JPS6163676A - 2-substituted amino-4(1h)-pyrimidone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The 2-substituted amino-4(1H)-pyrimidone derivative of formula I (R<1> is alkyl; R<2> is H or lower alkyl; m and n are 1-3) or its salt. EXAMPLE:2-{2-{{{2-[(Diaminomethylene)amino]-4-thiazolyl}methyl}thio}-e thyl amino}6-methyl-5-propyl-4(1H)-primidone. USE:Pharmaceuticals. It has histamine H2-receptor antagonistic activity and gastric mucosa protecting action, and is useful as a remedy for gastropathy, e.g. an agent to suppress the such as gastric acid secretion, remedy for gastric ulcer, etc., having low side effect. PREPARATION:The compound of formula I can be prepared e.g. by reacting the amine of formula II with 2-nitroamino-4(1H)-pyrimidone derivative of formula III in the absence of a solvent at a high temperature, or in an inert organic solvent under heat-refluxing, if necessary in the presence of a reaction accelerator such as pyridine, etc.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 2-substituted amino-4(IH)-pyrimides/derivatives or their salts represented by the following general formula CI) which are useful as pharmaceuticals. Regarding manufacturing methods.

(In the formula, R1 represents an alkyl group, R2 represents a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 3.) (Prior art) The compound of the present invention is a compound at the 2-position of 4(LH)-pyrimidone. This is a new compound that has the characteristics of a substituted amino group structure, and there are no documents describing such a compound.

(Problems to be Solved by the Invention and Means for Solving the Problems) The present inventors have synthesized a series of compounds having a side chain containing a guanidinothiazole atomic group at the 2-position of 4(LH)-pyrimidone. Compound (1) Earth Takesono 1'
The present invention was completed by recognizing that K is useful as an agent for suppressing gastric acid secretion.

The meaning of the symbol of the compound J represented by the general formula ill is as follows: i+T+. The "alkyl group" for R1 is a straight or branched carbon chain having 1 to 1() carbon atoms. Therefore, specific examples of the alkyl group in the above general formula CI) and the general formula below include methyl group, ethyl group, propyl group, butyl group, pentyl group, heptyl group, octyl group, decyl group, isopropyl a,
aec-butyl group, tert-butyl group, isobutyl group, a linear or branched carbon chain consisting of 1 to 4 tert-butyl groups. Typical examples of these include methyl, ethyl, propyl, butyl, and isobutyl groups.

The compound of the present invention represented by the above general formula (■) forms an acid addition salt. The present invention also encompasses pharmacologically acceptable salts of the compounds of general formula (I). Specific examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and sulfuric acid, and organic acids such as maleic acid, fumaric acid, and picric acid. can do.

Further, the two compounds of the present invention (I) exist as IH and 3H tautomers, and a small amount also exists as a hydroxy tautomer. The present invention includes all of these isomers.

(Production method) Compound (I) of the present invention and its salt can be produced by the following method.

First production method: (In the formula, R', R2, m and n represent the above-mentioned meanings.) The compound (1) of the present invention comprises an amine represented by the general formula (II) and an amine represented by the general formula (III). It is synthesized by reacting with the 2-nitroamino-4(IH)-pyrimidone derivative shown.

This reaction can be carried out using solvents. In this case, it is advantageous to carry out the reaction at elevated temperatures. This reaction can also be carried out using organic solvents that are inert to the reaction, such as methanol, ethanol , benzene, toluene, xylene, dimethylformamide, digalmethane, dichloroethane, etc., under heating, preferably under heating under reflux.Raw material compounds (I) and (n) are each It is preferable to use approximately equal moles, and use a slight excess of one.

During the reaction, the addition of a tertiary base such as pyridine, picoline, N,N-methylmorpholine, trimethylamine, etc. may accelerate the reaction.

Note that pyridine can also serve as a solvent.

Second production method: (In the formula, R3 means a lower alkyl group. Also,
R', R2, m and n have the above meanings. ) The compound (I) of the present invention can also be produced by a condensation cyclization reaction between a guanidine derivative represented by the general formula M) and an acylate derivative represented by the general formula M.

The reaction is carried out using approximately equimolar moles of compound (IV) and compound (V) or a slight excess of one of them. ).

Ethyl cellosolve (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. upon reaction.

If necessary, a base may be added (such bases include alkali metal alcolades such as sodium methoxide and sodium ethoxide, potassium hydroxide,
Sodium hydroxide and the like are preferably used.

The obtained compound of the present invention can be subjected to a commonly used salt-forming reaction to form its acid addition salt.

Isolation and purification of the compound of the present invention involves solvent distillation and crystallization.

It is carried out by applying ordinary chemical operations such as column chromatography and recrystallization.

Note that the starting material compound (III) of the present invention can be easily produced by the method described in Reference Examples below or in accordance therewith.

(Effects and uses of the invention) The compounds of the present invention and acid addition salts thereof provided by the present invention have histamine receptor antagonistic activity and gastric mucosal protective effect (cytoprotective effect), so they may cause side effects. It is useful as a gastric disease therapeutic agent, such as a gastric acid secretion inhibitor and a gastric ulcer treatment agent.

That is, 9 compounds of the present invention were prepared using the 5hay rat 4hr method (5hay et al.

Gastroenterology
gy), Volume 5.

43-61, 1945), 30 mg
It has been confirmed that gastric acid secretion can be effectively suppressed at a dose of less than /kg.

Furthermore, it has been confirmed that gastric mucosal damage in rats can be suppressed at doses of 30 mg/kg or less, according to a test method published in Gastroenterology, Vol. 77, p. 433 (1979).

The compounds of the present invention also include compounds with excellent long-lasting medicinal effects.

A preparation containing the compound represented by formula (I) or its acid addition salt as a main component can be prepared by any conventional method using any conventional pharmaceutical carrier or excipient.

Administration may be either oral or parenteral. The dosage is determined as appropriate for each individual case, taking into consideration the symptoms, the age and gender of the person to be administered, etc.

The amount is usually 50 to 400 mg per day for adults, and it is preferable to administer this at once or in 2 to 4 divided doses.

(Example) The present invention will be described in further detail with reference examples and examples below.

Reference Example 1 0.80 g of metallic sodium was dissolved in 35 ml of dry methanol, and 3.2 g of nitroguanidine was added to this solution.

After stirring for 50 minutes under reflux, 5.3 g of ethyl 2-propyl-3-oxobutanony was added dropwise over 5 minutes, and the mixture was stirred under reflux overnight. After distilling off the solvent under reduced pressure.

After adding 100 ml of water and washing this aqueous solution twice with 70 ml of chloroform, the solution was made acidic with C hydrochloric acid to separate out the precipitated crystals, and recrystallized with ethanol to obtain a melting point of 1720-173.0. Showing °C 6
-Methyl-2-nitroamino-5-propyl-4 (IH
)-pyrimidone (2.14 g) was obtained.

Mass spectrum # (El) m/z: 212 (M”)
Elemental analysis value C (%) H (%) N (%) Calculated value 45
,28 5.70 26.40 The truth is llf direct
45.45 5.69 26.49 Reference Example 2 In the same manner as in Reference Example 1, 6-ethyl-2-nitroamino-5-pemethyl-4 (IH)-pyrimidone was obtained.

Melting point 122.0-123.0°C Mass spectrum (EI) m/z: 254 (M”) Elemental analysis value C (%) H (%) N (%) Calculated value 51
,967.13 22.03 Actual value 52,04
7.23 22.18 Example 1 Dissolve 0.39 g of sodium metal in 20 ml of dry ethanol, and add 2-[[[2-[(diaminomethylene)aminoco-4-thiazolyl]methyl]thio]ethylamine dihydrochloride to this solution. After adding 2.58 g of salt and stirring under reflux for 30 minutes, the IJum was filtered and the P solution was distilled off under reduced pressure. To this residue, 6-thymer-2-nitroamino-5-propyl-4(LH)-pyrimidone 1.80
g and 40 ml of pyridine were added thereto, and the mixture was stirred under reflux overnight. The solvent was distilled off under reduced pressure, 100 mZ of water was added, and the mixture was distilled off again under reduced pressure. Furthermore, isopropyl alcohol/'100m
After adding 1 and distilling it off under reduced pressure, it was purified by column chromatography (silica gel eluent: chloroform-methanol), and the obtained crystals were recrystallized from ethanol to show a melting point of 22300C to 2250°C.2 −
[2-[[[2-[(diaminomethylene)amine]-4
-thiazolyl]methylcothio]ethylamino]-6-methyl-5-propyl-4(IH)-pyrimidone 026 g
I got it.

Mass spectrum (FAB) m/z: 382 (M++)
Elemental analysis value C (%) H (%) N (%) S (%) Calculated value 17.22 6.08 25.70 16.81 Actual value 47,13 6.19 25.55 16.54
Example 2 0.38 g of sodium metal in 20 ml of dry ethanol
Dissolve 2-[[[2-[(diaminome) in this solution.

After adding 2.50 g of ethylamine dihydrochloride and stirring under reflux for 50 minutes, the sulfur chloride was filtered, and 25 ml of dry ethanol and 25 ml of dry ethanol were added to the P solution. 2.1 g of 6-ethyl-2-nitroamino-5-pentyl-4(LH)-pyrimidone
and stirred under reflux for 36 hours. After distilling off the solvent under reduced pressure, it was purified by column chromatography (silica gel, eluent: chloroform-methanol), and the resulting crystals were recrystallized with ethanol to give a melting point of 216.
2-[2-[[[2-[(
diaminomethylene)aminoco-4-thiazolyl]methyl]thio]ethylamino]~6-ethyl-5-pentyl-
1.08 g of 4(IH)-pyrimidone was obtained.

Mass spectrum (EI) m/z: 423 (M”) Elemental analysis value

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is an alkyl group, R^2 is a hydrogen atom or a lower alkyl group, m and n are 1 2-substituted amino-4(1H)-pyrimidone derivative or its salt 2, represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, m and n are (means an integer from 1 to 3) and the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is an alkyl group, R^2 is a hydrogen atom or a lower alkyl group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^ 2, m and n have the above meanings.) A method for producing a 2-substituted amino-4(1H)-pyrimide derivative or a salt thereof.