KR960015004B1 - (ih-imidazol-1-ylmethyl) substituted benzimidazole derivative - Google Patents

Abstract

None.

Description

Method for preparing (1H-imidazol-1-ylmethyl) substituted benzimidazole derivatives

Numerous imidazole derivatives are known in the art as antifungal agents. Recently, ketoconazole as an oral dosage imidazole derivative exhibiting wide-area activity against yeast, dermatophytes and heteromorphic fungi has been reported to inhibit steroid synthesis [Annals of Internal Medicine, 97, 370. (1982). Some suggest that (1H-imidazol-1-ylmethyl) substituted indole derivatives are effective as thromboxane synthetase inhibitors (US Pat. No. 4,410,939). It has also been reported that pyridyl substituted 2-hydroxy or mercaptobenzimidazole derivatives are useful as cardiac agents (US Pat. No. 4,335,132).

The compound of the present invention differs from the above compound in that the benzimidazole moiety is always substituted with 1H-imidazol-1-ylmethyl radical and has an effect of inhibiting androgen hormone biosynthesis. Therefore, the compounds of the present invention can be effectively used to prevent or treat androgen hormone-induced diseases in mammalian animals.

The present invention relates to imidazole derivatives of general formula (I), pharmaceutically acceptable acid addition salts, metal or amine substituted salts and stereochemically isomers thereof.

Wherein R is hydrogen; C _1-10 alkyl: C _3-7 cycloalkyl Ar ¹ or Ar ¹ -C _1-6 alkyl, R ¹ is hydrogen; C _3-7 cycloalkyl; Ar ¹ ; C _1-10 alkyl; C _1-6 alkyl substituted with Ar ¹ or C _3-7 cycloalkyl; Hydroxy; C _1-10 alkyloxy; C _1-6 alkyloxy substituted by Ar ¹ or C _3-7 cycloalkyl; C _3-6 alkynyloxy optionally substituted by Ar ² ; C _3-6 alkynyloxy or Ar ¹ -oxy optionally substituted by Ar ² , wherein A is —CR ² = N- (a) or

a divalent group of (b), wherein the carbon atom of the divalent group (a) or (b) is bonded to —NR ¹ , wherein R ² is hydrogen; C _1-4 alkyl substituted with up to 4 halogen atoms halo; C _3-7 cycloalkyl; Ar ¹ ; Quinolinyl; Indolinyl; C _1-10 alkyl; C _1-6 alkyl substituted by Ar ¹ , C _3-7 cycloalkyl, quinolinyl, indolinyl or hydroxy; C _1-10 alkyloxy; C _1-6 alkyloxy substituted by Ar ¹ or C _3-7 cycloalkyl; C _2-6 alkynyl optionally substituted by Ar ¹ ; Ar ² -oxy; C _1-6 alkyloxycarbonyl; Carboxyl C _1-6 alkylcarbonyl; Ar ¹ carbonyl or Ar ^1- (CHOH)-, X is 0 or S, R ³ is hydrogen C _1-6 alkyl or AR ² -C _1-6 alkyl, Ar ¹ is phenyl, substituted phenyl, pyri Diyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl, Ar ² is phenyl or substituted phenyl, and the substituted phenyl at Ar ¹ and Ar ² is Halo, hydroxy, trifluoromethyl, C _1-6 alkyl, C _1-6 alkyloxy, cyano, amino, mono- and di (C _1-6 alkyl) amino, nitro, carboxyl, formyl and C ₁ Phenyl substituted by 1,2 or 3 substituents each independently selected from the group consisting of _-6 alkyloxycarbonyl.

In the above definition, "halo" means fluoro, bromo, chloro or iodo and "C _1-4 alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, for example methyl, ethyl 1- Methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, and the like, and "C _1-4 alkyl" and "C _1-10 alkyl" have C _1-4 alkyl and 6 to 10 carbon atoms Includes his higher homologues. "C _3-7 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. "C _3-6 alkynyl" is a straight chain or branched hydrocarbon group having 3 to 6 carbon atoms having one double bond, for example, 3-propenyl, 2-butenyl, etc., and "C _3-6 alkynyl" is one triple bond. A linear or branched hydrocarbon group having 3 to 6 carbon atoms having, for example, 3-propynyl, 2-butylide, wherein C _3-6 alkynyl or C _3-6 alkynyl is a heteroatom when substituted on a heteroatom; a C _3-6 alkynyl or C _3-6 alkynyl the carbon atom of the coupling is included.

The 1H-imidazol-1-ylmethyl moiety may be substituted at any of the 7, 4, 5, and 6 positions of the benzimidazole heterocyclic ring. On the other hand, the compounds of imidazole (I) may contain tautomers in their structure so that they may each be present as tautomers. The scope of the invention also includes hydrates and compounds of general formula (I) in additional forms.

Preferred compounds within the present invention are those in which A is a general formula (a) is a divalent group and R ¹ is hydrogen; C _3-7 cycloalkyl; Ar ² ; C _1-10 alkyl; C _1-6 alkyl substituted with Ar ¹ or C _3-7 cycloalkyl; Hydroxy or C _1-6 alkyloxy and R ² is hydrogen; Halo; C _1-4 alkyl substituted with up to 4 halogen atoms; _3-7 cycloalkyl; Ar ¹ ; Quinolinyl; C _1-6 alkyl substituted with indolinyl C _1-10 alkyl, Ar ¹ , quinolinyl or indolinyl; C _1-6 alkyloxy; A C _3-6 alkynyl or Ar ¹ optionally substituted with Ar ¹ - is a carbonyl compound.

Particularly preferred compounds of the present invention are those wherein the 1H-imidazol-1-ylmethyl moiety in the preferred compound is substituted on the 5 or 6 position of the benzimidazole ring, and R is hydrogen; C _1-6 alkyl or Ar ¹ and R ¹ is hydrogen; C _1-6 alkyl or Ar ² -C _1-6 alkyl, R ² is hydrogen; Di- or tri-halomethyl; C _1-6 alkyl substituted with Ar ¹ , quinolinyl or indolinyl; C _1-10 alkyl, Ar ¹ ; C _1-6 alkyloxy or Ar ² -carbonyl.

Particularly preferred compounds of the invention are those of the above particularly preferred compounds wherein R is C _1-6 alkyl or Ar ² , R ¹ is hydrogen and R ² is hydrogen, C _1-6 alkyl or Ar ¹ .

Most preferred compounds of the invention are 5-[(1H-imidazol-1-yl) phenylmethyl] -2-methyl-1H-benzimidazole and 5-[(3-chlorophenyl) (1H-imidazole-1 -Yl) methyl] -1H-benzimidazole, a pharmaceutically acceptable acid addition salt of 2 and stereochemical isomers.

Compounds of general formula (I) generally react with N-alkylation of 1H-imidazole of general formula (III), alkali metal salts thereof or tri C _1-6 alkylsilyl derivatives thereof with benzimidazole of general formula (II) Can be prepared.

W used in the above or later reaction scheme is a suitable reaction leaving group, for example halo, ie chloro, bromo, iodo or sulfonyloxy, for example methylsulfonyloxy or 4-methylphenylsulfonyloxy, where W is- Coupled with a C (═X)-group, it may also be C _1-6 alkyloxy, C _1-6 alkylthio, aryloxy or arylthio.

The N-alkylation reaction can be carried out by reacting the reactants with a suitable organic solvent such as aromatic hydrocarbons (e.g. benzene, methylbenzene, dimethylbenzene, etc.), ketones (e.g. 2-propanone, 4-methyl-2-pentanone, etc.), Ethers (e.g. 1,4-dioxane 1,1'-oxybisethane, tetrahydrofuran, etc.), polar aprotic solvents (e.g. N, N-dimethylformamide (DMF) .N, N-dimethylacetamide (DMA), nitrobenzene, dimethyl sulfoxide (DMSO), 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyrimidinone (DMPU), 1,3-dimethyl- Conveniently performed by stirring in the presence of 2-imidazolidinone (DMEU), 1-methyl-2-lipolidinone, acetonitrile, hexamethylphosphortriamide (HMPT), benzonitrile, and mixtures of these solvents It is advisable to raise the temperature slightly to speed up the reaction, but preferably at the reflux temperature of the reaction mixture. It is advisable to raise the reaction mixture at the reflux temperature of the reaction mixture, using an excess of imidazole to promote the reaction rate, or using a suitable base such as alkali metal carbonate, bicarbonate, sodium hydride or organic base (e.g. N, N-diethylethanamine, N- (1-methylethyl) -2-propanamine, etc.) is preferably added to the reaction mixture.

It may be advantageous if desired to convert 1H-imidazole (III) to its alkali metal salts or tri C _1-6 alkylsilyl derivatives thereof and then react with the salts or silyl derivatives of benzimidazole derivatives of formula (II). Can be. Compounds in the salt form can be prepared by reacting 1H-imidazole with an alkali metal base such as alkali metal hydroxy, alkoxide or hydride. Tri C _1-6 alkylsilyl derivatives of 1H-imidazole can be prepared by reacting imidazole with trialkylhalosilanes.

Compounds of formula (I) may be prepared by reacting intermediates of formula (IV) with 1,1′-carbonylbis [1II-imidazole].

In some instances 1,1′-carbonylbis [1H-imidazole] is reacted with a compound of formula (IV) to produce an intermediate material of formula (V), which is separated in situ or as needed It can be purified and converted to the target compound of formula (I).

The reaction may be conveniently carried out in a suitable solvent, which may include ether (e.g., 1,4-dioxane, tetrahydrofuran), halogenated hydrocarbon (e.g. di- or trichloromethane), hydrocarbon (e.g., benzene, Methylbenzene, etc.), ketones (eg 2-propanone, 4-methyl-2-pentanone), N, N-dimethylformamide, N, N-dimethylacetamide or mixtures of these solvents can be used. It may be advantageous to heat the reaction mixture preferably to the reflux temperature of the reaction mixture in order to increase the reaction rate.

On the other hand, the compound of general formula (I) may also be prepared under similar conditions described in the literature for preparing benzimidazole using benzenediamine or 2-nitrobenzeneamine as starting materials. For the compound of general formula (I) to be produced, for example, the following method may be used depending on the properties of -A-.

-A- is a divalent group of formula (a) and R ¹ is substituted by hydrogen, C _3-7 cycloalkyl, Ar ² , C _1-10 alkyl, or Ar ¹ or C _3-7 cycloalkyl A compound that is C _1-6 alkyl, wherein the compound is represented by formula (Ia), wherein R ¹ is represented by the formula R ^1-a , wherein 1,2-benzenediamine of formula (VI) is represented by formula (VII) And carboxylic acid or functional derivatives thereof.

Functional derivatives of formula (VII) mean halides, anhydrides, amides and ester forms (including esters in ortho and imino forms) of formula (VII). The functional derivative may be separated and purified before reacting with 1,2-benzenediamine of formula (VI) in situ or optionally. The ring-closure reaction of the compound of formula (VI) and the compound of formula (VII) can be carried out in an aqueous solution of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like. However, alcohols such as methanol, ethanol, 2-propanol, 1-butanol, halogenated hydrocarbons such as trichloromethane, dichloromethane, and mixtures of these solvents with water may also be used as solvents. In some cases, an excess of carboxylic acid of general formula or a corresponding alkyl ester may be used as a solvent. Stirring and heating may promote the reaction rate. When the compound of formula (VII) is an acid or a corresponding alkyl ester compound thereof, the ring closure of the compounds of formulas (VI) and (VII) may be carried out in the presence of a suitable dehydrating agent (e.g., polyphosphoric acid, phosphorus pentoxide). Can be. In a preferred method of the ring closure reaction, an imino ester compound of the compound of formula (VII) is used. The desired compound of formula (I-a) is readily prepared by stirring in an acidic medium, for example acetic acid or lower alkanol, at room temperature or at elevated temperature, at which appropriate acid (eg hydrochloric acid) is added. If the imino ester is in acid addition salt form, no acid needs to be added. If the compound of formula (VII) is an ortho ester, the ring closure of the compounds of formulas (VI) and (VII) is carried out in the presence of carboxylic acids (e.g. formic acid, acetic acid, etc.), For example alcohols (eg methanol, ethanol, 2-propanol), halogenated hydrocarbons (eg trichloromethane, dichloromethane, etc.) or this can be carried out in the presence of a mixture of solvents.

In some cases, compounds of formulas (VI) and (VII) are reacted first to produce an intermediate material of formula (VIII), which is separated and purified in situ or as needed, thereby producing an acid (e.g., In the presence of hydrochloric acid or a carboxylic acid such as an inorganic acid or formic acid), and the ring can be closed while heating or stirring.

In formula (VIII), one of R ⁴ and R ⁵ is hydrogen or

Group, the other is

Group.

Compounds of formula (Ia) also condense 1,2-benzenediamines of formula (VI) with aldehydes of formula (IX) or optionally with adducts thereof with alkali metal hydrogen sul fite You may make it react.

In some cases, the compounds of formulas (VI) and (IX) are reacted first to obtain an intermediate material of formula (X), which is separated or purified and in-line reacted if necessary to react with the general formula (Ia). ) Can be prepared.

The condensation reaction of the compounds of formulas (VI) and (IX) can be carried out in the presence of an acid, if necessary, in a suitable solvent. Examples of the solvent include water and alcohols (eg methanol, ethanol, 2-propanol, 1-butanol). , Halogenated hydrocarbons (e.g. trichloromethane, dichloromethane), hydrocarbons (e.g. benzene, hexane, etc.) or mixtures of these solvents may be used, and the acid may be hydrochloric acid, hydrobromic acid, formic acid, acetic acid, propanoic acid, etc. . The half silver mixture can be used as an oxidizing agent by adding a suitable oxidizing agent (e.g. nitrobenzene, mercury oxide, Cu (II) and Pb (II) salts) or an oxidizing agent known in the art, or by using an excess of aldehyde itself. Elevating temperature and stirring may promote the reaction.

A compound of formula (Ia) wherein R ^1-a is hydrogen by subjecting the intermediate material of formula (XI) to a reductive ring closure in a suitable solvent (eg t-butylbenzene) with a suitable reducing agent (eg triethylphosphite) This compound is represented by formula (Ia-1), and optionally, a compound of formula (Ia-1) is reacted with reagent WR ^1-a-1 of formula (XII) to R ^{1- A} compound of the general formula (Ia) in which ^a is other than hydrogen, which is represented by general formula (Ia-2), can be prepared.

In formula (XII), W is as defined above and R ^1-a-1 is C _3-7 cycloalkyl, Ar ² , C _1-10 alkyl, or Ar ¹ or C _3-7 cycloalkyl Substituted C _1-6 alkyl. The N-alkylation reaction is carried out with an inert organic solvent such as hydrocarbons such as methylbenzene and dimethylbenzene, alkanols such as methanol and ethanol, ketones such as 4-methyl-2-pentanone, 1,4-dioxane and tetrahydro. It can carry out conveniently in ether, such as furan, N, N- dimethylformamide (DMF), and N, N-dimethyl acetamide (DMA). Bases such as alkali or alkaline earth metal carbonates, bicarbonates or hydroxides or organic bases such as tertiary amines can be added to remove the acid produced during the reaction. It may be slightly warmed to promote the reaction.

A compound of formula (I), represented by a compound of formula (Ib-1), wherein -A- is a divalent group of formula (a) and R ¹ is hydroxy, is an intermediate of formula (XIII) The compound of formula (XIII) may be prepared by reacting an intermediate material of formula (XIV) with methanamine of formula (XV).

The compound of formula (Ib-1) obtained above was also O-alkylated with reagent WR ^1-b-1 , where -A- is a divalent group of formula (a), and R ¹ is C _1-10 alkyl aryloxy, Ar ¹ or C _3-7 a by a C _1-6 alkyloxy, Ar ² is substituted by cycloalkyl, optionally substituted C _3-6 alkynyloxy, optionally substituted C _3-6 alkynyl by Ar ² Compounds of the general formula (I) in which oxy, or Ar ¹ -oxy are represented by the general formula (Ib-2), wherein the group is R ^1-b-1 -O-, can be prepared.

In formula (XVI), W is as defined above and R ^1-b-1 is C _1-6 alkyl substituted by C _1-10 alkyl, Ar ¹ or C _3-7 cycloalkyl, Ar ² by an optionally substituted C _3-6 alkynyl, an optionally substituted C _3-6 alkynyl, or Ar ¹ by Ar ^2, in the general formula (XIV) W ¹ is a leaving group suitable for reaction, for example, a halogen atom (preferably Is a fluoro, chloro, bromo, etc.) or sulfonyloxy group (methylsulfonyloxy or 4-methylbenzenesulfonyloxy) or a C _1-6 alkyloxy or C _1-6 alkylthio group.

The ring closure reaction is carried out in a suitable reaction inert solvent such as alcohol (eg methanol, ethanol, 2-propanol, etc.), optionally in the presence of a base (eg alkali or alkaline earth metal carbonate, bicarbonate, hydroxide or alkoxide). It can be carried out.

The O-alkylation reaction can be conveniently carried out in a suitable reaction inert solvent or a mixture of these solvents. Suitable reaction inert solvents include aromatic hydrocarbons (e.g. benzene, methylbenzene, dimethylbenzene, etc.), lower alkanols (e.g. methanol ethanol, 1-butanol, etc.), polar aprotic solvents (e.g. N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphor triamide, dimethyl sulfoxide) and the like. It is preferably carried out in the presence of a suitable base such as an alkali metal hydride, alkoxide, hydroxide or carbonate. The compound of general formula (Ib-1) is reacted according to a conventional method, for example, with a metal base such as sodium hydroxide and the like, and the resulting metal salt is then general formula (XVI). It is advantageous to react with a compound of to convert in advance to its metal salt, preferably the sodium salt.

Compounds of formula (I) in which -A- is a divalent group of formula (a) may also be prepared by subjecting the imidazole derivatives of formula (XVII) to reductive ring closure in the presence of a suitable reducing agent. Depending on the nature of the reducing agent and / or the reaction conditions, compounds of the general formula (Ia-1) or (Ib-1) are obtained and these are the compounds of the general formula (Ia-2) or (Ib-2) as mentioned respectively. Can be transferred to

As suitable reducing agents, for example, sodium borohydride, sodium dithionite or hydrogen gas can be used, the latter being usually used in the presence of suitable catalysts such as palladium-charcoal, platinum-charcoal, raney-nickel and the like. The ring closure reaction is most conveniently carried out in a reaction inert solvent such as alkanol (eg methanol, ethanol, 2-propanol, etc.).

In the case where the compound of formula (I-b-1) is intended, it is preferable to perform the reduction reaction in the presence of an acid. It is advantageous to add a catalyst poison (eg thiophene, etc.) to the reaction mixture in order to prevent any further functionalization of certain functional groups in the reactants and reaction products.

-A- is a divalent group of formula (b) and R ¹ is hydrogen, C _3-7 cycloalkyl, Ar ² , C _1-10 alkyl or C substituted with Ar ¹ or C _3-7 cycloalkyl A compound of formula (I), which is _1-6 alkyl, represented by a compound of formula (Ic), wherein said group is R ^{1 -c,} represents 1,2-benzenediamine of formula (XVIII) )of

Group generating agents (e.g. urea, thiourea, 1,1'-carbonylbis (1H-imidazole), alkylcarbonohalidates, carboxylic acid dichlorides, carbonothioic acid dichlorides, trifluoromethyl carbo Halide, carbon disulfide, cyanic acid, carbon dioxide, diethylcarbamic acid chloride, and the like).

Compound of formula (XVIII) and of formula (XIX)

The reaction of the generating agent is carried out with a suitable solvent (e.g. ether, i.e. 1,1-oxybisethane, tetrahydrofuran; halogenated hydrocarbons, i.e. dichloromethane, trichloromethane, hydrocarbons; i.e. benzene, methylbenzene, alcohols i.e. methanol, ethanol) , Kenon, i.e. 2-propanone, 4-methyl-2-pentanone, polar aprotic solvent, i.e., N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile or a mixture of these solvents), Optionally, it can be conveniently carried out in the presence of a suitable container (eg, N, N-diethylethanamine, alkali or alkaline earth metal carbonate, bicarbonate, etc.). It is preferable to heat the reaction mixture to promote the reaction. In some cases, good results can be obtained by stirring and heating the reaction without solvent.

On the other hand, the compounds of formula (I) are also commonly treated by treating intermediate materials of formula (XX) with Raney nickel in the presence of alcohols (e.g. ethanol) or by reacting the starting materials with sodium nitrite in the presence of nitric acid in an aqueous medium. It can also be prepared by the desulfurization of the intermediate material of general formula (XX).

In the above, R ⁶ is C _1-6 alkyl.

In addition, the compounds of general formula (I) can be converted to each other according to a functional group converting method known in the art. Some of these switching methods will be described later in more detail.

Compounds of formula (Ic) wherein R ³ is hydrogen are, for example, hydrochloric acid, thionyl chloride, phosphoryl, phosphoric acid chloride, pentachlorophosphorane, thionyl bromide, phosphorus bromide according to halogenation methods known in the art. Treatment with a suitable halogenating agent such as may convert to the corresponding compound of formula (la) in which R ² is halo.

The halo substituents in the compounds of general formula (Ia) obtained above may be selected from the starting compounds with 1H-imidazole, optionally in the presence of a suitable solvent (e.g., N, N-dimethylolamide, N, N-dimethylacetamide). Stirring and heating can be converted to imidazolyl substituents.

Compounds of general formula (I) containing ester groups can be converted to the corresponding carboxylic acids by the saponification method known in the art, ie by treating the starting compounds with aqueous or aqueous alkali solutions. Conversely, carboxylic acid groups can be converted to the corresponding ester groups according to esterification methods known in the art.

For example, reagents suitable for converting carboxylic acids to reactive derivatives, and then carboxylic acids and alkanols to produce esters (e.g. dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinioda) Id) to react with the corresponding alkanols.

Compounds of formula (I) wherein R ² is an ester group can be converted to compounds of formula (I) wherein R ² is hydrogen by stirring the starting material in the presence of an acid and heating as necessary.

Compounds of formula (I) having hydroxymethyl substituents can be oxidized under standard oxidative conditions to produce the corresponding carboxylic acids by the action of suitable oxidizing agents (e.g., potassium permanganate, potassium dichromenite, etc.). Under similar reaction conditions, compounds of formula (I) having an Ar ^2- (CH-OH) substituent can be oxidized to the corresponding compounds having an Ar ² -carbonyl substituent.

Compounds of general formula (I) include acids (e.g., hydrochloric acid, ie hydrochloric acid, hydrobromic acid, etc., inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, etc., acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxy butanedioic acid, 2,3- Dihydroxy butanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfonic acid, 2- Hydroxybenzoic acid, 4-amino-2-hydroxy benzoic acid, etc.) to convert into therapeutically active non-toxic acid addition salt forms. Conversely, salt compounds can be converted to the free base form by treatment with alkali.

Compounds of formula (I) containing one or more acidic protons can be converted to therapeutically active non-toxic metals or amine substituted salts by treatment with a suitable organic or inorganic base. Suitable inorganic salts include, for example, bases derived from ammonia or alkali metals or alkaline earth metals, for example alkali metal or alkaline earth metal oxides or hydroxides (eg lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, Calcium oxide, etc.). Hydrides of alkali metals or alkaline earth metals (eg, sodium hydride, potassium hydride, etc.), carbonates or bicarbonates of alkali metals (eg, sodium carbonate, potassium carbonate, sodium bicarbonate, calcium carbonate, etc.). Suitable organic bases are, for example, primary, secondary or tertiary aliphatic and aromatic amines (e.g. methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, di Ethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, pyreridine, morpholine, N-methylmorpholine, trimethylamine, tripropylamine, quinuclidin, pyridine, quinoline Isoquinoline, diethanolamine and 1,4-diazabicyclo [2,2,2] octane) or quaternary ammonium bases such as tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, triethylbenzylammonium Hydroxide, tetraethylammonium hydroxide, trimethylethylammonium hydroxide, etc.) etc. are mentioned.

Some intermediate materials and starting materials in the above preparation can be prepared by methods known in the art for preparing these materials or similar compounds, while others are novel. Some of these methods are described in detail below.

Starting materials of formula (II), wherein W is a reactive ester group, may be prepared by converting the reactive ester of the intermediate of formula (IV) according to standard methods known in the art. Halides are usually prepared by reaction with a suitable halogenating agent, such as thionyl chloride, sulfuryl chloride, pentachlorophosphorane, pentabromophosphorane, phosphoryl chloride, and the like. If the reactive ester is an iodide, it can be prepared by substituting an iodide for a halogen atom from the corresponding chloride or bromide.

Other reactive esters, such as methanesulfonate and 5-methylbenzenesulfonate, can be obtained by reacting an alcohol with a suitable sulfonyl halide, such as methanesulfonylchloride or 4-methylbenzenesulfonylchloride, respectively.

-A- is a divalent group of formula (a) and R ¹ is hydrogen, C _3-7 cycloalkyl, Ar ² , C _1-10 alkyl or C substituted with Ar ¹ or C _3-7 cycloalkyl Intermediate material of general formula (IV), which is _1-6 alkyl, represented by general formula (IV-a), is a ketone of general formula (XXI) according to the process for preparing (Ia) from compounds (VI) and (VII) Alternatively, the aldehyde can be prepared by reacting with a carboxylic acid of formula (VII) and then reducing the aldehyde or ketone moiety with a suitable reducing agent such as sodium brohydride in a suitable solvent such as methanol.

On the other hand, intermediate materials of general formula (IV-a), wherein R is hydrogen, represented by general formula (IV-a-1), are suitable catalysts for forming formyl and nitro functional groups of intermediate materials of general formula (XXIII) Catalytic hydrophobicity in the presence of Ranickel), and then the intermediate material of formula (XXIV) obtained is subjected to the carboxyl of formula (VII) according to the process for preparing compound (Ia) from compounds (VI) and (VII). It may also be prepared by reacting with an acid.

In addition, intermediate materials of formula (IV-a-1) may be prepared from suitably substituted benzoic acids of formula (XXV) according to the following reaction process.

The intermediate material of formula (XXV) is reacted with a suitable amine of formula (XXVI), wherein R ^1-a is as defined above, in ^a manner analogous to the reaction of compounds (XIV) and (XV) above. . The resulting intermediate material of general formula (XX ') is subjected to a reduction reaction of nitro-amines to produce intermediate material of general formula (XXVIII). This is closed with the appropriate ring closure agent used to prepare the compound of formula (Ia) and converted to the benzimidazole derivative of formula (XXIX). The carboxylic acid of formula (XXIX) is converted to the carbonyl chloride of the general formula (XXX) by reaction with a conventional method, i.e. thionyl chloride, which is then converted to the suitable C _1-6 alkanol of formula (XXXI) And C _1-6 alkyl ester of (XXXII). It is reduced with the corresponding alcohol (IV-a-1) by treatment with a suitable reducing agent such as nitrile dihydrobis (2-methoxyethoxy) aluminate (Red-Al). Intermediate materials of formula (IV-a-1) may also be prepared by reducing the carboxylic acid of formula (XXIX) with a borane-methylsulfide complex in a suitable solvent such as tetrahydrofuran.

In the above scheme, R ^1-a is as defined above.

-A- is a divalent group of formula (a), R ¹ is hydroxy, C _1-10 alkyloxy, Ar ¹ or C _1-6 alkyloxy substituted by C _3-7 cycloalkyl, Ar ² as an intermediate material of the by-oxy, optionally substituted C _3-6 alkynyloxy in the formula (IV) [general formula (IV-b) - in an optionally substituted C _3-6 alkynyloxy, or Ar ² or Ar ¹ by Labeled] can be prepared according to the following reaction procedure, for example. Ketones or aldehydes of the general formula (XXXIII) are subject to ring closure in the presence of a suitable reducing agent according to the ring closure method [method of preparing (Ib-1) from compound (XVII)], and optionally the compound (Ib-2). O-alkylation can be carried out according to the method for preparing the compound. Purpose of Formula (IV-b) Alkanol compounds may be obtained by reducing the aldehyde or ketone of Formula (XXXV) in a suitable solvent (eg methanol) with a suitable reducing agent (eg sodium borohydride).

In the above, R ^1-b may be the same as R ^1-b or may be hydrogen.

Intermediate compounds of formula (IV), wherein R is other than hydrogen, represented by formula (IV-d), are suitable oxidizing agents of the compounds of formula (IV-c), such as manganese oxides ( IV)], followed by oxidation with the corresponding formyl group, and the resulting aldehydes of the general formula (XXXVI) are suitable as metalalkyl (e.g. methyllithium, butyllithium, metalaryl, ie phenyllithium) or complex metalalkyl (e.g. It can also be prepared from the corresponding intermediate material of formula (IV), wherein R is hydrogen by reaction in tetrahydrofuran).

Benzene diamine of the general formula (VI) used as a starting material may be prepared according to the following reaction process.

The intermediate material of formula (XXXVII) is reduced with a suitable reducing agent (e.g. sodium borohydride) and converted to reactive esters according to standard methods known in the art to afford intermediate materials of formula (XXXIX). The latter is reacted with 1H-imidazole (III) to afford the intermediate material of formula (XIV). The resulting intermediate material of formula (XIV) is reacted with a suitable amine of formula (XXVI) and then subjected to a standard reduction reaction of nitro-amines to give the desired starting material of formula (VI).

In the above scheme, R ^1-a , W and W ¹ are as defined above.

Starting materials of the general formula (VI) wherein R ^1-a is hydrogen (expressed as general formula (VI-a)) may be prepared according to the following reaction procedure.

1H-imidazole (III) is reacted with an intermediate material of formula (XLI) to obtain an intermediate material of formula (XLII). It is reduced, acylated, nitrated, deacylated and reduced to give the compound of formula VI-a. The reduction of the nitro amine is usually carried out by stirring the starting material in a hydrogen containing medium in the presence of a suitable amount of a suitable catalyst (eg platinum-charcoal, palladium-charcoal, Raney-nickel, etc.). The reduction reaction may be carried out by stirring the starting compound with sodium sulfide or sodium dithionite in a suitable solvent (eg methanol, ethanol, etc.). C _1-6 alkylcarbonyl or arylcarbonyl groups can be introduced by reacting amines with carboxylic acids or their reactive derivatives according to amidation methods known in the art. The nitrification reaction is conveniently carried out in the presence of a suitable acid (eg sulfuric acid or a mixture of acetic acid and acetic anhydride) in a suitable solvent (eg halogenated hydrocarbons such as trichloromethane, etc.). The deacylation reaction is conveniently carried out by treating the intermediate compound of formula (XVII) with an aqueous base solution or an aqueous acid solution.

Intermediate materials of formula (XL) that can be readily converted to compounds of formula (VI) include compounds (I) and compounds (I) with 1,1′-carbonylbis [1H-imidazole] as starting material The intermediate material of the general formula (XLV) may be prepared by reacting 1,1′-carbonylbis [1H-imidazole] according to the method of preparing

Suitable isothiocyanates (XLVI) in which intermediate material R ⁷ of formula (XX) is C _1-6 alkyl or Ar ² -C _1-6 alkyl are present in a suitable reaction inert solvent such as halogenated hydrocarbons such as dichloromethane Under stirring and heating with an appropriately substituted amine of the general formula (XL '), and the resulting thiourea of the general formula (XLVIII) is halide of the general formula (L), wherein R ⁶ is C _1-6 alkyl , Halo is reacted with chloro, bromo, or iodo is preferred) in the presence of a suitable reaction inert solvent (e.g. propanone) to convert to the corresponding carbamimidothioate (XLIX), which is an aqueous acidic solvent. It can be prepared by stirring and heating in (eg, aqueous sulfuric acid) and condensing the benzimidazole moiety according to the following ring closure method.

Of all the starting materials and intermediate materials used in the above method, those which do not specifically present QJQ are generally known and / or can be prepared according to the preparation methods known in the art described in the literature for preparing similar known compounds. to be.

For example, intermediates of formulas (XXI) and (XXI) can be prepared by methods analogous to known methods. See US Pat. No. 3,657,267 and J.Org. Chem. 44, pp. 4705 (1979).

The compounds of formula (I) and some intermediate compounds used in the present invention may have asymmetric carbons in other structures. Chiral centers can be in R- and S- configuration, with R- and S-notations following conventional rules. J. Org. Chem. 35,2849-2867 (1970).

Pure stereochemical isomers of the compounds of the present invention can be obtained according to methods known in the art. Diastereomers can be separated by physical separation methods such as selective crystallization chromatography techniques, such as counter current distribution, and enantiomers can be isolated by selectively crystallizing their diastereomeric salts with optically active acids. Can be

Pure stereochemical isomers may be derived from the corresponding pure stereochemical isomers of the suitable starting materials as long as the reaction proceeds stereospecifically.

Stereochemical isomers of the compounds of formula (I) are within the scope of the present invention.

The compounds of formula (I), their pharmaceutically acceptable acid addition salts, metal or amine substituted salts and stereochemically isomeric compounds have very interesting pharmacological action. They inhibit androgen formation from C ₂₁ -steroids, such as pregnenolone and prostagen, in mammalian animals. Thus they can be used to treat androgen-induced diseases by themselves. On the other hand, some compounds of the general formula (I) exhibit the ability to increase uric acid secretion, resulting in a decrease in plasma uric acid concentration, which is useful in various diseases related to the increase in uric acid concentration, that is, gout. In addition, some compounds of the general formula (I) exhibit an action of inhibiting the biosynthesis of thromboxane A ₂ .

Inhibition of androgen formation can be examined in vivo or in vitro, for example by measuring testosterone biosynthesis in isolated testicular cell suspensions (in vitro) or by measuring testosterone synthesis in the plasma of male rats or dogs (in vivo). Can be checked On the other hand, since cytochrome P-450 isozyme is known to be involved in biosynthesis of androgens from C ₂₁ -steroids, compounds of formula (I) are effectively inhibited from studies on cytochrome P-450 isozymes. (Journal of Bio logical Chemistry 256, 6134-6139 (1981)). The "Piglet Testes Microsomes" test and "Testosterone" test described below show that this compound inhibits androgen biosynthesis, which is based on the principles described above.

Since the compound of the present invention can inhibit androgen hormone biosynthesis, it can be effectively used to treat prostate tumors or hirsutism and androgen-derived diseases.

The useful effects of androgen inhibitors in the treatment of these diseases, especially prostate tumors, have been reported in the Journal of Urology 132, 61-63 (1984).

The compounds of the present invention are effective in treating androgen-derived diseases. The present invention also provides methods of treating mammals infected with androgen-derived diseases.

In particular, there is provided a method of inhibiting androgen synthesis in a mammal, particularly a method of inhibiting androgen formation from a C ₂₁ -steroid in a mammal.

The method consists in systemically administering an effective amount of a compound of formula (I), a pharmaceutically acceptable acid adduct thereof, a metal or amine substitution salt or stereoisomer, described below, for the treatment of androgen derived diseases.

Those skilled in treating androgen-related diseases will readily be able to determine the effective amount from the test results described below. Usually, the effective amount is 0.05 to 50 mg, more preferably 0.5 to 10 mg per kg body weight.

In particular, in the treatment of prostate tumors, the effective amount is an amount that drops serum androgens to castrated levels. On the other hand, since the concentration of uric acid in the plasma can be reduced, a method for treating a disease caused by increasing the concentration of uric acid is proposed. This method is a compound of formula (I) that reduces uric acid concentration, i.e. 5-[(1H-imidazol-1-yl) phenylmethyl] -2methyl-1H-benzimidazole, pharmaceutically acceptable acid moieties thereof An increase in uric acid concentration is treated by systemically administering an effective amount of a pseudonym, metal or amine substituted salt or stereochemical isomer.

An effective amount to reduce plasma uric acid concentration is 0.01 to 20 mg, preferably 0.1 to 2 mg per kg body weight. In view of its useful pharmacological action, the compounds of the present invention can be prepared with various medicaments depending on the method of administration.

In preparing a pharmaceutical composition of the present invention, the active ingredient is mixed with an effective amount of a specific compound in the form of a base or an acid addition salt with a pharmaceutically acceptable carrier, which can be used in various ways depending on the dosage form. These pharmaceutical compositions are suitable for oral, rectal, transdermal or parenteral administration in unit dosage form. For example, in the preparation of oral pharmaceutical compositions, oral solutions such as suspensions, syrups, elixirs and, in the case of solutions, pharmaceutical media such as water, glycols, oils, alcohols and the like; In the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like are used. Because of the ease of administration, oral unit dosage forms are most suitable for tablets and capsules, in which case a solid carrier is used. In the case of parenteral pharmaceutical compositions, the carrier usually uses a large amount of sterile water, although the dissolution aid may contain other components to increase solubility. As the carrier for monitoring, saline, glucose solution or a mixture of saline and glucose solution is used. Injectable suspensions may be prepared which may include suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with a small amount of suitable additives having certain properties that do not have a very harmful effect on the skin. Such additives may facilitate administration to the skin and / or may be helpful for preparing the desired compositions. These additives facilitate skin administration and help to produce the desired composition. These compositions can be administered in several ways, for example as a transdermal patch, drop or ointment.

The following examples are intended to illustrate the invention in detail, which do not limit the scope of the invention. Unless otherwise specified, all parts are expressed in parts by weight.

[Experimental part]

A. Preparation of Intermediate Material

Example 1

a-1) A solution of 40 parts 4-chloro-3-nitrobenzaldehyde and 338 parts 1-propanamine is stirred and refluxed for 1.50 hours. The reaction mixture is evaporated to afford 53.7 parts of 2-nitro-N-propyl-4-[(propylimino) methyl] benzeneamine as an residue (intermediate material 1).

a-2) A mixture of 53.7 parts 2-nitro-N-propyl-4-[(propylimino) methyl] benzeneamine, 360 parts concentrated hydrochloric acid and 300 parts water is stirred and refluxed for 30 minutes. And the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluant: trichloromethane). The pure fractions are combined and the eluent is evaporated to afford 20.4 parts of 3-nitro-4 (propylamino) benzaldehyde (intermediate material 2).

Melting Point: 73.6 ℃

a-3) A mixture of 10.4 parts of 3-nitro-4- (propylamino) benzaldehyde and 200 parts of methanol is subjected to hydrogenation with a 3 parts Raney-nickel catalyst in a Parr-apparatus. A calculated amount of hydrogen is consumed and the catalyst is filtered off and the filtrate is acidified with 3 parts of acetic acid. The solvent is evaporated to afford 12 parts (100%) of 3-amino-4- (propylamino) benzenemethanol acetate (1: 1) as an residue (intermediate material 3).

a-4) A mixture of 8 parts 3-amino-4- (propylamino) benzenemethanol, 14.05 parts ethyl 3-pyridinecarboximidate dihydrochloride, 9.8 parts sodium acetate and 96 parts ethanol for 16 hours at room temperature Stir. The reaction mixture is evaporated. The residue is dissolved in water and treated with ammonia. The precipitated product is filtered off, washed with water and dissolved in dichloromethane. The organic layer is dried, filtered and evaporated. The residue was washed with 2,2'-oxybispropane to afford 9.9 parts (84.1%) of 1-propyl-2- (3-pyridinyl) -1H-benzimidazole-5-methanol (intermediate material). 4).

In a similar manner to the above, the following compounds are also obtained:

1,3-Dihydro-5- (hydroxymethyl-2H-benzimidazol-2-one is obtained with the above compound (intermediate material 15):

Melting Point: 238.2 ℃

b-1) 4.01 parts of 1-propyl-2- (3-pyridinyl) -1H-benzimidazole-5-methanol was added to a stirred solution of 65 parts of dichloromethane and 3 parts of N, N-dimethylethanamine to 2.23 parts of methane. Sulfonylchloride is added. The whole is stirred at room temperature for 45 minutes. The mixture is mixed with ice cubes, the dichloromethane layer is separated, dried, filtered and evaporated. The residue is dissolved in methylbenzene. The precipitate is filtered off and the filtrate is evaporated to yield 2.3 parts (66%) of 5- (chloromethyl) -1-propyl-2- (3-pyridinyl) -1H-benzimidazole as an residue (intermediate material 16 ).

In the same manner as above, the following compounds are prepared.

5- (chloromethyl) -1,3-dihydro-2H-benzimidazol-2-one is obtained with the above compound (intermediate material 28).

Example 2

a-1) To a stirred solution in which 1.4 parts of ethyl glycine hydrochloride is dissolved in 10 parts of water, a solution of 1.7 parts of 4-fluoro-3-nitrobenzenealdehyde dissolved in 8 parts of ethanol is added. Then 1.76 parts of sodium bicarbonate are added and stirred for 48 hours at room temperature. The precipitated product was filtered off, washed successively with water, ethanol, and 2,2'-oxybispropane and then dried to give 2 parts (79%) of ethyl N- (4-formyl-2nitrophenyl) glycine. To obtain (intermediate material 29);

Melting point: 90 ° C.

a-2) 47.8 parts of ethyl N- (4-propyl-2-nitrophenyl) glycine is added in small amounts to 280 parts of sodium tetrahydroborate in a stirring solution of 280 parts of ethane. The whole is stirred for 30 minutes at room temperature. The reaction mixture is decomposed into a solution of 12 parts acetic acid in 50 parts water. The mixture is concentrated. The product is dichloromethane extracted. The extract is dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product was filtered off and dried to yield 34.1 parts (70.6%) of ethyl N- [4- (hydroxymethyl) -2-nitrophenyl] glycine (intermediate material 30).

a-3) A mixture of 2.6 parts ethyl N- [4- (hydroxymethyl) -2-nitrophenyl] glycine, 8.3 parts potassium carbonate and 40 parts ethanol is stirred and refluxed for 2 hours.

After cooling, a solution of 7.2 parts acetic acid in 8 parts ethanol is added and stirred for 1 hour. The reaction mixture is evaporated. The residue is purified by silica gel column chromatography [90:10 (volume ratio) mixture of eluent: troclomethane and ethanol]. Pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride in 2-propanol. The salts were filtered off and dried to yield 1.1 parts (40%) of ethyl 1-hydroxy-6- (hydroxymethyl) -1H-benzimidazole-2-carboxylate monohydrochloride (intermediate material 31 );

Melting point: 178.0 ° C.

a-4) 5.46 parts of ethyl 1-hydroxy-6- (hydroxymethyl) -1H-benzimidazole-2-carboxylate monohydrochloride was added to a stirred solution of 0.92 parts of naturium in 32 parts of ethanol. do. The whole is stirred for 10 minutes and then concentrated. 18 parts methylbenzene is added and the mixture is evaporated. A solution of 2.84 parts of iodomethane in 13.5 parts of N, N'-dimethylformamide and 4.5 parts of N, N-dimethylformamide is added. After stirring for 30 minutes, the reaction mixture is evaporated. The residue is purified by silica gel column chromatography [80:20 (volume ratio) mixture of eluent: trichloromethane and acetonitrile]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a 1: 4 (volume ratio) mixture of 2-propane and 2,2'-oxybispropane. The product was filtered off and dried to yield 2.5 parts (50%) of ethyl 6- (hydroxymethyl) -1-methoxy-1H-benzimidazole-2-carboxylate (intermediate material 32);

Melting point: 110.1 ° C.

a-5) 4.2 parts of ethyl 6- (hydroxymethyl) -1-methoxy-1H-benzimidazole-2-carboxylate and 60 parts of concentrated hydrochloric acid mixture are stirred at reflux for 1 hour. The reaction mixture is concentrated and the residue is crystallized from 2-propanol. The product was filtered off and dried to yield 3.1 parts (79.2%) of 6- (chloromethyl) -1-methoxy-1H-benzimidazole monohydrochloride (intermediate material 33);

Melting point: 158 ° C.

Example 3

a-1) A mixture of 20 parts of (3,4-diaminophenyl) (3-fluorophenyl) methanone, 27 parts of ethyl ethaneimidate hydrochloride and 80 parts of methanol is stirred at reflux for 17 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 10% potassium carbonate solution and the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [95: 5 (volume ratio) mixture of eluent: dichloromethane and methanol]. The pure fractions are combined and the eluent is evaporated to yield 15.6 parts (70.5%) of (3-fluorophenyl) (2-methyl-1H-benzimidazol-5-yl) methanone as a residue (intermediate material 34 ).

a-2) Sodium tetrahydro borate is added dropwise at room temperature to a stirred solution in which 14 parts of (3-fluorophenyl) (2-methyl-1H-benzimidazol-5-yl) methanone is dissolved in 80 parts of methanol. After dropping, stir at room temperature for 1 hour. The reaction mixture is poured into water and the product is extracted with ethyl acetate. The extract is dried, filtered and evaporated. The residue is converted to hydrochloride in 80 parts of methanol and ethanol. The mixture was concentrated and dried to yield 15.1 parts (93.7%) of α- (3-fluorophenyl) -2-methyl-1H-benzimidazole-5-methanol monohydrochloride as an residue (intermediate material 35). .

In a similar manner, the following compounds are also prepared.

2-methyl-α-phenyl-1H-benzimidazole-5-methanol hydrochloride (intermediate material 36);

Melting point:> 300 ° C. (decomposition);

1-methyl-α-phenyl-1H-benzimidazole-5-methanol (intermediate material 37);

Melting point: 170.7 ° C .;

1,2-dimethyl-α-phenyl-1H-benzimidazole-6-methanol (intermediate material 38);

Melting point: 206.6 ° C .;

1-methyl-2, α-diphenyl-1H-benzimidazole-6-methanol (intermediate material 39) as a residue; 2-phenyl-α (2-thienyl) -1H-benzimidazole-5-methanol (intermediate material 40);

Melting point: 243 ° C .;

2- (4-thiazolyl) -α- (2-thienyl) -1H-benzimidazole-5-methanol (intermediate material 41); Α- (5-bromo-2-furanyl) -1H-benzimidazole-5-methanol (intermediate material 42) as a residue; Α- (2-furanyl) -1H-benzimidazole-5-methanol (intermediate material 43) as residue and α- (3-fluorophenyl) -1H-benzimidazole-5-methanol (intermediate material) as residue 44).

b-1) A mixture of 13 parts α- (3-fluorophenyl) -2-methyl-1H-benzimidazole-5-methanol monohydrochloride and 81 parts thionyl chloride is stirred overnight at room temperature. The reaction mixture was concentrated to dryness to afford 12 parts (86.8%) of 5- [chloro- (3-fluorophenyl) methyl] -2-methyl-1H-benzimidazole monohydrochloride as an residue (intermediate material 45). .

In a similar manner, the following compounds are also prepared.

2-methyl-α-phenyl-1H-benzimidazole-5-methanol methanesulfonate (ester) (intermediate material 46) as residue and 5- [chloro (3-fluorophenyl) methyl] -1H-benz as residue Imidazole (intermediate material 47).

Example 4

a-1) 7.8 parts of acetyl chloride are added to a stirring solution in which 16 parts of phenyl (3-amino-4-nitrophenyl) methanone is dissolved in 195 parts of dichloromethane. After stirring for 17 hours at room temperature the reaction mixture is evaporated. The residue is crystallized from a mixture of ethyl acetate and 2,2'-oxybispropane. The product was filtered off and dried to yield 15 parts (81%) of N- (5-benzoyl-2-nitrophenyl) acetamide (intermediate material 48);

Melting point: 97.8 ° C.

a-2) A mixture of 5.6 parts N- (5-benzoyl-2-nitrophenyl) acetamide, 2 parts thiophene solution in 4% methanol, 200 parts methanol and 7 parts 2-propanol (saturated with hydrochloric acid) Was hydrogenated with 5 parts of a platinum-charcoal catalyst at atmospheric pressure and room temperature. A calculated amount of hydrogen is consumed and the catalyst is filtered off and the filtrate is evaporated. The residue is washed with 2-propanone and dried to afford 4.2 parts (73%) of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone monohydrochloride as a residue. (Intermediate material 49).

a-3) To a stirred solution of 1.84 parts of sodium in 80 parts of methanol is added 11.55 parts of (1-hydroxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone monohydrochloride. After stirring for 15 minutes at room temperature, the solvent is evaporated and the residue is dissolved in methylbenzene. The solution is evaporated and the residue is dissolved in 54 parts of N, N-dimethylformamide and 6.24 parts of iodomethane are added. The reaction mixture is stirred at room temperature for 2 hours. The N, N-dimethylformamide layer is evaporated in vacuo. The residue is dissolved in water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue was washed with 2,2'-oxybispropane to afford 6.4 parts (60.0%) of (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone (intermediate material 50 );

Melting point: 67.7 ° C.

a-4) 0.6 parts of sodium tetrahydroborate is added to a stirred solution of 3.4 parts of (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone in 64 parts of methanol. After stirring for 30 minutes at room temperature, the methanol layer is evaporated. Water is added to the residue and the product is extracted with dichloromethane. Extracts are dried, filtered and evaporated. The residue is crystallized from 45 parts of ethyl acetate. The product was filtered off and dried to yield 2.8 parts (80%) of 1-methoxy-2methyl-α-phenyl-1H-benzimidazole-5-methanol (intermediate material 51).

In a similar manner, the following compounds are also prepared: 1-methoxy-α, 2-diphenyl-1H-benzimidazole-6-methanol (intermediate material 52); 1-methoxy-α, 2methyl-diphenyl-1H-benzimidazole-5-methanol (intermediate material 53).

Melting point: 142.4 ° C .;

1-methoxy-α-phenyl-1H-benzimidazole-6-methanol (intermediate material 54); 1-methoxy-α, 2-dimethyl-1H-benzimidazole-6-methanol (intermediate material 55) and 1-methoxy-2-methyl-α-phenyl-1H-benzimidazole-6-methanol (intermediate) Substance 56).

Example 5

a-1) A mixture of 104 parts ethylbenzene carboximidate hydrochloride, 97.1 parts 3-amino-4- (propylamino) benzoic acid and 1200 parts acetic acid is stirred at room temperature for 60 minutes to reflux for 20 hours. The reaction mixture is added and water is added to the residue. The precipitated fish is separated by filtration, washed sequentially with water and acetonitrile and then crystallized with acetic acid to give 58.5 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylic acid (intermediate material 57). ;

Melting point: 223.4 ° C.

a-2) 142 parts of thionyl chloride are added to a stirred solution of 112.13 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylic acid in 525 parts of trichloromethane. Stirring is continued for 30 minutes at reflux. The reaction mixture is evaporated to yield 134 parts (100%) of 2-phenyl-1-propyl-1H-benzimidazole-5-carbonylchloride monohydrochloride as an residue (intermediate material 58).

a-3) 240 parts of methanol is added to a stirred solution of 134 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-carbonylchloride monohydrochloride in 300 parts of trichloromethane and stirred at reflux for 20 minutes. do. The reaction mixture is evaporated. The residue is washed with 4-methyl-2-pentanone and dissolved in water. The free base is dissociated with ammonium hydroxide according to a conventional method and extracted with methbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from 175 parts of 2,2'-oxybispropane. The product was filtered off and dried to yield 91 parts (77.3%) of methyl 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylate (intermediate material 59);

Melting point: 79.8 ° C.

a-4) 88.5 parts methyl 2-phenyl in 270 parts methylbenzene in a stirred and cooled (ice-cold) solution of 103.9 parts sodium dihydro-bis (2-methoxyethoxy) aluminate in 45 parts methylbenzene A solution of -1-propyl-1H-benzimidazole-5-carboxylate is added. After the addition was completed, the mixture was stirred for 1 hour at room temperature and then decomposed by adding a mixture of 200 parts of NaOH solution (7.5N) and 200 parts of water to the reaction mixture, but the methyl benzene layer was separated, dried, filtered and evaporated. . The residue was decomposed by adding a mixture of 210 parts of water, but the methine benzene layer was separated, dried, filtered and evaporated. The residue is washed with 210 parts 2,2'-oxybispropane. The product was filtered off and dried to yield 73 parts (91%) of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol (intermediate material 60);

Melting point: 112.9 ° C.

a-5) A solution of 70.5 parts of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol in 300 parts of trichloromethane is saturated with hydrogen chloride gas. Subsequently, 55.9 parts of thionyl chloride are added dropwise (exothermic reaction). After completion of the dropwise addition, the mixture is stirred at reflux for 30 minutes. After evaporation of the reaction mixture the residue is added 90 parts of methylbenzene and evaporated again. The residue was crystallized with 320 parts of 4-methyl-2-pentanone to give 80 parts (96%) of 5- (chlormethyl) -2-phenyl-1-propyl-1H-benzimidazole monohydrochloride ( Intermediate material 61);

Melting point: 138.5 ° C.

In a similar manner, the following compounds are prepared.

4- (chloromethyl) -1H-benzimidazole monohydrochloride (intermediate material 62) as a residue; 7- (chloromethyl) -2- (3-pyridinyl) -1H-benzimidazole monohydrochloride (intermediate material 63) and 7- (chloromethyl) -2-phenyl-1H-benzimidazole (intermediate) as residue Substance 64).

Example 6

a-1) A mixture of 17 parts of ethyl 2,3-diaminobenzoate, 14 parts of ethyl ethaneimide hydrochloride and 240 parts of ethanol is stirred at reflux for 19 hours. After evaporation, the residue was dissolved in potassium carbonate solution (10% and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated to 19 parts (98.6%) of ethyl 2-methyl-1H- as a residue. Obtain benzimidazole-4-carboxylate (intermediate material 65).

a-2) A cooled (0 ° C.) solution of 10 parts ethyl 2-methyl-1H-benzimidazole-4-carboxylate in 45 parts tetrahydrofuran was added 4 parts lithium tetrahydro alumina in 45 parts tetrahydrofuran. It is added dropwise to the suspension of Nate. After completion of the dropping, the temperature is kept at room temperature. After adding ethyl acetate and water, the reaction mixture is filtered through diatomaceous earth. The filtrate was evaporated to yield 6.3 parts (79.4%) of 2-methyl-1H-benzimidazole-4-methanol as intermediate (intermediate material 66).

a-3) A mixture of 10 parts 2-methyl-1H-benzimidazole-4-methanol, 10 parts manganese oxide (IV) and 180 parts ethyl acetate is stirred at room temperature for 19 hours. The reaction mixture is filtered through diatomaceous earth and washed with a mixture of ethyl acetate and methanol (volume ratio of 80: 20). The filtrate is evaporated and the residue is crystallized from 2-butanone. The product was filtered off and dried to yield 3.5 parts (35.2%) of 2-methyl-1H-benzimidazole-4-carboxaldehyde (intermediate material 67).

a-4) 15.3 parts of lithium phenyl are added at 20 degreeC to the stirred solution of 3 parts of 2-methyl- 1H- benzimidazole-4-carboxaldehyde in 45 parts of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 minutes at room temperature. Pour the mixture into water. The precipitated product was filtered off and then dried to yield 4 parts (89.7%) of 2-methyl-α-phenyl-1H-benzimidazole-4-methanol (intermediate material 68).

Example 7

a-1) In a stirred solution dissolved in 41 parts of 4-fluoro-3-nitrobenzenemethanol and 39 parts of N, N-diethylethanamine in 325 parts of dichloromethane, 30.3 parts of methanesulfonyl chloride was added to 65 parts of dichloromethane. The dissolved solution is added dropwise at 0 ° C to -5 ° C. The whole was stirred at 0 ° C. for 1 hour and then 100 parts of ice water was added. The dichloromethane layer was decanted and dried, filtered and evaporated. The residue is purified by silica gel column chromatography (eluent: trichloromethane). Pure fractions are collected and the eluent is evaporated. 35 parts of 1,1'-oxybisethane are added to the residue. The product was filtered off and dried to yield 35.9 (60%) of 4-fluoro-3-nitrobenzenemethanolmethanesulfonate (ester) (intermediate material 69).

a-2) 17.5 parts of 4-fluoro-3-nitrobenzenemethanol methanesulfonate (ester) are added all at once to a stirred solution of 10.5 parts of 1H-imidazole in 80 parts of acetonitrile. The mixture is stirred and refluxed for 15 minutes. After cooling, the precipitate is filtered off and the filtrate is evaporated. The residue is purified by silica gel column chromatography [mixture of eluent: 95: 5 (volume ratio) of trichloromethane and ethanol]. Pure fractions are collected and the eluent is evaporated. The solid residue is washed with 2,2'-oxybispropane and dried to yield 6.5 parts (42%) of 1-[(4-fluoro-3-nitrophenyl) methyl] -1 H-imidazole ( Intermediate material 70).

a-3) A mixture of 4.4 parts 1-[(4-fluoro-3-nitrophenyl) methyl] -1 H-imidazole, 4.33 parts 4-pyridinmethanamine and 80 parts pure ethanol was stirred at reflux for 4 hours do. The reaction mixture is evaporated. 50 parts of water is added to the residue and the product is washed twice with 130 parts of trichloromethane. The combined trichloromethane layer is dried, filtered and evaporated. The residue is crystallized from 48 parts of 2-propanol. The product was filtered off and dried to yield 5.1 parts (82%) of N- [4- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] -3-pyridinmethanamine (intermediate material 71 ); Melting point: 171.0 ° C.

In a similar manner, the following compounds are prepared.

N- [4- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] benzenemethanamine (intermediate material 72);

Melting Point: 110.2 ℃

4- (1H-imidazol-1-ylmethyl) -N-methyl-2-nitrobenzeneamine (intermediate material 73);

Melting point: 160.3 ° C.

4-fluoro-N- [4- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] benzenemethanamine (intermediate material 74);

Melting point: 116.7 ° C.

N- [5- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] benzenemethanamine (intermediate material 75);

Melting Point: 81.8 ℃

5- (1H-imidazol-1-ylmethyl) -N-methyl-2-nitrobenzeneamine (intermediate material 76);

Melting Point: 124.2 ℃

N- [5- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] benzenemethanamine (intermediate material 77);

Melting Point: 128.5 ℃

N- (cyclohexylmethyl) -5- (1H-imidazol-1-ylmethyl) -2-nitrobenzeneamine (intermediate material 78);

Melting point: 58.2 ℃ and

N- [5- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] cycloheptanamine (intermediate material 79);

Melting point: 129.6 ° C.

b-1) 6.2 parts N- [4- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] -3-pyridinmethaneamine, methanol solution of 1 part thiophene (4%) and 200 parts methanol Of the mixture was hydrogenated with 2 parts of platinum-charcoal catalyst (5%) at 50 ° C under atmospheric pressure. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated to 5.6 parts (100%) of 4- (1H-imidazol-ylmethyl) -N ^1- (3-pyridinylmethyl) -1,2-benzene Obtain diamine (intermediate material 80).

In a similar manner, the following compounds are prepared.

4- (1H-imidazol- ¹ -ylmethyl) -N ¹ -methyl-1,2-benzenediamine (intermediate material 81);

4- (1H-imidazol-1-ylmethyl) -N ^2- (phenylmethyl) -1,2-benzenediamine (intermediate material 82);

4- (1H-imidazol-1-ylmethyl) -N ² -methyl-1,2-benzenediamine (intermediate material 83);

4- (1H- imidazol-1-ylmethyl) -N ² - (2- phenylethyl) -1,2-benzenediamine (intermediate material 84);

N ^2- (cyclohexylmethyl) -4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine (intermediate material 85) and

N ² -cycloheptyl-4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine (intermediate material 86).

Example 8

a-1) A solution of 40 parts of methanamine in 160 parts of methanol is added to a stirred cooling solution of 50 parts of 1- (4-chloro-3-nitrophenyl) ethanone in 240 parts of methanol. The reaction mixture is stirred at 60 ° C. for 12 h. The reaction mixture is evaporated and dried to yield 50 parts (100%) of 1- [4- (methylamino-3-nitrophenyl] -ethanone as an residue (intermediate material 87).

a-2) 4 parts of sodium tetrahydroborate are added to a stirring mixture of 19.4 parts of 1- [4- (methylamino-3-nitrophenyl] ethanone and 160 parts of methanol, followed by stirring at room temperature for 1 hour. 1000 parts of water was added and the product was extracted three times with 120 parts of trichloromethane The combined extracts were dried, filtered and evaporated The residue was subjected to silica gel column chromatography [eluent: trichloromethane and methanol 98: 2 (A mixture of capacity ratios)] The pure fractions are collected and the eluent is evaporated to yield 17 parts (89%) of α-methyl-4- (methylamino) -3-nitrobenzenemethanol as an residue (intermediate). Substance 88).

a-3) A mixture of 17 parts of α-methyl-4- (methylamino) -3-nitrobenzenemethanol, 28 parts of 1,1'-carbonylbis [1H-imidazole] and 180 parts of tetrahydrofuran at room temperature Stir for 24 hours. The reaction mixture is added to a mixture of ice water and potassium carbonate solution (30%), and the product is extracted three times with 150 parts of trichloromethane. The combined extracts were dried, filtered and evaporated to yield 21 parts (99.1%) of 4- [1- (1H-imidazol-1-yl) ethyl] -N-methyl-2-nitrobenzeneamine as residue. (Intermediate material 89).

In a similar manner, the following compounds are prepared.

4-fluoro-N- [4- (1H-imidazol-1-yl) phenylmethyl] -2-nitrophenyl] benzenemethanamine (intermediate material 90);

Melting point: 67.7 ° C .;

4-[(1H-imidazol-1-yl) phenylmethyl] -N-methyl-2-nitrobenzeneamine (intermediate material 91);

Melting point: 159.5 ° C.

N- [4- [1- (1H-imidazol-1-yl) ethyl] -2-nitrophenyl] benzenemethanamine (intermediate material 92);

4-fluoro-N- [4- [1- (1H-imidazol-1-yl) ethyl] -2-nitrophenyl] benzenemethanamine (intermediate material 93); 4-fluoro-N- [4- [1- (1H-imidazol-1-yl) -2-methylphenyl] -2-nitrophenyl] benzenemethanamine (intermediate material 94) as a residue; N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrophenyl benzenemethanamine (intermediate material 95) as residue; And 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -N-methyl-2-nitrobenzeneamine (intermediate material 96).

b-1) A mixture of 21 parts of 4- [1- (1H-imidazol-1-yl) ethyl] -N-methyl-2-nitrobenzeneamine and 160 parts of ethanol was added to 20 parts under 0.5 10 ⁵ Pa in a Parrer. Hydrogenation at room temperature with Raney-Nickel catalyst. When the calculated amount of hydrogen is consumed, nitrogen gas is blown into the mixture and the catalyst is removed by filtration through diatomaceous earth. The filtrate was evaporated below 40 ° C. to give 18.5 parts (100%) of 4- [1- (1H-imidazol-1-yl) ethyl] -N ¹ -methyl-1,2-benzenediamine as a residue ( Intermediate material 97).

In a similar manner, the following compounds are prepared.

4-[(1H-imidazol-1-yl) phenylmethyl] -N ¹ -methyl-1,2-benzenediamine (intermediate material 98) as a residue; 4- [1- (1H-imidazol-1-yl) -2-methoxypropyl] -N ¹ -methyl-1,2-benzenediamine (intermediate material 99) as a residue; And 4- [1- (1H-imidazol-1-yl) ethyl] -N ^1- (phenylmethyl) -1,2-benzenediamine (intermediate material 100) as a residue.

Example 9

a-1) 50 parts of N- (4-formylphenyl) acetamide in a stirred and refluxed Grignard complex prepared from 110.7 parts of 2-bromopropane, 21.75 parts of magnesium and 900 parts of anhydrous tetrahydrofuran is less than 30 ° C. Drop by After completion, stir at room temperature for 1 hour. The reaction mixture is hydrolyzed with a mixture of ammonium chloride and ice cubes and the product is extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated to dryness to yield 63.5 parts (100%) of N- [4- (1-hydroxy-2-methylpropyl) phenyl] acetamide as an intermediate (intermediate material). 101).

a-2) 10.4 parts of N- [4- (1-hydroxy-2-methylpropyl) phenyl] acetamide-of 16 parts of 1,1'-carbonylbis [1H-imidazole] and 90 parts of tetrahydrofuran The mixture is stirred at rt for 12 h. The mixture is evaporated to dryness, the residue is dissolved in water and treated with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [mixture of 98: 2 (volume ratio) of eluent: trichloromethane and methanol]. The pure fractions were combined and the eluent was evaporated to yield 6.8 parts (53%) of N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] acetamide (intermediate material). 102); Melting point: 244 ° C.

a-3) 8.6 parts to a stirred and cooled (0 ° C.) mixture of 21.5 parts N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] phenyl] acetamide and 183 parts concentrated sulfuric acid Sodium nitrate is added in small portions at 0 ° to 5 ° C. The reaction mixture is poured into ice water and treated with ammonium hydroxide. The product is extracted three times with 150 parts trichloromethane. The extracts were combined, dried, filtered and evaporated to yield 20 parts (80%) of N- [4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrophenyl as a residue. Acetamide is obtained (intermediate material 103).

a-4) A mixture of 56 parts of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine and 300 parts of hydrochloric acid solution (3N) was heated at reflux for 1 hour. Stir. After cooling the reaction mixture is poured into 1000 parts of ice water and treated with ammonium hydroxide. The product is extracted three times with 150 parts trichloromethane. The extracts are combined, dried, filtered and evaporated to afford 31 parts (64%) of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine. (Intermediate material 104).

a-5) A mixture of 31 parts of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2-nitrobenzeneamine and 240 parts of ethanol was added to 30 parts under 0.5 10 ⁵ Pa in a Parrer. Hydrogenation with Raney-Nickel catalyst. When the calculated amount of hydrogen is consumed, the catalyst is separated by filtration through diatomaceous earth, the filtrate is evaporated to give 27.4 parts (99.9%) of 4- [1- (1H-imidazol-1-yl) -2-methylpropyl]-as a residue. 1,2-benzenediamine is obtained (intermediate material 105).

In a similar manner, the following compounds are prepared.

4- [1- (1H-imidazol-1-ylmethyl)]-1,2-benzenediamine (intermediate material 106) as a residue; 4-[(1H-imidazol-1-yl) ethyl] -1,2-benzenediamineoil (intermediate material 107) as an oil; 4- [1- (1H-imidazol-1-yl) -3-methylbutyl] -1,2-benzenediamine (intermediate material 108); 4- [1- (1H-imidazol-1-yl) propyl] -1,2-benzenediamine (intermediate material 109) as a residue; 4- [1- (1H-imidazol-1-yl) heptyl] -1,2-benzenediamine (intermediate material 110) and 4- [1- (1H-imidazol-1-yl) butyl]-as a residue 1,2-benzenediamine (intermediate material 111).

Example 10

a-1) 37.8 parts of methanesulfonylchloride is dissolved in 65 parts of dry dichloromethane in a stirred solution of 50.2 parts of α-methyl-4-nitrobenzenemethanol and 48.6 parts of N, N-dimethylethanamine in 390 parts of anhydrous dichloromethane The prepared solution is added dropwise at -5 ° to 0 ° C. The mixture is stirred at 0 ° C. for 1 h. 75 parts of cold water is added, the dichloromethane layer is decanted, dried, filtered and evaporated. The residue is purified by silica gel column chromatography (eluent: trichloromethane). Pure fractions are collected and the eluent is evaporated. The residue is shaken with 2,2'-oxybispropane. The product was filtered off and dried to yield 67.1 parts (91%) of [1- (4-nitrophenyl) ethyl] methanesulfonate (intermediate material 112); Melting point 70 캜.

a-2) A mixture of 37.5 parts 1H-imidazole, 61.3 parts [1- (4-nitrophenyl) ethyl] methanesulfonate and 200 parts aceXHnitrile is stirred and refluxed for 2.5 hours. After cooling, the whole is filtered and the filtrate is evaporated. 150 parts of water are added and the product is extracted three times with 130 parts of dichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by silica gel column chromatography [a mixture of eluent: 95: 5 (volume ratio) of trichloromethane and methanol]. The pure fractions are combined and the eluent is evaporated to give 34.4 (63.3%) of 1- [1- (4-nitrophenyl) ethyl] -1 H-imidazole as a solid residue (intermediate material 113).

a-3) A mixture of 34.4 parts 1- [1- (4-nitrophenyl) ethyl] -1H-imidazole, a methanol solution of 2 parts thiophene (4%), 200 parts methanol and 200 parts ammonia saturated methanol Hydrogenate with 4 parts of platinum-charcoal catalyst (5%) at normal pressure and room temperature. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated. The oily residue is crystallized from a mixture of 2-propane and 2,2'-oxybispropane (volume ratio of 2: 1). The product was filtered and dried to afford 27 parts (91.3%) of 4- [1- (1H) -imidazol-1-yl) ethyl] benzeneamine (intermediate material 114); Melting point: 130 ° C.

a-4) 9 parts of acetic anhydride in 24 parts of formic acid in a stirred solution of 15 parts of 4- [1- (1H) -imidazol-1-yl) ethyl] benzeneamine and 2.7 parts of sodium formate in 60 parts of formic acid The solution is added dropwise at 50 ° C. The reaction mixture is stirred at 100 ° C. for 1 hour and the solvent is evaporated. The residue is dissolved in a small amount of ice water and the solution is cooled and treated with ammonium hydroxide. The product is extracted twice with dichloromethane. The combined extracts are dried, filtered and evaporated. The residue was crystallized twice with tetrahydrofuran to give 13.8 parts (80%) of N- [4- (1- (1H-imidazol-1-yl) ethyl] phenyl] formamide (intermediate material 115); Melting point: 129.4 ° C.

a-4) 6.1 parts of potassium nitrate in -5 ° to -6 ° C in a cooling and stirring solution of 13 parts of N- [4- (1- (1H-imidazol-1-yl) ethyl] phenyl] formamide in 92 parts of concentrated sulfuric acid Small portions are added at 10 ° C. After completion, stirring is continued for 1.5 hours at 0 ° C. and the reaction mixture is poured into ice cubes, treated with ammonium hydroxide at 0 ° to −10 ° C. The product is treated with 195 parts of dichloromethane. Extract three times The extract is dried, filtered and evaporated The residue is crystallized from 48 parts of 2-propanol The product is filtered off and dried to give 5.4 parts (34.6%) of N- [4- (1- ( 1H-imidazol-1-yl) ethyl] -2-nitrophenyl] formamide is obtained (intermediate material 116);

In a similar manner, the following compounds are prepared.

N- [4- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] acetamide (intermediate material 117);

N- [4- (1- (1H-imidazol-1-yl) ethyl] -2-nitrophenyl] acetamide (intermediate material 118);

N- [3- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] acetamide (intermediate material 119);

Melting point: 182.1 ° C and

N- [5- (1H-imidazol-1-ylmethyl) -2-nitrophenyl] acetamide (intermediate material 120);

Melting point: 136.0 ° C .;

b-1) 5.4 parts of N- [4- (1- (1H-imidazol-1-yl) ethyl) -2-nitrophenylformamide, methanol solution of 1 part thiophene (4%) and 200 parts methanol The mixture is hydrogenated with 2 parts of platinum-charcoal catalyst (5%) at 50 ° C under atmospheric pressure. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated to give 5 parts (100%) of N- [2-amino-4- [1- (1H-imidazol-1-yl) ethyl] phenyl] form An amide is obtained (intermediate material 121).

In a similar manner, the following compounds are prepared.

N- [2-amino-4- (1H-imidazol-1-ylmethyl) phenyl] acetamide (intermediate material 122) and N- [2-amino-4- [1- (1H-imidazole) as a solid residue -1-yl) ethyl] phenyl] acetamide (intermediate material 123); Melting point: 211.7 ° C.

Example 11

To the stirring and cooling (water bath) solution of a mixture of 48.5 parts of (4-amino-3-nitrophenyl) phenylmethanone and 320 parts of methanol is added 11.4 parts of sodium tetrahydroborate. After completion, stirring is continued for 15 minutes at room temperature. 100 parts of water is added and the methanol is evaporated. The precipitated product was filtered off, washed with water, dried, filtered and crystallized twice with a mixture of methanol and water to give 19.6 parts of 4-amino-3-nitro-α-phenylbenzenemethanol (intermediate material 124); Melting point: 125 ° C.

a-2) 6.4 parts of 1,1'-carbonylbis in a stirred solution of 7.5 parts of 4-amino-3-nitro-α-phenyl-benzenemethanol, 0.1 parts of sodium hydride dispersion (50%) and 90 parts of tetrahydrofuran [1H-imidazole] is added. The whole is stirred and refluxed for 1 hour. The reaction mixture is evaporated. The residue is purified by silica gel column chromatography [mixture of 93: 7 (volume ratio) of eluent: trichloromethane and methanol]. Pure fractions are collected and the eluent is evaporated. The residue was crystallized with 180 parts of methylbenzene and melted at 80 ° C. for 2 hours, yielding 6.33 parts (71%) of 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzeneamine. (Intermediate material 125).

a-3) 3.4 parts 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzeneamine, 1 part methanol solution of thiophene (4%), 80 parts methanol and 80 parts ammonia saturated Methanol is hydrogenated with 2 parts platinum-charcoal catalyst (5%) at atmospheric pressure and room temperature. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated to yield 2.64 parts (99%) of 4-[(1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine as residue. (Intermediate material 126). In addition, it can carry out as follows by another method.

a-4) A mixture of 1.45 parts of 4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzeneamine, 0.78 parts of acetyl chloride and 25 parts of acetic acid is stirred at room temperature for two days. The methanol layer is evaporated in vacuo and the residue is dissolved in dichloromethane with water. After treating with ammonium hydroxide, the dichloromethane layer was dried, filtered and evaporated to give 1.6 parts (95%) of N- [4- (1H-imidazol-1-yl) phenylmethyl] -2-nitro as a residue. Phenyl] acetamide is obtained (intermediate material 127).

In a similar manner, the following compounds are prepared.

Example 12

a-1) 68.4 parts of (-)-[S (R ^* , R ^* ) in 544 parts of methanol to a stirred solution of 110 parts of (+)-4-amino-3-nitro-α-phenylbenzenemethanamine in 880 parts of methanol )]-2,3-dihydroxybutanedioic acid solution is added. The crystal product is isolated by filtration and recrystallized from a mixture of methanol and water (volume ratio of 85:15). The product is filtered off and treated with 2,3,4,6-tetraacetate-α, D-glucopyranosyl isocyanide. The product was filtered off and dried to give 26 parts (14.4%) of (+)-4-amino 3-nitro-α-phenylbenzenemethanamine (-)-[S (R ^* , R ^* )]-2,3 Obtain dihydroxybutanedioic acid (intermediate material 139).

a-2) water from (+)-4-amino-3-nitro-α-phenylbenzenemethanamine (-)-[S (R ^* , R ^* )]-2,3-dihydroxybutanedioic acid, Ammonium hydroxide and dichloromethane dissociate the base according to conventional methods. The extract is dried, filtered and evaporated. The residue, a mixture of 8.6 parts 2-isothiocyanato-1,2-dimethoxyethane and 80 parts methanol is stirred at reflux for 1.5 hours. After cooling, the reaction mixture is evaporated. The residue is purified by silica gel column chromatography [a mixture of eluent: 99: 1 (volume ratio) of trichloromethane and methanol]. The pure fractions were combined and the eluent was evaporated to give 22.3 parts (98.3%) of (+)-N-[(4-amino-3-nitrophenyl) phenylmethyl] -N '-(2,2-dimethoxyethyl as residue. ) Thiourea is obtained (intermediate material 140).

a-3) 22.3 parts (+)-N-[(4-amino-3-nitrophenyl) phenylmethyl] -N '-(2,2-dimethoxyethyl) thiourea, 10.2 parts iodomethane, 11.8 parts A mixture of potassium carbonate and 240 parts of 2-propanone is stirred at room temperature for two days. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is purified by silica gel column chromatography (eluent: mixture of 98: 2 (volume ratio) of trichloromethane and methanol), the pure fractions are collected and the eluent is evaporated to give 23 parts (100%) of (+ ) -Methyl N-[(4-amino-3-nitrophenyl) phenylmethyl] -N '-(2,2-dimethoxyethyl) carbamimidothioate is obtained (intermediate material 141).

a-4) of 23 parts of (+)-methyl N-[(4-amino-3-nitrophenyl) phenylmethyl] -N '-(2,2-dimethoxyethyl) carbamimidothioate and 450 parts of concentrated sulfuric acid The mixture is stirred for 1 hour while cooling with ice cold water. The reaction mixture is poured onto ice cubes and treated with ammonium hydroxide solution. The product is extracted three times with trichloromethane. The Handemo extract is dried, filtered and evaporated. The residue is purified by silica crab column chromatography [a mixture of 98: 2 (volume ratio) of eluent: trichloromethane and methanol]. Pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride in 2-propanol. The salt is filtered off and methanolol crystallized. The product was filtered off and dried to give 5.5 parts (25.6%) of (+)-4-[(2- (methylthio) -1H-imidazol-1-yl) phenylmethyl] -2-nitrobenzeneamine monohydro Chloride is obtained (intermediate material 142).

a-5) 5.5 parts (+)-4-[(2- (methylthio) -1H-imidazol-1yl) phenylmethyl] -2-nitrobenzeneamine monohydrochloride, 24 parts concentrated hydrochloric acid, 2 parts thi A mixture of methanol (4%) solution of Offen, 120 parts methanol and 100 parts water is hydrogenated with 2 parts palladium-charcoal catalyst (10%) at 0 ° C. under atmospheric pressure. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water and treated with ammonium hydroxide solution. The product is extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated to give 5.6 parts (100%) of (+)-4-[(2- (methylthio) -1H-imidazol-1yl) phenylmethyl] -1,2 as a residue. Obtain benzenediamine (intermediate material 143).

a-6) 5.6 parts of (+)-4-[(2- (methylthio) -1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine, 2.8 parts of ethyl ethaneimidate hydrochloride and A mixture of 60 parts of methanol is stirred overnight at room temperature and then at reflux for 2 hours. After cooling the reaction mixture is evaporated. The residue is treated with alkaline water and the product is extracted three times with dichloromethane. The residue is purified by silica gel column chromatography [a mixture of eluent: 96: 4 (volume ratio) of dichloromethane and methanol]. The pure fractions were combined and the eluent was evaporated to afford 3.2 parts (79.3%) of (+)-2-methyl-5-[[2- (methylthio) -1H-imidazol-1-yl] phenylmethyl] -1H-. Benzimidazole is obtained (intermediate material 144).

In a similar manner, the following compounds are prepared.

(-)-2-methyl-5-[[2- (methylthio) -1H-imidazol-1-yl] phenylmethyl] -1H-benzimidazole (intermediate material 145) as a residue.

B. Preparation of Final Compound

Example 13

A mixture of 6.8 parts 1H-imidazole, 4.9 parts 5- (chloromethyl) -2-ethyl-1-methyl-1H-benzimidazole monohydrochloride and 80 parts acetonitrile is stirred and refluxed for 3 hours. The reaction product is evaporated. The residue is purified by silica gel column chromatography [a mixture of eluent: 95: 5 (volume ratio) of trichloromethane and methanol]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized with ethyl acetate. The product was isolated by filtration, washed with 2,2'-oxybispropane and dried to give 2.6 parts (54%) of 2-ethyl-5- (1H-imidazol-1-ylmethyl) -1-methyl- 1H-benzimidazole is obtained (Compound 1); Melting point: 127.3 ° C.

In a similar manner, the following compounds are prepared.

5-[(3-fluorophenyl) (1H-imidazol-1-yl) methyl] -2-methyl-1H-benzimidazole (Compound 21); Melting point: 128.8 ° C. and 5-[(3-fluorophenyl) (1H-imidazol-1-yl) methyl] -1H-benzimidazole (Compound 22); Melting point: 85.6 ° C.

Example 14

7.5 parts of 1H-imidazole, 12.6 parts of 2-methyl-α-phenyl-1H-benzimidazole-5-methanol methanesulfonate (ester) and 80 parts of a mixture of acetonitrile are stirred and refluxed for 18 hours. The reaction mixture is evaporated. Water is added to separate the oil layer and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is purified twice with silica gel column chromatography [eluent: mixture of 90: 5: 5 (volume ratio) of trichloromethane, methanol and ammonia saturated methanol]. Pure fractions are collected and the eluent is evaporated. The residue was subjected to reversecd phansechromatography (HPLC) (using a mixture of 60% methanol containing 0.8% N- (1-methylethyl) -2-propanamine and 40% water containing 0.5% ammonium acetate). Purification by The pure fractions were combined, the residue was evaporated and dried in vacuo at 95 ° C. for 12 hours to give 1.8 parts (15%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -2-methyl-1H-benzimi To give a dozol (Compound 23); Melting point: 118.4 캜.

Example 15

A mixture of 6.35 parts 5- (chloromethyl) -1,3-dihydro-2H-benzimidazol-3-one, 11.9 parts 1H-imidazole and 135 parts N, N-dimethylformamide was stirred at 80 ° C. overnight. do. Evaporate the whole. The residue is purified by silica gel column chromatography [mixture of eluent: 80:20 (volume ratio) of trichloromethane and methanol]. Pure fractions are collected and the eluent is evaporated. Leave for 2 days at room temperature and solidify the residue. The product is triturated and stirred in acetonitrile. The product was isolated by filtration and purified by silica gel column chromatography [eluant: trichloromethane and dried with dry pistol at 130 ° C., 0.75 part (10%) of 1,3-dihydro-5- (1H-imidazol-1-yl Methyl) -2H-benzimidazol-2-one (compound 24); Melting point 254.5 ° C.

Example 16

A mixture of 2.8 parts 1-methoxy-2-methyl-α-phenyl-1H-benzimidazole-5-methanol, 1.95 parts 1,1'-carbonylbis [1H-imidazole] and 72 parts tetrahydrofuran Stir at reflux for 17 h. After evaporation, the residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue was again purified twice by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 95: 5)]. The pure fractions are combined and the eluent is evaporated to yield 2 parts (59.8%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -1-methoxy-2-methyl-1H-benzimidazole. (Compound 25).

In a similar manner, the following compounds are prepared.

Example 17

A mixture of 3 parts 1-methoxy-α, 2-dimethyl-1H-benzimidazole-6-methanol, 2.73 parts 1,1'-carbonylbis [1H-imidazole] and 90 parts tetrahydrofuran was refluxed at Stir for 17 hours. The tetrahydrofuran layer is evaporated in vacuo and the residue is dissolved in 90 parts of methylbenzene. After stirring for 3 hours at reflux, the mixture is evaporated and the residue is purified by silica gel column chromatography [mixture of eluent: trichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue was dried in vacuo to yield 1.2 parts (32.0%) of 6- [1- (1H-imidazol-1-yl) ethyl] -1-methoxy-2-methyl-1H-benzimidazole as an oil residue. (Compound 38).

Example 18

A mixture of 9 parts 4- [1- (1H-imidazol-1-yl) heptyl] -1,2-benzenediamine, 5 parts 4-fluorobenzoic acid and 100 parts polyphosphoric acid is stirred at 100 ° C. for 2 hours. . Cool and pour the reaction mixture into ice water and treat with ammonium hydroxide. The product is extracted three times with 120 parts trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 98: 2)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized with a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered and dried to give 5.8 parts (47%) of 2- (4-fluorophenyl) -5- [1- (1H-imidazol-1-yl) heptyl] -1H-benzimidazole ( Compound 39); Melting point: 121.9 ° C.

In a similar manner, the following compounds are prepared.

Example 19

A mixture of 3.6 parts of 4- [1- (1H-imidazol-1-yl) ethyl] -1,2-benzenediamine, 5 parts of trifluoroacetic acid and 100 parts of hydrochloric acid solution (4N) was added at reflux for 6 hours. Stir. The reaction mixture is concentrated to dissolve the concentrate in 50 parts of water. The mixture is alkalized with sodium bicarbonate and the product is extracted with dichloromethane. The extract is dried, filtered, evaporated and concentrated. The concentrate is purified by silica gel column chromatography [mixture of eluent: trichloromethane and methanol (volume ratio of 97.5: 2.5)]. Pure fractions are collected and the eluent is concentrated. The concentrate is crystallized with 20 parts ethyl acetate. The product was isolated by filtration and dried to afford 3.4 parts (69.3%) of 5- [1- (1H-imidazol-1-yl) ethyl] -2- (trifluoromethyl) -1H-benzimidazole. (Compound 64); Melting point: 164.6 ° C.

In a similar manner, the following compounds are prepared.

Example 20

A mixture of 10 parts 4 (1H-imidazol-1-ylmethyl-1,2-benzenediamine, 8 parts 1,3-isobenzofurandione and 80 parts hydrochloric acid solution (3N) is stirred at reflux for 4 hours. After cooling, the mixture is treated with 3N NaOH solution to adjust the pH to 5.5 The reaction mixture is evaporated to dryness The residue is dissolved in ethanol at 60 ° C. The mixture is filtered while hot and the filtrate is evaporated to dryness. Purification by silica gel column chromatography [Eluent: mixture of trichloromethane and methanol (volume ratio of 70: 30)] Collect the pure fractions and evaporate the eluent The residue is 2-propanol, water and 1,1 '. Convert to hydrochloride in oxybisethane, evaporate the mixture and solidify it by scratching in a mixture of 30 parts 2-propanol and 2-propanone The product is filtered off, dried and dried to 2.4 parts (10.5%). 2- [5- (1H-imidazole-1- Methyl] -1H- benzimidazol-2-yl] benzoic acid dihydrochloride, to give the dihydrate (compound 82); melting point: 245.0 ℃.

Example 21

A mixture of 6.1 parts 4- [1- (1H-imidazol-1-yl) propyl] -1,2-benzenediamine and 90 parts trifluoroacetic acid is stirred at 80 ° C. for 15 minutes. The reaction mixture is poured onto ice cubes and treated with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonium hydroxide (volume ratio of 90: 10: 1)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane (4 parts to 17.5 parts). The product was isolated by filtration and dried to afford 1.8 parts (22%) of 5- [1- (1H-imidazol-1-yl) propyl] -2- (trifluoromethyl) -1H-benzimidazole. (Compound 83); Melting Point: 173.2 ℃

In a similar manner, the following compounds are prepared.

5- [1- (1H-imidazol-1-yl) -2-methylpropyl] -2- (trifluoromethyl) -1H-benzimidazole ethanedioate (1: 1), hemihydrate (compound 84 );

Melting point: 106.2 ° C .;

5- [1- (1H-imidazol-1-yl) heptyl] -2- (trifluoromethyl) -1H-benzimidazole ethanedioate (2: 3), hemihydrate (Compound 85);

Melting point: 96.2 ° C.

5- [1- (1H-imidazol-1-yl) heptyl] -1H-benzimidazole ethanedioate (1: 1) (Compound 86);

Melting point: 210.7 ° C and

5- [1- (1H-imidazol-1-yl) ethyl] -1-methyl-1H-benzimidazole ethanedioate (2: 5) (Compound 87);

Melting point: 166.5 ° C.

Example 22

A mixture of 5 parts 4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine, 5 parts ethyl 2-chlorobenzoate and 30 parts polyphosphoric acid was stirred at 140 ° C. for 4 hours and then 200 Mix with pour water and ice cubes. The mixture is treated with ammonium hydroxide. The product is extracted three times with 120 parts trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonium hydroxide (volume ratio of 90: 10: 0.05)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized with a mixture of 2-propanone and 1,1'-oxybisethane. The product is filtered, separated and dried in vacuo at 100 ° C. to give 2.1 parts (26%) of 2- (2-chlorophenyl) -5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole. (Compound 88); Melting point: 115.2 ° C.

In a similar manner, the following compounds are prepared.

2- (4-chlorophenyl) -5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole dihydrochloride, hemihydrate (Compound 89);

Melting point: 287.1 ° C .;

2- (4-chlorophenyl) -5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazole (Compound 90);

Melting point: 236.3 ° C .;

2- (2-fluorophenyl) -5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole hemihydrate (Compound 91);

Melting point: 156.1 ℃ and

2- (2-fluorophenyl) -5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazole ethanedioate (2: 3) (Compound 92);

Melting Point: 112.5 ℃

Example 23

2.99 parts of 4-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1,2-benzenediamine, 50 parts of trimethoxymethane and 2.4 parts of formic acid were stirred at room temperature for 16 hours do. The reaction mixture is evaporated and the residue is taken up in hydrochloric acid solution (2N). The solution is treated with ammonia to extract the product with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [mixture of eluent: trichloromethane, methanol and ammonia saturated methanol (volume ratio of 90: 5: 5)]. The pure fractions were combined and the eluent was evaporated to yield 1.8 parts (58.2%) of 5-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -1H-benzimidazole (Compound 93) ; Melting point: 108.2 ° C.

In a similar manner, the following compounds are prepared.

In a similar manner, the following compounds are also prepared.

1-cyclohexyl-6- (1H-imidazol-1-ylmethyl) -1H-benzimidazole (Compound 107);

6- (1H-imidazol-1-ylmethyl) -1-phenyl-1H-benzimidazole (Compound 108);

6- (1H-imidazol-1-ylmethyl) -1- (2-thienylmethyl) -1H-benzimidazole (Compound 109) and

5- [1- (1H-imidazol-1-yl) -2-phenylethyl] -1H-benzimidazole (Compound 110).

Example 24

A mixture of 2.64 parts of 4-[(1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine, 50 parts of trimethoxymethane and 1,2 parts of acetic acid is stirred and refluxed for 8 hours. The reaction mixture is evaporated in vacuo. The residue is dissolved in dilute hydrochloric acid. The solution is treated with ammonia and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonia saturated methanol (volume ratio of 90: 5: 5)]. Pure fractions are collected and the eluent is evaporated. The solid residue was washed with 2-propanone to give 1.8 parts (65%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazole (Compound 111); Melting Point: 186.2 ℃

In a similar manner, the following compounds are prepared.

5-[(1H-imidazol-1-yl) (3H-pyridinyl) methyl] -1H-benzimidazole (Compound 112);

Melting point: 186.2 ° C .;

5-[(1H-imidazol-1-yl) (2-thienyl) methyl] -1H-benzimidazole (Compound 113);

Melting point: 101.0 ℃ and

6- (1H-imidazol-1-ylmethyl) -1,2-dimethyl-1H-benzimidazole (Compound 114);

Melting point: 139.6 ° C.

Example 25

A mixture of 2.6 parts 4-[(1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine, 10 parts tetramethoxymethane, 0.6 parts acetic acid and 6.5 parts dichloromethane is stirred at room temperature for two days. The residue is treated with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue is purified again by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and methanol containing ammonia (volume ratio of 90: 5: 5)]. Pure fractions are collected and the eluent is evaporated. The residue was dried in vacuo to afford 1 part (32.8%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -2-methoxy-1H-benzimidazole (Compound 115); Melting point: 109.5 ° C.

Example 26

A mixture of 5.6 parts 4- (1H-imidazol- ¹ -ylmethyl) -N ^1- (3-pyridinylmethyl) -1,2-benzenediamine, 20 parts triethoxyethane, 2 parts acetic acid and 200 parts methanol It is stirred at reflux for 2 hours. The reaction mixture is evaporated. Methanol and ammonia saturated methanol are added. Evaporate the mixture. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonia saturated methanol (volume ratio of 88:10:10)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 40 parts of 4-methyl-2-pentanone. The product was filtered off and dried to afford 2.5 parts (41%) of 5- (1H-imidazol-1-ylmethyl) -2-methyl-1- (3-pyridinylmethyl) -1H-benzimidazole. (Compound 116); Melting point: 174.0 ° C.

In the same manner as above, the following compound is prepared using an equivalent amount of a suitable starting material.

5- (1H-imidazol-1-ylmethyl) -1- (3-pyridinylmethyl) -1H-benzimidazole (Compound 117); Melting point: 156.4 ° C.

Example 27

A mixture of 4.4 parts 4- [1-1H-imidazol-1-yl) 2-methylpropyl] -1,2-benzenediamine and 45 parts methyllidinetris (oxy) trisethane is stirred at reflux for 4 hours. . The reaction mixture is poured into 100 parts of water and the mixture is dried dry. After cooling, the residue is dissolved in trichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 98: 2)]. Pure fractions are collected and the eluent is evaporated. The residue is converted to an ethanedioate salt in 16 parts 2-butanone and 2-propanol. The salts are separated by filtration and crystallized from a mixture of methanol and propanol. The product was isolated by filtration and dried to give 2.5 parts (40%) of 5- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1H-benzimidazole ethanedioate (1: 1) To give (Compound 118); Melting point: 222.0 ° C.

In a similar manner, the following compounds are prepared.

5 [1- (1H-imidazol-1-yl) propyl] -1H-benzimidazole dihydrochloride (Compound 119); Melting point: 225.5 ° C. and 5- [1- (1H-imidazol-1-yl) pentyl] -1H-benzimidazole ethanedioate (2: 3) (Compound 120); Melting point: 148.8 deg.

Example 28

A mixture of 5.3 parts of 4- [1- (1N-imidazol-1-yl) -2-methylpropyl] -1,2-benzenediamine, 2.2 parts of fluoroacetamide and 80 parts of hydrochloric acid solution (20%) was prepared at room temperature. Stir for 12 h. After cooling, the reaction mixture is poured into ice water and the whole is treated with ammonium hydroxide. The product is extracted three times with 75 parts of trichloromethane. All extracts are dried, filtered and evaporated. The residue was purified by silica gel column chromatography [eluent; A mixture of trichloromethane and methanol (volume ratio of 95: 5). Pure fractions are collected and the eluent is evaporated. The residue is converted to ethanoate salt in ethanol. The salts are separated by filtration and crystallized from a mixture of 2-propanone and ethanol. The product was isolated by filtration and dried to 1.7 parts (20.3%) of 2- (fluoromethyl) -5- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1H-benzimidazole Ethanedioate (1: 1) is obtained (compound 121); Melting point: 191.6 deg.

Example 29

A mixture of 2.99 parts of 4-[(3-chlorophenyl)) (1H-imidazol-1-yl) methyl] -1,2-benzenediamine, 1.85 parts of ethyl ethanedioate hydrochloride and 40 parts of methanol was prepared at room temperature. Stir for hours. The solvent is evaporated and the residue is dissolved in dilute hydrochloric acid solution. The whole is alkalized with ammonia and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was subjected to silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonia saturated methanol (90: 5: 5 volume ratio)] 5-[(3-chlorophenyl) (1H-imidazol-1-yl ) Methyl] -2-methyl-1H-benzimidazole (Compound 122); Melting point: 177.1 ° C.

In a similar manner, the following was also made.

Prepare compounds in a similar manner.

1-cyclohexyl-6- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazole (Compound 164); 6- (1H-imidazol-1-ylmethyl) -2-methyl-1-phenyl-1H-benzimidazole (Compound 165); 6- (1H-imidazol-1-ylmethyl) -2-methyl-1- (2-thienylmethyl) -1H-benzimidazole (Compound 166) and 5- [1- (1H-imidazole-1 -Yl) -2-phenylethyl] -2-methyl-1H-benzimidazole (Compound 167).

Example 30

A mixture of 3.3 parts 4- (1H-imidazol-1-ylmethyl) -1.2-benzenediamine, 2.88 parts ethyl cyclopropanecarboxyimilate hydrochloride and 64 parts ethanol was stirred at room temperature for 4 hours and then at 1 reflux temperature. Stir for hours. The reaction mixture is cooled and treated with ammonia saturated methanol and then evaporated. The residue is purified twice by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio 90:10) first and mixture of trichloromethane and methanol (volume ratio 92: 8) secondly]. . Pure fractions are collected and the eluent is evaporated. The residue was crystallized with ethyl ethanol to yield 2.57 parts (61.6%) of 2-cyclopropyl-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole (Compound 168); Melting point: 184.3 ° C.

In a similar manner, the following compounds are also prepared.

In a similar manner, the following compounds are prepared.

6- (1H-imidazol-1-ylmethyl) -1,2-diphenyl-1H-benzimidazole (Compound 188).

Example 31

5.05 parts 4- [1- (1H-imidazol-1-yl) ethyl] -1,2-benzenediamine, 6.45 parts ethyl-3-pyridinecarboxyimilate dihydrochloride, 4.27 parts sodium acetate and 80 parts anhydrous ethanol The mixture is stirred at room temperature for 16 hours and then at reflux for 1 hour. The reaction mixture is evaporated. 50 parts of water and ammonium hydroxide are added continuously. The product is isolated by filtration, washed with water and 2-propanol and crystallized with ethanol. The product was isolated by filtration and dried to yield 5.1 parts (70%) of 5- [1- (1H-imidazol-1-yl) ethyl] -2- (3-pyridinyl) -1H-benzimidazole. (Compound 18

9); Melting point: 253.7 ° C.

In a similar manner, the following compounds are also prepared.

5-[(1H-imidazol-1-yl) phenylmethyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 190);

Melting point: 133.1 ° C .;

5- (1H-imidazol-1-ylmethyl) -2- (3-pyridinyl) -1-benzimidazole (Compound 191);

Melting point: 212.9 ° C .;

5- (1H-imidazol-1-ylmethyl) -2- (3-pyridinyl) -1- (3-pyridinylmethyl) -1H-benzimidazole (Compound 192);

Melting point: 179.7 ° C .;

5-[(1H-imidazol-1-yl (2-thienyl) methyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 193);

Melting point: 135.4 ° C .;

5-[(4-fluorophenyl) (1H-imidazol-1-yl) methyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 194);

Melting point: 237.6 ° C .;

5-[(1H-imidazol-1-yl) (3-pyridinyl) methyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 195);

5-[(3-chlorophenyl) (1H-imidazol-1-yl) methyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 196);

Melting point: 232.0 ° C .;

5- [bis (1H-imidazol-1-yl) methyl] -2- (3-pyridinyl) -1H-benzimidazole (Compound 197);

Melting point: 271.0 ° C .;

5- [1- (1H-imidazol-1-yl) ethyl] -2- (4-pyridinyl) -1H-benzimidazole (Compound 198);

Melting point: 205.6 ° C .;

(E) -2- [2- (2-furanyl) ethenyl] -5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazole (Compound 199);

Melting point: 134.7 ℃ and

(E) -5-[(1H-imidazol-1-yl) phenylmethyl] -2- (2-phenylethenyl) -1H-benzimidazole (Compound 200);

Melting point: 140.6 ° C.

Example 32

To a stirring and cooling solution of 5.3 parts of 40-[(1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine in 50 parts of acetic acid is added 3.3 parts of methyl 2-pyridinecarboximilate with stirring. . The whole is stirred at room temperature for 8 hours and then left for two days. The reaction mixture is evaporated. The residue is dissolved in water and treated with activated carbon. The whole is filtered and the filtrate is alkalized with ammonium hydroxide. The product is isolated by filtration and purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue was dried in vacuo at 50 ° C. for 24 hours to afford 2.8 parts (40%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -2- (2-pyridinyl) -1H-benzimidazole. To give (Compound 201); Melting point 123.3 ° C.

Example 33

2.75 parts N ^2- (cyclohexylmethyl) -4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine, 1.85 parts methyl 2,2,2-trifluoroethaneimidate, 40 parts A mixture of methanol and 2.3 parts trifluoroacetic acid is stirred at room temperature for 7 hours. The reaction mixture is alkalized with ammonia saturated methanol. The solvent is evaporated in vacuo and the residue is purified by silica gel column chromatography [eluent: mixture of trifluoro and methanol (volume ratio of 95: 5)]. Pure fractions are collected and the eluent is evaporated in vacuo. The residue is taken up in 11 parts of 2.2'-oxybispropane. The crystallized product was isolated by filtration and dried to give 1.9 parts (52.4%) of 1- (cyclohexylmethyl) -6- (1H-imidazol-1-ylmethyl) -2- (trifluoromethyl) -1H- Benzimidazole is obtained (Compound 202). Melting point: 165.4 占 폚.

In a similar manner, the following compounds are prepared.

5-[(1H-imidazol-1-yl) (3-pyridinyl) methyl] -2- (trifluoromethyl) -1H-benzimidazole (Compound 203); Melting point 124.9 to 131.5 ° C. and 6- (1H-imidazol-1-ylmethyl) -1- (phenylmethyl) -2- (trifluoromethyl) -1H-benzimidazole (Compound 204); Melting point: 120.7 ° C.

Example 34

A mixture of 5 parts 4- (1H-imidazol-1-ylmethyl) -1,2-benzenediamine, 3 parts 3-thiophenecaraldehyde and 50 parts hydrochloric acid solution (3N) was stirred at reflux for 36 hours. do. After cooling, poured into 100 parts ice cubes and ammonium hydroxide. The product is extracted three times with 75 parts of trichloromethane. The combined extracts are dried, filtered and evaporated. The residue is purified by silica gel column chromatography (HPLC) [eluent: mixture of trichloromethane, methanol and ammonium hydroxide (volume ratio of 90: 10: 0.1)]. Pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride at 0 ° C. in 8 parts 2-propanone and ethanol. The salts are separated by filtration and crystallized with a mixture of methanol and 2-propanone. The product was isolated by filtration and dried to afford 0.8 part (8.5%) of 5- (1H-imidazol-1-ylmethyl) -2- (3-thienyl) -1H-benzimidazole dihydrochloride ( Compound 205); Melting point:> 300 ° C. (decomposition).

Example 35

7. A mixture of 4 parts of N- [2-amino-4- [1- (1H-imidazol-1-yl) ethyl] phenyl] acetamide, 10 parts of acetic acid and 100 parts of hydrochloric acid solution (4N) is stirred and 3.5 hours Reflux. The reaction mixture is evaporated. It is dissolved in 20 parts of 2-propanol. The product is crystallized at room temperature. The product was filtered off and dried to yield 8.1 parts (90.2%) of 5 [1- (1H-imidazol-1-yl) ethyl] -2-methyl-1H-benzimidazole dihydrochloride (Compound 206) ;

Melting point: 236.2 ° C.

In a similar manner, the following compounds are prepared.

5- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazole dihydrochloride (Compound 207);

Melting point: 257.4 ℃ and

5- [1- (1H-imidazol-1-yl) ethyl] -1H-benzimidazole dihydrochloride (Compound 208);

Melting point: 224.5 ° C.

Example 36

A mixture of 13.2 parts 1-[(4-fluoro-3-nitrophenyl) methyl] -1 H-imidazole, 13 parts 4-pyridinemethaneamine and 80 parts ethanol is stirred at 60 ° C. for 6 hours. After adding 14.5 parts of sodium hydroxide, the whole is stirred at 60 ° C. for 30 minutes. The reaction mixture is evaporated. Dissolve the residue in 100 parts of water. Hydrochloric acid is added dropwise to adjust the pH of the solution to 6-7. The product is isolated by filtration, washed with water and 2-propanol and crystallized with 80 parts 2-propanol. The product was isolated by filtration and dried to afford 10.7 parts (61%) of 6- (1H-imidazol-1-ylmethyl) -2- (4-pyridinyl) -1H-benzimidazol-1-ol. (Compound 209); Melting point: 198.1 ° C.

Example 37

To a stirring mixture of 5.1 parts of 4-fluoro-N- [4- (1H-imidazol-1-ylethyl) -2-nitrophenyl] benzenemethanamine and 80 parts of methanol was added 2.6 parts of sodium hydroxide, and 10 at room temperature. Stirring is continued for minutes and at reflux for 20 hours. After cooling, the reaction mixture is neutralized with hydrochloric acid solution (2N). The precipitated fish was isolated by filtration, and then water, methylbenzene and 2,2'-oxybispropane were washed sequentially and dried to give 4.2 parts (91%) of 2- (4-fluorophenyl) -6- (1H- To give imidazol-1-ylmethyl) -1H-benzimidazol-1-ol (Compound 210); Melting point: 82 ° C.

In a similar manner, the following compounds are prepared.

6- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazol-1-ol monohydrate (Compound 211);

Melting point: 136.8 ° C .;

6- (1H-imidazol-1-ylmethyl) -2- (3-pyridinyl) -1H-benzimidazol-1-ol (Compound 212);

Melting point: 207.5 ° C .;

2- (4-fluorophenyl) -6-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazol-1-ol (Compound 213);

Melting point: 150 ° C .;

6- [1- (1H-imidazol-1-yl) ethyl] -2-phenyl-1H-benzimidazol-1-ol ethanedioate (2: 3) (Compound 214);

Melting point: 179.6 ° C .;

2- (4-fluorophenyl) -6-di- (1H-imidazol-1-yl) ethyl] -1H-benzimidazol-1-ol (Compound 215) as residue;

2- (4-fluorophenyl) -6- [1- (1H-imidazol-1-yl) -2-methylpropyl] -1H-benzimidazol-1-ol (Compound 216);

Melting point 271.2 ° C .;

6- [1- (1H-imidazol-1-yl) -2-methylpropyl] 2-phenyl-1H-benzimidazol-1-ol (Compound 217);

Melting point: 208.2 ℃ and

5- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazol-1-ol (Compound 218);

Melting point: 203.1 캜.

Example 38

4.9 parts N- [4-[(1H-imidazol-1-yl) phenylmethyl] -2-nitrophenyl] acetamide, a mixture of 12 parts hydrogen chloride saturated 2-propanol and 200 parts methanol, 2 parts platinum-charcoal (5%) The catalyst was hydrogenated at atmospheric pressure and room temperature. When the calculated amount of hydrogen is consumed, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in dichloromethane and water and the solution is neutralized with ammonium hydroxide solution. The dichloromethane layer is separated, dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 85:15)]. The pure fractions were combined and the eluent was evaporated to yield 2.2 parts (40.6%) of 6-[(1H-imidazol-1-yl) phenylmethyl] -2-methyl-1H-benzimidazol-1-ol as a residue. (Compound 219).

In a similar manner, the following compounds are prepared.

6- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazol-1-ol (Compound 220); Melting point: 224.9 ° C. and 5- (1H-imidazol-1-ylmethyl) -2-methyl-1H-benzimidazol-1-ol dihydrochloride (Compound 221).

Example 39

4.04 parts 4- (1H-imidazol-1-ylmethyl) -N'-methyl-1,2-benzenediamine, 3.6 parts 1,1'-carbonylbis [1H-imidazole] and 80 parts tetrahydrofuran The mixture is stirred at room temperature for 100 hours. The precipitate formed was filtered, washed with tetrahydrofuran, dried and purified twice with a mixture of silica gel column chromatography [eluent: trichloromethane, methanol and ammonia saturated methanol (volume ratio of 90: 5: 5, respectively), respectively. do. Pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2-propanol. The product was isolated by filtration, washed with 2-propanol and 2,2'-oxybispropane and then dried to 3.5 parts (77%) of 5- (1H-imidazol-1-ylmethyl) -1-methyl To obtain -1H-benzimidazol-1-ol (Compound 222); Melting point: 207.2 ° C.

In a similar manner, the following compounds are prepared.

1,3-dihydro-5-[(1H-imidazol-1-yl) phenylmethyl] -2H-benzimidazol-2-one (Compound 223);

Melting point: 162.1 ° C and

5-[(3-chlorophenyl) (1H-imidazol-1-yl)] methyl-1,3-dihydro-2H-benzimidazol-2-one (Compound 224);

Melting point: 172.0 ° C.

Example 40

5.28 parts of a mixture of 4- [1H-imidazol-1-yl) phenylmethyl] -1,2-benzenediamine, 2,31 parts of carbon disulfide, 80 parts of ethanol, 1.68 parts of potassium hydroxide, and 11 parts of water at a reflux temperature of 3 Stir for hours. After evaporation, 100 parts of water are added to the residue and the mixture is neutralized with 1.8 parts of 0.03 M acetic acid solution. After stirring, the resulting precipitate was isolated by filtration, washed with 2-propanone and dried to give 4.3 parts (70.1%) of 5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benz To give imidazole-2-thiol (Compound 225); Melting point: 260.1 ° C.

Example 41

4.5 parts 5- (1H-imidazol-1-ylmethyl) -1-methyl-1H-benzimidazol-2-ol. A mixture of 0.46 parts sodium hydride dispersion (50%) and 56 parts N, N-dimethylformamide is stirred at 50 ° C. for 30 minutes. 2.53 parts of (chloromethyl) benzene are added and then stirred at 50 ° C. for 2 hours. The N, N-dimethylformamide layer is evaporated in vacuo. The residue is diluted with water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 27 parts ethyl acetate and 44 parts 2,2'-oxybispropane. The product was isolated by filtration and dried to give 5 parts (78.5%) of 1,3-dihydro-5- (1H-imidazol-1-ylmethyl) -1-methyl-3- (phenylmethyl) -2H-benz To give imidazol-2-one (Compound 226); Melting point: 129.4 ° C.

Example 42

6.16 parts of 6- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazole-1-in the above prepared stirred sodium methoxide solution using 0.46 parts of sodium and 32 parts of methanol as starting materials. Add ol. Stirring was continued for a while, and the whole was concentrated. Then, 18 parts of methylbenzene was added in two portions. After evaporation, a solution of 17 parts of N, N-dimethylformamide and 2.84 parts of iodine methane dissolved in 9 parts of N, N-dimethylformamide was added sequentially. The mixture is stirred at room temperature for 10 minutes and then at 60 ° C. for 30 minutes. The reaction mixture is evaporated and 50 parts of water is added to the residue. The precipitated product is isolated by filtration and washed with water and then purified by filtration through silica gel [a mixture of eluent: trichloromethane and methanol (volume ratio of 92.5: 7.5)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized with 2.2'-oxybispropane. The product was isolated by filtration and dried to give 5.4 parts (88.7%) of 6- (1H-imidazol-1-ylmethyl) -1-methoxy-2-phenyl-1H-benzimidazole (Compound 227) ; Melting point: 142.1 ° C.

In a similar manner, the following compounds are prepared.

Example 43

2.7 parts 2- (4-fluorophenyl) -6-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazol-1-ol, 7 parts aqueous sodium hydroxide solution (1N) and 20 parts The mixture of methanol is stirred at room temperature for 15 minutes. After evaporation, the residue is dissolved in methylbenzene and the solvent is evaporated (this process is repeated twice). The residue is dissolved in 22.5 parts of N, N-dimethylformamide, and 0.89 parts of (chloromethyl) benzene is dissolved in a small amount of N, N-dimethylformamide and added dropwise. After dropping, stir at room temperature for 1 hour. After standing overnight at room temperature, the solvent is evaporated. Water is added to the residue and the product is extracted with dichloromethane. The extract is dried, filtered and concentrated. The concentrate is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized with 17.5 parts of 2-propanol. The product was isolated by filtration, washed with 2,2'-oxybispropane and 2-propane and dried to 2.1 parts (63.5%) of 2- (4-fluorophenyl) -6-[(1H-imidazole- 1-yl) phenylmethyl] -1- (phenylmethoxy) -1H-benzimidazole (Compound 241); Melting point: 177.6 ° C.

In a similar manner, the following compounds are prepared.

2- (4-fluorophenyl) -6-[(1H-imidazol-1-yl) phenylmethyl] -1- (2-propynyloxy) -1H-benzimidazole (Compound 242); Melting point: 152.4 ° C .; 2- (4-fluorophenyl) -6-[(1H-imidazol-1-yl) phenylmethyl] -1- (2-propenyloxy) -1H-benzimidazole (Compound 243); Melting point: 109.8 ° C .; 2- (4-fluorophenyl) -6- (1H-imidazol-1-ylmethyl) -1- (phenylmethoxy) -1H-benzimidazole (Compound 244); Melting Point: 130.9 ° C. and 2- (4-Pluorophenyl) -6- (1H-imidazol-1-ylmethyl) -1-yl (2-propenyloxy) -1H-benzimidazole (Compound 245) ; Melting point: 97.2 ° C.

In a similar manner, the following compounds are also prepared.

6- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (2-thienylmethoxy) -1H-benzimidazole (Compound 246); 6- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (3-pyridinylmethoxy) -1H-benzimidazole (Compound 247); 1- (cyclohexylmethoxy) -6- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazole (Compound 248); 6- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (3-phenyl-2-propenyloxy) -1H-benzimidazole (Compound 249); 6- (1H-imidazol-1-ylmethyl) -2-phenyl-1- (2-propynyloxy) -1H-benzimidazole (Compound 250) and 6- (1H-imidazol-1-ylmethyl ) -2-phenyl-1- (2-pyrimidinyloxy) -1H-benzimidazole (Compound 251).

Example 44

2.7 parts 6- [1- (1H-imidazol-1-yl) ethyl] -2-phenyl-1H-benzimidazol-1-ol, 0.2 parts sodium hydride dispersion (50%) and 56 parts N, N- The mixture of dimethylformamide is stirred at 60 ° C. for 30 minutes. Then 0.5 parts of 2- (2-methoxyethoxy) -N, N-bis [2- (2-methoxyethoxy) ethyl] ethanamine and 1.11 parts of (chloromethyl) benzene were added and the whole was heated at 50 ° C. Stir for 3 hours. The N, N-dimethylformamide layer is evaporated. The residue is dissolved in hydrochloric acid solution (1N). The whole is washed with methylbenzene and treated with ammonium hydroxide solution. The product is extracted with methylbenzene and the extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and ammonia saturated methanol (volume ratio of 95: 5)]. Pure fractions are collected and the eluent is evaporated. The residue is converted to nitrate in 64 parts of ethyl acetate. Drying in vacuo gave 3.3 parts (72.0%) of 6- [1- (1H-imidazol-1-yl) ethyl] -2-phenyl-1- (phenylmethoxy) -1H-benzimidazole dinitrate (Compound 252); Melting point: 180.6 ° C.

Example 45

A mixture of 3 parts 5- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazol-1-ol and 47 parts N, N-dimethylformamide is stirred until a clear solution is obtained. . 0.5 part sodium hydride dispersion (50%) is added in small portions and stirring is continued until hydrogen evolution is complete. 1.2 parts of (chloromethyl) benzene are then added all at room temperature. After the addition, the N, N-dimethylformamide layer is evaporated. The residue is dissolved in water and the product is extracted with a mixture of methylbenzene and trichloromethane and methanol (volume ratio of 90:10). The combined extracts are dried, filtered and then evaporated. The residue is purified by silica gel column chromatography [mixture of eluent: trichloromethane and methanol (volume ratio of 95: 5)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethyl acetate. The product was isolated by filtration, washed with a small amount of ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 50 ° C. to 2.64 parts (66.7%) of 5- (1H-imidazol-1-ylmethyl) 2-Phenyl-1- (phenylmethoxy) -1H-benzimidazole is obtained (Compound 253).

In a similar manner, the following compounds are prepared.

1-ethoxy 5- (1H-imidazol-1-ylmethyl) -2-phenyl-1H-benzimidazole (Compound 254);

Melting point: 112.9 ℃ and

5- (1H-imidazol-1-ylmethyl) -1-methoxy-2-phenyl-1H-benzimidazole (Compound 255);

Melting point: 106.7 ° C.

Example 46

To a mixture of 14.5 parts 1,3-dihydro-5-[(1H-imidazol-1-yl) methyl] -2H-benzimidazol-2-one and 255 parts phosphoryl chloride, add hydrogen chloride gas at 90 ° C. Infuse daily. The resulting solution is evaporated and 300 parts of ice water is added to the residue. Ammonium hydroxide is added dropwise to alkalinize the solution and precipitate the product. This was isolated by filtration (filtrate stored separately), washed with water and dried in vacuo to yield 14.1 parts of 2-chloro-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole as a first fraction. (Compound 256). The aqueous filtrate is salted out with potassium carbonate and extracted with dichloromethane. The organic extracts are dried, filtered and evaporated. The residue was dried in vacuo to afford 1.4 parts of 2-chloro-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole as a second fraction (Compound 256).

Total yield: 15.5 parts (98.4%) of 2-chloro-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole (Compound 256).

In a similar manner, the following compounds are prepared. 2-Chloro-5- (1H-imidazol-1-ylmethyl) -1-methyl-1H-benzimidazole (Compound 257) as a residue.

Example 47

A mixture of 4.4 parts 1H-imidazole and 5 parts 2-chloro-5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole is melted at 140 ° C. for 1 hour. The sticky mixture is dissolved in a mixture of ethanol and potassium carbonate. The supernatant is decanted and evaporated to dryness. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane, methanol and ammonium hydroxide (volume ratio of 90: 10: 0.1)]. Pure fractions are collected and the eluent is evaporated. The residue is dissolved in 15 parts of water. The product was isolated by filtration and crystallized with a mixture of methanol and ethyl acetate to give 0.95 parts (17%) of 2- (1H-imidazol-1-yl) -5- (1H-imidazol-1-ylmethyl) -1H -Benzimidazole is obtained (Compound 258); Melting point: 226.2 ° C.

Example 48

A mixture of 3 parts ethyl 4- [5- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl] benzoate and 50 parts hydrochloric acid solution (6N) is stirred and stirred for 12 hours. . The reaction mixture is evaporated to dryness. The residue is dissolved in 2 parts of water and 2-propanone. The product was isolated by filtration and dried to give 2 parts (59%) of 4- [5- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl] benzoic acid dihydrochloride. Monohydrate is obtained (Compound 259); Melting point: 288.2 캜.

In a similar manner, the following compounds are prepared.

3- [5- (1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl] benzoic acid dihydrochloride. Hemihydrate (Compound 260); Melting point: 283.0 ° C.

Example 49

A mixture of 2.4 parts ethyl 4- [5-[(1H-imidazol-1-ylmethyl) -1H-benzimidazol-2-yl] benzoate and 30 parts sodium hydroxide solution (3N) was stirred at room temperature for 12 hours. Stir. The mixture is poured into 50 parts of ice water and acidified with sulfuric acid to pH 5.5. The product is extracted with a mixture of trichloromethane and methanol. The extract is dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of trichloromethane and methanol (volume ratio of 80:20)]. Pure fractions are collected and the eluent is evaporated. The residue is converted to hydrochloride in 2-propanol. The mixture is evaporated to dryness and the residue is dissolved in a mixture of 2-propanol, water and 2-propanone. The product was isolated by filtration and dried to 1.41 parts (49.1%) of 4-[(5- (1H-imidazol-1-yl) phenylmethyl) -1H-benzimidazol-2-yl] benzoic acid dihydrochloride. Hydrate (2: 5) is obtained (compound 261): Melting point: 225.5 占 폚.

In a similar manner, the following compounds are prepared.

4- [5- [1- (1H-imidazol-1-yl) ethyl] -1H-benzoimidazol-2-yl] benzoic acid dihydrochloride. Monohydrate (Compound 262); Melting point: 260.8 ° C. and 4- [5-1- (1H-imidazol-1-yl) ethyl] -methyl-1H-benzimidazol-2-yl] benzoic acid dihydrochloride. Dihydrate (Compound 263); Melting point: 182.9 ° C.

Example 50

A mixture of 1.5 parts of 5-[(1H-imidazol-1-yl) phenylmethyl] -α-phenyl-1H-benzimidazole-2-methanol, 1.4 parts of potassium dichromate and 25 parts of acetic acid for 45 minutes at room temperature Stir. Water is added to the mixture and the whole is alkalized with concentrated ammonium hydroxide solution. The product is extracted with a mixture of trichloromethane and methanol (volume ratio of 95: 5). The extract is dried and evaporated. The residue was purified by silica gel column chromatography [eluent; A mixture of trichloromethane, methanol and ammonia saturated methanol (volume ratio of 90: 5: 5)] twice. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 63 parts of ethyl acetate. The product was isolated by filtration and dried at 100 ° C. for 17 hours to yield 0.8 parts (54%) of [5-[(1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazol-2-yl] phenyl To obtain methanone (compound 264); Melting point: 223.3 ° C.

Example 51

11.1 parts of potassium permanganate is added dropwise to a stirring and heating (60 ° C.) solution of 8 parts of 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-methanol, 4.7 parts of potassium carbonate and 100 parts of water. . After the addition is completed, stirring is continued at 60 ° C. for 15 minutes. Manganese oxide (IV) is filtered through diatomaceous earth. After cooling, the filtrate is adjusted to pH 5.5 with glacial acetic acid. The whole is evaporated to dryness. The residue is dissolved in a small amount of water. The product was isolated by filtration and dried for 24 hours to yield 3.1 parts (31.8%) of 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylic acid dihydrate (compound 265).

In a similar manner, 5- [1- (1H-imidazol-1-yl) ethyl] -1H-benzimidazole-2-carboxylic acid is prepared as a residue (Compound 266).

Example 52

A mixture of 2.3 parts 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylic acid and 80 parts thionyl chloride is stirred at reflux for 3 hours. The reaction mixture was evaporated to dryness and 4.3 parts 3,9-bis (1H-imidazol-1-yl-methyl) -6H, 13H-pyrazino [1,2-a: 4,5-a] bisbenzimidazole- 6,13-dione is produced and poured into a mixture of 3.8 parts sodium methoxide in 40 parts methanol. The whole is stirred at room temperature for 1 hour. The whole is neutralized with 10 parts of acetic acid and evaporated to dryness. The concentrate is dissolved in 10% sodium bicarbonate solution and the product is extracted with a mixture of dichloromethane and methanol (volume ratio of 90:10). The combined extracts are dried, filtered and evaporated. The residue is purified by silica gel column chromatography [eluent: mixture of dichloromethane and methanol (volume ratio of 90:10)]. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanone. The product was isolated by filtration and dried to afford 0.7 parts (26.9%) of methyl 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylate (Compound 267); Melting point 228 ° C.

In a similar manner, the following compounds are prepared.

Methyl 5- [1- (1H-imidazol-1-yl) ethyl] -1H-benzimidazole-2-carboxylate (Compound 268); Melting point 161.5 ° C.

Example 53

A solution of 0.7 parts methyl 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylate in 2.7 parts sodium hydroxide solution (1N) is stirred at 20 ° C. for 3 hours. After adding ethanol the whole is evaporated to dryness below 60 ° C. The residue is dissolved in 2-propanone. The product was isolated by filtration and dried at 80 ° C. for 1 hour to yield 0.7 parts (94.8%) of sodium 5- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-2-carboxylate hemihydrate. To give (Compound 269); Melting point 253.3 ° C.

In a similar manner, the following compounds are prepared.

Sodium 5- [1- (1H-imidazol-1-yl) ethyl] -1H-benzimidazole-2-carboxylate (Compound 270); Melting point: 245.6 ° C.

Example 54

3.2 parts (+)-2-methyl-5-[(2- (methylthio) -1H-imidazol-1-yl) phenylmethyl] -1H-benzimidazole, 0.1 part Raney-nickel catalyst and 200 parts methanol Stir at reflux for 3 hours. The reaction mixture was heated, filtered through diatomaceous earth, washed with boiling ethanol and the filtrate was evaporated to yield 1.5 parts (52.0%) of (+)-5-[(1H-imidazol-1-yl) phenylmethyl)] as a residue. 2-Methyl-1H-benzimidazole is obtained (Compound 271).

In a similar manner, the following compounds are prepared.

(-)-5-[(1H-imidazol-1-yl) phenylmethyl] -2-methyl-1H-benzimidazole (Compound 272) as a residue.

C. Pharmacological Examples

Useful inhibition of androgen hormone biosynthesis of compounds of formula (I) is demonstrated by the following test method.

Example 55

Porcine testicle microsome test

For example, cytochrome P-450 isozyme in subcellular fractions (eg, pig testicular microsomes, adrenal cortex microsomes and bovine adrenal cortex mitochondria) isolated from compounds of formula (I) (the cyt. Spectral changes can be analyzed in cytochrome P-450 (cyt P-450) induced by the interaction of -450 isozyme.

Piglets (up to 21 days) testicles are castrated. The sample is stripped, crushed and washed in 0.15 M KCl and homogenized in 2 volumes (initial volume) of 0.25M sucrose containing 20mM KCl, 1mM EDTA and 20mM Tris-buffer (pH 7.4). The homogenate is centrifuged at 1500 g for 10 minutes and the supernatant from which cells have been removed is centrifuged at 10,000 g for 20 minutes. The agglomerated mitochondrial fraction is removed and the microsomal membrane is collected by centrifugation at 105,000 g for 60 minutes. Pellets containing microsomal membranes are suspended in 0.1 M potassium phosphate buffer (pH 7.4) and stored at -80 ° C. Cytochrome P-450 (cyt. P-450) content can be examined by measuring the spectral difference of the reduced carbon monoxide at an absorption coefficient of 91 cm ^-1 mM ^-1 . An absorbance increase of 450 nm to 490 nm is used to calculate the cytochrome P-450 content. The interaction of cytochrome P-450 isozyme in the isolated membrane fraction with the compound of formula (I) was examined by measuring the spectral change of cytochrome P-450 induced by the action of the compound of formula (I). can do. This membrane fraction is diluted in 0.1 M potassium phosphate buffer (pH 7.4) to give a component having a cytochrome P-450 content of 0.1 nmol / ml. The suspension is divided into cuvettes for comparison and sample. Obtain the same absorption baseline. The compound of formula (I) dissolved in dimethyl sulfoxide (DMSO) is added to the sample cuvette with increasing concentration while the same amount of DMSO is added to the comparative cuvette. Cytochrome P-450 isozyme is reduced with a small amount of sodium dithionite. Blow carbon monoxide into the cuvette for 30 seconds and seal the cuvette. After addition of the reducing agent dithionite and saturation with carbon monoxide, the reduced cytochrome P-450 complex shows a representative spectrum with an absorption peak at 450 nm. However, if the cytochrome P-450 isozyme is reduced and contacted with a compound of formula (I) before saturation with carbon monoxide, a small absorption peak appears at 450 nm after carbon monoxide treatment. The spectral difference thus obtained is recorded 30 seconds after the addition of the reducing agent.

The non-linear regression method is used to fix the sigmoidal dose-response model for individual observations, and the corresponding IC ₅₀ value (peak height in the Soret band of the reduced CO-complex is 50%). Reduced value). The IC ₅₀ value of several compounds of the general formula (I) is shown in Table 1 (a).

Example 56

In vivo testosterone test

Test compounds are orally administered to male rats as solutions or suspensions in aqueous medium. One hour after test or placebo administration, luteinizing hormone-releasing hormone analogs are injected intramuscularly and anesthetics are administered intraperitoneally. After 2 hours of oral administration of test compounds, the test rats are cut off and blood is collected on heparin. Bloodwell testosterone concentrations are measured according to standard radio-immunological methods. The 50% inhibition of placebo value is taken as the criterion of testosterone inhibitory activity. The value of ED ₅₀ is determined by probit analysis. The value of said ED ₅₀ for several compounds of general formula (I) is shown in column (b) of Table 1. The results shown in this table are intended to illustrate useful pharmacological properties for the compounds of the present invention and are by no means limiting of the present invention.

D. Composition Examples

The following formulations illustrate representative pharmaceutical compositions in dosage unit form according to the invention suitable for systemic administration to an animal or human. The active ingredient used throughout the examples below is a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Example 57

ORAL DROPS

500 g of A.I were dissolved in 0.5 L of 2-hydroxypropanoic acid and 1.5 L of polyethylene glycol at 60-80 ° C. After cooling to 30-40 [deg.] C., 35 liters of polyethylene glycol was added thereto, and the mixture was thoroughly stirred. Then, a solution of 1750 g of sodium saccharin in 2.5 liters of purified water was added thereto, and while stirring, an appropriate amount of polyethylene glycol was added to the volume of 2.5 liters and 50 liters of cocoa fragrance to add A.I. An oral dropping agent solution containing 10 mg was obtained. The resulting solution was charged to a suitable container.

Example 58

Oral solution

9 g of methyl-4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 L of boiling purified water. After dissolving 10 g of 2,3-dihydroxybutanedioic acid in 3 L of this solution, the A.I. 20 g was dissolved. The latter solution was combined with the rest of the former solution, to which 12 l of 1,2,3-propanetriol and 3 l of 70% sorbitol solution were added. 40 g of sodium saccharin was dissolved in 0.5 L of water and 2 ml of raspberry and 2 ml of gooseberry essence were added. The latter solution is combined with the former solution, and an appropriate amount of water is added so that the volume is 20 liters, per teaspoon amount (5 ml), A.I. An oral solution containing 5 mg was obtained. The resulting solution was filled into a suitable container.

Example 59

Capsule

A.I. 20 g, 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide and 1.2 g magnesium stearate were vigorously stirred together. The resulting mixture was then separated into A.I. 1000 suitable hard gelatin capsules were charged to contain 20 mg each.

Example 60

Film-coated tablets

Preparation of Purified Nuclei

A mixture of 100 g of AI, 570 g of lactose and 200 g of starch is mixed well, then 5 g of sodium dodecyl sulfate and about 200 ml of polyvinylpyrrolidone (Kollidon K90) in about 200 ml of water. ) Was wetted with 10 g of solution. The wet powder mixture is sieved, dried and sifted again. Thereafter, microcrystalline cellulose (Avicel ) 100 g and hydrogenated vegetable oil (Sterotex 15 g was added. The whole was mixed well and compressed into 10,000 tablets containing 10 mg of active ingredient per tablet.

covering

Methyl cellulose in 75 ml of denatured ethanol (Methocel 60HG Ethyl cellulose (Ethocel 22cps) in 150 ml of dichloromethane in a 10 g solution ) 5 g of solution was added. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. 10 g of polyethylene glycol was melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former solution, followed by 2.5 g magnesium octadecanoate, 5 g polyvinylpyrrolidone and concentrated pigment suspension (Opaspray K-1-2109). ) 30 ml was added and the whole was homogenized. The mixture thus obtained was coated with tablet nuclei in a coating apparatus.

Example 61

Injectable Solution

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate were dissolved in about 0.5 liter of boiling water for injection. After cooling to about 50 ° C., 4 g of lactic acid, 0.05 g of propylene glycol and 4 g of active ingredient were added with stirring. The solution was cooled to room temperature and supplemented with an appropriate amount of water for injection to make 1 liter to obtain a solution containing 4 mg of active ingredient per ml. The solution was sterilized by filtration (U.S.P.XVIII p.811) and filled into sterile containers.

Example 62

Suppository

3 g of AI was dissolved in a solution of 3 g of 2,3-dihydroxybutanedioic acid in 25 ml of polyethylene glycol 400. Surfactant (SPAN Triglycerides (Witepsol 555) to fill 12 g and 300 g ) Were melted together. The latter mixture was mixed well with the former solution. The mixture thus obtained was poured into a mold at a temperature of 37 to 38 ° C. to prepare 100 suppositories containing 30 mg of each active ingredient per ml.

Claims (2)

A compound of formula (I), a pharmaceutically acceptable compound thereof, characterized by reacting benzimidazole of formula (IV) with 1,1'-carbonylbis [1H-imidazole] in a reaction-inert medium Methods for preparing acid addition salts, metal substitution salts or stereochemical isomers thereof: Wherein R is hydrogen; C_1-10Alkyl; C_3-7Cycloalkyl; Ar^OneOr Ar^One-C_1-6Alkyl, R^OneSilver hydrogen; C_3-7Cycloalkyl; Ar^One; C_1-10Alkyl; Ar^OneOr C_3-7C substituted by cycloalkyl_1-6Alkyl; Hydroxy; C_1-10Alkyloxy; Ar^OneOr C_3-7C substituted by cycloalkyl_1-6Alkyloxy; Ar²C unsubstituted or substituted by_3-6Alkynyloxy; C_3-6Alkynyloxy or -Ar^One-Oxy and A is -CR²= N- (a) orThe divalent group of (b), wherein the carbon atoms of the two (a) or (b) groups is -NR^OneCombined, where R²Is hydrogen; Halo; C substituted by up to 4 halo atoms_1-4Alkyl; C_3-7Cycloalkyl; Ar^One; Quinolinyl; C_1-10Alkyl; Ar^One, _3-7Substituted C by cycloalkyl, indolinyl or hydroxy_1-6Alkyl; Ar^OneC substituted by_2-6Alkynyl; C_1-10Alkyloxy; C_1-6Alkyloxycarbonyl; Carboxyl; Ar^OneCarbonyl or Ar^One-(CHOH)-, X is O or S, R³Is hydrogen; C_1-6Alkyl or Ar²-C_1-6Alkyl, Ar^OneIs phenyl, substituted phenyl, pyridinyl, aminopyridinyl, imidazolyl, thienyl, halothienyl, furanyl, halofuranyl or thiazolyl and Ar²Is phenyl or substituted phenyl; Ar^OneAnd Ar²Wherein the substituted phenyl is halo, hydroxy, trifluoromethyl, C_1-6Alkyl, C_1-6Alkyloxy, carboxyloxyl, formyl and C_1-6Phenyl substituted by one, two or three substituents each selected from a group consisting of alkylosoxycarbonyls. The method according to claim 1, wherein the reaction intermediate formed by the reaction of the compound of formula (IV) with 1,1'-carbonylbis [1H-imidazole] is separated and purified. Process for preparing a compound of formula (I) characterized by the conversion to a compound: Wherein R, R ¹ and A are as defined in claim 1.