JPH03215488A - Pyrimidobenzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I [R<1> is (substituted)phenyl; R<2> is H, nitro, lower alkyl, lower alkenyl, lower alkoxycarbonyl or benzyl; (n) is 0 or 1]. EXAMPLE:3-n-Propyl-4-hydroxy-10-benzyl-2-oxo-2-pyrimido[2.1-b]benzimid azole. USE:An antibacterial agent, an antiviral agent, an antiinflammatory agent and an antirheumatic. PREPARATION:A compound of formula II is made to react with a compound of formula III (R<2a> is H, lower alkyl, lower alkenyl, lower alkoxycarbonyl or benzyl; R<3> is lower alkyl) in the presence of a base (e.g. sodium methoxide), as necessary, in a solvent (e.g. DMF) preferably at 25-200 deg.C for 5-24hr to obtain the objective compound of formula I in which R<2> group is R<2a>.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to pyrimidobenzimidazole derivatives and salts thereof.

BACKGROUND OF THE INVENTION The pyrimidobenzimidazole derivatives and salts thereof of the present invention are novel compounds that have not been described in any literature.

Problems to be Solved by the Invention The purpose of the present invention is to provide a compound useful as a pharmaceutical, as described later.

Means for Solving the Problems According to the present invention, a benzimidazole derivative represented by the following general formula (1) is provided.

011 (Clh) n R1 [In the formula, R+ is a phenyl group which may have 1 to 3 groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group as a substituent, and R2 is a hydrogen atom, a nitro group, lower alkyl group, lower alkenyl group,
Lower alkoxy represents a carbonyl group or a benzyl group, and n represents 0 or 1. ] The compound of the present invention represented by the above general formula (1) and its salt exhibit pharmacological properties such as antibacterial, antiviral, antiinflammatory, and antirheumatic properties, and therefore can be used as an antibacterial agent, antiviral agent, antiinflammatory agent,
Arikawa is used as a pharmaceutical product such as anti-rheumatic drugs.

In this specification, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, lerl-butyl, pentyl, and hexyl.

Examples of lower alkoxy groups include methoxy, ethoxy, proboxy, isoproboxy, butoxy, isobutoxy,
Examples include xy, lerf-butoxy, pentyloxy, and hexyloxy groups.

Examples of lower alkenyl groups include vinyl, allyl, 2
Examples include -butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-methyl-2-butenyl, and 2-hexenyl groups.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, Erl-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.

Halogen atoms include fluorine atoms, chlorine atoms, bromine atoms and iodine atoms.

The pyrimidobenzimidazole derivative of the present invention can be produced by various methods. A specific example thereof is shown in the reaction scheme below.

Reaction process formula 1 〉 (C II 2 ) n (3) R + (2) OTI (CII2).

1 R' (la) [In the formula, R1 and R2 are the same as above. R2a is a hydrogen atom,
R3 represents a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl group or a pencil group, and R3 represents a lower alkyl group. ] Compound (2) shown in the above reaction scheme-1
) and compound (3) is carried out in the presence of a base, without a solvent or in an appropriate solvent. Examples of the base used here include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium-tcrt-butoxide, and metal hydrides such as sodium hydride and lithium hydride. These are usually 0.0 for compound (3). It can be used in an amount of about 3 to 3 moles. Further, when a solvent is used, an inert solvent such as N,N-dimethylformamide (DMF) or benzene can be used as the solvent.

The reaction is generally carried out at a temperature range of about 25 to 200°C.
The reaction takes about 5 to 24 hours, and the target compound (1a) can thus be obtained.

<Reaction scheme-2> O II O IIR'
(1-b) R' (lc) [
In the formula, R1 and n are the same as in nif. ]The above reaction process formula-
The nitration reaction of compound (1b) shown in 2 can be carried out in accordance with a conventional method using, for example, nitrate, nitric acid, nitric acid monosulfuric acid, nitric acid monoacetic acid, etc. as a nitrating agent, without a solvent or in a suitable solvent.

The above-mentioned nitration agent is usually used in a large excess amount relative to the raw material compound. It is preferable to use acetic acid, sulfuric acid, etc. as the solvent. The reaction temperature is generally in the range of about 0 to 30°C.

The target compounds obtained by the methods shown in each of the above reaction schemes can be easily isolated and purified by conventional separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, and the like.

Furthermore, the compound (1) of the present invention can be easily converted into a pharmaceutically acceptable metal salt by treating it with a metal hydride such as sodium hydride or lithium hydride in a conventional manner. Furthermore, the compound (1) of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method. Examples of acidic compounds that can form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid; Examples include organic acids such as benzenesulfonic acid.

The metal salts and acid addition salts described above have similar pharmacological activities as the free form of the compounds of the present invention, and the present invention also includes such metal salts and acid addition salts.

EXAMPLES In order to explain the present invention in more detail, examples of producing raw material compounds for producing the compounds of the present invention will be given as reference examples, and then examples of producing the compounds of the present invention will be given as examples.

Example 1 Preparation of 3-n-propyl-4-hydroxy-10-benzyl-2-oxo-2-pyrimido[2.1-b]benzimidazole - 5 g of benzyl-2-aminobenzimidazole and 3 1 of sodium methoxide 8 mg was suspended in 481 liters of diethyl n-probylmalonate and stirred at 150°C for 9 hours. After the reaction is complete, let it cool and collect the precipitated crude crystals. It was taken out and washed with ether.

The crude crystals were dissolved in -14 chloroform, washed with water, dried over anhydrous magnesium sulfate, concentrated, and the resulting crystals were further washed with ether to obtain 3.95 g of the target compound.
I got it.

Structure and physical properties of the obtained compound (melting point and IIIM
R value) is shown in Table 1 as compound Na1.

Examples 2 to 10 In the same manner as in Example 1, each compound (Compound Nα2 to Compound Nα10) shown in Table 1 was produced.

The structure and physical properties of each compound obtained are also listed in Table 1.

Example 11 3-Nitro-4-hydroxy-10-benzyl 2-oxo-211-pyrimide [2.1. -b] Preparation of penzimidazole 650 μl of the compound obtained in Example 2 was suspended in 9.3 y/l of acetic acid and 2.3 zl of water, and 175 mg of sodium nitrite was added thereto under cooling with water. , and stirred for 5 hours. After the reaction was completed, the precipitated crude crystals were collected and washed with ether. The crude crystals were once dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, concentrated,
The obtained crystals were further washed with ether to obtain the target compound 4.
70 mg was obtained.

The structure and physical properties of the obtained compound are shown in Table 1. Compound Nα1
Shown as 1.

Example 12 Sodium 3-n-propyl-10-benzyl 2-oxo 2TI-pyrimide [2.1. -b] Preparation of penzimidazole-4-oleate 1.7 g of the compound obtained in Example 1 was added to 266 μl of sodium hydride (60%).
．． The mixture was added to a suspension of 2057 liters of 2-dimethoxyethane and stirred at room temperature for 30 minutes. After the completion of the reaction, two precipitated crude crystals were collected, washed with ether, and ethanol/1,2
-Recrystallize from dimethoxyethane to obtain the target compound 1.
．． 5g was obtained.

The structure and physical properties of the obtained compound are shown in Table 2.
Shown as 8.

Examples 19 and 20 Compound Nα19 shown in Table 2 was prepared in the same manner as in Example 18.
and 20 were produced.

The structure and physical properties of each compound are shown in Table 2.

No. 1 table (CII2) R No. 2 table ONa (CTI2) n R (Hereafter Up)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a substituent selected from 1 to 3 halogen atoms, lower alkyl groups, lower alkoxy groups, and hydroxy groups] R^2 represents a hydrogen atom, a nitro group, a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl group or a benzyl group, and n represents 0 or 1. ] A pyrimidobenzimidazole derivative and a salt thereof.