JPS58414B2 - Pyrrole derivative - Google Patents

Description

[Detailed description of the invention] The present invention relates to pyrrole derivatives.

The pyrrole derivative of the present invention is a new compound, and has the following general formula: , an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a morpholino group, or an alkyl group having 1 to 6 carbon atoms substituted with a phenyl group that may have a lower alkoxy group as a substituent. shows.

] The pyrrole derivative of the present invention represented by the above general formula [I] has a gastric acid secretion inhibitory effect and is useful as a gastric acid secretion inhibitor and an antiulcer agent.

Furthermore, the pyrrole derivative of the present invention has a hypotensive effect and is useful as an antihypertensive agent.

Carbon number 1 to 3 represented by the above general formula hood R1 and R,
The alkyl group includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

The alkyl group having 1 to 6 carbon atoms represented by R3 includes methyl group, ethyl group, n-propyl group, isopropyl group, n-
Butyl group, tert-butyl group, n-pentyl group, n-
Includes hexyl group and the like.

The alkenyl group having 2 to 4 carbon atoms represented by R3 is
Vinyl group, allyl group, 2-butenyl group, ■-methyl-2
-Allyl groups, etc. are included.

1 to 6 carbon atoms substituted with a morpholino group represented by R
The alkyl group includes a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, n-pentyl group, n-hexyl group in which one hydrogen atom is substituted with a morpholino group. etc. are included.

Examples of the alkyl group having 1 to 6 carbon atoms and substituted with a phenyl group that may have a lower aldoxy group as a substituent include a phenyl group, a 3゜4-dimethoxyphenyl group, and a 4-methoxyphenyl group. , 3,5-jethoxyphenyl group, and the like, include alkyl groups having an alkoxy-substituted or unsubstituted phenyl group.

In addition, the cycloalkyl group represented by R3 has 4 to 7 carbon atoms.
Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.

Representative examples of the pyrrole derivatives represented by the above general formula [■] of the present invention are as follows.

02.5-dimethyl-1-thioureidopyrrole 02.5-dimethyl-1-(3-methylthioureido)
Pyrrole o 1-(3-tert-butylthioureido)-2
,5-dimethylpyrrole ol-(3-benzylthioureido)-2,5-dimethylpyrrole 01-(3-cyclohexylthioureido)-2,5-
Dimethylpyrrole o 2,5-dimethyl-1-(3-(2-phenethyl)
Thiouridocopyrrole 02.5-dimethyl-1-(3-(3-morpholinopropyl)thiouridocopyrrole o1-(3-cyclohexylthioureido)-2,5-
Diethylpyrrole 01-(3-cyclopentylthioureido)-2,5-
Dimethylpyrrole 01 = (3-benzylthioureido)-2,5-dimethylpyrrole 02.5-dimethyl-1-1:3-(β-3,4-dimethoxyphenethyl)thiouridocopyrrole 02.5-dimethyl- 1-(3-p-methoxybenzylthioureido)pyrrole o 2,5-dimethyl-1-(3-(2-methyl-3-
phenylpropyl)thiouridocopyrrole 02.5-dimethyl-1-(3-propylthioureido)pyrrole 02.5-dipropyl-1-(cyclohexylthioureido)pyrrole o 2,5-diisopropyl-1-(3 −(β−3,4
-dimethoxyphenethyl)thiouridocopyrrole 02.5-dimethyl-1-(3-n-hexylthioureido)pyrrole 01-(3-allylthioureido)-2,5-dimethylpyrrole o 2,5-dimethyl- 1-(3-(1,1-dimethyl-2-phenylethyl)thiouridocopyrrole02.5-dimethyl-1-(3-(6-phenylhexyl)thiouridocopyrrole) The pyrrole derivatives of the present invention can be It can be manufactured by a method.

For example, by a method of reacting a thiosemicarbazide derivative represented by the general formula (in which R3 is the same as above) with a 1,4-diketone derivative represented by the general formula (in which R1 and H are the same as above). Can be manufactured.

The compounds represented by the above general formulas (9) and 1 are all known compounds.

Although the above reaction can be carried out without a solvent, it is usually carried out using aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme, carboxylic acids such as formic acid, acetic acid, and propionic acid, methanol, and ethanol. , alcohols such as isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, and the like.

There is no particular restriction on the proportion of the raw material compounds used in the above reaction, but usually 1 to 5 moles of diketones represented by the general formula I are used per 1 mole of the thiosemicarbazide derivative represented by the general formula, preferably 1 to 1. It is preferable to use about 2 moles.

The reaction temperature is usually 0 to 200°C, preferably room temperature to 12°C.
The temperature is preferably about 0°C, and the reaction is completed at this temperature in about 30 minutes to 30 hours, usually about 30 minutes to 5 hours.

In this way, the pyrrole derivative represented by the general formula [I] of the present invention can be obtained.

After the completion of the above reaction, the compound can be isolated according to a conventional method, for example, by distilling off the solvent if a solvent is used, or by subsequent extraction; this can be done by fractional recrystallization, column chromatography,
It can be purified by conventional means such as thin layer chromatography.

Examples of the production of the compounds of the present invention are listed below as examples.

Example 1 6.3 g of thiosemicarbazide was suspended in 50 ml of acetic acid, 5.0 g of acetonyl acetone was added, and the bath temperature was 100-1
Heat and stir at 10°C for 100 minutes.

Cool to room temperature and collect the precipitated crystals to form 2,5-dimethyl-1
- 7 g of colorless needles of thiouridopyrrole are obtained.

Recrystallize from acetic acid to obtain a colorless needle-like pure product.

Melting point: 219-221°C. Example 2 5g of 4-methylthiosemicarbazide was added to 40TLl of acetic acid.
5.5 I of acetonylacetone is added, and the mixture is heated and stirred in an oil bath at 100 to 110°C for 100 minutes.

Acetic acid was distilled off under reduced pressure, and the residue was dissolved in ethanol and treated with activated carbon. After ethanol was distilled off, it was crystallized with petroleum ether to obtain 2,5-dimethyl-1-(3-methylthioureido)pyrrole. 6 g of colorless crystals are obtained.

The P solution is separated by silica gel column chromatography to obtain an additional 1.2 g of crystals.

This product is recrystallized from ethanol-ligroin to obtain a colorless needle-like pure product.

Melting point: 93.5-95.5°C.

Examples 3 to 12 Each compound listed in Table 1 below is obtained in the same manner as in Example 2 above using appropriate starting materials.

Table 1 shows the obtained compounds with the following general formula, and also shows their crystal forms and melting points.

Pharmacological Tests The pharmacological activities of the following compounds were tested according to the Siei rat pylorus ligation method, which is the most common test method for testing gastric juice secretion suppressive effects.

Wistar male rats weighing approximately 170 g were used in this test.

The rats were fasted for 24 hours, the compound to be tested was administered subcutaneously (500 to 9) 30 minutes before pyloric ligation, and gastric fluid volume was measured 4 hours after ligation.

The inhibition rate was calculated as %, with the physiological saline administration group set as 0.

The results are shown in Table 1 below. In addition, the evaluation of the inhibition rate (%) in the table is as follows.

(12) 10 to less than 50% ++: 50% or more Test compound No., 12.5-dimethyl-1-[3-methylthioureido]pyrrole No., 22.5-dimethyl-1-(3-(3-morpholinopropyl) ) Thiouridocopyrrole No., 2,5-dimethyl-1-[3-benzylthioureido]pyrrole

Claims (1)

[Scope of Claims] [In the formula, R1 and R are an alkyl group having 1 to 3 carbon atoms, and R3 is a hydrogen atom, a cycloalkyl group, an alkenyl group having 2 to 4 carbon atoms, or an alkyl group having 1 to 6 carbon atoms. , represents an alkyl group having 1 to 6 carbon atoms substituted with a morpholino group or an alkyl group having 1 to 6 carbon atoms substituted with a phenyl group which may have a lower alkoxy group as a substituent. ] A pyrrole derivative represented by