HK1018048B - 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 biologyThe art describes a number of such GABAs_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 recognition sites for specific steroids. When GABA interacts with the receptor, the ion channel opens, 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, halogen, CF₃Amino, nitro, cyano, amido, acyl, phenyl and monocyclic heteroaryl; and is

R⁶And R⁷One is hydrogen and the other is-CR '═ NOR "where R' and R" are independently hydrogen, alkyl, alkenyl, alkynyl or phenyl; the above compound which is 1- (3- (3-furyl) phenyl) -5-formyl-benzimidazole O-methyloxime, 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-ethyloxime, 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole oxime, 5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-methyloxime, 5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-ethyloxime, or 5-acetyl-1- (3- (2-thiazolyl) phenyl) benzimidazole O-methyloxime, 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_AReceptor complex modulated responses comprising the use of a therapeutically effective amount of the aboveAny of the compounds is administered 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.

Alkenyl refers to a straight or branched chain having 2 to 6 carbon atoms containing one double bond, and includes, but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

Alkynyl refers to a straight or branched chain having 2 to 6 carbon atoms containing a triple bond and includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

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

Acyl means- (C ═ O) -H or- (C ═ O) -alkyl, where 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 l- (tartrate, mandelate, or camphorsulfonate) salt. 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).

Furthermore, when the compounds of the invention are oximes, these compounds may exist in two forms, Z-and E-depending on the arrangement of the substituents around the-C ═ N-double bond. The invention includes both Z-and E-form compounds and mixtures thereof.

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. 1a, 1b, 2-4 depict the preparation of compounds of the present invention wherein R⁶Is oximino and R⁷Is a hydrogen process. In the compounds of the invention R⁷Is oximino 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 sites are selectively available³An 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, pH7.4) for 5-10 seconds using an Ultra-Turrax homogenizer. 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 pellets were in 20ml bufferHomogenized and incubated in a water bath (37 ℃) for 30 minutes to remove endogenous GABA, 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, pH7.1 using an Ultra-Turrax homogenizer and centrifuged at 27,000 Xg for 10 min. The pellet was resuspended in 50mM Tris-citrate, pH7.1(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:

TABLE test Compound IC₅₀(nM)1- (3- (3-furyl) phenyl-5-methyl-benzimidazole O-methyloxime 1.55-acetyl-1 (3- (3-pyridyl) -phenyl) -benzimidazole O-ethyloxime 1.45-acetyl-1- (3- (1-imidazolyl) -phenyl) -benzimidazole O-methyloxime 0.65-acetyl-1- (3- (1-imidazolyl) -phenyl) -benzimidazole O-ethyloxime 1.25-acetyl-1- (3- (2-thiazolyl) -phenyl) -benzimidazole O-methyloxime 1.7

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 presented as solids, such as tablets, or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same for oral administration, or as 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 oil bases 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 table 1.

Example 1

4-fluoro-3-nitroacetophenone (1 g): concentrated sulfuric acid (200ml) was cooled to 5 ℃. 4-Fluoroacetophenone (20ml, 0.16mol) was added maintaining the temperature below 10 ℃. The mixture was cooled to 0-5 ℃ and potassium nitrate (25g, 0.25mol) was added in portions over 2 hours, maintaining the temperature in this range. After the addition was complete, the mixture was stirred cold for 2 hours. The mixture was poured into 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 pure 1g (18.2g, 60%). Mp 48-49 ℃.

4-amino-3-nitroacetophenone (1 h): a suspension of 4-aminoacetophenone (25g, 184mmol) in 250ml of acetic anhydride is stirred for 30 minutes at ambient temperature. The mixture was cooled to 0 ℃ and concentrated nitric acid (18ml) was added dropwise, maintaining the temperature at-5 to 5 ℃. After the addition was complete, the mixture was warmed to room temperature and stirred continuously at ambient temperature overnight. The mixture was poured into ice water (700ml) and the product was filtered off: n- (4-acetyl-2-nitrophenyl) acetamide, washed thoroughly with water and dried. Yield: 26.5g (65%). This product was added to a hot mixture of water (500ml) and concentrated sulfuric acid (100ml) and the resulting mixture was stirred for 15 minutes. Precipitated from the cooled mixture 1h after dilution with water. The product is filtered off. Washed with water and dried. Yield: 91 percent. Mp121-123 ℃.

Example 2

3- (3-pyridyl) aniline (2 a): a mixture of diethyl 3-pyridylborane (16.3g, 0.11mol), 3-bromoaniline (12.2ml, 0.11mol), potassium carbonate (45.9g, 0.33mol) and tetrakis (triphenylphosphine) palladium (O) (80mg) in a mixture of water (40ml) and dimethoxyethane (80ml) was heated to 80 ℃ overnight under a stream of nitrogen. 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 combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol. Water was added and the mixture was evaporated to dryness. The residue crystallized after trituration with ice cold water. The crystals were collected, dried and washed with petroleum ether to give pure 2a (16.3g, 87%), Mp 75-76 ℃.

3- (5-pyrimidinyl) aniline (2 b): a suspension of 5-bromopyrimidine (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. After cooling, the mixture was poured into ice water. The precipitate was filtered off, washed with water and dried to give 2b (15g, 93%), Mp 164-.

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%). Mp 181-.

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.

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 3

Isopropyl 4- (3-bromophenyl) amino-3-nitrobenzoate (24): a mixture of isopropyl 4-chloro-3-nitrobenzoate (25.88g, 0.11mol), 3-bromoaniline (17.36ml, 0.16mol) and potassium carbonate (14.63g, 0.11mol) in N-methyl-2-pyrrolidone (25ml) was heated to 150 ℃ for 3 days. After cooling, the mixture was poured into dilute hydrochloric acid (300ml, 1M). The precipitate was filtered off, washed with water and dried (37.4 g). The crude product was washed with hot 2-propanol to give pure 24(26.25g, 65%). Mp 162-165 ℃.

Example 4

3-amino-4- (3-bromophenyl) aminobenzoic acid isopropyl ester (25): 24 from example 3 (3.79g, 10mmol) was suspended in a mixture of ethanol (30ml) and dichloromethane (30 ml). Wet Raney nickel (0.5g) was added and the mixture hydrogenated until absorption of hydrogen ceased. The mixture was filtered through celite and the solvent was removed under reduced pressure to give a theoretical amount of 25. Mp 82-85 ℃.

A mixture of 5-acetyl-2- ((3-bromophenyl) amino) aniline and 5-acetyl-2- ((3-iodophenyl) amino) aniline (35) was prepared analogously to 34 (example 16). The product was isolated as an oil.

Example 5

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole (32 a): a solution of 31a from example 13 (7g, 23.1mmol) in formic acid (20ml) was stirred at ambient temperature overnight. The mixture was poured into water (750ml) and made basic with concentrated aqueous ammonia. The precipitate is filtered off, washed with water and dried. The crude product was dissolved in refluxing ethanol. Water was added until precipitation started. The mixture was cooled. The product was filtered off and dried to give 4.3 (60%), Mp 200-.

1- (3-bromophenyl) -5- (iso-propylcarboxy) benzimidazole (26) was prepared analogously from 25 (example 4). Yield: 85 percent. Mp102-104 ℃.

A mixture of 5-acetyl-1- (3-iodophenyl) benzimidazole and 5-acetyl- (3-olfactory phenyl) benzimidazole (36) was prepared analogously from 35 (example 4). The yield was 91% (2 steps over 34).

5-acetyl-1- (3- (5-pyrimidinyl) phenyl) benzimidazole (32b) was prepared analogously from 31b (example 13). Yield: 71 percent. Mp253-254 ℃.

5-acetyl-1- (3- (2-pyridyl) phenyl) benzimidazole (32c) was prepared analogously from 31c (example 13). Yield: 91 percent. Mp158-159 ℃.

5-acetyl-1- (3- (2-aminopyrimidin-5-yl) phenyl) benzimidazole (32d) was prepared analogously from 31d (example 13). Yield: 84 percent and Mp275-278 ℃.

Example 6

1- (3-bromophenyl) -5- (hydroxymethyl) benzimidazole (27): a stirred suspension of 26(18g, 50.18mmol) of dry ether (300ml) from example 5 was maintained under a nitrogen atmosphere at room temperature. LiAlH is added in portions₄(1.9g, 50mmol) and the mixture was stirred overnight. The mixture was poured into a mixture of ice-water and ethyl acetate. The resulting emulsion was filtered through celite and the phases were separated. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purifying the residue by silica gel column chromatography; ethyl acetate and a mixture of ethyl acetate and methanol (9: 1) were used as eluents in this order. 7.96g (51%) of 27, Mp107-109 ℃ are obtained.

Example 7

1- (3-bromophenyl) -5-formylbenzimidazole (28): a mixture of 27(3.9g, 12.9mmol) from example 6 and phenylselenious acid (3.04g, 16.1mmol) in toluene was stirred at 70 ℃ overnight. The product is precipitated by cooling. The precipitate is filtered off, washed with petroleum ether and dried. Washing with sodium carbonate aqueous solution and water in sequence to obtain pure 28. Yield: 2.99g (77%), Mp179-181 ℃.

Example 8

1- (3-bromophenyl) -5-formylbenzimidazole O-methyloxime (29 a): to a suspension of example 7 in 28(2.95g, 9.8mmol) of absolute ethanol (100ml) was added methoxylamine hydrochloride (1.23g, 14.7mmol) and the mixture was heated to 70 ℃. Sodium bicarbonate (1.23g, 14.7mmol) was added portionwise over 20 minutes. After the addition was complete, the mixture was stirred for a further 2 hours at 70 ℃. After cooling, the solvent was removed under reduced pressure. Water is added to the residue, the product is filtered off, washed with water and dried to give 2.77g (86%), Mp119-120 ℃.

Example 9

1- (3- (2-thienyl) phenyl) -5-formylbenzimidazole O-methyloxime (29 d): a mixture of 29a from example 8 (0.7g, 2.1mmol), 2- (tributylstannyl) thiophene (1.59g, 4.3mmol) and tris (triphenylphosphine) palladium chloride (50mg) in DMF (5ml) was heated to 80 ℃ overnight. The cooled reaction mixture was diluted with 4 volumes of water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1: 1) as eluent. Yield 0.56g (80%), Mp184-185 ℃.

Example 10

1- (3- (3-furyl) phenyl) -5-formylbenzimidazole O-methyloxime (29 c): a mixture of 1- (3-bromophenyl) -5-formylbenzimidazole O-methyloxime (29a) (0.7g, 2.1mmol) from example 8, 3-furylboronic acid (0.26g, 2.34mmol), sodium hydrogencarbonate (0.89g, 10.6mmol) and tetrakis (triphenylphosphine) palladium (O) (50mg) in a mixture of water (5ml) and dimethoxyethane (10ml) was stirred under a nitrogen atmosphere at 80 ℃ overnight. After cooling, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was eluted through celite with a mixture of ethyl acetate and petroleum ether (1: 1). The pure fractions were evaporated to dryness. White crystal product is obtained by trituration with petroleum ether. Yield: 0.42g (63%), Mp147-148 ℃.

Example 11

1- (3- (1-imidazolyl) phenyl) -5-formylbenzimidazole O-methyloxime (29 b): a mixture of 1- (3-bromophenyl) -5-formylbenzimidazole O-methyloxime (29a) (0.7g, 2.13mmol) from example 8, imidazole (0.33g, 4.85mmol), potassium carbonate (0.29g, 2.13mmol) and a catalytic amount of copper-bronze in 5ml of N-methyl-2-pyrrolidone was heated to 140 ℃ under a nitrogen stream and held for 24 hours. After cooling, the mixture was poured into water. A small amount of methanol was added and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was eluted through celite with a mixture of dichloromethane and ethanol (10: 1) to give pure 29 b. Yield: 0.23g (34%), Mp197-199 ℃.

5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole (37) was prepared similarly from 36 (example 5). Yield: 26%, Mp205-206 ℃.

Example 12

4-acetyl-2-nitro-N- (3- (3-pyridyl) phenyl) aniline (30 a): a mixture of 1g (5g, 27.3mol) from example 1 and 2a (4.62g, 27.2mmol) from example 2 in dry N-methyl-2-pyrrolidone (10ml) was stirred at 40-50 ℃ overnight. The resulting solid reaction mixture was suspended in ice-water and basified by addition of aqueous sodium carbonate (1M). The product was filtered off, washed with water and dried to give 7.68g of 30a (85%) Mp112-113 ℃.

4-acetyl-2-nitro-N- (3- (5-pyrimidinyl) phenyl) aniline (30b) was prepared analogously from 1g (example 1) and 2b (example 2). Yield: 65% and Mp131-132 ℃.

4-acetyl-2-nitro-N- (3- (2-pyridyl) phenyl) aniline (30c) was prepared analogously from 1g (example 1) and 2f (example 2). Yield: 87% and Mp195-196 ℃.

4-acetyl-2-nitro-N- (3- (2-aminopyrimidin-5-yl) phenyl) aniline (30d) was prepared analogously from 1g (example 1) and 21 (example 2). Yield: 80% and Mp233-236 ℃.

Example 13

5-acetyl-2- (3- (3-pyridyl) phenylamino) aniline (31 a): 30a from example 12 (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 catalyst. The resulting solution was filtered through celite, followed by evaporation of the solvent to give an oil. Trituration with a mixture of diethyl ether and petroleum ether yielded 1.46g of pure 31a (80%). Mp175-176 ℃.

5-acetyl-2- (3- (5-pyrimidine) phenylamino) aniline (31b) is prepared analogously from 30b (example 12). The crude oily product was used in the next step without further purification (example 5).

5-acetyl-2- (3- (2-pyridyl) phenylamino) aniline (31c) is prepared analogously from 30c (example 12). Yield: 92% and Mp145-146 ℃.

5-acetyl-2- (3- (2-aminopyrimidin-5-yl) phenylamino) aniline (31d) is prepared analogously from 30d (example 12). Yield: 71 percent and Mp228-230 ℃.

Example 14

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-ethyloxime (33 a): 32a from example 5 (5g, 15.97mmol) was suspended in absolute ethanol (50ml) and heated to 70 ℃. O-ethylhydroxylamine hydrochloride (2.4g, 24.61mmol) was added and the mixture was heated to reflux for 1.5 h. After cooling, the solvent was evaporated off and the residue was stirred with aqueous sodium hydroxide (50ml, 1M). The crude product is filtered off. Purification by column chromatography on silica gel using a mixture of ethyl acetate and ethanol (9: 1) as eluent gave pure 33 a. Yield: 3.7g (65%), Mp105-106 ℃.

The following compounds are prepared analogously from 32a (example 5) and the appropriate O-alkyl-, O-alkenyl-and O-alkynylhydroxylamine hydrochlorides:

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-propynyloxime (33 b). Yield: 49 percent and Mp138-140 ℃.

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-allyloxime (33 c). Yield: 73% and Mp87-89 ℃.

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-isobutyl oxime (33 f). Yield: 38% and Mp90-92 ℃.

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-methyloxime (33 g). Yield: 59% and Mp145-146 ℃.

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazoloxime (33 i). Yield: 82% and Mp218-220 ℃.

The following compounds were prepared analogously from the appropriate O-alkylhydroxylamine hydrochloride and 32b, 32c and 32d (example 5), respectively:

5-acetyl-1- (3- (5-pyrimidinyl) phenyl) benzimidazole O-ethyloxime (33 d). Yield: 54% and Mp187-188 ℃.

5-acetyl-1- (3- (2-pyridyl) phenyl) benzimidazole O-ethyloxime (33 e). Yield: 53% and Mp107-108 ℃.

5-acetyl-1- (3- (2-aminopyrimidin-5-yl) phenyl) benzimidazole O-methyloxime (33 h). Yield: 62% and Mp236-238 ℃.

The following compounds were prepared analogously from 37 (example 11) and O-methylhydroxylamine hydrochloride and O-ethylhydroxylamine hydrochloride, respectively:

5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-methyloxime (38 a). Yield: 67%, Mp230-231 ℃.

5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-ethyloxime (38 b). Yield: 67% and Mp135-138 ℃.

Example 15

5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-isopropyloxime (33 j): to a suspension of 33i (example 14) (0.4g, 1.22mmol) in anhydrous DMF (5ml) was added sodium hydride (50mg of a 60% dispersion in mineral oil). The mixture was stirred at 30-40 ℃ for 30 minutes. 2-bromopropane (0.14ml, 1.49mmol) was added and the mixture was stirred at 40 ℃ overnight. After cooling, the mixture was diluted with 4 volumes of water and extracted with dichloromethane. The organic phase was concentrated and eluted through celite with ethyl acetate to give 0.15g 33j (33%), Mp77-80 ℃.

Example 16

Mixture of 4-acetyl-N- (3-bromophenyl) -2-nitroaniline and 4-acetyl-N- (3-iodophenyl) -2-nitroaniline (34): a mixture of 4-acetyl-2-nitroaniline from example 1 (1h) (15.0g, 86.7mmol), 3-bromo-1-iodobenzene (13.3ml, 104mmol), potassium carbonate (12g, 87mmol) and catalytic amounts of cuprous iodide and copper-bronze was heated to 180 ℃ under a stream of nitrogen with stirring and for 24 hours. The mixture was cooled to 70 ℃ and the tarry reaction cake was extracted 2 times with hot ethyl acetate. The combined organic phases are purified by column chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (3: 7) as eluent to give 9g of product mixture.

Example 17

2- (tributylstannyl) thiazole (50): to a solution of thiazole (0.71ml, 10mmol) in dry THF (20ml) was added dropwise a solution of 1.6M BuLi in hexane (6.9ml, 11mmol) under an argon 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 1h and at room temperature for 1h, the reaction mixture was concentrated, triturated with water (50ml) and extracted with ether (100 ml. times.13). The extract was washed with brine, dried and concentrated under reduced pressure to give a colorless oil (50) (3.7g, theoretical amount).

Example 18

5-acetyl-1- (3- (2-thiazolyl) phenyl) benzimidazole (51): to a solution of (50) from example 17 (3.6g, 9.7mmol) in anhydrous THF (20ml) under an argon atmosphere was added 5-acetyl-1- (3-bromophenyl) benzimidazole (52) (1.5g, 4.8mmol) and (PPh)₃)₂PdCl₂(340mg, 0.48 mmol). The reaction mixture was stirred at 80 ℃ for 24 hours in a 50ml sealed tube. After cooling, the mixture was concentrated, triturated with water (100ml) and with CH₂Cl₂(200 ml. times.3) extraction. The extract was washed with brine, dried and concentrated under reduced pressure. Washing the residue with diethyl ether to obtain crystals (51)(1.5g，89％)。

5-acetyl-1- (3-bromophenyl) benzimidazole (52) 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 concentrated sulfuric acid (150ml (1: 2)). 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, 38.06mmol), potassium carbonate (2.62g, 19mmol) and a catalytic amount of copper-bronze was heated to 180 deg.C under a stream of nitrogen with stirring and held 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 and the residue was eluted through silica gel with a mixture of petroleum ether and ethyl acetate (4: 1) to give the pure product. Yield: 0.67g (10.6%) Mp142-144 ℃.

5-acetyl-1- (3-bromophenyl) benzimidazole (52): 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 and the mixture was filtered through celite and evaporated in vacuo to give 8.03g of an oil. To this oil 80ml of formic acid was 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 19

5-acetyl-1- (3- (2-thiazolyl) phenyl) benzimidazole O-methyloxime (53): (51) of example 18 (300mg, 0.94mmol) was added to a mixture of ethanol (5ml), methoxylamine hydrochloride (300mg, 3.5mmol) and triethylamine (0.17ml, 1.2mmol), and the mixture was stirred at 60 ℃ for 0.5 hour. After cooling, the mixture was poured into 5% NaHCO₃In aqueous solution (100ml), the precipitate was filtered off, washed with water and dried under reduced pressure. Purifying the crude product by silica gel column chromatography using CH₂Cl₂A mixture with methanol (100: 1) was used as eluent to give (53) (270mg, 86%) Mp157-159 ℃.

Example 20

5-cyano-1- (3- (2-thiazolyl) phenyl) benzimidazole (54) was synthesized as described in example 18, except that 5-cyano-1- (3-iodophenyl) benzimidazole (2.0g, 5.9mmol) was used instead of (52), (PPh)₃)₂PdCl₂(100mg, 0.14mmol) and (50) (3.6g, 9.7 mmol). This gave 5-cyano-1- (3- (2-thiazolyl) phenyl) benzimidazole (1.5g, 86%).

The preparation of 5-cyano-1- (3-iodophenyl) benzimidazole is described below:

n- (3-iodophenyl) -4-cyano-2-nitroaniline: to a solution of 4-chloro-3-nitrobenzonitrile (1.82g, 10mmol) in anhydrous 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 ℃.

2-amino- (N- (3-iodophenyl) -4-cyanoaniline, to a suspension of N- (3-iodophenyl) -4-cyano-2-nitroaniline (2.1g, 5.75mmol) in methanol (50ml) were added ammonium chloride (0.92g, 17.25mmol) and sodium sulfide non-hydrate (4.14g, 17.25mmol), the mixture was heated to reflux for 1.5 h after cooling, the mixture was poured into ice-water (200ml), the product was filtered off, washed with water and dried to give 1.8g (93%) of the title compound, Mp170-172 ℃.

5-cyano-1- (3-iodophenyl) benzimidazole: a suspension of 2-amino- (N- (3-iodophenyl)) -4-cyanoaniline (1.8g, 5.36mmol) in formic acid (20ml) was heated to 80-100 ℃ for 1.5 hours. The hot reaction mixture was filtered through a cotton plug into ice-water (100ml), the precipitate was filtered off, washed with water and dried. The crude product was dissolved with dichloromethane and precipitated by addition of petroleum ether. The product is filtered off and dried. 1.38g (75%) of the title compound are obtained, Mp177-179 ℃.

Example 21

5-formyl-1- (3- (2-thiazolyl) phenyl) benzimidazole (55): raney nickel (2.0g) was added to (54) (1.5g, 4.9mmol) in HCO₂H (18ml) and water (6 ml). The mixture was stirred at 110 ℃ for 1 hour under an argon atmosphere. After cooling, the mixture was filtered. The filtrate was concentrated in 5% NaHCO₃The aqueous solution was partitioned with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure to give (55) (1.3g, 87%).

Example 22

5-formyl-1- (3- (2-thiazolyl) phenyl) benzimidazoloxime (55): (55) (700mg, 2.29mmol) was added to ethanol (25ml) and NH₂OH.HCl (600mg, 6.9mmol) in a mixture. The mixture was stirred at 90 ℃ for 1 hour. After cooling, the mixture was poured into water (100ml), and the precipitate was filtered off, washed with water and dried under reduced pressure to give 5-formyl-1- (3- (2-thiazole) phenyl) benzimidazole oxime (690mg, 94%).

5-formyl-1- (3- (2-thiazolyl) phenyl) benzimidazole O-methyloxime (56) was synthesized similarly, but using NH₂Replacement of NH by OMeHCl₂OH HCl，Mp154-160℃。

Example 23

4- (3-nitrophenyl) pyrimidine (57): 4-phenylpyrimidine (10g, 64mmol) and concentrated H at 0 deg.C₂SO₄(30ml) of the mixture was added to concentrated H₂SO₄(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 of MgSO 2₄Dried and concentrated under reduced pressure. The residue was triturated with isopropanol and the precipitate was filtered off and dried under reduced pressure to give (57) (6.4g, 50%).

Example 24

4- (3-aminophenyl) pyrimidine (58): to a suspension of (57) (6.3g, 31ml) in a mixture of MeOH (60ml) and THF (30ml) was added 5% palladium on activated carbon (300mg) and the mixture was hydrogenated at normal pressure for 1 hour. The mixture was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate as an eluent to give (58) (5.1g, 96%).

Example 25

N- (3- (4-pyrimidinyl) phenyl) -4-cyano-2-nitroaniline (59): to a mixture of 4-chloro-3-nitrophenylnitrile (5.5g, 30mmol) and (58) (5.1g, 30mmol) in THF (120ml) was added sodium hydride (2.3g, 50% dispersion in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and CH was added₂Cl₂And (4) extracting. The extract was concentrated under reduced pressure and the residue was triturated with ether to give crystal (59) (9.2g, 96%).

Example 26

N- (3- (4-pyrimidinyl) phenyl) -4-cyano-2-aminoaniline (60): the synthesis was as described in example 24, but using (59) (9.2g, 29mmol) instead of (57) and 600mg of catalyst. Reaction gave (60) (8.3g, theoretical amount).

Example 27

5-cyano-1- (3- (4-pyrimidinyl) phenyl) benzimidazole (61): mixing (60) (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 taken up in 5% NaHCO₃Aqueous solution and CH₂Cl₂And (6) distributing. With MgSO₄The organic phase was dried and the solvent was removed by evaporation. The residue was triturated with ethyl acetate to give crystals (61) (2.6g, 85%).

Example 28

5-formyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazole (62): the synthesis was carried out as described in example 21, using (61) (2.5g, 8.4mmol) instead of (54) and 1.5g of Raney Ni. Reaction gave (62) (1.9g, 73%).

Example 295-formyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazole oxime (63): synthesized as described in example 22, using (62) (150mg, 0.50mmol) instead of (55) and NH₂OH.HCl (100mg, 1.5 mmol). The reaction yielded (63) (120mg, 76%) MP220-221 ℃.

5-formyl-1- (3- (4-pyrimidinyl) phenyl) benzimidazole O-methyloxime (64): synthesized as described in example 22, but using (62) (200mg, 0.66mmol) instead of (55) and NH₂OMe & HCl (250mg, 2.0 mmol). Reaction to give (64) (61mg, 28%) Mp180-182 ℃.

Example 30

N- (3- (2-pyrimidine) phenyl) -4-cyano-2-nitroaniline (65): the synthesis was performed as described in example 25, using 2- (3-aminophenyl) pyrimidine (4.50g, 26.3mmol) instead of (58). Reaction gave (65) (5.08g, 61%).

Example 31

N- (3- (2-pyrimidinyl) phenyl) -4-cyano-2-aminoaniline (66): the synthesis was as described in example 24, but using (65) (1.2g, 3.8mmol) instead of (57). Reaction gave (66) (1.0g, 93%).

Example 32

5-cyano-1- (3- (2-pyrimidinyl) phenyl) benzimidazole (67): the synthesis was performed as described in example 27, using (66) (1.0g, 3.5mmol) instead of (60). Reaction yielded (67) (840mg, 80%).

Example 33

5-formyl-1- (3- (2-pyrimidinyl) phenyl) benzimidazole (68): DIBAL-H in toluene (2.5ml, 1.0M) was added to (67) (367mg, 1.2mmol) and CH at-78 deg.C₂Cl₂(60ml) in a mixture. The mixture was stirred at-78 ℃ for 1 hour and at room temperature for 1 hour. Saturated NH₄The Cl solution was added to the reaction mixture and stirring was continued for 0.5 h. The mixture was poured into water and CH was used₂Cl₂And (4) extracting. The organic extract was MgSO₄Dried and the solvent evaporated under reduced pressure to give (68) (142mg, 38%).

Example 34

5-formyl-1- (3- (2-pyrimidinyl) phenyl) benzimidazole O-methyloxime (69): synthesized as described in example 22 but using (68) (210mg, 0.70mmol) instead of (55), NH₂OMe·HCl(300mg, 3.6mmol) in place of NH₂OH & HCl. Reaction to obtain (69) (192mg, 83%) MP158-159 ℃.

The compounds prepared in the above examples are listed in table 1 below

TABLE 1Compound number X R' R "m.p

No.

29d 2-thienylmethyl-hydrogen 184-

29b 1-Imidazolylmethylhydrogens 197-

29c 3-Furanylmethyl hydrogen 147-

33a 3-pyridylethylmethyl 105-at 106 ℃ 14

33b 3-pyridyl-2-propynylmethyl 138-140 ℃ 14

33c 3-pyridyl-2-propenylmethyl 87-89 deg.C 14

33d 5-pyrimidinylethylmethyl 187-

33e 2-pyridylethylmethyl 107-

33f 3-pyridylisobutylmethyl radical 14 ℃ at 90-92

33g of 3-pyridylmethyl 145-146 ℃ 1433h 2-amino-5-methyl 236-238 ℃ 14

Pyrimidinyl 33i 3-pyridylhydromethyl 218-

Claims (7)

1. A 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 phenyl, benzimidazolyl, or a 5-or 6-membered monocyclic heterocyclic radical, which may be chosen from alkylAlkoxy, halogen, CF₃Amino, nitro, cyano, acyl, acylamino, phenyl and 5-or 6-membered monocyclic heterocyclyl; and is

R⁶And R⁷One is hydrogen and the other is-CR '═ NOR ", where R' is alkyl and R" is hydrogen, alkyl, alkenyl, alkynyl or phenyl.

2. The compound of claim 1 which is 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-ethyloxime (compound 33a), 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole oxime (compound 33j), 5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-methyloxime (compound 38a), 5-acetyl-1- (3- (1-imidazolyl) phenyl) benzimidazole O-ethyloxime (compound 38b), or 5-acetyl-1- (3- (2-thiazolyl) phenyl) benzimidazole O-methyloxime (compound 53), or a pharmaceutically acceptable salt or oxide thereof.

3. The compound of claim 1 which is 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-propynyloxime (compound 33 b); 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-allyloxime (compound 33 c); 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-isobutyl oxime (compound 33 f); 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-methyloxime (compound 33 g); 5-acetyl-1- (3- (5-pyrimidinyl) phenyl) benzimidazole O-ethyloxime (compound 33 d); 5-acetyl-1- (3- (2-pyridyl) phenyl) benzimidazole O-ethyloxime (compound 33 e); 5-acetyl-1- (3- (2-aminopyrimidin-5-yl) phenyl) benzimidazole O-methyloxime (compound 33 h); 5-acetyl-1- (3- (3-pyridyl) phenyl) benzimidazole O-isopropyloxime (compound 33 j); or a pharmaceutically acceptable salt or oxide thereof.

4. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable addition salt or oxide thereof, and at least one pharmaceutically acceptable carrier or diluent.

5. Use of a compound according to any one of claims 1-3 for the manufacture of a medicament for the treatment of a disorder or disease of a living animal body including a human being, said disorder or disease being GABA of the central nervous system_AReceptor complex modulated responses.

6. Use of a compound according to any one of claims 1-3 for the manufacture of a medicament for the treatment of a disorder or disease of a living animal body including a human being, said disorder or disease being GABA of the central nervous system_AA receptor complex up-regulated response.

7. The use of a compound according to any one of claims 1-3 for the manufacture of a medicament for the treatment of disorders and diseases selected from anxiety, sleep disorders, memory disorders, epilepsy and other convulsive disorders.