying out condensation and cyclization.

In the reaction, Compound (II) or a salt thereof and Compound (m) are used in equimolar amounts or in a slightly excess amount of one of them.

For example, alcohols such as methanol, ethanol, impropatul, dimethylformamide.

Dimethyl sulfoxide, methylseronlube (methoxyethanol), ethylseronlube (ethoxyethanol)
, diglyme [bis(2-methoxyethyl)ether],
It is advantageous to carry out the reaction in an organic solvent inert to the reaction, such as dioxane, at room temperature or with heating. During the reaction, a base may be added as necessary; examples of such bases include alkaline metal alcoholides such as sodium, hydroxide, etc.
IJum and potassium hydroxide are preferably used.

The raw material compound (n) was prepared by the method described in JP-A-55-118476 filed by the applicant, and the raw material compound (R1) was prepared by lower alkylene civalide and N as shown in the reference example below. -N-substituted N/-halochenoalkyl-biperazine obtained by reacting with -substituted-piperazine or N-substituted-hexahydro-1゜4-diazepine or N- to -N'-halochenoalkyl Xahydro-
It can be easily prepared manually by reacting 1°4-diazepine with an acylacetic acid ester.

Second Production Method (IV) (V) 3 (1) (In the reaction formula, R8 and R9 are the same or different and mean a lower alkyl group. The same applies hereinafter) The compound of the present invention (Il is also a compound of the general formula (IIV ) can also be produced by reacting the imitate derivative represented by formula (V) with a 3-aminoacrylic acid ester derivative represented by general formula (V) to undergo condensation and cyclization.

The reaction can be carried out under substantially the same reaction conditions as in the first reverse method. That is, in this cyclocondensation reaction, raw materials compounds (IV) and (V) are used in equimolar amounts or in a slightly excess amount of one of them, dissolved in the same organic solvent as in the first production method, and if necessary, in the same manner as in the first production method. A base is added thereto, and the compound of the present invention (Il) is produced by reacting with heating.

Note that the starting compound (IV) can be produced by the method described in JP-A-55-118'476 filed by the present applicant, and the compound (V) can be produced by a conventional method.

The compound of the present invention thus obtained is either in its free form or as an acid addition salt thereof, and when produced as an acid addition salt, it is isolated and purified as a salt form or as a free compound. Ru. Isolation and purification can be carried out by applying conventional chemical operations such as filtration, distillation, distillation, recrystallization, and various chromatography.

The present invention will be explained in further detail by referring to Reference Examples and Examples below.

Reference example 1 1-(
T)-fluorophenyl)piperazine 25.0 g,)
! A solution prepared by dissolving 140 g of J ethylamine in 30 mZ of chloroform was added dropwise at 30° C. or below, and then stirred at room temperature for 48 hours. Add 200 ml of chloroform to the reaction solution.

After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent, resulting in an oily 1
26.7 g of -(3-chloropropyl)-4-(p--fluorophenyl)piperazine are obtained.

Mass spectrum (EI) m/z 256 (M+), 1
93° Reference Examples 2 to 19 The following compounds were obtained in the same manner as in Reference Example 1.

Reference example 20 Ethanol 200 mZ and metallic sodium 2 in nitrogen stream
135 g of ethyl acetoacetate and 1-(3-chloropropyl)-4-(p
- Add 267 g of piperazine (fluorophenyl),
Heat to reflux for an hour. The precipitated salt was removed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of chloroform and ethyl acetate as a developing solvent.
12.69 g of oily ethyl α-[3-[4-(p-fluorophenyl)-1-piperazinyl]propyl]acetoacetate are obtained.

Mass spectrum (EI) m/z 350 (M+),
305° Reference Examples 21-38 The following compounds were obtained in the same manner as in Reference Example 20.

Example 1 0.117 g of metallic sodium in a nitrogen stream was dissolved in ethanol 3
3-[
[[2-[(diaminomethylene)amine]-4-thiazolyl]methyl]thio]propionamidine hydrochloride 1.
Add a solution of 5g of OmZK in methanol and mix for 15 minutes.
After stirring for a minute, a solution of 1.78 g of ethyl α-[3-[4-(p-fluorophenyl)-1-piperazino]propyl]acetoacetate) dissolved in 10 ml of ethanol was added, and the temperature was returned to room temperature and stirred for 48 hours. do. After removing the precipitated salt and distilling off the solvent under reduced pressure, the product was purified by silica gel column chromatography using a chloroform-methanol mixed solvent as a developing solvent, and recrystallized from ethanol-acetonitrile to obtain the desired product with a melting point of 182-183°C. 2-[2-[[[2-[(diaminomethylene)aminoco-4-thiazolyl]methyl]thio]ethyl]-5-[
3-[4-(p-fluorophenyl)-1-piperazino]propyl]-6-methyl-4(IH)-pyrimidone 1
42 g is obtained.

Mass spectrum (FAB), m/z; 545 (M++1
) Elemental analysis value (as C25Hls Ns O82F)
HNS Calculated value (%155.13 6.11 20.57 11
．． 77 Actual value (%) 55.02 6.21 20.63
11.99 Examples 2 to 19 The following compounds were obtained in the same manner as in Example 1.

Reference example 39 1-(3-phenylthiopropyl)piperazine 184g
Triethylamine 1 in a chloroform (80 mt) solution of
After adding 0.9 ml 2-bromoethanol5.
5 m/, dropwise and stirred at room temperature for 3 days. After washing this solution with water and drying with magnesium sulfate, the solvent was distilled off under reduced pressure and purified by column chromatography (silica gel, eluent chloroform) to 1-(2-hydroxyethyl)-4-[3- (phenylthio)globil]
169 g of piperazine was obtained.

This was dissolved in 100 ml of benzene, and under water cooling, a solution of 13.0 ml of thionyl chloride in benzene (100 ml) was added dropwise, stirred at room temperature for 2 hours, and then refluxed for 2 hours.

After cooling, take one portion of the precipitate and dissolve it in 200 ml of warm methanol. The precipitate obtained by concentrating under reduced pressure is collected and added to 100 ml of water. After adding potassium carbonate to the mixture to make it alkaline, the mixture is extracted with ethyl acetate and dried over magnesium sulfate. By distilling off the solvent under reduced pressure, 1
-(2-chloroethyl)-4-[3-(phenylthio)
147 g of [clovir]hyperazine were obtained.

Mass spectrum (El) m/z: 298 (M”)
, 262 Reference Example 40 The following compound was obtained in the same manner as in Reference Example 20.

thio)propyl]-1-piperazinyl]ethyl 249ruco7cetoacetate Reference Example 41 m-chloropenzyl chloride 8.
Dissolve 7g of 2-methylpiperazine in this solution.
After stirring at room temperature overnight, stir at 60°C for 1 day. The solvent was distilled off under reduced pressure, and added to 50 mt of OO form.
Wash with water and dry with condensed magnesium sulfate. After removing the solvent under reduced pressure, 1-(m-chlorobenzyl)-3-
103 g of methylpiperazine was obtained. (bp 93-10
2℃/0.3 mmHg)
After adding 6.4 ml of triethylamine, 4.5 ml of ■-bromo-3-chloropropane was added dropwise. After stirring for 3 days at room temperature.

Wash the solution with water. After drying the chloroform layer with magnesium sulfate, distilling off the solvent under reduced pressure, and purifying with column chromatography (silica gel, eluent chloroform), ]-(]m-chlorobenzyl-4-(3-chloropropyl) 365 g of )-3-methylpiperazine were obtained.

Mass spectrum (CI) m/z; 301 (M”+1)
, 238 Reference Example 42 The following compound was obtained in the same manner as in Reference Example 20.

Ethyl α-[3-[4-(m-ri-p-lovenru)-2
-Methyl-1-piperazinyl]bupyl]7cetoacetate Examples 20 to 21 The following compounds were obtained in the same manner as in Example 1.

Reference example 43 1.68 g of metallic sodium in 150 ml of absolute ethanol
and 954 g of ethyl acetoacetate and 1
-(3-chloropropyl)-4-(m-)lifluoromethylphenyl)piperazine (15.0 g) was added and heated under reflux for 48 hours.

After removing the precipitated salt and distilling off the solvent under reduced pressure.

When the residue was purified by silica gel column chromatography using chloroform as a developing solvent, 643 g of ethyl 5
[4-(m-)lifluoromethylphenyl)piperazinocopentanoate is obtained.

Mass spectrum (FAB) m/z + 359 (
M++1) Example 22 0 finely chopped metallic sodium in 30 ml of anhydrous ether
．． A solution of 6.43 g of ethyl 5-[4-(m-trifluoromethylphenyl)piperazinocopentanoate and 1946 g of ethyl formate dissolved in 20 m4 of anhydrous ether was added, keeping the temperature below 0°C. Add. After the addition was completed, the mixture was stirred at 0°C or below for 2 hours, and then returned to room temperature and stirred for 18 hours.

The solvent was evaporated under reduced pressure, the residue was dissolved in 30 ml of ethanol, and 57 g of 3-[[[1-[(diaminomethylene)amine]-4-thiazolyl]methyl]thio]globionamidine hydrochloride was added to the solution in 30 ml of methanol. Add the solution dissolved in and stir at room temperature for 48 hours.

After removing the precipitated salt and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography using a chloroform-methanol mixed solvent as a developing solvent, resulting in a melting point of 1.
2-[2-4[[1-[(diaminomethylene)aminoco-4=thiazolyl]methyl]thio]ethyl]-5-13-[4(m-)'J 7
0.5 g of fluoromethylphenyl)-1-biverazinylcopropyl]-4(IH)-pyrimidone are obtained.

Mass spectrum (FAB) m/z; 581 (M
”+1) Elemental analysis value (C25HsrNsO8tFs
CHN, S Calculated value (%) 51.71 5.38 19.30 1
1.04 Actual value (%) 51.98 5.43 19.
55 11.26 Patent Applicant Yamanouchi Pharmaceutical Co., Ltd. Representative Patent Attorney Shozo Nagai Continued from page 1

Claims (1)

[Claims] (1) General formula "The symbols in the formula have the following meanings. R1: a hydrogen atom or a lower alkyl group. ]; ] an integer of ~6; m: a group represented by 2 or 3°; R3: a hydrogen atom or Lower alkyl group. n s O or an integer of 1 to 4. or a lower alkoxy group.Or both together form a lower alkylenedioxy group.R6; hydrogen atom or halogen atom] BiIJ midone compound or its acid addition salt (2
) An amidine derivative represented by the formula or an acid addition salt thereof, and the general formula [symbols in the formula have the following meanings. R1: hydrogen atom or lower alkyl group. l: An integer from 1 to 6. m: a group represented by 2 or 3°. R3; hydrogen atom or lower alkyl group. R7; lower alkyl group. n: 0 or an integer of 1 to 4. X: single bond, oxygen atom or sulfur atom R4 and R5: same or different, hydrogen atom, halogen atom, lower alkyl group, trifluoromethyl group or lower alkoxy group, or both together form lower alkylene di Oxy group. R6; hydrogen atom or halogen atom. A process for producing a pyrimidone compound represented by the general formula or an acid addition salt thereof, characterized by reacting the pyrimidone compound with an acylacetate derivative represented by [the same applies hereinafter]