HK1015359A - 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 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 new benzimidazoleCompounds which can react 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 an alkyl, halogen, CF₃The amino group,nitro, cyano, acylamino, alkoxy, acyl, phenyl and monocyclic heteroaryl, one or more times; and is

R⁶And R⁷One is hydrogen and the other is pyrrolyl, which may be substituted one or more times by substituents selected from the group consisting of halogen, alkyl, phenyl and alkoxy; the above compound which is 1- (3- (3-pyridyl) phenyl) -5- (1-pyrrolyl) benzimidazole, or 1- (3- (5-pyrimidinyl) phenyl) -5- (1-pyrrolyl) 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 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 to a diseased, living animal, including human, a therapeutically effective amount of any of the compounds described above.

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 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 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.

FIG. 1 depicts the preparation of a compound of the present invention wherein R⁶Is pyrrolyl and R⁷Is a hydrogen process. In the compounds of the invention R⁷Is pyrrolyl 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 substituted by, for example, GABA, muscimol, andisotetrahydronicotinic acid is activated but cannot be 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, 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, 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:

watch (A)

Test compounds: IC (integrated circuit)₅₀(nM)1- (3- (3-pyridinyl) -phenyl) -5- (1-pyrrolyl) benzimidazole 8.4

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 100 mg, preferably from 0.1 to 50 mg, 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.

Example 1

2-nitro-4- (1-pyrrolyl) fluorobenzene (1 a): to a suspension of 4-fluoro-3-nitroaniline (20g, 0.13mol) in toluene (200ml) was added 2, 5-dimethoxytetrahydrofuran (33ml, 0.26mol) and a catalytic amount of pTSA. The mixture was heated to reflux for 2.5 hours. After cooling the solvent was removed by evaporation 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: 23.1g (87%), Mp 79-81 ℃.

2-nitro-4- (2, 5-dimethylpyrrol-1-yl) fluorobenzene (1 b): prepared analogously from 4-fluoro-3-nitroaniline and 2, 5-hexanedione in 98% yield, Mp 99-101 ℃.

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 (45.8g, 0.33mol) and tetrakis (triphenylphosphine) palladium (0) (80mg) was heated to 80 ℃ overnight under a stream of nitrogen in a mixture of water (40ml) and dimethoxyethane (80 ml). 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 ℃.

Example 3

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 (0) (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-.

N-acetyl 3- (5-pyrimidinyl) aniline (2 c): acetylation of 2b with acetic anhydride gave 2c (15.4g, 82%) Mp157-158 ℃.

Example 4

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 nitrogen 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-.

Example 5

3- (2-pyridyl) aniline (2 f): to a solution of 2- (3-nitrophenyl) pyridine (prepared according to the method of J.chem.Soc.1958p.1795) (12.7g, 63.5mmol) in anhydrous ethanol was added a palladium catalyst (1.3g, 5% Pd on activated carbon) and the mixture was hydrogenated at atmospheric 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.

N-acetyl 3- (2-pyridyl) aniline (2 g): a mixture of 2f (5.6g, 32.9mmol) and acetic anhydride (20ml) was stirred at ambient temperature for 1 hour. The mixture was poured into ice water and basified with 10M sodium hydroxide. The product is filtered off, washed with water and dried. Yield: 5.5g (79%). Mp133-134 ℃.

Example 6

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%). Mp 162-.

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- (dimethylamino) -5-pyrimidinyl) aniline (2 i): 2h acetylation of 2g as described in example 5 gave 2 i. Mp 183-188 ℃.

Example 7

N- (3- (3-pyridyl) phenyl) -2-nitro-4- (1-pyrrolyl) aniline (3 a): a mixture of 1a (0.5g, 2.4mmol) and 2a (0.41g, 2.4mmol) was heated to 120-135 ℃ in N-methyl-2-pyrrolidone (2.5ml) for 2 days. After cooling, water and dilute sodium hydroxide were added and extracted with ethyl acetate. The extract was dried over sodium sulfate and the solvent was evaporated to give crude 3 a. The crude product was purified by column chromatography on silica gel using dichloromethane followed by a mixture of dichloromethane and methanol (9: 1) as eluent to give pure 3a (0.61g, 71%) as an oil.

Example 8

N- (3- (5-pyrimidinyl) phenyl) -2-nitro-4- (1-pyrrolyl) aniline (3 b): to a stirred suspension of 2c (4.55g, 21.36mmol) in dry DMF (40ml) was added sodium hydride (0.85g of a 60% dispersion in mineral oil) at 0 ℃ under a nitrogen atmosphere. When the evolution of hydrogen had ceased, 1a (4g, 19.42mmol) was added and the resulting mixture was stirred overnight at 40 ℃ under nitrogen. After cooling, the mixture was poured into water (200ml) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography using ethyl acetate as an eluent to give an acetylated product (2.8g), which was stirred at room temperature overnight in a mixture of dimethoxyethane (40ml) and 1M aqueous sodium hydroxide solution. The resulting mixture was diluted with water. The product was filtered off, washed with water and dried to give 3b (2.4g, 35%). Mp 82-84 ℃.

N- (3- (1-imidazolyl) phenyl) -2-nitro-4- (1-pyrrolyl) aniline (3c) was prepared analogously from 1a and 2e, yield: 28%, Mp 129-.

N- (3- (1-imidazolyl) phenyl) -2-nitro-4- (2, 5-dimethylpyrrol-1-yl) aniline (3d) was prepared analogously from 1b and 2e, yield: 35%, Mp 191-.

N- (3- (2-pyridyl) phenyl) -2-nitro-4- (1-pyrrolyl) aniline (3e) was prepared analogously from 1a and 2 g. Yield: 30 percent. The product was isolated as an oil.

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -2-nitro-4- (1-pyrrolyl) aniline (3f) was prepared analogously from 1a and 2 i. Yield: 20% and Mp166-168 ℃.

Example 9

N- (3- (3-pyridyl) phenyl) -2-amino-4- (1-pyrrolyl) aniline (4 a): 3a (6g, 16.85mmol) was dissolved in a mixture of ethanol (100ml) and THF (25 ml). Sodium sulfide monohydrate (13.35g, 56.62mmol) and ammonium chloride (3g, 55.62mmol) were added and the mixture was heated to reflux for 1 hour. After cooling, the mixture was poured into water (400ml), the product was filtered off, washed with water and dried. Yield: 5.1g (93%), Mp178-179 ℃.

N- (3- (5-pyrimidinyl) phenyl) -2-amino-4- (1-pyrrolyl) aniline (4b) was prepared similarly from 3 b. Yield: 89%, Mp 190-.

N- (3- (1-Imidazoyl) phenyl) -2-amino-4- (1-pyrrolyl) aniline (4c) was prepared similarly from 3 c. Yield: 83% and Mp207-212 ℃.

N- (3- (1-Imidazoyl) phenyl) -2-amino-4- (2, 5-dimethylpyrrol-1-yl) aniline (4d) was prepared analogously from 3 d. Mp 190 deg.C (decomposition).

N- (3- (2-pyridyl) phenyl) -2-amino-4- (1-pyrrolyl) aniline (4e) was prepared similarly from 3 e. Yield: 98% and Mp135-140 ℃.

Example 10

N- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) -2-amino-4- (1-pyrrolyl) aniline (4 f): to a suspension of 3f (0.2g, 0.5mmol) in anhydrous ethanol was added a palladium catalyst (5% Pd on activated carbon) and the mixture was hydrogenated at ambient temperature until hydrogen uptake ceased. Filter through celite and concentrate the filtrate under reduced pressure. The crude Lu is used directly in the next step. See example 11.

Example 11

1- (3- (3-pyridyl) phenyl) -5- (1-pyrrole) benzimidazole (5 a): a solution of 4a (5g, 15.34mmol) in formic acid (50ml) was heated to reflux for 45 min. After cooling, the mixture was poured into a vigorously stirred mixture of crushed ice (100g) and aqueous sodium hydroxide (100ml, 12M). The precipitate is filtered off, washed with water and dried. The crude product was dissolved in a mixture of dichloromethane and ethyl acetate and filtered through a short silica gel column. The filtrate was evaporated to dryness and the residue was recrystallized from toluene. Yield: 3.5g (68%). Mp 176-.

1- (3- (1-imidazolyl) phenyl) -5- (1-pyrrolyl) benzimidazole (5c) was prepared similarly from 4 c. Yield: 70 percent. Mp 131-.

1- (3- (2-pyridyl) phenyl) -5- (1-pyrrolyl) benzimidazole (5e) was prepared similarly from 4 e. Yield: 49 percent. Mp 147-.

Preparation of 1- (3- (2- (dimethylamino) pyrimidin-5-yl) phenyl) 5- (1-pyrrolyl) benzimidazole (5f) from 4 f. Yield: 32 percent. Mp 237-.

Example 12

1- (3- (5-pyrimidine) phenyl) -5- (1-pyrrolyl) benzimidazole (5 b): a mixture of 4b (1.6g, 4.9mmol), dimethylformamide dimethyl acetal (1ml, 7.35mmol) and catalytic amount of pTSA was heated to reflux in dry toluene (15ml) for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel using, in succession, ethyl acetate and a mixture of ethyl acetate and methanol (9: 1) as eluent. Obtaining 5 b: 1.5g (91%). Mp 197-198 ℃.1- (3- (1-Imidazoyl) phenyl) -5- (2, 5-dimethylpyrrol-1-yl) benzimidazole (5d) was prepared similarly from 4 d. Yield: 23%, Mp 141-.

Claims (10)

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 monocyclic heteroaryl, which may be selected from alkyl,halogen, CF₃Amino, nitro, cyano, amido, alkoxy, acyl, phenyl and monocyclic heteroaryl are substituted one or more times; and is

R⁶And R⁷One is hydrogen and the other is pyrrolyl, which may be substituted one or more times by substituents selected from halogen, alkyl, phenyl and alkoxy.

2. The compound of claim 1 which is

1- (3- (3-pyridyl) phenyl) -5- (1-pyrrolyl) benzimidazole, or

1- (3- (5-pyrimidinyl) phenyl) -5- (1-pyrrolyl) benzimidazole, or a pharmaceutically acceptable salt thereof

Or an oxide thereof.

3. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-2, 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 any of claims 1-2 for the preparation of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is GABA of the central nervous system_AReceptor complex modulated responses.

5. Use of a compound according to any one of claims 1-2 for the manufacture of a medicament for the treatment of a disorder or disease of a living animal body, including a human, which disorder or disease is GABA of the central nervous system_AA receptor complex up-regulated response.

6. The use of a compound according to any one of claims 1-2 for the preparation of medicaments for the treatment of anxiety, sleep disorders, memory disorders, epilepsy and other convulsive disorders.

7. Method for treating a disorder or disease of a living animal body, including a human, which disorder or disease is GABA in the central nervous system_AA receptor complex modulated response, which method comprises administering to such a living animal body, including a human, in need of such treatment an effective amount of a compound according to any one of claims 1-2.

8. The method of claim 7 wherein the disorder or disease treated is GABA_AA receptor complex up-regulated response.

9. The method of claim 7, wherein the disorder treated is anxiety, sleep disorders, memory disorders, epilepsy or other convulsive disorders.

10. The method of claim 7 wherein the active ingredient is administered in the form of a pharmaceutical composition thereof together with a pharmaceutically acceptable carrier or diluent.