HK1015674B - Benzimidazole compounds and their use as modulators of the gaba(a) receptor complex - Google Patents

Description

Benzimidazole compounds and their use as GABAAUse of receptor complex modulators

The present invention relates to novel benzimidazole compounds, pharmaceutical compositions containing such compounds, methods of using them to treat diseases, and methods of preparing such benzimidazole compounds. These novel compounds are useful for the treatment of central nervous system diseases and disorders, which are GABA_AReceptor complex modulated responses, such as: anxiety, sleep disorders, memory disorders, and epilepsy or other convulsive disorders.

Background of the invention

GABA as a receptor for gamma-aminobutyric acid (GABA) in mammalian brain_AReceptors are the most abundant inhibitory receptors. GABA_AThe receptor is structurally a macromolecular heteromultimeric assembly (binding of α, β, and γ/δ protein subunits). Modern molecular biology techniques describe a number of such GABA_AA subtype of receptor. Each GABA_AThe receptor complex contains a chloride channel that controls chloride flux through the neuronal membrane, and multiple small regulatory molecules such as benzodiazepines, barbiturates, and specific steroid recognition sites. When GABA is involved in the receptorUpon action, ion channels open, chloride influx increases, the membrane is hyperpolarized, and the cell response to excitatory stimuli decreases. This GABA-directed ion flux can be modulated by various agents, including agents that interact with benzodiazepine receptors or recognition sites.

And GABA_AAgents that bind to or interact with the regulatory site on the receptor complex, e.g., benzodiazepine receptors, either increase the effect on GABA action, i.e., positive modulation of the receptor (agonists, partial agonists), decrease the effect on GABA action, i.e., negative modulation of the receptor (inverse agonists, partial inverse agonists), or block agonism and inverse agonism by competitive blockade (antagonists or no original active ligand).

Agonists generally produce muscle relaxant, hypnotic, sedative, anxiolytic, and/or anticonvulsant effects, while inverse agonists produce convulsant, anti-narcotic, and anxiogenic effects. Partial agonists are characterized by compounds having an anxiolytic effect but no or less muscle relaxant, hypnotic and sedative effects, whereas partial inverse agonists are believed to be useful as recognition enhancers.

Over the last three decades, a large number of compounds with affinity for benzodiazepine receptors have been synthesized belonging to different families. However, although the benzodiazepine receptor site is still considered to be a very attractive biological site for interfering with the CNS for the treatment of various disorders and diseases, almost all previously synthesized compounds acting at this site have failed in clinical research because of unacceptable side effects.

The present invention provides a novel benzimidazole compound which is useful in combination with GABA_AThe benzodiazepine receptor of the receptor complex interacts. The compounds of the present invention are valuable GABA_AA receptor complex modulator.

Object of the Invention

It is an object of the present invention to provide novel benzimidazole compounds and pharmaceutically acceptable acid addition salts thereof, which are useful for treating central nervous system disorders, diseases or conditions in which GABA is implicated_AReceptor complex modulated responses, particularly to GABA_AA receptor complex up-regulated response.

It is another object of the present invention to provide pharmaceutical compositions containing the novel benzimidazole compounds for the above purpose. It is a further object of the present invention to provide novel therapeutic methods using the novel benzimidazole compounds.

It is also an object of the present invention to provide a process for the preparation of novel pharmaceutical compositions.

Other objects of the present invention will become more apparent from the following detailed description, and these will be apparent to those skilled in the art.

Summary of The Invention

The invention specifically includes the following, alone or in combination: a compound having the formula:or a pharmaceutically acceptable salt or oxide thereof wherein

R³Is thatWherein

A, B and D are each CH, or one or two of A, B and D are N and the others are CH;

R¹¹is phenyl, benzimidazolyl, or monocyclic heteroaryl, which may be substituted by a group selected from alkyl, alkoxy, phenyl, halogen, CF₃Amino, nitro, cyano, acyl, acylamino, phenyl and monocyclic heteroaryl, one or more times; and is

R⁶And R⁷One being hydrogen and the other being furyl or isoxazolyl, whichThey may be substituted by one or more substituents selected from halogen, alkyl, alkoxy and phenyl; the above compound which is 1- (3- (1-imidazolyl) phenyl) -5- (3-furyl) benzimidazole, 1- (3- (2-methyl-1-imidazolyl) phenyl) -5- (3-furyl) benzimidazole, or 1- (3- (5-pyrimidinyl) phenyl) -5- (3-furyl) benzimidazole, or a pharmaceutically acceptable salt or oxide thereof;

a pharmaceutical composition comprising an effective amount of any of the compounds described above, or a pharmaceutically acceptable addition salt or oxide thereof, together with at least one pharmaceutically acceptable carrier or diluent;

use of any of the above compounds for the manufacture of a medicament for the treatment of a disorder or disease of the central nervous system of GABA in living animals including humans_AReceptor complex modulated responses;

use of any of the above compounds for the manufacture of a medicament for the treatment of a disorder or disease of the central nervous system of GABA in living animals including humans_AA receptor complex positive-modulated response;

the use of any of the above compounds for the manufacture of a medicament for the treatment of a disorder or disease selected from anxiety, sleep disorders, memory disorders, epilepsy and any other convulsive disorder;

method of treatment of a disorder or disease of a living animal including a human, which disorder or disease is GABA to the central nervous system_AA receptor complex modulated response comprising administering a therapeutically effective amount of any of the compounds described above to a diseased, living animal, including a human.

In the above method, the disorder or disease treated is GABA_AA receptor complex positive-modulated response;

in the above method, anxiety, sleep disorders, memory disorders, epilepsy or other convulsive disorders are treated; and

the above method, wherein the active ingredient is administered in the form of a pharmaceutical composition thereof, which comprises a pharmaceutically acceptable carrier or diluent.

Halogen is fluorine, chlorine, bromine or iodine.

Alkyl means straight or branched chain alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methyl, ethyl, propyl, isopropyl and tert-butyl are preferred.

Alkoxy means an-O-alkyl group wherein alkyl is as defined above.

Acyl refers to- (C = O) -H or- (C = O) -alkyl, wherein alkyl is as defined above.

Acylamino means acyl-NH-, wherein acyl is as defined above.

Amino means-NH₂or-NH-alkyl or-N- (alkyl)₂Wherein alkyl is as defined above.

Monocyclic heteroaryl refers to 5-or 6-membered heterocyclic monocyclic groups. Such monocyclic heteroaryl groups include, for example, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2, 4-oxadiazol-3-yl, 1,2, 4-oxadiazol-5-yl, 1,2, 4-thiadiazol-3-yl, 1,2, 4-thiadiazol-5-yl, 1,2, 5-oxadiazol-3-yl, 1,2, 5-oxadiazol-4-yl, 1,2, 5-thiadiazol-3-yl, 1,2, 5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.

Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulphonate, stearate, succinate, glutamate, glycolate, p-toluenesulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and acetate.

Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in preparing salts useful as intermediates in the preparation of the compounds of the invention or pharmaceutically acceptable acid addition salts thereof. These salts can be prepared according to methods known in the art.

In addition, the compounds of the present invention may exist in the form of a non-solvate or a solvate with a pharmaceutically acceptable solvent such as water, ethanol, etc. In general, the solvated forms are considered to be the same as unsolvated forms for the purposes of the present invention.

Some of the compounds of the invention exist in (+) and (-) as well as racemic forms. The racemic form can be resolved into the optical antipodes by known methods, for example, separation of the diastereomeric salts thereof using an optically active acid and treatment with a base to liberate the optically active amine compound. Another method for resolving the racemate into the optical antipodes is chromatography using an optically active matrix. Racemic compounds of the present invention can be resolved into their optical antipodes, for example, by fractional crystallization of the d-or 1- (tartrate, mandelate, or camphorsulfonate) salts. The compounds of the present invention may also be resolved to form diastereomeric amides by reaction of the compounds of the present invention with a photoactive activated carboxylic acid derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphoric acid, or by reaction of the compounds of the present invention with a photoactive chloroformate or the like to form diastereomeric carbamates.

Other methods of resolving optical isomers that can be used are known to those of ordinary skill in the art. These methods include the methods discussed in j.jaques, a.colet and s.wilen in "enantiomers, racemates, and resolution", John Wiley and Sons, new york (1981).

The compounds of the present invention can be prepared by a number of methods.

The compounds of the present invention and pharmaceutically acceptable derivatives thereof can be prepared by any method known in the art for the preparation of structurally similar compounds, and the preparation thereof is as described in the examples below.

FIGS. 1-6 depict the preparation of compounds of the present invention wherein R⁶Is furyl or isoxazolyl and R⁷Is a hydrogen process. In the compounds of the invention R⁷Is furyl or isoxazolyl and R⁶Compounds which are hydrogen can be synthesized in a similar manner.

The starting materials used in the process described in this patent application are known or can be prepared from commercially available chemicals using known methods.

The reaction products described herein may be isolated using conventional methods such as extraction, crystallization, distillation, chromatography, and the like.

Biology of the species

4-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and acts throughout the central and peripheral nervous systems. Two types of GABA receptors are now known, GABA_AAnd GABA_BA receptor. Recent molecular biology proves that GABA_AThe receptors can be subdivided into multiple sub-receptors (subreceptors) consistent with the selectivity and or partial pharmacological effects observed with specific benzodiazepine receptor ligands as opposed to the nonselectivity observed with standard benzodiazepine receptor ligands such as diazepam. Activation of GABA receptors results in a change in membrane potential (hyperpolarization). GABA_AReceptor-associated chloride influx through it binds and modulates chloride channels, whereas GABA_BIndirect activation of receptors alters potassium and calcium channels and modifies second messenger production. GABA_AThe recognition site can be activated by, for example, GABA, muscimol, and isonicotinic acid, but not by GABA_BAgonists such as baclofen. Modulation of GABA at benzodiazepine receptor sites_ARecognition sitesIs selectively usable³An H-fluornitrazepam label. By estimating test compound substitution³The ability of H-fluornitrazepine to determine the affinity of different potential ligands for the benzodiazepine receptor site.

Method tissue preparation: unless otherwise indicated, the preparation is carried out at 0-4 ℃. The cerebral cortex of male Wistar mice (150-200g) was homogenized in 20ml Tris-HCl (30mM, pH 7.4) using an Ultra-Turrax homogenizer for 5-10 seconds. The suspension was centrifuged at 27,000 Xg for 15 min and the pellet was washed 3 times with buffer (27,000 Xg for 10 min). The washed pellet was homogenized in 20ml of buffer and incubated in a water bath (37 ℃) for 30 minutes to remove endogenous GABA, and then centrifuged at 27,000 Xg for 10 minutes. The pellet was homogenized in buffer and centrifuged at 27,000 Xg for 10 minutes. Finally the pellet was resuspended in 30ml buffer and the preparation was stored frozen at-20 ℃. And (3) determination: the membrane preparation was thawed and centrifuged at 27,000 Xg for 10 minutes at 2 ℃. The pellets were washed twice with 20ml50mM Tris-citrate, pH 7.1 using an Ultra-Turrax homogenizer and centrifuged at 27,000 Xg for 10 min. The pellet was resuspended in 50mM Tris-citrate, pH 7.1(500ml buffer/g of original tissue) and then subjected to binding assay. Aliquots of 0.5ml of tissue were added to 25. mu.l of test solution and 25. mu.l³H-FNM (final concentration 1nM), mixed and incubated at 2 ℃ for 40 min. Non-specific binding was determined using clonazepam (1 μ M, final concentration). After incubation, 5ml of ice-cold buffer was added to the samples and poured directly onto Whatman GF/C glass fiber filters under suction conditions and immediately washed with 5ml of ice-cold buffer. Radioactivity on the filters was determined using conventional liquid scintillation counting. Specific binding is the total binding number minus the non-specific binding number.

Test value is IC₅₀(test substance inhibits 50%)³Concentration (nM) of H-FNM specific binding).

The results of the tests performed with the compounds of the invention are given in the following table:

watch (A)

Test compounds: IC₅₀(nM)1- (3- (1-imidazolyl) -phenyl) -5- (3-furyl) benzimidazole 0.41- (3- (2-methyl-1-imidazolyl) -phenyl) -5- (3-furyl) benzene 0.4

Benzimidazole (I) derivatives

Pharmaceutical composition

For use in therapy, the compounds of the present invention may be administered in the form of their crude compounds, but preferably in the form of pharmaceutical compositions using the compounds of the present invention as active ingredients.

The invention further provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, in combination with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or for administration by inhalation or insufflation.

The compounds of the present invention, together with conventional adjuvants, carriers, or diluents, may be formulated in the form of pharmaceutical compositions and unit dosage forms, and these forms may be solid, such as tablets, or filled capsules, or liquid, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same for oral administration, or suppositories for rectal administration; or as a sterile injectable solution for parenteral administration (including subcutaneous). These pharmaceutical compositions and unit dosage forms may contain conventional ingredients in conventional amounts, with or without additional active compounds or substances, and these unit dosages may contain suitable effective amounts of the active ingredient within the same daily dosage range to be employed. Compositions containing one (1) milligram or more of the active ingredient, 0.01 to one hundred (100) milligrams per tablet, are suitable representative unit dosage forms.

The compounds of the present invention may be administered in widely varying oral or parenteral dosage forms. As will be apparent to those skilled in the art, the following dosage forms contain as the active ingredient either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.

A solid carrier can be one or more substances and can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a mixture of finely divided solid and finely divided activating component.

In tablets, the active ingredient is mixed with a carrier having viscosity in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 1 to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. By "formulation" is meant a capsule comprising the active ingredient and an encapsulating material as a carrier, wherein the active ingredient, with or without a carrier, is surrounded by the carrier so that they are integral. Similarly, cachets and lozenges can be prepared. Tablets, powders, capsules, pills, cachets, and lozenges can be used as suitable solid forms for oral administration.

For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool, and solidified.

Compositions suitable for vaginal administration may take the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known to those skilled in the art.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For example, parenteral injection liquid preparations can be prepared as solutions in aqueous propylene glycol.

The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, such as bolus (bolus) injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes (pre-filled syringes) for small volume infusion or in multi-dose containers with an added preservative. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may also contain a formulating agent (formulation) such as a suspending, stabilizing and/or dispersing agent. Alternatively, the active ingredient may be presented in powder form, isolated aseptically as a sterile solid or lyophilized from solution, and combined with suitable excipients, for example, sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and, if desired, adding suitable colorants, flavors, stabilizers, and thickening agents.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water containing viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.

Also included are solid dosage forms that need to be converted to liquid dosage forms for oral administration prior to use. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial or natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis, the compounds of the invention may be formulated as ointments, creams or lotions, or as transdermal patches. Ointments and creams may, for example, be prepared with water or an oil base, with the addition of suitable thickening and/or gelling agents. Ointments are formulated with water or an oil base and typically also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

Forms suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, typically sucrose and acacia or tragacanth; pastilles comprise the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; while mouthwashes contain the active ingredient in a suitable liquid carrier.

The solution or suspension can be applied directly to the nasal cavity in a conventional manner, e.g., by dropper, pipette or spray. The formulations may be provided in single or multiple dose forms. In the latter case, a suitable, predetermined volume of solution or suspension may be administered to the patient by means of a dropper or pipette. In spraying, this can be achieved by means of a metering spray pump.

Administration via the respiratory tract may be in the form of an aerosol in which the active ingredient is encapsulated by a suitable propellant fuel (propellant) such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas pressure. Aerosols generally contain a surfactant such as lecithin. The dose of medicament may be controlled by a metering valve.

Alternatively, the active ingredient may be formulated in dry powder form, for example, as a powder mix of the compound of the invention with a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Typically, the powdered carrier forms a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in the form of capsules or cartridges filled with, for example, gelatin or blisters, to allow the powder to be administered by means of an inhaler.

In formulations for administration via the respiratory tract, including intranasal formulations, the compounds typically have a small particle volume, e.g., around 5 microns. Such small particle sizes may be obtained by methods known in the art, such as micronization.

Sustained release formulations of the active ingredient may also be used if desired.

The pharmaceutical preparations are preferably formulated in unit dosage form. In this form, the preparation may be subdivided into unit doses containing appropriate quantities of the active ingredient. Unit doses may be presented as a packaged preparation in which the individual quantities of preparation are contained, e.g., in packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dose itself may be formulated as a capsule, tablet, cachet, or lozenge, or in the form of a suitable number of packets.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

Method of treatment

The compounds of the invention are particularly useful in the treatment of living organisms due to GABA_AA disorder or disease caused by the affinity of the benzodiazepine binding site of the receptor. These properties make the compounds of the invention useful in the treatment of convulsions, anxiety, sleep disorders, memory disorders and in GABA_AReceptor modulation sensitive diseases are particularly effective. Thus, reduction or elimination of GABA and GABA may be achieved by using the compounds of this invention in patients in need thereof, including humans_AA receptor-associated disorder or disease. These disorders include inter alia convulsions, anxiety, sleep disorders and memory disorders.

Suitable daily dosages range from 0.01 to 100mg, preferably from 0.1 to 50mg, more preferably from 0.1 to 30 mg, depending on the particular form of administration, route of administration, site of administration, condition of the patient and body weight of the patient, and the preference and experience of the attending physician or veterinarian.

The following examples will further illustrate the invention; they are not intended to limit the invention. The compounds of the invention prepared in the following examples are listed in the table of P37-39.

Example 1

4-fluoro-1-iodo-3-nitrobenzene (1 c): a suspension of 4-fluoro-3-nitroaniline (100g,0.64mol) in concentrated hydrochloric acid (500ml) was cooled to-20 ℃. A solution of sodium nitrite (48.6g,0.7mol) in 100ml of water was added with stirring, maintaining the temperature at-15 ℃. After the addition, the mixture was stirred at-20- (-15) deg.C for 45 minutes. To the resulting solution was added a solution of potassium iodide (132.8g,0.8mol) in 260ml of water at a rate that maintained the temperature below 0 ℃. The mixture was stirred until nitrogen evolution ceased. Aqueous sodium sulfite (200ml,1M) was added and the mixture was extracted with diethyl ether. The ether extract was washed twice with ice-cooled 1M sodium hydroxide and twice with brine. Finally, the extract was dried over magnesium sulfate, concentrated and purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 9) as eluent. Isolate 1c as an oil, freeze-crystallize. Yield: 132.6g (78%).

Example 2

3- (5-pyridyl) aniline (2 b): a suspension of 5-bromopyridine (15g,94.3mmol), 3-aminophenylboronic acid hemisulfate ester (19.3g,104mmol), sodium bicarbonate (39.6g,472mmol) and tetrakis (triphenylphosphine) palladium (O) (1g) in a mixture of water (75ml) and dimethoxyethane (150ml) was heated to 80 ℃ under a stream of nitrogen overnight. The mixture was cooled and poured into ice water. The precipitate was filtered off, washed with water and dried to yield 2b (15g, 93%). Mp.164-165 ℃.

3- (2-thiazolyl) aniline (2t) was prepared from 2-bromothiazole in a similar manner. The product was purified by column chromatography using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield: 25 percent. Mp43-49 ℃.

Example 3

3- (1-imidazolyl) aniline (2 d): a mixture of 1-iodo-3-nitrobenzene (90g,0.36mol), imidazole (54g,0.79mol), potassium carbonate (54g,0.39mol) and ground copper powder (1g) was heated to 200 ℃. The melt was stirred under a nitrogen atmosphere for 2 hours. The water vapor during the reaction is captured by a molecular sieve placed between the reaction vessel and the condenser. After completion of the reaction, the mixture was cooled to 100 ℃ and water was added. The reaction mixture was cooled to room temperature and the crude product was filtered off and dried. Recrystallization from toluene (200) and 250ml) gave pure 3- (1-imidazolyl) nitrobenzene (54.2g, 79%). Mp.101-102 ℃.

To a solution of 3- (1-imidazolyl) nitrobenzene (51.6g,0.27mol) in acetic acid (500ml) was added a palladium catalyst (5g, 5% palladium on activated carbon) and the mixture was placed under hydrogen pressure (P)_{Start of}: 4bar) until hydrogen uptake ceased. The mixture was filtered through celite and the filtrate was evaporated to dryness to give 2d as a pale brown oil. Yield 40.4g (93%).

N-acetyl 3- (1-imidazolyl) aniline (2 e): 2d (5.88g,37mmol) was stirred in acetic anhydride at room temperature for 1 hour. The mixture was poured into ice water and basified by addition of aqueous sodium hydroxide (12M). The product was filtered off, washed with water and dried to yield 2e (6.34g, 85%). Mp181-183 ℃.

Example 4

3- (2-pyridyl) aniline (2 f): to a solution of 2- (3-nitrophenyl) pyridine (prepared according to the method of J.chem.Soc.1958 p.1795) (12.7g,63.5mmol) in anhydrous ethanol was added a palladium catalyst (1.3g, 5% Pd on activated charcoal) and the mixture was hydrogenated at room temperature under hydrogen pressure until hydrogen uptake ceased. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and petroleum ether (9: 1) as eluent to give 2f (9.5g, 88%) as a pale brown oil.

5- (3-furyl) -2- (3-carboxyphenyl) aminoaniline (13r) was prepared in a similar manner from 12r (example 21). Chromatographic purification using ethyl acetate as eluent. Yield: 91 percent. Mp211-212 ℃.

Example 5

2- (dimethylamino) pyrimidine: a solution of 2-chloropyrimidine (5g,43.65mmol) in dry THF (50ml) was saturated with gaseous dimethylamine. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was partitioned with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated to give the product as a brown oil. Yield 5.07g (94%).

5-bromo-2- (dimethylamino) pyrimidine: the above product (5.07g,41.22mmol) was dissolved in glacial acetic acid (25ml) and bromine (2.15ml,41.95mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then poured into ice water. The mixture was alkalised by the addition of 10M sodium hydroxide. The product is filtered off, washed with water and dried. Yield 4.72g (57%). Mp162-164 ℃.

3- (2- (dimethylamino) -5-pyrimidinyl) aniline (2 h): a mixture of 5-bromo-2- (dimethylamino) pyrimidine (6.76g,33.17mmol), 3-aminophenylboronic acid hemisulfate ester (7.4g,39.78mmol), potassium carbonate (13.73g,99.49mmol),1, 3-propanediol (12ml,166mmol) and tetrakis (triphenylphosphine) palladium (O) (0.2g) in a mixture of water (30ml) and dimethoxyethane (60ml) was heated to 80 ℃ under a stream of nitrogen overnight. After cooling the mixture was diluted with water and ethyl acetate and filtered through fluted filter paper. The layers were separated and the aqueous phase was extracted once with ethyl acetate. The organic phases are combined and dried over sodium sulfate and evaporated to dryness. The residue was triturated with a mixture of ethyl acetate and petroleum ether (1: 1). Crystal 2h (5.26g, 74%) was obtained. Mp.115.5-117 deg.C.

N-acetyl 3- (2-methylimidazol-1-yl) aniline (2 j): 3- (2-methylimidazol-1-yl) aniline (11g,63.6mmol) was added portionwise to acetic anhydride (100ml) at room temperature. The mixture was stirred for 1 hour, poured into water (300ml) and the resulting solution was cooled in an ice bath and basified by the addition of aqueous sodium hydroxide (12M). The product was filtered off, washed thoroughly with water and dried to give 2j (12.3g, 97%). Mp 238-.

Example 6

1- (3-nitrophenyl) pyrrole: a mixture of 3-nitroaniline (15g,0.11mol), 2, 5-dimethoxytetrahydrofuran (42ml,0.33mol) and a catalytic amount of pTSA in dry toluene (150ml) was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as an eluent. Obtaining: 16g (78%). Mp 65-70 ℃.

3- (1-pyrrolyl) aniline: to a solution of the above product (16g,85.1mmol) in glacial acetic acid (100ml) was added a palladium catalyst: (1.5g, 5% palladium on activated carbon) and the mixture is brought under hydrogen pressure (P)_{Start of}: 4bar) until hydrogen uptake ceased. The mixture was filtered through celite and the solvent was evaporated. The crude product was used in the next step without purification.

N-acetyl 3- (1-pyrrolyl) aniline (2 k): acetic anhydride (40ml) was added to the above product and the mixture was stirred at room temperature overnight. The mixture was poured into water. The crude product was filtered off, washed with water and dried. Recrystallization from a mixture of water and ethanol (3: 2) gave pure 2 k. Yield 9.93g (58%). Mp 134-136.

Example 7

3- (2-aminopyrimidin-5-yl) aniline (21): a mixture of 2- (acetylamino) -5-bromopyrimidine (5.4g,25mmol), 3-aminophenylboronic acid hemisulfate (5.58g,30mmol), potassium carbonate (10.4g,75mmol),1, 3-propanediol (9ml, 0.13mol) and tetrakis (triphenylphosphine) palladium (O) (0.5g) in a mixture of water (25ml) and dimethoxyethane (50ml) was heated to 80 ℃ under a stream of nitrogen overnight. After cooling, it was poured into ice water. The product was filtered off (deacetylation during the reaction), washed with water and dried to yield 21(4.1g, 90%). Mp.171-172 ℃.

Example 8

N-acetyl N- (3- (1-imidazolyl) phenyl) -2-nitro-4-iodoaniline (6 c): a solution of 2e (30g,0.15mol) from example 3 in dry DMF (200ml) was cooled to 0 ℃ under nitrogen. Sodium hydride (7.2g of a 60% dispersion in mineral oil) was added in portions. A solution of 1c (52g,0.19mol) from example 1 in 50ml of DMF was added to the solution when the evolution of hydrogen was stopped. The mixture was stirred at 120 ℃ for 5 hours and left overnight at room temperature. The reaction mixture was poured into 4 volumes of water and the crude product was filtered off. Purification on silica gel using ethyl acetate and petroleum ether (3: 17) as eluent gave 6c as an oil (17g, 25%).

Example 9

N- (3- (2-methyl-1-imidazolyl) phenyl) -2-nitro-4 iodoaniline (6 j): to a solution of 2j (2g,9.3mmol) obtained in example 5 in dry N-methyl-2-pyrrolidone (20ml) was added sodium hydride (0.37g of a 60% dispersion in mineral oil) in portions at 0 ℃ under a nitrogen atmosphere. The mixture was stirred for 1 hour at room temperature for at least 30 minutes. 1c (2.67g,10mmol) from example 1 was added and the temperature was raised to 40-50 ℃ overnight. After cooling, the mixture was poured into water (100ml) and extracted with dichloromethane. The organic phase was extracted with 4M hydrochloric acid. The acid extract was cooled in ice, basified by addition of sodium hydroxide (12M) and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue was extracted with dichloromethane and diethyl ether (1: 1). The extract was concentrated under reduced pressure and the residue was dissolved in dimethoxyethane (60 ml). Aqueous sodium hydroxide (28ml,1M) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water (200ml) and a small amount of ethanol was added with stirring. The product was filtered off, washed with water and dried to yield 6j (2g, 51%). Mp 135-.

From 1c (example 1) and 2k (example 6), N- (3- (1-pyrrolyl) phenyl) -2-nitro-4-nitroaniline (6k) was prepared in a similar manner. The yield was 30%. Mp 116-.

Example 10

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -2-nitro) 4-iodoaniline hydrofluoride (6 j): a mixture of 1c (3g,11.2mmol) from example 1 and 2h (2.4g,11.2mmol) from example 5 in dry N-methyl-2-pyrrolidone (10ml) was stirred at 120-135 ℃ for 6h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and stirred overnight. Water was added to the resulting suspension. The product was filtered off, dried and washed with ethyl acetate to yield 6h (3.46g, 64%). Mp 202-.

N- (3- (2-aminopyrimidin-5-yl) phenyl) -2-nitro-4-iodoaniline hydrofluoride (61) was prepared in a similar manner from 1c (example 1) and 21 (example 7). Yield: 79 percent. Mp 236-238 ℃.

In a similar manner, N- (3- (1-pyrazolyl) phenyl) -4-iodo-2-nitrophenylaminehydro (6m) was prepared from 1c (example 1) and 2m (example 16). The base is liberated by treatment with sodium carbonate. Yield: 23 percent. Mp 165-166 ℃.

In a similar manner, N- (3- (2-methylthiazol-4-yl) phenyl) -4-iodo-2-nitroaniline (6N) was prepared from 1c (example 1) and 2N (example 17). Yield: 32 percent. Mp 137-.

In a similar manner, N- (3- (5-pyrimidinyl) phenyl) -4-iodo-2-nitroaniline (6b) was prepared from 1c (example 1) and 2b (example 2). Yield: 79 percent. Mp 214-.

In a similar manner, N- (3- (2-pyridyl) phenyl) -4-iodo-2-nitroaniline (6f) was prepared from 1c (example 1) and 2f (example 4). Yield: 40 percent. Mp 195-196 ℃.

Example 11

N- (3- (1-imidazolyl) phenyl) -4- (3-furyl) -2-nitroaniline (7 c): a mixture of 6c (17g,38mmol) from example 8, 3-furylboronic acid (5.6g,50mmol),1, 3-propanediol (14ml,0.17mol), potassium carbonate (15.7g,0.11mmol) and tetrakis (triphenylphosphine) palladium (O) (0.5g) in a mixture of water (60ml) and dimethoxyethane (120ml) was heated under reflux under a stream of nitrogen for 4 hours. After cooling it was poured into water (800ml) and stirred at 0 ℃ until the oily crystalline precipitate was complete. The crude product (mixture of acetylated and deacetylated product) was filtered off and dissolved in dimethoxyethane (200 ml). Aqueous sodium hydroxide (114ml,1M) was added, and the mixture was stirred at room temperature overnight. The mixture was poured into water (500ml), the product was filtered off, washed with water and dried. Obtaining: 13.1g (100%). Mp.129-131 ℃.

N- (3- (1-imidazolyl) phenyl) -4- (2-furyl) -2-nitroaniline (7o) was prepared in a similar manner from 6c (example 8) and 2-furylboronic acid. Yield: 77 percent. Mp 147-.

Example 12

N- (3- (2-methylimidazol-1-yl) phenyl) -4- (3-furyl) -2-nitroaniline (7 j): a mixture of 6j (1g,2.38mmol) from example 9, 3-furylboronic acid (0.4g,3.57mmol), potassium carbonate (1g,7.25mmol), 1, 3-propanediol (0.9ml,11.2mol), and tetrakis (triphenylphosphine) palladium (O) (50mg) in a mixture of dimethoxyethane (7ml) and water (3.5ml) was heated under reflux under a stream of nitrogen for 4 hours. After cooling, it was poured into water (30ml) and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethanol and ethyl acetate (1: 4) as eluent. Yield 0.8g (93%). The isolated product was an oil.

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -4- (3-furyl) -2-nitroaniline (7h) was prepared in a similar manner from 6h (example 10). Yield: 87 percent. Mp 181-.

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -4- (2-furyl) -2-nitroaniline (7m) was prepared in a similar manner from 6h (example 10) and 2-furylboronic acid. Yield: 89 percent. Mp 160-.

N- (3- (1-pyrrolyl) phenyl) -4- (3-furyl) -2-nitroaniline (7k) was prepared in a similar manner from 6k (example 9) and 3-furylboronic acid. Yield: 86 percent. Mp 129-131 ℃.

N- (3- (1-pyrrolyl) phenyl) -4- (2-furyl) -2-nitroaniline (7N) was prepared in a similar manner from 6k (example 9) and 2-furylboronic acid. Yield: 83 percent. Separation gave a brown-red oil.

N- (3- (2-aminopyridin-5-yl) phenyl) -4- (3-furyl) -2-nitroaniline (71) was prepared in theoretical yield from 61 (example 10) and 3-furylboronic acid in a similar manner. Mp 185-.

N- (3- (2-aminopyridin-5-yl) phenyl) -4- (2-furyl) -2-nitroaniline (7p) was prepared in theoretical yield from 61 (example 10) and 2-furylboronic acid in a similar manner. Mp 178-.

1- (3- (5-pyrimidinyl) phenyl) -5- (3-furyl) benzobenzoxazole (9b) was prepared in a similar manner from 11b (example 15) and 3-furylboronic acid. Chromatographic purification uses a mixture of dichloromethane and methanol (19: 1) as eluent. Yield: 48 percent. Mp 216-.

1- (3- (2-methylthiazol-4-yl) phenyl) -5- (3-furyl) benzimidazole (9N) was prepared in a similar manner from 11N (example 15) and 3-furylboronic acid. A mixture of ethyl acetate and petroleum ether (1: 1) was used as eluent in the chromatographic purification. Yield: 73 percent. Mp 136-138 ℃.

1- (3- (1-pyrazolyl) phenyl) -5- (3-furyl) benzimidazole (9M) was prepared in a similar manner from 11M (example 15) and 3-furylboronic acid. Yield: 64% and Mp170-173 ℃.1- (3- (2-pyridyl) phenyl) -5- (2-furyl) benzimidazole (9f) was prepared in a similar manner from 11m (example 15) and 2-furylboronic acid. The purification of the crude product was carried out using an ethanol solution containing activated carbon. Yield: 42 percent. Mp 135-.

1- (3- (3-furyl) phenyl) -5- (3-furyl) benzimidazole (9q) was prepared in a similar manner from 14q (example 15). Yield: -15%. Mp 149-150 ℃.

N- (2- (1- (imidazolyl) pyridin-6-yl) -4- (3-furyl) -2-nitroaniline (16c) was prepared analogously from 16a (example 25). chromatographic purification was omitted, the product crystals were obtained theoretically with addition of water, Mp 173-.

Example 13

N- (3- (1- (imidazolyl) phenyl) -2-amino) 4- (3-furyl) aniline (8 c): to a solution of 7c (13g,37.6mmol) obtained in example 11 in ethanol (25ml) were added ammonium chloride (6.03g,113mmol) and anhydrous sodium sulfite (27.05g,113 mmol). The mixture was heated to reflux for 1 hour. After cooling, the mixture was poured into 700ml of water. The product is filtered off, washed with water and dried in air. Yield 8c (8.7g, 73%). Mp 188-.

N- (3- (2-methylimidazol-1-yl) phenyl) -2-amino-4- (3-furyl) aniline (8j) was obtained in theoretical yield from 7j (example 12) in a similar manner. Mp 98-99 ℃.

N- (3- (1-pyrrolyl) phenyl) -2-amino-4- (3-furyl) aniline (8k) was prepared in a similar manner from 7k (example 12). The yield was 80%. Mp 194-195 ℃.

N- (3- (1-imidazolyl) phenyl) -2-amino-4- (2-furyl) aniline (8o) was prepared in a similar manner from 7o (example 11). The yield was 94%. Mp 191-194 ℃.

N- (3- (1-pyrrolyl) phenyl) -2-amino-4- (2-furyl) aniline (8N) was prepared in a similar manner from 7N (example 12). The yield was 77%. Mp 163-.

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -2-amino-4- (3-furyl) aniline (8h) was prepared in a similar manner from 7h (example 12). As an oil.

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -2-amino) 4- (2-furyl) aniline (8m) was prepared in a similar manner from 7m (example 12). As an oil.

In a similar manner N- (3- (1-pyrazolyl) phenyl) -2-amino-4-iodoaniline (10m) was obtained from 6m (example 10). Yield: 75 percent. Mp134-135 ℃.

In a similar manner to that described for 6b (example 10), N- (3- (5-pyrimidinyl) phenyl) -2-amino-4-iodoaniline (10b) was obtained. Yield: 82 percent. Mp166-169 ℃.

N- (3- (2-pyridyl) phenyl) -2-amino-4-iodoaniline (10f) was prepared in a similar manner from 6f (example 10). The product was used directly in the next step, see example 15.

N- (3- (2-methylthiazol-4-yl) phenyl) -2-amino-4-iodoaniline (10N) was prepared in a similar manner from 6N (example 10). Yield: 73 percent. Mp151-152 ℃.

A mixture of N- (3-bromophenyl) -2-amino-4- (3-furyl) aniline and N- (3-iodophenyl) -2-amino-4- (3-furyl) aniline (13q) was prepared in analogy to the procedure described for 12q (example 20). The mixture separated out was oily. Yield: -76%.

N- (3- (2-thiazolyl) phenyl) -2-amino-4-nitroaniline (20t) was prepared in a similar manner from 19t (example 27). Yield: 96 percent. Mp 146-.

Example 14N- (3- (2-Aminopyrimidin-5-yl) phenyl) -2-amino-4- (2-furyl) aniline (81)

To a suspension of 7p (0.87g,2.33mmol) obtained in example 12 in ethanol (10ml) was added 0.1g of palladium catalyst (5% Pd on activated carbon) and the mixture was hydrogenated under hydrogen pressure until hydrogen uptake ceased. The mixture was filtered through celite, washing successively with ethanol and DMF. The filtrate was evaporated under reduced pressure and the residue was triturated with water. The product was filtered off, washed with water and dried in air. Yield 81(0.5g, 63%). Mp211-212 ℃. N- (3- (2-aminopyrimidin-5-yl) phenyl) -2-amino-4- (3-furanyl) aniline (8 p): hydrogenation of 71 (example 12) as described above gave 8p (43%). Mp 208-.

Example 15

1- (3- (1-imidazolyl) phenyl) -5- (3-furyl) benzimidazole (9 c): a solution of 8c (8.7g,27.5mmol) from example 13 in formic acid (100ml) was heated at reflux for 30 min. After cooling, the mixture was poured into water (500ml) and basified by addition of aqueous sodium hydroxide (12M). The crude product was filtered off, washed with water and dried in air. A solution of this crude product in a mixture of ethanol (200ml) and dichloromethane (400ml) was treated with activated carbon at reflux for 15 minutes. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure until a precipitate appeared. The precipitate was completed by cooling in an ice bath. The product is filtered off and dried. Yield 7.5g (84%) mp.203-204 ℃.

In a similar manner from 8h (example 13) 1- (3- (2- (dimethyl) pyrimidin-5-yl) phenyl) -5- (3-furyl) benzimidazole (9h) was prepared. Purification was performed by column chromatography on silica gel using a mixture of dichloromethane and acetone (9: 1) as eluent. Yield: 32% (from 7 h). Mp 183-.

1- (3- (2-methylimidazol-1-yl) phenyl) -5- (3-furyl) benzimidazole (9j) was prepared in a similar manner from 8j (example 13). Purification was performed by silica gel column chromatography using a mixture of ethyl acetate and methanol (9: 1) as eluent. Yield: 71 percent. Mp 105-.

1- (3- (1-pyrrolyl) phenyl) -5- (3-furyl) benzimidazole (9k) was prepared in a similar manner from 8k (example 13). Purification was carried out by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield: 42 percent. Mp 144-145 ℃.

1- (3- (2-Aminopyrimidin-5-yl) phenyl) -5- (2-furyl) benzimidazole (91) was prepared in a similar manner from 81 (example 14). Purification was performed by column chromatography on silica gel using a mixture of ethyl acetate and methanol (9: 1) as eluent. Yield: 11 percent. Mp 220-.

1- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -5- (2-furyl) benzimidazole (9m) was prepared in a similar manner from 8m (example 13). Purification was carried out by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield: 42 percent. Mp 170-.

1- (3- (1-pyrrolyl) phenyl) -5- (2-furyl) benzimidazole (9n) was prepared in a similar manner from 8n (example 13). And purified according to the method of 9 m. Yield: 53 percent. Mp 137-.

1- (3- (1-Imidazoyl) phenyl) -5- (2-furyl) benzimidazole (9o) was prepared in a similar manner from 8o (example 13). And purified according to the method of 9 c. Yield: 46 percent. Mp 175-.

1- (3- (2-Aminopyrimidin-5-yl) phenyl) -5- (3-furyl) benzobenzoxazole (9p) is prepared in a similar manner from 8p (example 14). And purified according to the method of 91. Yield: 5 percent. Mp222-223 ℃.

1- (3- (5-pyrimidinyl) phenyl) -5-iodobenz-dazole (11b) was prepared in a similar manner from 10b (example 13). The crude product was not further purified. Yield: 91 percent. Mp 197-.

1- (3- (2-methylthiazol-4-yl) phenyl) -5-iodobenzimidazole (11n) was prepared in a similar manner from 10n (example 13). Yield: 98 percent. Mp 163-.

1- (3- (1-pyrazolyl) phenyl) -5-iodobenzimidazole (11m) was prepared in a similar manner from 10m (example 13). Yield: 86 percent. Mp 209-.

1- (3- (2-pyridinyl) phenyl) -5-iodobenzimidazole (11f) was prepared in a similar manner from 10f (example 13). Yield: 53% (from 6 f). Mp 157-.

A mixture of 1- (3-bromophenyl) -5- (3-furyl) benzimidazole and 1- (3-iodophenyl) -5- (3-furyl) benzimidazole (14q) was prepared in analogy to the procedure from 13q (example 13). The crude product was not purified (example 12). Yield: and 47 percent.

In a similar manner to that described for 1- (4- (1-imidazolyl) pyrimidine) 6-yl) -5- (3-furyl) benzimidazole (18b) was prepared from 17b (example 26). Yield: 27% (from 16 b). Mp 294-.

In a similar manner to that described for 1- (2- (1-imidazolyl) pyridine) 6-yl) -5- (3-furyl) benzimidazole (18c) was prepared from 17c (example 26). The product was isolated by extraction and recrystallized from ethyl acetate. Yield: 29 percent. Mp 170-.

1- (3- (2-thiazolyl) phenyl) -5 nitrobenzimidazole (21t) was prepared in a similar manner from 20t (example 13) in theoretical amount yield. Mp 251-.

Example 16

1- (3-nitrophenyl) pyrazole: a mixture of 1-iodo-3-nitrobenzene (18.7g,75mmol), pyrazole (7.66g,113mmol), potassium carbonate (11.2g,81mmol) and catalytic amounts of cuprous iodide and copper-bronze (copper-bronze) in N-methyl-2-pyrrolidone (50ml) was heated to 180 ℃ for 4.5 hours. After cooling, the mixture was filtered through celite. The filtrate was poured into ice water (700ml) and the product was filtered off, washed with water and dried to give 13.57 g. Yield: 96 percent. Mp 85-87 ℃.

3- (1-pyrazolyl) aniline (2 m): a suspension of 3- (1-pyrazolyl) -1-nitrobenzene (5.5g,34.6mmol) in concentrated hydrochloric acid (50ml) was heated to reflux. Stannous chloride dihydrate (24.2g,0.11mol) was added in portions and refluxing was continued for half an hour. After cooling, the precipitate was filtered off and dissolved in 200ml of water. The resulting solution was cooled in an ice bath, basified with 12M aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated to give the product as a brown oil. Yield 3.9g (71%).

From 21t (example 15) in a similar manner to give 1- (3- (2-thiazolyl) phenyl-5-aminobenzimidazole (22t), isolated as an oil, yield 65%.

Example 17

3- (2-methylthiazol-4-yl) aniline (2 n): a mixture of 2-bromo-3' -nitroacetophenone (5g,20.5mmol) and thioacetamide (1.4g,18.6mmol) in glacial acetic acid (50ml) was heated at reflux overnight. After cooling, the precipitate was filtered off, washed with water and dried to give 2-methyl-4- (3-nitrophenyl) thiazole (3.47g, 85%). Mp 87-88 ℃.

The product was hydrogenated according to the method of example 4 to obtain 2n theoretically. Mp 80-81 ℃.

Example 18

N-acetyl 4-bromo-2-nitroaniline (1 d): a solution of 4-bromoacetamide (20g,93.4mmol) in methanesulfonic acid was cooled to 10 ℃. Concentrated nitric acid (12.6ml) was added and the mixture was stirred at 40 ℃ for 2 hours. The mixture was poured into ice water. The product is filtered off, washed with water and dried. Yield 23.59g (97%). Mp 99-100 ℃.

4-bromo-2-nitroaniline (1 f): a mixture of 1d (3.5g,13.5mmol), dimethoxyethane (100ml) and aqueous sodium hydroxide (50ml, 1M) was heated to 80 ℃ for 1 hour, after cooling the mixture was poured into ice water, the product was filtered off, washed with water and dried, yielding 2.77g (94%). Mp 109-.

Example 19

N-acetyl 4- (3-furyl) -2-nitroaniline (1 e): a mixture of 1d (8.5g,32.8mmol) obtained in example 18, 3-furylboronic acid (3.67g,32.8mmol), sodium bicarbonate (13.8g,0.16mol) and tetrakis (triphenylphosphine) palladium (O) (0.5g) in a mixture of water (40ml) and dimethoxyethane (80ml) was heated to 80 ℃ overnight under a stream of nitrogen. After cooling, it was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 40ml of dimethoxyethane. Aqueous sodium hydroxide (78ml,1M) was added and the mixture was stirred at room temperature overnight. The mixture was poured into water and acidified with dilute hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 1e (5.09g, 76%). Mp 152-.

Similar procedure was followed from 23t (example 28) until (x) 1- (3- (2-thiazolyl) phenyl) -5- (3-furyl) benzimidazole (9t) was prepared. The residue was eluted with silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield: 9 percent. Mp 102-105 ℃.

Example 20

N- (3-bromophenyl) -4- (3-furyl) -2-nitroaniline and N- (3-iodophenyl) -4- (3-furyl) -2-nitroaniline (12 q): a mixture of 1-bromo-3-iodobenzene (2.65ml,20.8mmol), 1e from example 19 (4g,19.6mmol), potassium carbonate (2.93g,21.2mmol) and a catalytic amount of copper-bronze (copper-bronze) in N-methyl-2-pyrrolidone (50ml) was heated to 180 ℃ overnight. After cooling, the mixture was poured into water. Ethyl acetate was added and the mixture was filtered through celite. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The organic extracts were combined and dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 9) as eluent. The product mixture (12q) isolated was a red oil (1.44g) which was used directly in the next step (see example 13).

Example 21

N- (3-carboxyphenyl) -4- (3-furyl) -2-nitroaniline) (12 r): a mixture of 1e from example 19 (5g,24.5mmol), 3-iodobenzoic acid (6.69g,27mmol), potassium carbonate (3.79g,27.5mmol) and a catalytic amount of copper-bronze (copper-bronze) in 30ml of N-methyl-2-pyrrolidone was heated to 180 ℃ overnight. After cooling, water was added to the mixture, and the mixture was washed twice with ethyl acetate. The aqueous phase was acidified with dilute hydrochloric acid and the oily precipitate was filtered off. The precipitate was extracted with ethyl acetate and the extract was purified by column chromatography on silica gel using ethyl acetate and petroleum ether (1: 1) as diluents. Yield 2.56g (32%). Mp 203-.

Example 22

1- (3-carboxyphenyl) -5- (3-furyl) benzimidazole (14 r): to 13r (2.4g,8.16mmol) obtained in example 4 was added formic acid (25ml), and the mixture was stirred at 80 ℃ for 1.5 hours. After cooling, the mixture was poured into ice water. The precipitate was filtered off, washed with methanol and dried to yield 14r (0.89g, 40%). Mp 272 and 274 ℃.

1- (3- (3- (2-pyridyl) oxazol-5-yl) phenyl) -5- (3-furyl) benzimidazole (9 r): a solution of 14r (0.43g,1.41mmol) in dry THF (10ml) was heated to reflux under nitrogen. Carbonyldiimidazole (0.4g,2.48mmol) was added and refluxing was continued for 3 hours. 2- (Oximelimidine) pyridine (0.48g,3.54mmol) was added and the resulting mixture was refluxed overnight. After cooling the solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (15ml), a catalytic amount of pTSA was added and the mixture was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield 9r:0.16g (28%). Mp183-186 ℃.

In a similar manner to 14r and cyclopropyloxime imine, 1- (3- (3-cyclopropyloxadiazol-5-yl) phenyl) -5- (3-furanyl) benzimidazole (9s) was obtained. Yield: 19 percent. Mp 144-.

Example 232-chloro-6- (1-imidazolyl) pyridine (15 a): a mixture of 2, 6-dichloropyridine (5g,33.78mmol), imidazole (2.3g,33.78mmol) and potassium carbonate (4.66g,33.78mmol) in DMF (50ml) was heated to 85 ℃ overnight. The cooled mixture was poured into ice water and the unreacted material was filtered off. The filtrate was acidified with dilute hydrochloric acid and extracted once with ethyl acetate. The aqueous phase was basified by addition of aqueous sodium hydroxide (10M) and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, concentrated under reduced pressure and eluted through silica gel using a mixture of ethyl acetate and methanol (9: 1) as eluent. Evaporation of the solvent gave 15 a. Yield: 2.37g (39%). Mp 71-73 ℃.

Example 24

4-chloro-6- (1-imidazolyl) pyrimidine (15 b): a mixture of 4, 6-dichloropyrimidine (5g,33.56mmol), imidazole (2.28g,33.56mmol) and potassium carbonate (4.63g,33.56mmol) in DMF (50ml) was stirred at room temperature overnight. The mixture was diluted with four times the volume of water and extracted with dichloromethane. The organic extracts were concentrated under reduced pressure and eluted through silica gel using a mixture of diethyl ether and petroleum ether (1: 1) as eluent 15b (4.07g, 67%). Mp 198-.

Example 25

N- (2- (1-imidazolyl) pyridin-6-yl) -4-bromo-2-nitroaniline (16 a): to a solution of 1f (2.7g,12.5mmol) obtained in example 18 in DMF (25ml) was added sodium hydride (0.5g, 60% dispersion in mineral oil) and the mixture was stirred for 30 minutes. 15a (example 23) (2.25g,12.5mmol) was added to the mixture and the mixture was heated to 100 ℃ overnight. After cooling, the mixture was poured into ice water. The precipitate is filtered off, dried and dissolved in ethyl acetate. The filtrate was extracted with ethyl acetate. The product-containing solutions were combined, concentrated and purified by silica gel column chromatography using a mixture of ethyl acetate and methanol (9: 1) as eluent. The solvent was evaporated and the residue triturated with a mixture of petroleum ether and diethyl ether (1: 1) to give 16a (0.93g, 21%). Mp 194-195 ℃.

N- (4- (1-imidazolyl) pyrimidin-6-yl) -4- (3-furyl) -2-nitroaniline (16b) was prepared in a similar manner from 15b (example 24) and 1e (example 19). For chromatographic purification ethyl acetate was used as eluent. Yield: 23 percent. Mp 198-.

Example 26N- (4- (1-Imidazoyl) pyrimidin-6-yl) -2-amino-4- (3-furanyl) aniline (17b)

A suspension of 16b (example 25) (0.38g,1.1mmol) in a mixture of ethanol and dichloromethane was hydrogenated at room temperature using Raney nickel (a slurry in 50% water) as a catalyst. When the hydrogen uptake ceased, the mixture was filtered through celite and the filtrate was evaporated to give 17b as an oil which was used without purification. N- (2- (1-Imidazoyl) pyridin-6-yl) -2-amino) 4- (3-furyl) aniline (17c)

To a suspension of 16c (0.9g,2.6mmol) from example 12 in 50ml of a mixture of ethanol and dichloromethane (4: 1) was added the Pd catalyst (0.15g, 5% on activated carbon) and hydrogenated at room temperature until hydrogen uptake ceased. The mixture was filtered through celite and the filtrate was evaporated to give 17c as an oil which was used without purification.

Example 27

N- (3- (2-thiazolyl) phenyl) -2,4 dinitroaniline (19 t): a mixture of 2, 4-dinitrobenzene (1.14ml,9.1mmol), 2t (1.6g,9.1mmol) from example 2 and potassium carbonate (1.51g,10.9mmol) in dry N-methyl-2-pyrrolidone (10ml) was heated to 80 ℃ for 2 hours. The cooled mixture was poured into ice water. The precipitate was filtered off, washed with water and dried to give: 3.05g (98%). Mp 197-203 ℃.

Example 28

1- (3- (2-thiazolyl) phenyl) -5-iodobenzimidazole (23 t): a suspension of 22t (0.85g,2.91mmol) of the product from example 16 in hydrochloric acid was cooled to-5 ℃. A solution of sodium nitrite (0.22g,3.2mmol) in 3ml of water was added dropwise while maintaining the temperature below 0 ℃. After the addition was complete, the mixture was stirred at (-5) -0 ℃ for 20 minutes. A solution of potassium iodide (0.6g,3.64mmol) in 3ml of water was added thereto and the mixture was stirred at room temperature overnight. An aqueous sodium sulfite solution was added to the reaction mixture until the color of iodine disappeared. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with aqueous sodium carbonate solution, dried over sodium sulfate and filtered through silica gel. The filtrate was evaporated to dryness to give 23 t. Yield: 23 percent. The melt starts to decompose at 175 ℃.

Example 29

N- (3-iodophenyl) -4-cyano-2-nitroaniline (29): to a solution of 4-chloro-3-nitrophenylnitrile (1.82g,10mmol) in dry DMF (25ml) were added triethylamine (1.54ml,11mmol) and 3-iodoaniline (1.2ml,10mmol) and the mixture was heated to 80-100 ℃ overnight. After cooling, the mixture was poured into 4 volumes of ice water. The precipitate is filtered off, washed with water and dried. The crude product was washed with hot ethanol to give 2.1g (58%) of the title compound. Mp211-212 ℃.

Example 30

2-amino- (N- (3-iodophenyl)) -4-cyanoaniline (30): to a suspension of (29) (2.1g,5.75mmol) in methanol (50ml) were added ammonium chloride (0.92g,17.25mmol) and anhydrous sodium sulfite (4.14g,17.25mmol) and the mixture was heated under reflux for 1.5 h. After cooling, the mixture was poured into ice-water (200ml) and the product was filtered off, washed with water and dried to yield 1.8g (93%) of the title compound. Mp 170-.

Example 31

5-cyano-1- (3-iodophenyl) benzimidazole (31): a suspension of (30) (1.8g,5.36mmol) in formic acid (20ml) was heated to 80-100 ℃ for 1.5 h. The hot reaction mixture was filtered through packed cotton into ice water (100 ml). The precipitate is filtered off, washed with water and dried. The crude product was dissolved in dichloromethane and precipitated by addition of petroleum ether. The product is filtered off and dried. 1.38g (75%) of the title compound are obtained. Mp.177-179 ℃.

Example 32

5-cyano-1- (3- (3-pyridyl) phenyl) benzimidazole (32 a): a mixture of (31) (4g,11.6mmol), diethyl 3-pyridylborane (2.04g,13.9mmol), potassium carbonate (4.8g,34.8mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2g) in a mixture of water (20ml) and dimethoxyethane was stirred under nitrogen at 80 ℃ overnight. After cooling, the resulting suspension was poured into ice water. Purification was performed by column chromatography on silica gel using a mixture of ethyl acetate and methanol (9: 1) as eluent. 2.46g (72%) of the title compound are obtained. Mp.191-193 ℃.

5-cyano-1- (3- (1-imidazolyl) phenyl) benzimidazole (32b) was prepared in a similar manner.

Example 33

2-Tributylstannyl (thiazole) (3)3): to a solution of thiazole (0.71ml,10mmol) in dry THF (20ml) was added dropwise 1.6M-BuLi in hexane (6.9ml,11mmol) under a hydrogen atmosphere at-78 ℃. The reaction mixture was stirred at-78 ℃ for 0.5 h and Bu was added dropwise₃SnCl (3.1ml,11 mmol). After stirring at-78 ℃ for 1 h and at room temperature for 1 h, the mixture was concentrated, triturated with water (50ml) and extracted with ether (100 ml. times.3). The extract was washed with brine, dried and concentrated under reduced pressure to give (33) as an anhydrous oil. (3.7g, quant.)

Example 34

5-acetyl-1- (3- (2-thiazolyl) phenyl) benzimidazole (34): to a solution of (33) (3.6g,9.7mmol) in dry THF (20ml) under an argon atmosphere was added 5-acetyl-1- (3-bromophenyl) benzimidazole (1.5g,4.8mmol) and (PPh)₃)₂PdCl₂(340mg,0.48 mmol). The reaction mixture was stirred at 80 ℃ in a 50ml sealed test tube for 24 hours. After cooling the mixture was concentrated, triturated with water (100ml) and CH₂Cl₂(200 ml. times.3) extraction. The extract was washed with brine, dried and concentrated under reduced pressure. The residue was washed with ether to give crystal (34) (1.5g, 89%). 5-acetyl-1- (3-bromophenyl) benzimidazole was prepared as follows:

4-acetyl-2-nitroaniline: n- (4-acetyl-2-nitrophenyl) acetamide (26.5g,11.94mmol) was added to a mixture of water and 150ml (1: 2) of concentrated sulfuric acid. After 15 minutes the mixture was poured into water. The product is filtered off, washed with water and dried.

N- (3-bromophenyl) -4-acetyl-2-nitroaniline: a mixture of 4-acetyl-2-nitroaniline (3.41g,18.94mmol),1, 3-dibromobenzene (4.6ml,38.065mmol), potassium carbonate (2.62g,19mmol) and a catalytic amount of copper-bronze (copper-bronze) was heated to 180 ℃ under a stream of nitrogen with stirring for 2 days. After cooling the solid reaction cake was extracted with a mixture of dichloromethane and methanol (9: 1). The extract was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extracts were concentrated under reduced pressure and the residue was purified by elution on silica gel using a mixture of petroleum ether and ethyl acetate (4: 1) as eluent to give the pure product. 0.67g (10.6%). M.p.142-144 ℃.

5-acetyl-1- (3-bromophenyl) benzimidazole (34): n- (3-bromophenyl) -4-acetyl-2-nitroaniline (9.0g,26.63mmol) was suspended in 99% ethanol (100 ml). Raney nickel was added and the mixture was hydrogenated at atmospheric pressure for 20 hours. Chloroform was added. The mixture was filtered through celite and evaporated in vacuo to give 8.03g of an oil. To this oil 80ml of formic acid were added and the mixture was heated to 80 ℃ for 1.5 hours. Excess formic acid was removed in vacuo. The residue was stirred in water and basified with aqueous sodium hydroxide solution. The product is filtered off, washed with water and dried.

Example 35

5-cyano-1- (3- (2-thiazolyl) phenyl) benzimidazole (35): (31) (2.0g,5.9mmol) was used instead of 5-acetyl-1- (3-bromophenyl) benzimidazole, (PPh)₃)₂PdCl₂(100mg,0.14mmol) and 2- (tributylstannyl) thiazole (3.6g,9.7mmol) 5-cyano-1- (3- (2-thiazolyl) phenyl) benzimidazole was synthesized according to the procedure described for example 34 to give 5-cyano-1- (3- (2-thiazolyl) phenyl) benzimidazole (1.5g, 86%).

Example 36

4- (3-nitrophenyl) pyrimidine (36): 4-phenylpyridine (10g,64mmol) and concentrated H at 0 deg.C₂SO₄(33ml) of the mixture concentrated H was added₂SO₄(22ml) and concentrated HNO₃(16ml) in a mixture. The resulting mixture was stirred at 0 ℃ for 2 hours, poured into crushed ice and washed with CH₂Cl₂And (4) extracting. The extract was extracted with 5% NaHCO₃Washing with aqueous solution, MgSO₄Dried and concentrated under reduced pressure. The residue was triturated with isopropanol, the precipitate filtered off and dried under reduced pressure to give (36) (6.4g, 50%).

Example 37

4- (3-aminophenyl) pyrimidine (37): to a suspension of (36) (6.3g,31mmol) in a mixture of MeOH (60ml) and THF (30ml) was added 5% palladium on charcoal (300mg) and the mixture was hydrogenated at normal pressure for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of hexane and ethyl acetate (3: 1) as an eluent to give (37) (5.1g, 96%).

Example 38

N- (3- (4-pyrimidinyl) phenyl) -4-cyano-2-nitroaniline (38): to a mixture of (37) (5.5g,30mmol) and 4-chloro-3-nitrophenylnitrile (5.1g,30mmol) in THF (120ml) was added sodium hydride (2.3g, 50% suspension in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and CH was added₂Cl₂And (4) extracting. The extracts were concentrated under reduced pressure and the residue triturated with ether to give crystal (38) (9.2g, 96%).

Example 39

N- (3- (4-pyrimidinyl) phenyl) -4-cyano-2-aminoaniline (39): using (38) (9.2g, 29mmol) in place of 4- (3-nitrophenyl) pyrimidine and 600g of catalyst, the reaction was carried out as described in example 37 to give (39) (8.3g, theoretical amount).

Example 40

5-cyano-1- (3- (4-pyrimidinyl) phenyl) benzimidazole (40): mixing (39) (3.0g,10mmol) and HCO₂A mixture of H (20ml) was stirred at 110 ℃ for 1 hour. The mixture was concentrated in vacuo. The residue was washed with 5% NaHCO₃Solution and CH₂Cl₂Are distributed among the devices. The organic phase is MgSO₄Dried and the solvent evaporated. Trituration of the residue with ethyl acetate gave crystal (40) (2.6g, 85%).

EXAMPLE 41

5-formyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazole (41 a): to (40) (3.9g) in HCO₂Raney nickel (2.2g) was added to a solution in a mixture of H (48ml) and water (18 ml). The mixture was stirred at 100 ℃ for 0.5 hour under argon atmosphere. After cooling, the mixture was filtered. Concentrating the filtrate in 1M NaHCO₃The solution was partitioned with ethyl acetate. The ethyl acetate extract was washed with brine, dried and concentrated under reduced pressure to give (41a) (2.7g, 69%).

From (35) in a similar manner, 5-formyl-1- (3- (2-thiazolyl) phenyl) benzimidazole (41b) was obtained

From (32b) in a similar manner, 5-formyl-1- (3- (1-imidazolyl) phenyl) benzimidazole (41c) was obtained, and

from (32a), 5-formyl-1- (3- (3-pyridyl) phenyl) benzimidazole (41d) was prepared in a similar manner.

Example 42

5-formyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazoloxime (42 a): 41a (2.7g) was added to ethanol (100ml), NH₂OH, HCl (1.9g,3 equivalents) and triethylamine (1.3ml,1 equivalent) and the mixture was stirred at 60 ℃ for 1 hour. The mixture was frozen to 0 ℃ and the precipitate was filtered off, washed with water and dried under reduced pressure to give (42a) (2.2g, 77%).

From (41b) in a similar manner, 5-formyl-1- (3- (2-thiazolyl) phenyl) benzimidazoloxime (42b) is obtained

From (41c) in a similar manner, 5-formyl-1- (3- (1-imidazolyl) phenyl) benzimidazoloxime (42c) is obtained, and

from (41d), 5-formyl 1- (3- (3-pyridyl) phenyl) benzimidazoloxime (42d) was obtained in a similar manner.

Example 435- (3-isoxazolyl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (43 a):

a mixture of 42a (2.1g) and N-chlorosuccinimide (1.1g, 1.2 equivalents) in DMF (100ml) was stirred under argon at 60 ℃ for 0.5 h. Vinyl bromide (25ml) was added to the reaction mixture under ice-cooling, and then a solution of triethylamine (4.8ml,5 equivalents) in 15ml of DMF was added dropwise over about 1 hour. The mixture was stirred at 0 ℃ for 3 hours and at room temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂And methanol (30: 1) as eluent, to give 5- (3-isoxazolyl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (1.5g, 64%). M.p.214-215 ℃.

From (42b) 5- (3-isoxazolyl) -1- (3- (2-thiazolyl) phenyl) benzimidazole (43b) m.p.157-158 ℃ was prepared in a similar manner.

From (42c), 5- (3-isoxazolyl) -1- (3- (1-imidazolyl) phenyl) benzimidazole (43c) m.p.230-234 ℃ was prepared in a similar manner.

From (42d) 5- (3-isoxazolyl) -1- (3- (3-pyridyl) phenyl) benzimidazole (43d) m.p.208-210 ℃ was prepared in a similar manner.

Example 445-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole (44 a):

4-fluoro-3-nitroacetophenone: concentrated sulphuric acid (200ml) was cooled to 5 ℃ and 4-fluoroacetophenone (20ml,164.76mmol) was added at this temperature and the temperature was maintained at no more than 10 ℃. The mixture was cooled to 0-5 ℃ and potassium nitrite (25g,247.14mmol) was added portionwise maintaining the temperature at 0-5 ℃. After the addition was complete, the mixture was stirred at this temperature for 2 hours. The mixture was poured onto ice (600g) and the crude product was filtered off. Purification by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 9) as eluent gave 18.19g of pure 4-fluoro-3-nitroacetophenone (60%). 3- (3-pyridyl) nitrobenzene: to a solution of 3-bromopyridine (8.53g,54mmol) in ethylene glycol dimethyl ether (180ml) were added 3-nitrophenylboronic acid (10g,59.95mmol), aqueous potassium carbonate (90ml,2M) and tetrakis (triphenylphosphine) palladium (0.5g,0.43 mmol). The mixture was gently refluxed overnight under nitrogen atmosphere. The cooled reaction mixture was filtered and water (600ml) was added to the filtrate. The precipitate is filtered off and washed with water. The crude product was dissolved in hot water (400ml) and hydrochloric acid (25ml,4M) was added. The mixture was filtered hot. The filtrate was cooled in an ice bath and 12M NaOH was added to give a pure 3- (3-pyridyl) nitrobenzene precipitate. Yield: 9.14g (85%).

3- (3-pyridyl) aniline: 3- (3-pyridyl) -nitrobenzene (9.1g,45.5mmol) was hydrogenated in ethanol (125ml) at normal pressure for 1.75 h using Raney nickel as catalyst. The resulting solution was filtered through celite, and then the solvent was evaporated to yield 3- (3-pyridyl) aniline theoretically.

4-acetyl-2-nitro-N- (3- (3-pyridyl) phenyl) aniline: will be provided withA mixture of 4-fluoro-3-nitroacetophenone (5g,27.3mmol) and 3- (3-pyridyl) aniline (4.62g,27.2mmol) in dry 1-methyl-2-pyrrolidone (10ml) was stirred at 40-50 ℃ overnight. The resulting solid reaction mixture was suspended in ice water (50ml) and 1M NaHCO was added₃Alkalizing. The product is filtered off, washed with water and dried to yield 7.68g of 4-acetyl-2-nitro-N- (3- (3-pyridyl) phenyl) aniline (85%).

5-acetyl-2- (3- (3-pyridyl) phenylamino) aniline: 4-acetyl-2-nitro-N- (3- (3-pyridyl) phenyl) aniline (2g,6mmol) was suspended in a mixture of ethanol (50ml) and dichloromethane (10ml) and hydrogenated at normal pressure using palladium (5% on activated carbon) as a catalyst. The resulting solution was filtered through celite and the solvent was evaporated to give an oil, which was triturated with a mixture of diethyl ether and petroleum ether (1: 1) to give 1.46g of pure 5-acetyl-2- (3- (3-pyridyl) phenylamino) aniline (80%).

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole: 5-acetyl-2- (3- (3-pyridyl) phenylamino) aniline (5g,16.5mmol) in formic acid (50ml) was stirred at 90 ℃ for 1.5 h. The cooled reaction mixture was basified by addition of 12M NaOH. The 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole was filtered off, washed with water and dried. The theoretical amount of product was obtained. m.p.195-97 deg.C

The following compounds were prepared in a similar manner:

5-acetyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazole (44 b).

Example 45 5- (5-isoxazolyl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (45a) was prepared as follows:

5- (3-dimethylamino-1-oxo-2-propen-1-yl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole: (44b) (314mg) was reacted with DMF-dimethyl acetal (1.5ml) under an argon atmosphere in DMF (3ml) at 120 ℃ for 5 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂Mixing with methanol (30: 1)This gave 5- (3-dimethylamino-1-oxo-2-propen-1-yl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (320mg, 87%) as an eluent.

5- (5-isoxazolyl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole: 5- (3-dimethylamino-1-oxo-2-propen-1-yl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (307mg) and NH₂A mixture of OH, HCl (135mg,2.5 equiv.) in methanol (14ml) was stirred at 80 ℃ for 2 h. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure. The residue was purified by Chromatography (CH)₂Cl₂Methanol 40: 1(v/v)) yielded 5- (5-isoxazolyl) -1- (3- (4-pyrimidinyl) phenyl) benzimidazole (226mg, 80%).

The following compounds were prepared according to a similar procedure:

5- (5-isoxazolyl) -1- (3- (2-thiazolyl) phenyl) benzimidazole (45b), M.p.186-188 ℃ was prepared from (34) in a similar manner

From (44a) 5- (5-isoxazolyl) -1- (3- (3-pyridyl) phenyl) benzimidazole (45c) was prepared in a similar manner, m.p.218-219 ℃. The compounds prepared in the above examples are listed in tables 1 and 2 below.

TABLE 1

Compound number	Ar	D	A	B	Furan substituted position	m.p.(℃)	Example No. 2
								9c	1-imidazolyl	CH	CH	CH	3	203-204	15
9h	2- (dimethylamino) -5-pyrimidinyl	CH	CH	CH	3	183-184	15
								9j	2-methyl-1-imidazolyl	CH	CH	CH	3	105-107	15
9k	1-pyrrolyl	CH	CH	CH	3	144-145	15
								9l	2-amino-5-pyrimidinyl	CH	CH	CH	2	220-222	15
9m	2- (dimethylamino) -5-pyrimidinyl	CH	CH	CH	2	170-172	15
								9n	1-pyrrolyl	CH	CH	CH	2	137-139	15
9o	1-imidazolyl	CH	CH	CH	2	175-177	15
								9p	2-amino-5-pyrimidinyl	CH	CH	CH	3	222-223	15
9b	5-pyrimidinyl radicals	CH	CH	CH	3	216-218	12
								9N	2-methyl-4-thiazolyl	CH	CH	CH	3	136-138	12
9M	1-pyrazolyl radical	CH	CH	CH	3	170-173	12
								9f	2-pyridyl group	CH	CH	CH	2	135-136	12
9q	3-furyl radical	CH	CH	CH	3	149-150	12
								9r	3- (2-pyridinyl) -oxadiazol-5-yl	CH	CH	CH	3	183-186	22

9s	3-cyclopropyl-oxadiazol-5-yl	CH	CH	CH	3	144-146	22
								9t	2-thiazolyl group	CH	CH	CH	3	102-105	19
18b	1-imidazolyl	CH	CH	CH	3	294-296	15
								18c	1-imidazolyl	CH	CH	CH	3	170-173	15

TABLE 2

Ar	Isoxazole substituent position	m.p.(℃)	Examples
				4-pyrimidinyl radicals	3	214-215	43
3-pyridyl group	3	208-210	43
				2-thiazolyl group	3	157-158	43
1-imidazolyl	3	230-234	43
				2-thiazolyl group	5	186-188	45
3-pyridyl group	5	218-219	45

Claims (6)

1. A benzimidazole compound of the formula or a pharmaceutically acceptable salt or oxide thereofWherein

R³Is thatWherein

A, B and D are each CH, or one or two of A, B and D are N and the others are CH;

R¹¹is 2-pyridazinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl5-pyrimidinyl, 1-pyrazolyl, 3-pyrazolyl or 4-pyrazolyl, which may be chosen from linear or branched C₁-C₈Alkyl or C₃-C₇Cycloalkyl, straight or branched C₁-C₈Alkoxy or C₃-C₇Cycloalkoxy, phenyl, halogen, CF₃Substituted one or more times with substituents of amino, nitro, cyano, acyl and acylamino, where acyl is- (C = O) -H or (C = O) -alkyl, alkyl being straight-chain or branched C₁-C₈Alkyl or C₃-C₇A cycloalkyl group; and is

R⁶And R⁷One being hydrogen and the other being furyl or isoxazolyl, which may be selected from halogen, straight or branched C₁-C₈Alkyl or C₃-C₇Cycloalkyl, straight or branched C₁-C₈Alkoxy or C₃-C₇Cycloalkoxy and phenyl substituents, or 1- (3- (2-thiazolyl) phenyl) -5- (3-furyl) benzimidazole or 1- (3- (1-imidazolyl) phenyl) -5- (3-furyl) benzimidazole or 1- (3- (2-methyl-1-imidazolyl) phenyl) -5- (3-furyl) benzimidazole, or 1- (3- (2-methylthiazol-4-yl) phenyl) -5- (3-furyl) benzimidazole, or a pharmaceutically acceptable salt or oxide thereof.

2. The benzimidazole compound of claim 1, which is 1- (3- (2-aminopyrimidin-5-yl) phenyl) -5- (2-furanyl) benzimidazole; 1- (3- (2-aminopyrimidin-5-yl) phenyl) -5- (3-furanyl) benzimidazole; or 1- (5-pyrimidinyl) -5- (3-furyl) benzimidazole; or a pharmaceutically acceptable salt or oxide thereof.

3. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable addition salt or oxide thereof, and at least one pharmaceutically acceptable carrier or diluent.

4. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of a disorder or disease in a living animal body, including a humanThe use in a subject, such disorders or diseases are GABA in the central nervous system_AReceptor complex modulated responses.

5. The use according to claim 4 wherein the disorder or disease is GABA of the central nervous system_AA receptor complex up-regulated response.

6. Use according to claim 4, wherein the disorders and diseases are anxiety, sleep disorders, memory disorders, epilepsy and other convulsive disorders.