JPH0331267A - 2-anilino-1,6-dihydro-6-oxo-4-pyrimidine carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> and R<2> are H, lower alkoxy, lower alkylthio, lower alkyl, lower alkoxycarbonyl, halogen, di-lower alkylamino, OH, CF3 or NO2; R is H, CH3 or C2H5). EXAMPLE:2-[2-(2-methylpropoxy)anilino]-1,6-dihydro-6-oxo-4-pyrimidine carboxylic acid. USE:Medicine. Remedy for ulcer exhibiting enhancing action for gastrointestinal membrane mucosa protection factor. PREPARATION:An N-phenylguanidine derivative expressed by formula II obtained by reaction of aniline derivative and cyanamide is reacted with acetylene dicarboxylic acid diesters in an inert solvent such as toluene at from about room temperature to boiling point of the solvent for 5-24hr to obtain a compound expressed by formula I for R is CH3 or C2H5. Then, resultant compound is hydrolyzed with alkali by normal method to afford the compound expressed by formula I for R is H.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel 2-anilino-1,6-cyhydro-6-oxo-4-pyrimidinecarboxylic acid derivative useful as an agent for treating ulcers.

[Conventional technology]

Examples of pyrimidine derivatives having antiallergic and antiulcer effects include JP-A-60-100559 and JP-A-6
2-267229 and the like are known.

[Problems to be Solved by the Invention] The present inventors conducted intensive studies focusing on these pyrimidine rings, with the aim of developing pyrimidine compounds having anti-ulcer effects.

[Means for Solving the Problems] As a result of research to solve the above problems, the present inventors found that the conventional 2-anilino-1,6-sihydro-6-oxo-5
- It was discovered that a new 2-anilino-1,6-sihydro-oxo-4-pyrimidinecarboxylic acid derivative, which is different from the pyrimidinecarboxylic acid derivative, also has an antiulcer effect, and the present invention was completed.

That is, the present invention relates to the general formula (1) (wherein R1 and R2 are the same or different, a hydrogen atom, a lower alkoxy group, a lower alkylthio group, a lower alkyl group, a lower alkoxycarbonyl group, a halogen atom, a di-lower alkyl group) 2-anilino-1,6-, which represents an amino group, a hydroxy group, a trifluoromethyl group, or a nitro group, and R represents a hydrogen atom, a methyl group, or an ethyl group.
This invention relates to sihydro-6-oxo-4-pyrimidinecarboxylic acid derivatives.

In the above general formula (1), R1 and R2 lower alkoxy groups include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, hexyloxy, heptyloxy or (2,
Examples include 3,4,5-tetrahydrofuran-2-yl)methoxy, and examples of lower alkylthio groups include methylthio,
Ethylthio, propylthio, 1-methylethylthio, butylthio, 2-methylpropylthio, pentylthio,
Examples include hexylthio, heptylthio or (2,3,4,5-tetrahydrofuran-2-yl)methylthio,
Specific examples of lower alkyl groups include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and pentyl groups, and examples of lower alkoxycarbonyl groups include methoxycarbonyl groups and ethoxycarbonyl groups. Examples include carbonyl group or butoxycarbonyl group, and examples of halogen atoms include fluorine, chlorine,
Examples include bromine or iodine, and examples of the di-lower alkylamino group include dimethylamino and diethylamino.

The compound of the present invention is a novel compound that has not been described in any literature, and is useful as an antiulcer drug.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention can be produced by the method shown in the reaction formula below.

(II) ([) (wherein, R1
and RZ and R have the same meanings as above. ) N-phenylguanidine derivative (If
) with acetylene dicarboxylic acid diesters,
It proceeds easily by heating in an inert solvent, but
The solvent used is not particularly limited, and examples include ethanol, dioxane, toluene, tetrahydrofuran, and dimethylformamide.

The reaction temperature used is room temperature to the boiling point of the solvent, and the reaction time is preferably 5 to 24 hours.

When the 2-anilino-1,6-sihydro-6-oxo-4-pyrimidinecarboxylic acid ester obtained in the above reaction is hydrolyzed with an alkali in a conventional manner, 2-anilino-1゜6 is obtained in which R is a hydrogen atom. -Sihydro-6-oxo-4-pyrimidinecarboxylic acid is obtained.

Next, the present invention will be explained by giving examples.

[Example 1] N-(2-butoxyphenyl) in toluene (200d)
While guanidine (19.3 g) was dissolved and stirred, acetylene dicarboxylic acid dimethyl ester (14.2 g) was added, and the mixture was heated and stirred overnight. After distilling off the solvent under reduced pressure,
The residue was dissolved in a small amount of ethanol and cooled with ice water. By filtering the precipitated crystals and recrystallizing them from a mixture of DMF and water, 2-(2-butoxyanilino)-1,6-
Sihydro-6-oxo-4-pyrimidinecarboxylic acid methyl ester (5.9 g) was obtained.

Melting point: 219-221°C r Rv RujO'cn+-': 3350 (N
-) 1), 1755.1680 (C=O) 9 has a mountain X Ma ss m/z: 317 (M”).

Otori 11-NMR (DMSO-d&) δ:
0.95 (311,t,, J ・7H2゜0 (C1l
z) zcjil) , 1.47 (2H, l, 0
CHzC)IzCLLCHi), 1, 77 (21
1, m, QC)lzcllzcI12CHs),
3.85 (3)1. s, C(hCL), 4
．． 06 (2H+t, J-6Hz, OC!LLC
HzCIIxCHs) + 6.36 (ill, s
+ pyrimidine-H), 6.89-7.0
7 (3H, s, benzene-H) + 8.32 (IH
.

51 NH) + 8.46 (LH+ d+-JJH
z+benzene-H) + 12.00 (IH
,S.

NH).

Elemental analysis (C+ h H19N 204 ) theoretical value (%
) :C, 60,56; H, 6,03; N, 13.24
Actual value (%): C, 60,45; H, 6,17; N,
13.40 Examples 2 to 7 obtained similarly to Example 1
Table 1 shows all the compounds in Table 1.

Table 1 Example No.

ill R" R Melting point ("C) -0CHx 2-OCHzCH2 2-OCHzCHxClh 2-OCHzCH(C1h)z 4-OCHzCH(CHs) x 2-SCHyo CHICH, CH2 231-232 252-253 211 -213 199~200 200-202 146-147 [Example day] After dissolving sodium hydroxide (5.0 g) in a mixture of water (250 d) and methanol (50 Id), 2- (2-(2
-Methylpropoxy)anilino)-1,6-cyhydro-6-oxo-4-pyrimidinecarboxylic acid methyl ester (12 g) was added, and the mixture was heated under reflux for 2 hours. After cooling the reaction solution, 5% hydrochloric acid was added to make it acidic. The precipitated crystals were collected by filtration and recrystallized from a mixture of DMF and water.

Add the obtained crystals to water (500 d) and stir for 9 hours.
Heated at 0°C for 4 hours. The crystals were collected by filtration and dried to obtain 2-(2-(2-methylpropoxy)anilino)-1,6-cyhydro-6-oxo-4-pyrimidinecarboxylic acid (8.2 g).

Melting point: 268-269°C I Rv "jo'cm-': 3370 (N-H
), 2400-33004R(L)1 (NH and OH), 1730.1685(C=0)M
a ss m/z: 303 M”).

'I(-NMR(DMSO-di)δ: 1.02(6
1(, t, J=7H2゜0CHICI (CLL) ri, 2.11 (11,tm, 0CIhCl((CH
3) Z) , 3.83 (2H, d, J=7H2,0
CLLCI((C)!s) z) + 6.45 (i
ll, s, pyrimidine-H), 6.90
~7.06 (3H, m, benzene-H), 8.2
2 (IH, s.

NH), 8.49 (IH, d, J=7Hz, benz
ne-H), 11.50-14.00 (2H, br, N
H and C00H) Elemental analysis (Cls H17N x O4) Theoretical value (%)
=C, 59,40; H, 5,65; N, 13.85
Actual value (%) FC, 59,34; H, 5,69;
N, 13.98 Example 9 obtained in the same manner as Example 8
-14 compounds are collectively shown in Table 2.

Table 2 Example No.

ill I? 1 2-OCR.

2-OCHIC112 2-OCHxGHzC)Is 2-OCHzCHxCH*CL 4-OCHzCll(CHs) t 2- SCHzcHzcHzcH3 Melting point (°C) 284-285 267-268 267-268 266- 267 279-280 258-259 Test example (hydrochloric acid -Effect on ethanol ulcer) Mizu
i et al.'s method (Japan, J, Pharmacol
The test compound was orally administered to a group of 6 rats fasted for 24 hours, and 30 minutes later, 0.5 ml of hydrochloric acid-ethanol (containing 150 mM hydrochloric acid in 60% ethanol) was administered per 100 g of body weight. Oral administration caused gastric mucosal damage. One hour later, the rats were sacrificed by analogous dislocation, and the stomachs were removed and injected with 1% formalin.
ml was injected into the stomach, immersed in the same solution for 10 minutes to fix it, and then incised along the greater curvature under a dissecting microscope (10x magnification).
The length of the damage occurring in the glandular area was measured, and the sum total per animal was taken as the ulcer coefficient.

The control group was administered only the solvent (0.5% carboxymethyl cellulose aqueous solution).

The inhibition rate against ulcer formation was calculated using the following formula.

-B Inhibition rate = X100 (%) A: Ulcer coefficient of control group B: Ulcer coefficient of test compound administration group As a result, the compound of Example 11.12.13.14
Excellent gastric mucosal protective effect was shown at a dose of 100 mg/kg.

[Effects of the Invention] The compound represented by the general formula (1) relates to a novel 2-anilino-1,6-cyhydro-6-oxo-4-pyrimidinecarboxylic acid derivative, which has an effect of enhancing gastrointestinal mucosal protective factors on ulcers. It was synthesized for the purpose of developing therapeutic agents, and can provide more useful pharmaceuticals than ever before.

Claims (1)

[Claims] General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼ [I] group, lower alkyl group, lower alkoxycarbonyl group, halogen atom, di-lower alkylamino group, hydroxy group, trifluoromethyl group, or nitro group; 2-anilino-1,
6-dihydro-6-oxo-4-pyrimidinecarboxylic acid derivative.