JPS6165848A - Novel compound, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to be/z-1 midazoles, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

[Problems to be solved by conventional technology and invention]

It is known that arachidonoic acid metabolites, which consist of arachidonoic acid, exert harmful effects on humans. For example, products produced via riboxidation of acids, such as leukotrienes, are implicated in the production and pathology of neuralgia and inflammation, as well as in the production and pathology of asthma and other allergic diseases. Therefore, compounds capable of selectively inhibiting 5-lipoxygenase while having a weak inhibitory effect on the 7-cyclooxygenase enzyme have little to no effect next to gastroprotective gummy brand compounds or bronchodilating cyclooxygenase products such as glostacycline. While it does not have a depressant effect, it is useful by preventing inflammation and the formation of bronchoconstrictor mesoiators.

Furthermore, products of the lipoxydigenase pathway may adversely affect the integrity of the gastrointestinal mucosa. Inhibition of lipoxygenase activity may lead to stimulation of cytoprotective glostagrandin production, particularly glostaculin and PGE. This inhibition is therefore used to preserve or establish the integrity of the gastrointestinal mucosa.

The inventors have found that benzimidazoles inhibit the 5-lipoxygenase enzyme and the present invention therefore provides a hydroxy group which may be etherified or nisalated in the 4-position and a lipophilic group (the latter advantageously being 2nd place)).

The compounds of the invention are useful for the treatment of inflammatory conditions such as rheumatoid arthritis and neuralgia; for the treatment and prevention of bronchial asthma, rhinitis, hay fever and allergic eczema; and for disorders related to loss of gastrointestinal integrity such as peptic ulcers, mucous membranes, sores and sores. Used to treat gastritis.

US Permit No. 2663712, DE-08fs192
No. 1911 and G.C., x, (J, O, a
) (1956) 569 discloses benzimidazoles consisting of, but none of these documents equally teaches that any of the compounds disclosed may have pharmaceutical uses. These compounds consist of J.Pharm.

and Pharmacol), l 956.
8, 661-5 and was reported to have no appreciable antibacterial activity.

[Means for solving problems]

More particularly, the present invention relates to the general formula (1) (wherein R1' represents hydrogen or a lower alkyl group,
represents hydrogen, a lower alkyl group or -CR8, R3 represents hydrogen, a lower alkyl group or -OR,8, No. 8 represents hydrogen or a lower alkyl group, 几6 represents hydrogen or a lower alkyl group, R6 represents hydrogen, lower alkyl, substituted or unsubstituted aryl group, or -000R1'',
B'r represents hydrogen, halogen or lower alkyl, 几6 represents lower alkyl or a substituted or unsubstituted carbocyclic aryl group, FL+5 represents hydrogen or lower alkyl, and n is 0
~8 and n is 0 when R6 represents lower alkyl) or a salt or solvate thereof, such as a hydrate, as an active therapeutic substance.

The term "lower" as used herein in reference to an alkyl or alkoxy group means that the group has up to 6 carbon atoms! AIJX preferably means containing up to 44 carbon atoms. The alkyl group may be straight chain or branched and for example methyl, ethyl, n-glopyru, 1-glopyru, n
-butyl, 1-butyl or tertiary-butyl.

In formula (1), the symbol means that R3 may be bonded to any of the nitrogen atoms of the midazole term, and when Ba represents a hydrogen atom, tautomerism exists, and both tautomers are included within the scope of the present invention. When R1 does not represent hydrogen t-, the two compounds differ due to the asymmetry of the substituents on the benzene ring and both compounds are included within the scope of this invention.

When R1 represents a lower alkyl group it is preferably methyl. When both R2 and R3 are hydrogen and either of them represents B, a, it is advantageous for R3 to represent methyl. Preferably, both number 8 and R,50 represent hydrogen, and when either of them represents lower alkyl, methyl is preferred.

It will be appreciated that stereoisomerism occurs when numbers 8 and 1 differ and the present invention provides all isomers individually and in mixtures.

When 几6 or Ba represents aryl, the group is a carbocyclic group, preferably R1'' (which is preferred) or. 7, lower alkoxy such as methoxy, lower alkyl such as methyl or halogen, preferably chlorine or bromine, trifluoromethyl, nitrile, nitro, amino, NBtzBu (wherein R+" and R" are independently hydrogen or lower alkyl ), (wherein R1
(4 is lower alkyl or aryl) or 1 and R'O are combined and together represent methylenedioxy or C1-C4 alkylene.

In the case of substituted naphthyl groups the direct substituents or each substituent (if more than one is present) ri may be independently on either the bonded or non-bonded ring.

R6 will also preferably represent a heterocyclic aryl group in which 几9 and P-1° have the above definitions.

When 6 represents imidasyl or pyridyl, it preferably represents 1-1 midazole or 8- or 4-pyridyl.

Ba is C! When representing 0OR16, advantageously R4 and B
g represents hydrogen.

When 7 represents bald, chlorine is preferred, and when it represents an alkyl group, tertiary butyl is preferred.

Among the compounds of formula (1), formula (II) 几8 (in the formula, FL" represents lower alkyl, especially a natyl group, and 8 represents hydrogen or lower alkyl, especially a tertiary butyl group, R6
is a mono-, di- or tri-substituted phenyl by an aryl group, especially methoxy or methyl, and n is from 0 to 5, especially 1).

The present invention further relates to the general formula (to) 8 (wherein a2 and R1 represent hydrogen or lower alkyl,
In compounds where 几6 represents hydrogen, lower alkyl or carbocyclic aryl, R+7 represents H or alkyl and n = 0, 几1 does not represent hydrogen and 几1,
R1! , R' and R7 represent hydrogen or methyl, and in the compound where n = 0, R1 is hydrogen or 4
1(,1,几=1几1.R number,几6.几・
, R], 几6 and 几16 are as defined for formula (1)) or a salt or solvate thereof.

Preferred substituents within the above-mentioned substituents are those of formula (1) and formula (I
As indicated for I). It will be understood that tautomerism exists correspondingly as exists in formula (I) when R1 represents hydrogen.

The present invention also provides physiologically acceptable compounds of general formula (1) or physiologically acceptable salts or solvates thereof for use in the treatment of the human or animal body.

The present invention provides pharmaceutical formulations comprising a physiologically acceptable compound of general formula (1) or a physiologically acceptable salt or solvate thereof mixed or combined with a parent pharmaceutically acceptable carrier.

Preferably, the pharmaceutical formulations of the invention are in the form or unit dosage form intended for use in the medical or veterinary field. For example, these preparations may be in the form of a pack with a printed or wrapped insert for use as an agent for the treatment or prevention of the aforementioned disorders.

Suitable dosage ranges for the formulations of this invention will vary from compound to compound and will depend on the condition being treated. It will also depend inter alia on the absorption capacity relationship and the chosen mode of administration.

The compounds or formulations of the invention are formulated for administration by any route, the preferred route depending on the disorder for which treatment is sought and preferably in unit dose form or in a form that the human patient administers to himself in a single dose. be.

Advantageously, the formulations are suitable for oral, rectal, topical, parenteral-intravenous or intramuscular administration or intrarespiratory tract administration. The formulation may be designed to provide sustained release of the active ingredient.

The formulation may be in the form of, for example, a tablet, capsule, puncture, vial, powder, granule, troche, reproducible powder, or liquid, such as a solution or suspension, or a waste tablet. Formulations particularly suitable for respiratory and topical administration are described in more detail below.

Preparations, e.g. those suitable for oral administration, may contain conventional auxiliaries such as binders such as 70g, gum arabic,
Gelate/, sorbitol, tragacanth or polyvinylpyrrolidone; excipients such as lactose, cornstarch, corn starch, calcium phosphate, sorbitol or glycol; tableting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone , sodium starch glycolate or microcrystalline cellulose; or a pharmaceutically acceptable solid agent such as sodium lauryl sulfate.

Solid formulations may be obtained by conventional methods such as mixing, filling, tabletting, etc. Repeated mixing operations distribute the active ingredients in these formulations using large quantities of excipients.

When the preparation is in the form of a tablet, powder or troche, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples of which include magnesium 2-naalate, starch, glycose, lactose, sugar sugar, rice flour and chalk. It is. The tablets may be coated according to methods well known in ordinary pharmaceutical practice, particularly with an enteric coating.

Preparations for oral administration as liquids include, for example, emulsions,
It may be provided in the form of a flonog or elixir or as a dry product which is reconstituted with water or other suitable medium before packaging. This solution may be prepared by adding conventionally used additives such as suspending agents such as sorbitol, methyl cellulose, gelatin, hydroquine ethyl cellulose, carboquine methyl cellulose, aluminum suarate gel, hydrogenated edible fats, emulsifiers such as salt/tin, monoion, etc. 1
norbitane acid, or gum arabic: water a or non-aqueous media (including edible oils) such as almond oil, fractionated coconut oil, oily nisals, eg glycerin nisals, glopyre/glycols or ethyl alcohol, glycerin, water or ordinary saline; preservatives such as mimethyl or gummy pyl p-hydro-dibenzoate or norbic acid; and, if desired, conventional flavoring or coloring agents.

For parenteral administration, liquid forms are prepared using the compound and a sterile vehicle and, depending on the concentration used, either suspended or dissolved in the vehicle. To prepare solutions, the compound may be dissolved in water for injection, sterile filtered, filled into a suitable vial or ampoule, and sealed. Advantageously, auxiliary agents such as local anesthetics, preservatives and buffers can be dissolved in the vehicle.

To increase stability, the composition is frozen after being placed in a vial and the water is removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, but the compound is suspended in the vehicle instead of being dissolved, and sterilization is not accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide before being suspended in a sterile medium. Advantageously, a surfactant or wetting agent is included in the composition to aid in uniform distribution of the compound.

Particularly suitable formulations for administration to the respiratory tract include, among others, drug drugs, needle solutions, drug solutions or fine powders for inhalation (alone or in combination with inert carriers such as lactose). In this case, the particles of active compound suitably have a diameter of less than 50 microns, preferably less than 10 microns.

For topical administration, the formulations may also be presented as ointments, creams, lotions, gels, gels, or skin creams for topical application.

Suitable dosage units in the aforementioned formulations for use in the treatment or prevention of allergic disorders are 0.01 to 500.
q of active ingredient, more preferably 1 to 500 η (for applications via the oral route), 0.01 to tO 11 q (via inhalation), the latter being preferred. The effective dosage of a compound will vary depending on the particular compound used, the condition of the patient, and the frequency and route of administration, but will generally be approximately 1,000 kg/Kf of patient body weight.
The range is from wy/day to 100q/day.

If appropriate, small amounts of other anti-asthmatic agents and bronchodilators such as sympathomimetic amines such as 1-sogrenalin, 1-soetalin, salbutamol, phenylephrine and ephedrine; such as prednisolone and adrenal stimulants such as AOTH.

For use in the treatment of inflammatory diseases, the formulations of the invention will preferably be in a form suitable for oral administration, such as tablets or capsules or punctures containing reconstituted powders.

A unit dose generally contains 20-1000 kg and preferably 30-500 yli especially 50,100,150,2
00°250.300,850,400,450 or S
It will include Cape OO. The preparation should be administered at least once a day, e.g. 2 times a day.
．． It is administered in 8 or 4 doses and the total daily dose for an adult of 70 to 9 years usually ranges from 100 to 200 ml of active ingredient, or a unit dose contains from 2 to 20 111 P of active ingredient and can be administered in multiple doses if desired. Give the daily dosing meter as described above.

For the treatment of disorders related to loss of gastrointestinal integrity, a unit dose will normally contain from 1 to 2000 to, for example, 5 to 1000 μ of active ingredient. Unit doses are usually administered once per day, e.g., 1, 2, 3, 4, 5 or 6 times, and the total daily dose is usually 0.1 to 30 kg/Ky body weight/day, e.g. 7
For adults between 0 and 7, it will be in the range of 7-2000 kg/day.

For the treatment of all the aforementioned disorders, the compositions will contain from 0.1% to 99% by weight of active ingredient, preferably from 10 to 60% by weight, depending on the method of administration.

The present invention also provides a method of treatment comprising administering to the human or animal body a physiologically acceptable compound of formula (1) or a physiologically acceptable salt thereof.

The present invention also provides 2 (IV) represents an atom, one 2s represents hydrogen, the other 2s represents hydrogen or a lower alkyl group, or a group or atom convertible thereto, and R'' represents hydrogen, halogen, alkyl, or a group convertible thereto, or Representing an atom) is a compound of formula (g) R,2600R28(V) [formula 几! 6 is -(C4R5)n-几・ or can be converted into & (wherein 4.FL5 and R6 and n have the definitions given above for formula (I) and formula (Jl), respectively) and 28 represents a leaving group or hydrogen] are reacted to form the compound 1 of formula (6) and, if necessary, the nitrogen atom of the benzimidazole nucleus and/or 4 -oxygen atom with formula 11
Acylated or alkylated with a group of "OR", formula (1) or a method for preparing the formula (1) with the removal of protecting groups, if necessary, is provided.

Preferably the group or Vi solvent is pharmaceutically acceptable. However, pharmaceutically unacceptable salts or solvents, f
1] The proboscis may be useful as an intermediate in the manufacture of pharmaceutically acceptable salts or the compound itself.

The present invention reduces the compound of Wenmu G/ID 几2I (wherein R"l, R+" and EI1 and R1" have the definitions given above for the formula Xun) and, if desired or if necessary, Then, a method for producing a compound of formula (I) or formula (υ) is provided in which a compound of formula (X) is obtained by removing the protecting group to form a compound of formula (T).

The compound of Shikihata where 几23 groups are alkyl R4 groups is this R''
When the group is in the meta position relative to the 0R22 group, an alkyl R4 group is produced, for example, by nitration in the meta position, reduction of the nitro group, alkylation of the amine group and nitration in the ortho position. Q) A compound that is ortho to the $22 group is, for example, an ortho, metadinitro compound '# with the formula "N
may be prepared from K by treatment with an amine of H, to selectively replace the orthonitro group.

Reduction of compounds of formula (→) may be carried out by conventional chemical methods or preferably by catalytic methods.

Catalytic reduction using, for example, palladium or Raney nickel on charcoal is conveniently carried out in conventionally used hydrogenation solvents such as lower r-alkanols such as ethanol. When R1'' flames hydrogen, then 1flJ is 200./KI or td for acetate/benzyl halide/
00.00 by benzyl 4 introduced into the N a I system or by CH1I / in acetone. will be protected by the methyl group introduced by

Compounds of formula (B) of formula (V), whether obtained by a process of preparation by reducing the compound of formula The reaction of the compound is preferably of the formula (g)R16C
This is carried out by heating with a compound of oR128(v) (in the formula, 2a represents a leaving group). For example, the compound f
iR"ooOH acids, acid chlorides, acid anhydrides, including mixed anhydrides and haloformate esters.

As an acid catalyst, the presence of 1 (CI may be necessary).

The compound with the formula RJ"acHo is an aryl group,
Forsch, ) 1967, 17 + 55. Another generally applicable method for the synthesis of benz-1 midanol is described in Ohem Revs 1974.74(a), 729.
It is described in.

This may be carried out in a circular manner per se by removing the group or carrying out a catalytic hydrogenation using eg Baladicum/charcoal as a catalyst to remove the be/zyl group.

The present invention further provides a method by which one compound of formula (1) is converted into a compound of formula (I).

The present invention particularly relates to a compound obtained by treating a compound of formula (1) in which 1 represents H with a suitable acylating agent.

Provided is a method for preparing a compound of formula (I) in which 11 represents OR, &. If R2 represents hydrogen, it is preferably protected during the reaction by a benzyl group.

Advantageously, the reaction is carried out using a suitable acyl halide, preferably chloride, and under basic conditions using, for example, triethylamine and chloroform as medium.

The present invention further provides for acylating the compound of formula (1) in which 2 is hydrogen t- with a dihydrogen which prevents or suppresses the acylation of the N atom of the benzimidazole nucleus in a trifluoroacetic acid medium, and A method is provided for preparing esters of compounds of formula (I) in which the reactive group of the compound is optionally protected by a protecting group. Acylation preferably involves bonding the group No. 8 to the oxygen atom at the 2-position.

Compounds of formula (1) where 7 is other than hydrogen may themselves be prepared by a circular process. For example, in a compound in which R7 represents a halogen such as bromine or chlorine, the proboscis can be formed by halogenating the alkyrule at the 2-position if desired, optionally converting the 5- and 6-positions to nido-a, and protecting the phenolic hydrogen at the necessary stage. It will be manufactured. There are 8 similar ways? will be used in one modification of the alkyl process, and the subsequent reduction to the diamino precursor and its conversion to the benz1 midazole of formula (1) will be carried out as described above.

The reactions for the preparation of compounds of the formula (V'l+) in which 5-substituted benzimidazole and one R+"! contain hydrogen are shown below for illustration. 几1, R+"l, R
1” and 几26 are respectively formula (■) (or formula [phase]),
IV. R with the definitions given above for M and V
' is preferably methyl. The intermediates comprising these compounds are standard and the present invention also provides these compounds and methods for their preparation.

In particular, the present invention is based on the formula 1 (where 1 is as defined for formula (1), 8 is benzyl or mesyl, or R1 as defined for formula (1), Ry is hydrogen, No, and father is Ni(.

and 几2 is NO, father is NH, and R7
is a tertiary butyl).

L)H*Jie” f-711/(7net(J,F,Bun
net) and 7-R, 1-' Zahler (R,E
, Zahler).

[Cem, Rev J 1951. Dan, 3547-# * (-11?-Quell (几, J
Markwell).

[Ke A-:I7 Miyu:y (Ohem, Oommun
) J 1979°428.

The present invention is also advantageously prepared by reacting a compound of formula (IV) with a compound of formula (v) (the compound of formula (IV) is preferably prepared by reducing the nitro group of the compound of formula (IV) to an amine group). 7'c) The physiologically tolerable compound of formula (1) can be isolated by removing the i8 group, if desired, and forming a physiologically tolerable salt thereof if desired. - Provides a method for preparing a pharmaceutical formulation of a compound of formula (1), which comprises mixing a tolerable compound or salt with a pharmaceutically acceptable auxiliary agent.

〔Example〕

The reference examples below illustrate the preparation of intermediates for compounds of the invention. The following examples illustrate the invention.

Reference Example 1 4-Penzyloquino 2,3-dinitrotoluene 4-methyl-2,3-dinitrophenol [M, F, Dadswel 1
) and J.K. Kenner (J.K.A.N.O., (J.Ohem, 8oc.) J.
580 (1927)) (12, Of), anhydrous potassium carbonate (15F), potassium iodide (0, lj'), benzyl chloride (25f) in acetone (A, R, 150d) under reflux for 18 hours. The mixture was heated and stirred. Cool the mixture;
Filter and evaporate solution F to dryness under reduced pressure, transfer the residue to chloroform (400 d) and wash with water 1-dry (Na2S
O4) was filtered and evaporated to half under reduced pressure. Penta 7
Add (15oi) to the title compound*t6.22 (98%)
A melting point of 116-118°C was obtained.

Reference Example 2 2.3-diyminor 4-benzyloxy/toluene 4-benzyloxy-2,3-di-a toluene:y (7?) and 0' Raney nickel (3q) in hydrogen Hydrogenation was carried out at room temperature and normal pressure until absorption ceased (3 hours). The colorless solution was filtered overnight (Cera 1) and evaporated to dryness under pressure F to form an unstable oil (5?) Title! Hiai → Nazu was obtained and used immediately in the next step.

Reference Example 3 2-benzyl-4-benzyloxy-methylbenzimidazole Z, a-diamino-4-benzylox7toluene (5?
) and phenyl vinegar r11 (zar) for 1 hour.
Heated at 20°C. The mixture was cooled, dissolved in chloroform and washed with 10 sodium dicarbonate solution, then water, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain the title compound* (4,4f), melting point 198-200°C.

Analysis 1st shift: 0ztHt. N, 0 as 0,80.45
;)(,6,15:N, 8.55%.

Actual value: c, so, as9 I(,6,05: N,
IL45%.

Reference Example 4 2-Phenethyl-4-penzyloquine-7-methylbenzimidazole Produced in the same manner as in Example 8.

Melting point 208-4°C (ethanol).

Reference example 5 4-benzyloxy-7-methyl-2-phenylbenzimidazole 2,3-diamino-4-be/) in (75m)
A mixture of toluene (5,Of) and C)'benzaldehyde (5,52F, 2 molar equivalents) was heated under reflux for 3 hours and then left at room temperature for 18 hours. The crystalline product obtained was filtered, washed with ether and recrystallized from ethanol to give the title compound (4,13?), mp 2.
21-224°C was obtained.

Analysis value 20! IHI8N, 0 as 0,80,25
*i(,5,75:N,8.9% Actual value: 0,80.15; 1(,5,60:N,
8.8'16: , :Reference Example 6 2-n-7'biru-4-benzyloxy-7-methylbenzimidazole Produced in the same manner as in Example 5.

Melting point 192-194℃ (ethanol/ethyl acetate) Analysis value: 0.77.11 as C15H1oN20: ) (
,7,19;N,9,99chi.

Actual value: 0,76.85; H, 7,19: N, 9
, 91chi.

Reference row 7 2-(4'-methoxybenzyl)-4-benzyloxy-7-methylbenzimidazole Produced in the same manner as in Example 5.

Melting point 181-183°C (ethyl acetate) Analysis III: C, 77 as 0tsHz*Nz0t
, 07; H, 6, 19; N, 7.32%.

Actual value: 0,77.22: d, 6,26; N, 7
．． 81%.

Reference Example 8 2-Nitro-4-hydroxy-5-tertiary phthyltoluene-O-mesylate e Mesyl chloride (1472) was dissolved in pyridine (500d) at 0°C.
3-tertiary butyl-4-human mixitoluene (200
The solution f) was added dropwise over 0.5 hours.

The solution was stirred for 1 hour at 10°C and then for an additional 3 hours at room temperature. It was poured into excess 5N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with 5N hydrochloric acid and water and dried (N31SO4).

Evaporate to dryness under reduced pressure to obtain 8-tertiary butyl-4-hydroxy 7.
Toluene 10-mesylate (250f) was obtained which was dissolved in #sulfuric acid (7so-) and cooled to 0°C.

A mixture of concentrated nitric acid (93f) and concentrated nitric acid (175rnt) was added dropwise over 1 hour while maintaining the temperature at t-O<0>C.

The solution was poured onto ice and the resulting solid was collected, washed with water and air dried to give the title compound (260
F) A melting point of 69-78°C was obtained. A portion was recrystallized in c1cI form. Melting point: 91-92°C.

Analysis value: O+! H1? 0,50 as NOs S
．． 16: +(,5,96;N,4.37 trowel.

Actual value: 0,4'), 98: d, 5,98; N,
4.85%.

The product from Reference Example 8 (260r) was heated at 60-70°C.
Sodium hydroxide (18(1) in water (800rnt) at
) was stirred until all the solids were dissolved (1.5 hours). Administer cG fluid and remove excess ice and
Poured into N-hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer was washed with water and dried (Na, So,...)
did. Evaporation to dryness under reduced pressure afforded the title compound (1407) which was sufficiently pure for the next step.

A portion was recrystallized from dichloromethane/pentane. Melting point: 96-98°C.

Analysis IIE: 0IIH15NO3 as 0,6;3
,4:H,7,23:N,6.69ch.

Actual value: 0.6; (, 22: H, 7, 2; N, 6
．． 69.

Reference Example 1O A solution of fuming nitric acid (to,ozy) in 2,3-dinitro-4-hi-tertiarybutyltoluenebutyltolueneacetic acid (15-) was dissolved in acetic acid (60d) while keeping the temperature at 18-20°C. It was added dropwise to a solution of the crude product (85f) from Reference Example 9 over 15 minutes. After another 10 minutes the solution was poured onto ice and the resulting solid was collected and washed with water. It was dissolved in dichloromethane, washed with water and dried (NazSOa). The product was eluted with dichloromethane on silica gel 60 (2
5Of) was purified by column chromatography.

Recrystallization from dichloromethane/pentane gave the title compound (25F), melting point It) 4-105°C.

Analysis 1iE: 011H14N! 05 as 0,51
．． 97: f(, 5, 55; N, 11.02 chi.

Actual value: 0,51.88; f(,5,G2; N,
11.00%.

Reference Example 11 2.8-Diamino-4-hydroxy-5-tert-butyltoluene (2,3-dini)Ilf in ethanol (350+nt)
A solution of f-4-hydroxy-5-tertiary butyltoluene (Reference Example 10) (7,59) was heated for 10 minutes until hydrogen absorption stopped.
Hydrogenated over tipalladium on carbon (2,5F) at M@latent pressure. The solution was flushed with nitrogen F and evaporated to dryness under reduced pressure to give the unstable title compound, mp 129-136°C, which was immediately used in the next reaction.

Reference Example 12 0-Benzyl-2,3-dinitrophenol Bz 2,3-dinitrophenol in acetone (25(ld))
A/ (x −-/< :/triy (A, Bantl
in) [Berichte J 11,
2104 (1378)] CI0. Of), anhydrous potassium carbonate (11,Of) and benzyl chloride (8,22F)
) was heated at reflux F for 8 hours.

Ta. The solution was poured and the p-liquid was evaporated to dryness under reduced pressure.

The residue was recrystallized from it-chloroform/hexane to obtain the title compound (14,2F), melting point 100-101°C.

Example 1 2-Benzyl-4-hydroxy-7-methylbenzimidazole A solution of 2-benzyl-4-benzyloxy-methylbenzimidazole (a, or) in ethanol (400 me) and 10% palladium on carbon (1, 5F) was hydrogenated at room temperature and normal pressure until hydrogen absorption stopped.

The mixture was filtered (Cerato) and the P solution was evaporated to dryness under reduced pressure and recrystallized from ethanol-ether to give the title compound (1,85S') mp 204-205°C.

Analysis value: 0.75.6 as C'++sH+4HtO:
d, 5.9:N, 11.75%.

Actual value: 0,75.85: H, 5,85; N, 1
1.7 chi.

δ((CDi)tso) 2.4(3d,s)4.
2 (2H, s) 6.45 (LH, d, J=8) (Z) 6.75
(LH, d, J=8Hz) 7.3 (5H, m) 9.6 (LH, br, s) Example 2 2-(4-chlorobenzyl)-4-methoxy-7-methylbenzimidazole2. 3-Diamino-4-methoxytoluene [prepared by hydrogenation of 4-methoxy-2,El-dinitrotoluene (7,sr) over 10% Balazitum carbon (2,5t) in ethanol] and 4 -chlorophenylacetic acid (21)
The mixture was heated at 130-150° C. for 4.5 hours under nitrogen. The mixture was cooled, dissolved in chloroform, washed with 10% sodium carbonate solution, then water and dried (Na, 5o
4) L and evaporated to dryness under reduced pressure. The product was recrystallized from chloroform/pentane to give the title compound (5,75
F) A melting point of 195-197°C was obtained.

Analysis value "*sH+5ONtOf" is 0.67.
00: k(,5,25;N,9.75: C1,12
, 85 chi.

Actual value; 0,67.05; H, 5,30; N, 9
．． 85: Of, 12.60% Example 8 2-(4-chlorobenzyl)-4-hydroxy-7-methylbenzimidazole hydrogen bromide d [2 in 48% aqueous hydrobromic acid (400 d) of nitrogen -(4-chlorobenzyl)-4-methoxy-7-methylbenzimidazole (
The suspension of 4,Or) was heated at 180° C. for 5 hours and then evaporated to dryness under reduced pressure. The remaining residue was recrystallized from ethanol/ether to give the title compound (3,95-P), melting point 275~
277°C was obtained.

Analysis value: C,,H,. 0NtO1, HB r , 0.50.95;) (,4,0: N, 7.9chi Actual value: 0,50.60: H,a,9; N,?,
8 After preparing the free base in a manner similar to that described in Example 1, the following compounds were prepared by adding ethereal hydrogen chloride to a solution of the free base in ethanolic.

Example 4 2-7enethyl-4-hydroxy-7-methylbenzimidazole hydrochloride Melting point 238-40°C Analysis value: 0IsH□N, 0.66 as 0Hot,
55:) (,5,98S N, 9.70ch Actual value: C, 66,71: ) (,5,96: N,
9.67 Example 5 2-phenyl-4-hydroxy-methylbenzimidazole hydrochloride Melting point 252-6°C (decomposition) Analysis value: 0.41(,,0N2t(01 as C,6
4,5: E(,5,00; N, 10,75: C1
, 13,60% actual measurement: C164,2; t(94,8
5SN, 10.55; Of, ia, 55'
% Compound F was prepared in a similar manner.

Example 6 2-(pyrid-3-yl)methyl-4-human akiku-7
-Methylbenzimidazole Melting point 264-268°C (methanol/ethyl acetate/ether) Analysis value: 0,70,28 as C,, H,, N, O:
H, 5, 48: t'(, 17, 56 Chimi Kenyoi: (j; 70 J3; t (+5, 62; N,
17.28%.

Implementation-17 2-(S7-2-ylmethyl)-4-hydroxy7-methylbenzimidazole salt M salt HH Melting point >280°C (min S) Analysis value: C1°H,,)(tO,)(C! 0 as l,
70.25:i(,5,28;N,8.6a:
C1, 10, 92%.

Actual value: 0,70,41; g, 5.31: N, 8
．． 59; C1, 11, 04%.

Example 8 2-benzyl-4-hydroxy-5-3e7'thyl-7
-Methylbenzumidazole 2.3-diamino-4-hydroxy-5-tertiary-butyltoluene (Reference Example tt) (manufactured from z, a-dinitro-4-hydroxy-5-tertiary-butyltoluene 12f) and phenylacetic acid ( aor) mixture under nitrogen at 120-130
Heated at ℃ for 1 hour. The reaction product was extracted with chloroform, washed with 10% sodium carbonate, washed with water, and dried (N
31SO4). The chloroform solution was evaporated to dryness under pressure and recrystallized from chloroform/ethyl acetate/penta/ to give the title compound (9,i), melting point 226-228°C.

Analysis value: 0.77.52 as C□H,, N, O; H
, 7,58; N, 9.52%.

Actual value: 0,7? , 31; H, 7, 64: N, 9
．． 76 me.

Examples (9a) and (9b) 5-tertiary butyl-4-hydroxy7-2-(4'-methylbenzyl)-7-methylbenzimidazole (9a) and hydrochloride (9b) Example 9bHO1 Title compound ( 9a) was prepared in a similar manner to Example 8. Melting point 269-270°C (ethanol/ether).

Treatment of the free base (9a) with ethanolic hydrogen chloride gave the hydrochloride salt (Example 9b). Melting point 232-285℃
(ethanol/ether).

Analysis value 20. H,,N,O,1(Of 0,66
．． 56:f(,6,98; N,?,76:C1,9
,32%.

Actual value: 0,66.58: H, 7,06: N,?
, 79; 01,10,00chi.

Example 10 2-(4'-methylbenzyl)-4-hydroxy-7-
Methylbenzimidazole This compound was prepared in a manner similar to Example 1.

Melting point 217-8°C.

Analysis value: O,, H,, N, C1 as 0, 815;
l(,6JO;N, 11.04%.

Actual value: 0,75.25: d, +), 37. N,
11.06 chi.

The following compounds were prepared in a manner similar to Example 4.

Example 11 2-n-probyl-4-hydroxyfufumedylbenzimidazole hydrochloride Melting point 204-206°C (ethanol/ethyl acetate/ether).

Analysis value: O,, H,, N, 01) (0.0 as C1l)
58.27:1(,6,66:N,12J5;01
, 15, 63 chi.

Actual value: 0,58.25; t(,6,97;N,1
2, ao; 31, 15.79%.

Example 12 2-(4'-methoxybenzyl)-4-hydroxyy-7
-Melbenz 1 Midanol 4! Salt melting point 228-22
9°C (ethanol/water).

Analysis value 'O+sH+aNt Ox, 0,63,05 as HOI: H, 5,62; N, 9. t9;
C1,tt,63chi.

Actual value: 0,62,95; l(,5,88; N,
9,08: C! 1,11.68%.

Example 18 2-(3'-t'Jfluoromethylbenzyl)-4-
and d-axy-7-methylbenzimidazole hydrochloride Melting point 〉280℃ (decomposition) Analysis value: C□H, IF, N, 00) (0.5 as 01
4,80;)(,3,68;N,8.52;0
1,10.79%.

Actual value: 0,54,58; ) I, 3.62: N,
8,45; 01,10.50%.

Example 14-2-(4'-N,N-dimethylaminobenzyl)-4-
Hydroxy-7-methylbenzimidazole hydrochloride melting point 175-194°C.

Analysis 1st shift: C! +? H+@N*0j (0.
63.26:d, 5.97; N, t3,81; C1
, u, 67 chi.

Actual measurement +if: 0,68.25; +-1,5,99
: lma, 13,40: 01,11.6chi.

Row 15 2-(naphth-1-ylmethyl)-4-hydroxy-methylbenzimidazole hydrochloride mp 262-8°C.

Analysis 11i1: CnH+11N10, ) (0,70.26 as Ol;) (,5,28; N, 8.62
3; 01,10.92%.

Actual measurement 1st shift: 0.70, d6: H2S, d2:
N, 8, 57; C1, 11, 49%.

Example 16 2-Benzyl-4-hydroxybenzimidazole A solution of 0-benzyl-2,3-dinitrophenol (Reference Example 12) (4°5?) in ethanol (aood) was heated to atmospheric pressure until hydrogen absorption ceased. Hydrogenated over Raney nickel (2t). The entire solution was stirred and evaporated to dryness under reduced pressure to give unstable O-benzyl-2,8-diaminophenol, which was immediately heated with phenylacetic acid (20?) at 140-150 DEG C. for 3 hours. The product was heated under reflux for 3 hours with 5N hydrochloric acid (70m/) and neutralized with 10% sodium carbonate. The γ-miai and proboscis were extracted with chlora and form, and the organic layer was extracted with 10% sodium carbonate,
Washed with water and dried (Nag 804). The recovered product was purified by atomography on silica gel 60 (250F) eluting with ethyl acetate-chloroform (1:19) to give the title compound $1J (1,62), mp 172-1.
74°C (ethanol/neal) was obtained.

Analysis 1st shift: 014 le, 0.74.98 as N20;
L4,5J91N, 12.49 person.

Actual Hi: c, 75. a9: H, 5, 36; N
, t2.6%.

The following compounds were produced in the same manner.

Example 17 8 points of 2-(4′-methogishib/zyl)-4-hydroquinobenz 1 midazole hydrochloride 194-196°C (methanol/needle).

N, 9.60%.

Actual value: 0,61.91; 115,25; N, 9
．． 58-16° Example 18 6-(4-Hydroxy-7-methyl-benzimidazole-2-1)-hexanoic acid hydrochloride water! a thing (a: a
:B Example 19 Ethyl 6-(4-hydroxy7-7-methyl-benzimidazol-2-yl)-hextenoate hydrochloride Compound of Example 18* (1,95F) was purified with nitrogen. 5
+fJ] Dry ethanol containing 5 drops of concentrated hydrochloric acid (LO
(Od) and then evaporated to dryness under reduced pressure.

Product #Recrystallized from total ethanol/ninal to obtain the title compound (1,99F) melting point 144-146°C.

Analysis value 20+6HzN20. , get 0 as
．． 58.8: H, 7,09; N, 8,57; C1,
10.84%.

Actual j1 shift: 0,58,59; i(,?,0
0; N, 8,3: 01,10.97chi.

The following compound was obtained in the same manner.

Example 20 Ethyl 5-(4-hydroxy-7-methyl-benz 1migsol-2-yl)betanoate melting point 183-135
°C (Near) Analysis 1st shift: C+5) (C as toN203, 65,2
0; f(,7JO:IN, 10.15%.

Actual value: 0,64.95; H, 7, 13: N, 9
．． 96%.

Example 21 5-(4- and doloki7-7-methyl-benzimidazol-2-yl)-pentanoic acid hydrochloride hemihydrate melting point 136-191°C (water) Analysis value: C HIgNtO,,) (C1 ,0,5)(t
0.5B as O, 13:,)(,6,17; N,9
．． 53%.

Actual picture 11 shifts: 0,58.56; k(,5,7
9; N, 9.46%.

The following compounds were prepared in a similar manner to Example 4.

Example 22 2-(2′-furyl)-4-hydroxy-7-methylbenzimidazole hydrochloride: Ethanol (2:l) 0H Melting point 256-8°C (decomposition) (ethanol/ether) Analysis value 2c, 2+ -x, ON, o, , I (Ol:0
．． 0.56.29 as 50tH40: l(,5,1
2; N, 10,10; 01.14,06 Chi.

Actual measurement 1st shift: 0,55,95: H, 4,90; N,
9.91; Of, 13,88%.

Example row 28 2(thien-2-ylmethyl)-4-hydroxy-7-
Methylbenzimidazole hydrochloride 8 points 206~8℃ (ethanol/ether) analysis lK: C13H,,N,
O8,1 (Ca as CI, 55,61:d, 4.
67: N, 9.98: S, 11,42: Ca1,
12.6H%.

Actual value: 0,56.22: ) (+4,77; N,
9,72: S, 11.03; Of, 12,63 Chi.

Example 24 2-(4'-methoxybenzyl)-4-hydroxy-7
-Methylbenzimidazole hydrochloride 8 points 227~9℃ (
Ethanol/ether) Analysis value: OI'tHIsNt
Ot, HOl as O,+34.05:)(,6,
01; N, 8,79; Ca1, 11.12%.

Actual value: 0,63,98; f(,5,96: N,
8,62; Cal, 10.91%.

Example 25 2-(8',4',5'-trimethoxybenzyl)-4
-Hydroxy-methylbenzimidazoleee Melting point: 250-1°C (decomposition) (ethanol/ether) Analysis value: C-6H1°N, No. 0, 0.5 as HOI
9.26:f(,5,80;N,7,68;C
1, 9, 72 chi.

Actual measurement value 20, 59.06; H, 5, 96: N, 7.
65; 01.9, 96th.

Example 26 2-(1,4'-dimethoxy7benzyl)-4-hydroxy-7-methylbenzimidazole hydrochloride 8 points 264~
5℃ (decomposition) (ethanol/ether) Analysis value: 0t
tH+5NtOs, Ho 1 and -(0,60,9
8; L5, 72; N, 8J7; 31, to, s9%
.

Actual value: 0,60.69; l(,5,71:N,8
, 23; 01, 10.78%.

Example 27 2-(3'-methΦdibenzyl)-4-hydroquine-7
-Methylbenzimidazole hydrochloride: Ethanol melting point 289-241°C (ethanol/ether) Analysis value: C16) (1gN, o, , HOI, 0tHsO
as 0,61,62;)(,6,61; N,7.9
9%.

Actual value: 0.61.91: H, 6, 70: N, 8
．． 02%.

Example 28 2-(4'-,7'toxyphenyl)-4-hydroxy 7
-Methylbenzimidazole hydrochloride; Ethanol e Melting point 283-5°C (ethanol/ether) Analysis value:
C,,Hl,N,0. ]CI, O, C as H60
,60,44;)(,6,56;N,8.29:C
1, 10, 50%.

Actual measurement 1st shift: C, 60, 46; H, 6, 21; N,
8, 31: 01, 10.26 section.

Example 29 2-(2'-Methoquinobenzyl)-4- and doxy-methylbenzimidazole hydrochloride, melting point 244-245°C (
Ethanol) Analysis value: O,,i(,,N,0.,E(C as Ol,
6JO5:)(,5,62:N,9.19ch.

Actual value: 0,6; 3.02; )(,5,56; N
, 9.24ch.

Example 80 2-(4'-and droxybenzyl)-4-hydroxy-
7-Methylbenzimidazole hydrochloride Melting point 273-5℃
(Ethyl acetate) Analysis value 2C□H,,N, O,,dcl 0,
61,96; f(,5,20; N, 9.64%.

Actual value: 0,61.71: l(,5,40: N,
9.36 section.

The following compounds are prepared in a similar manner.

Example 81 2-(1-phenylethyl)-4-hydroxy-7-methylbenzimidazole Example 32 2-(thien-2-yl)-4-hydroxy-7-methylbenzimidazole Example 88 2-(imidazole -1-yl)methyl-4-hydroxy-7-methylbenzimidazole Example 8
4 2-Benzyl-3-acetyl-4-hydroxy-7-methylbenzimidazole and l-acetel-2-benzyl-4-hydroxy-7-methylbenzimidazole.

Example 35 2-benzyl-4-hydroxy-7-5-ri-7-methylbenzimidazole Example 36 2-n-hexyl-4-hydroxyfu-5-tert-butyl-
7-Methylbenz-midazoleExample 37 2-benzyl-4-hydroxy-5-3gbutyl-benzimidazoleExample 38 2-benzyl-3-acetyl-4-hydroxy-5-lya lobenzimidazole and 1- Acetyl k-2-hensyl-4-hydroxy-5-chlorobenz1 midazole [Effect] The pharmacological activity of representative compounds of the present invention was determined using the following method.

Method: Adjuvant Arthritis Model in Human Rats This test is based on the Newbold [
Buriti, Gee, Fur? ko/l/ (B r i
t, J, Pharmaco November 196;3.
21. 127-136.

It is used to demonstrate anti-rheumatic activity demonstrated by suppressing the progression of arthritis in an adjuvant arthritis model in rats.

The compound of Example 1 is active at a concentration of 251q/Kf (i,p,).

Method B RBL-15-Lipoxygenase Screen 5-Lipoxygenase enzyme was added to Jaksahik
) (7) Method [Hee Ni Jaksink.

E.F. Sun (g, F, Sun), L.M. (L, M, Lee) and 0' M. Steinhoff (M9M, 5steinhoff), 198
0 r Biochem Biophysics v Suniam (
Biochem, Biophys, Res.

Oomm, )J 95. 103), R, BL-
The to, ooor-human fluid from LM cells was used as a real solution.

The 10,000f supernatant was diluted from homogenization buffer UK to the equivalent of 1.5-2.5XIO"m cells/mt and 2mM for 0aCl. The 0.5-portion was then diluted into tubes. and incubated at 29°C for 2 minutes with desired concentrations of compounds in ethanol or 5 μt of ethanol.C114) Arachidonic acid was then added to the buffer to a final concentration of 6.3 μt for each incubation.
M and 0.2 μC1 and the reaction continued for 2 minutes at 29°C. The reaction was terminated by the addition of 1-l acetone and cooled with ice, then 0.5-l water-cold saline and 10 μt 2N formic acid were added and the mixture was extracted with 2 x 2-chloroform.

The extract was stored in N at -20°C until analysis by Chromatograph 1.
I stored it under storage. The activity was determined by 5-f (ETE and 5,12-diH
The total radioactivity found in E'rE was measured as the decrease in the total formation of these two species in compound-treated versus control incubations.

This test is used to demonstrate the inhibition of 5-lipoxygenase enzyme in milk-IIh R,BL-1 cells without quantification of 5-lipoxygenase.

The inhibition rate by the compound of Example 1 at 5 pMIlk degree was 78
, t (1)<0.001), while 0.5μ
M! The inhibition rate was 36, o(p(o, ox)).

Method C This model of carrageenin-induced pleuritic monocyte accumulation in rats was developed by R. Vinegar.
, ji x -- z7 @ ) a ri (J, F.

Truax), Z-E Eluce K7 (J
, L, 5elph) and Fkennie Belker (F, A
, Voelker) (R7 Edition) (FederaLion Proceedin)
gs) 4L 2588-2595. Based on the method of 1932'l.

0.2 of carrageenin (Viscarin 402) in physiological saline. O1 solution was injected into the breast of anesthetized rats (approximately 175-200 f body weight). Compounds were administered 1 hour before carrageenin and 24 and 48 hours after carrageenin.
．． 9% saline and 325 cape phenol red (saline was added to make It) was injected into the breast meat after the animals were sacrificed, and the exudate was removed through the membrane with a syringe needle. The volume of exudate was calculated by dilution of the injected phenol red, determined spectrophotometrically (560 nm) and the cell content was determined by DNA quantification [Karsten, U.
) and Niebohlenberger (A, Wollenb
erger) [7 Anal Hyokem (Anal,
Biochem Mon 77, 464-470.1977
].

This test is used to demonstrate anti-inflammatory activity against carrageenin-induced pleurisy in rats.

The compound of Example 10 is 251! v/Kq([), 0. )
So, the compound of Example 12 has 25η/4(p,o,) and the compound of Example 18 has 12■/Kq(i,p,)
It was active in

Method D: Passive peritoneal atherosclerosis (PPA) method in rats was developed by Ross et al.
Etch Smith (H18mith) and 0 Barbara
Knee 1 Suba 1 Sir (Barbara A, 5pice
r) Increased v.
ascular permeability duri
ng passiveperitoneal anap
hylaxis in the r31) ``(7t al and allergy apple int y (Int.

Arch, Allergy Appl, Innum,)
226.19763.

Animals 225-275? charles e river bite graug
Dawley male rats and 300~? A male white guinea fowl from the Dungin Hartley building of 00 r was used.

Antiserum 225-275v of Charles m IJ Bar Sgrag Dawley male rats were tested with 0.5- of Bordetella pertussis.
sis) vaccine (4X10”/co; Burroughs Wellcome, London) or harvested perthusis (pe
rtussis) Vaccine (4 A, u, or more B. pertussis antigens with aluminum hydroxide: The Risk-〇Institute Tutor Else Free.

(England) intramembrane injection and ovalbumin in pseudosaline 2- and incomplete adjuvant 3d; crystallization and lyophilization; Great v1 Nogma, London) ioo■
An emulsion (1.5 doses) was injected subcutaneously.The rats were anesthetized with ether and underwent cardiac puncture on the 18th day to collect blood, separate the serum, store it at -200°C, and use it only once before use. The serum produced passive cutaneous anaphylactic activity in rats for 72 hours at a dilution of 1:64, which was reduced to a dilution of 1:2 by heating at 56 DEG C. for 4 hours.

Passive peritoneal anaphylaxis 7 = Rats were given an intraperitoneal injection of a 2-1:5 dilution of rat antiserum in isomorphic saline. After 2 hours Bontamine Sky Blue (Raymond A.
Control rats received an intravenous injection of 0.3-ml of 516 solution (Lam, London) followed by an intraperitoneal injection of the test compound in 1 rnt of saline (control rats received 1 rnt of saline), This was followed by an intraperitoneal injection of Tyrode's solution containing 2.5 kg/- of heparin and 0.4 kg/- of ovalbumin. Concentrations of compounds were taken as those in fluid 6- injected intraperitoneally. Exactly 5 minutes after the injection, the rats were stunned and bled and their intraperitoneal fluid was collected by opening their abdominal cavity and passing it through a funnel into a submerged polycarbonate tube. The supernatant was separated from cell debris by centrifugation at 1502 for 5 min and the sample obviously contaminated with blood was discarded for determination of dye, histamine and 5R8-A. at least 5
Groups of 1 rat were used for each dose of compound and treatments were randomized.

Determination of intraperitoneal fluid The collected intraperitoneal fluid was immediately cooled to 0 °C and centrifuged, then the supernatant fluid was placed in a boiling water bath for 5 minutes and poured into a boiling water bath.
The samples were frozen and stored at -20°C until quantification of A.

5R8-A QuantificationSR,8-A was quantified on isolated guinea pig ileum preparations in the presence of atropine (5X10-1M) and mehyramine maleate (10-'M) (to eliminate histamine responses) [Double・Brocklehurst
Of A Slow Reacti ng Length Bustance (
SR, 5-A) ・The release ofhista
mial and form31ion of slo
w reacting substances (5R8-
A) during anaphyl31ic 5ho
ck) J
siol,.

LO bite) J 151.416.1 Harm]. The collected intraperitoneal fluid from passively sensed and injected rats was centrifuged, stored at -20 °C in 0.5- and 5-
It was used as a standard R8-A product and was arbitrarily named as containing 910 units. The concentrations of unreleased samples were grouped together based on the SR8-A sample. Compounds tested at the concentrations used were quantifiable.

Results The results obtained in this test are shown in the table below and demonstrate the ability of the compounds of Examples 12.25 and 26 to suppress the amount of 5R8-A in this in vivo system.

All compounds were given at a final concentration of 2 x 10'M.

In all of these tests no toxicity was found and to

Claims (62)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents hydrogen or a lower alkyl group, and R^
2 represents hydrogen, a lower alkyl group, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^3 represents hydrogen, lower alkyl groups, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R^4 represents hydrogen or Represents a lower alkyl group, R^5 represents hydrogen or a lower alkyl group, R^6 represents hydrogen, a lower alkyl group, a substituted or unsubstituted aryl group, or -COOR
^1^5 represents hydrogen, R^7 represents hydrogen, halogen or lower alkyl, R^8 represents lower alkyl or a substituted or unsubstituted carbocyclic aryl group, R^1^5 represents hydrogen or lower alkyl and n is 0 to 8 and n is 0 when R^6 represents lower alkyl) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. Composition. (2) The composition according to claim (1) in unit dosage form. (3) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R^2 and R^3 represent hydrogen or lower alkyl, and R^6 represents hydrogen, lower alkyl, or carbocyclic aryl. and R^7 represents H or alkyl and n=0, R^1 does not represent hydrogen and R^1, R
R^1 with the proviso that in compounds where ^2, R^6 and R^7 represent hydrogen or methyl and n = 0, R^3 does not represent hydrogen or an alkyl group having up to 4 carbon atoms. , R^2, R^3, R^4, R^5, R^
6, R^7, R^8 and R^1^5 are as defined for formula (I) in claim (1)) or a salt or solvate thereof. (4) R^5 or R^8 represents ▲ There is a mathematical formula, chemical formula, table, etc. ▼ or ▲ There is a mathematical formula, chemical formula, table, etc. ▼ Or R^6 represents ▲ There is a mathematical formula, chemical formula, table, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ , and in the formula, each R^9, R^1^0,
R^1^1 is independently hydrogen, hydroxy, lower alkoxy, lower alkyl, halogen, trifluoromethyl, nitrile, nitro, amino, NR^1^2R^1^3 (in the formula R^1^2 and R ^1^3 is independently hydrogen or lower alkyl), -COOH, -COOR^1^4, ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼ (in the formula, R^1^4 is lower alkyl or aryl), or R^9 and R^1^
0 is combined with methylenedioxy or C_3
A compound according to claim (3) representing -C_4 alkylene. (5) Claim No. (3) or (
4) Compound described in section 4). (6) The compound according to any one of claims (3) to (5), wherein R^4 and R^5 are hydrogen atoms. (7) The compound has the general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^1 represents a lower alkyl group, R^7 represents hydrogen or a lower alkyl group, and R^ (3) represents an aryl group and n is 0 to 5), or a salt or solvate thereof. (8) The compound according to any one of claims (3) to (7), wherein R^7 is hydrogen or a tertiary butyl group. (9) The compound according to any one of claims (3) to (8), wherein R^6 is a phenyl group mono-, di- or tri-substituted with a methoxy or methyl group. (10) The compound according to claim (9), wherein n=1. (11) Claim No. 3 in which R^1 is a methyl group
) to (10). (12) The compound is 2-benzyl-4-hydroxy-7-
Claim No. 3 which is methylbenzimidazole
) Compounds described in section 2. (13) The compound according to claim (3), wherein the compound is 2-(4-chlorobenzyl)-4-methoxy-7-methylbenzimidazole. (14) The compound according to claim (3), wherein the compound is 2-(4-chlorobenzyl)-4-hydroxy-7-methylbenzimidazole. (15) The compound is 2-phenethyl-4-hydroxy-7
- methylbenzimidazole (
Compound described in section 3). (16) The compound is 2-phenyl-4-hydroxy-7-
Claim No. 3 which is methylbenzimidazole
) Compounds described in section 2. (17) The compound is 2-(pyrid-3-yl)methyl-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (18) The compound is 2-(naphth-2-ylmethyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (19) The compound is 2-benzyl-4-hydroxy-5-
The compound according to claim (3), which is tertiary-butyl-7-methylbenzimidazole. (20) The compound is 5-tertiary-butyl-4-hydroxy-
The compound according to claim (3), which is 2-(4'-methoxybenzyl)-7-methylbenzimidazole. (21) The compound is 2-(4'-methylbenzyl)-4-
The compound according to claim (3), which is hydroxy-7-methylbenzimidazole. (22) The compound is 2-n-propyl-4-hydroxy-
The compound according to claim (3), which is 7-methylbenzimidazole. (23) The compound is 2-(4'-methoxybenzyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (24) The compound according to claim (3), wherein the compound is 2-(3'-trifluoromethylbenzyl)-4-hydroxy-7-methylbenzimidazole. (25) The compound according to claim (1), wherein the compound is 2-(4'-N,N-dimethylaminobenzyl)-4-hydroxy-7-methylbenzimidazole. (26) The compound is 2-(naphthyl-1-ylmethyl)-
The compound according to claim (3), which is 4-hydroxy-7-methylbenzimidazole. (27) The compound according to claim (3), wherein the compound is 2-benzyl-4-hydroxybenzimidazole. (28) The compound is 2-(4'-methoxybenzyl)-4
The compound according to claim (3), which is -hydroxybenzimidazole. (29) The compound is 6-(4-hydroxy-7-methyl-
The compound according to claim (3), which is benzimidazol-2-yl)-hexanoic acid. (30) The compound according to claim (3), wherein the compound is ethyl 6-(4-hydroxy-7-methyl-benzimidazol-2-yl)-hexanoate. (31) The compound according to claim (3), wherein the compound is ethyl 5-(4-hydroxy-7-methyl-benzimidazol-2-yl)-pentanoate. (32) The compound is 5-(4-hydroxy-7-methyl-
The compound according to claim (3), which is benzimidazol-2-yl)pentanoic acid. (33) The compound according to claim (3), wherein the compound is 2-(2'-furyl)-4-hydroxy-7-methylbenzimidazole. (34) The compound is 2-(thien-2-ylmethyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (35) The compound is 2-(4'-ethoxybenzyl)-4
The compound according to claim (1), which is -hydroxy-7-methylbenzimidazole. (36) The compound according to claim (3), wherein the compound is 2-(3',4',5'-trimethoxybenzyl)-4-hydroxy-7-methylbenzimidazole. (37) The compound according to claim (3), wherein the compound is 2-(3',4'-dimethoxybenzyl)-4-hydroxy-7-methylbenzimidazole. (38) The compound is 2-(3'-methoxybenzyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (39) The compound is 2-(4'-methoxyphenyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (40) The compound is 2-(2'-methoxybenzyl)-4
The compound according to claim (3), which is -hydroxy-7-methylbenzimidazole. (41) The compound is 2-(4'-hydroxybenzyl)-
The compound according to claim (1), which is 4-hydroxy-7-methylbenzimidazole. (42) The compound according to claim (3), wherein the compound is 2-(1-phenylethyl)-4-hydroxy-7-methylbenzimidazole. (43) The compound according to claim (3), wherein the compound is 2-(thien-2-yl)-4-hydroxy-7-methylbenzimidazole. (44) The compound according to claim (3), wherein the compound is 2-(imidazol-1-yl)methyl-4-hydroxy-7-methylbenzimidazole. (45) The compound according to claim (3), wherein the compound is 2-benzyl-3-acetyl-4-hydroxy-7-methylbenzimidazole. (46) The compound according to claim (3), wherein the compound is 1-acetyl-2-benzyl-4-hydroxy-7-methylbenzimidazole. (47) The compound is 2-benzyl-4-hydroxy-5-
The compound according to claim (3), which is chloro-7-methylbenzimidazole. (48) The compound is 2-n-hexyl-4-hydroxy-
The compound according to claim (3), which is 5-tertiary-butyl-7-methylbenzimidazole. (49) The compound is 2-benzyl-4-hydroxy-5-
The compound according to claim (3), which is tertiary-butyl-benzimidazole. (50) The compound according to claim (3), wherein the compound is 2-benzyl-3-acetyl-4-hydroxy-5-chlorobenzimidazole. (51) The compound according to claim (3), wherein the compound is 1-acetyl-2-benzyl-4-hydroxy-5-chlorobenzimidazole. (52) Formula (IX) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) (In the formula, R^1 is as specified for Formula I, and R
^x is benzyl or mesyl or R^2 as defined for formula I, R^y is hydrogen, NO_2 or NH_2, R^z is NO_2 or NH_2, and R^7 is tertiary butyl) compound. (53) The compound according to claim (52), wherein the compound is 2-nitro-4-hydroxy-5-tertiary-butyltoluene-0-mesylate. (54) The compound according to claim (52), wherein the compound is 2-nitro-4-hydroxy-5-tertiary butyltoluene. (55) The compound is 2,3-dinitro-4-hydroxy-
Claim No. 52 which is 5-tertiary butyltoluene
) Compounds described in section 2. (56) The compound is 2,3-diamino-4-hydroxy-
Claim No. 52 which is 5-tertiary butyltoluene
) Compounds described in section 2. (57) Formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, R^2^1 represents hydrogen or a lower alkyl group, or a group or atom convertible thereto, and R^2^2 represents hydrogen or a lower alkyl group or a group or atom convertible thereto, one R^2^3 represents hydrogen and the other R^2
^3 represents hydrogen or a lower alkyl group, or a group or atom convertible thereto, and R^2^7 represents hydrogen, halogen, or alkyl, or a group or atom convertible thereto) A compound of the formula (V) R ^2^6COR^2^8 (V) [In the formula, R^2^6 is -(CR^4R^5)n-R^6 or a group convertible thereto (in the formula, R^4, R^5 and R^6
and n are each defined in claim 1 with respect to formula III.
), R^2^5 represents a leaving group or hydrogen] to form a compound of the formula (V
I) VI ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VI) and, if necessary, the nitrogen atom and/or 4-oxygen of the benzimidazole nucleus. A claim in which an atom is acylated or alkylated with a group of formula ▲ which may be a mathematical formula, chemical formula, table etc. ▼ and if necessary removing the protecting group and if necessary forming a salt or solvate. A method for producing a compound according to scope item (3). (58) Formula (VII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^2^1, R^2^2 and R^2^3 and R^
2^7 has the definition given above for formula IV) and, if desired or necessary, removing the protecting groups to form a compound of formula (IV).
A method according to claim (57) for obtaining a compound of IV. (59) The method according to claim (58), wherein the reduction of the compound of formula (VII) is carried out by catalytic reduction in a conventionally used hydrogenation solvent. (60) The reaction of the compound of formula (IV) with the compound of formula (V) is an acid, an acid chloride, an acid anhydride, a mixed anhydride of acid R^2^8COOH and a haloformate ester of formula ) Claim No. (57)
) to (59). (61) The benzimidazole according to claim (3), which has a hydroxyl group which may be esterified or etherified and a lipophilic group in the 4-position, which is used as an active therapeutic substance. (62) Claim No. (61) in which the lipophilic group is at the 2-position
) Compounds described in section 2.