CN101141958A - Benzimidazole derivatives and their use for modulating the GABAA receptor complex - Google Patents
Benzimidazole derivatives and their use for modulating the GABAA receptor complex Download PDFInfo
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- CN101141958A CN101141958A CNA2006800082378A CN200680008237A CN101141958A CN 101141958 A CN101141958 A CN 101141958A CN A2006800082378 A CNA2006800082378 A CN A2006800082378A CN 200680008237 A CN200680008237 A CN 200680008237A CN 101141958 A CN101141958 A CN 101141958A
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Abstract
This invention relates to novel benzimidazole derivatives of formula (I), pharmaceutical compositions containing these compounds, and methods of treatment therewith. The compounds of the invention are useful in the treatment of central nervous system diseases and disorders, which are responsive to modulation of the GABA receptor complex, and in particular for combating anxiety and related diseases.
Description
Technical field
The present invention relates to novel benzimidizole derivatives, the method that contains the pharmaceutical composition of described chemical compound and utilize described chemical compound to treat.
The compounds of this invention can be used for treatment to GABA
AThe adjusting of receptor complex has the central nervous system disease and the obstacle of replying, especially for to anxiety and relevant disease.
Background technology
Be positioned at GABA
ARegulatory site on the receptor complex (for example benzodiazepine binding site) is the action target of anxiolytic drugs (as traditional anxiety benzodiazepine).Yet they are relevant with a series of features of not expecting.
GABA
AReceptor has multiple isotype to exist; Each receptor is all a kind of pentamer complex, and described complex comprises by α
1-6, β
1-3, γ
1-3, the subunit selected of δ, ε and θ subunit isotype.Traditional antianxiety drugs benzodiazepine is not had a selectivity to hypotype.Advise one of key factor of the shortcoming of traditional benzodiazepine (as sedation, dependency and cognitive impairment) and GABA
Aα 1 subunit of receptor is relevant.Therefore, expectation has the side effect feature of improvement to the chemical compound that the selectivity of α 2 and/or α 3 subunits is higher than α 1 subunit.
Therefore, the chemical compound of suitable pharmacological characteristic still has tight demand for having.In addition, also need find the chemical compound of the side effect that the existing chemical compound of effective but nothing is not expected strongly.
Summary of the invention
Aspect first, the invention provides formula I chemical compound of the present invention, or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt;
Wherein, R
a, R
b, R
cAnd R
dBe defined as follows.
Aspect its second, the invention provides pharmaceutical composition, it comprises the The compounds of this invention for the treatment of effective dose, or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt, and at least a pharmaceutically acceptable carrier, excipient or diluent.
Of the present invention further aspect, the invention provides any mixture of The compounds of this invention or its N-oxide, any its isomer or its isomer, or the purposes of its pharmaceutically acceptable salt, it is used to prepare treatment, prevention or releasing mammal, the pharmaceutical composition that comprises human diseases, obstacle or disease, described disease, obstacle or disease are to central nervous system's GABA
AThe adjusting of receptor complex is replied.
Further aspect of the present invention the invention provides a kind of treatment, prevention or alleviates the method for disease, obstacle or the disease of mobiles (comprising the mankind), and described obstacle, disease or disease system are for central nervous system's GABA
AThe adjusting of receptor complex is replied, this method comprises each the chemical compound of claim 1 to 6 of the animal body treatment effective dose of the work that these needs are arranged, or any mixture of its N-oxide, any its isomer or its isomer, or the step of its pharmaceutically acceptable salt.
By following detailed description and embodiment other purpose of the present invention is conspicuous for those skilled in the art.
Detailed Description Of The Invention
Substituted benzimidizole derivatives
First aspect of the present invention provides general formula (I) chemical compound, or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt;
Wherein,
R
a, R
bAnd R
cIndependent separately hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl, alkoxyalkyl, aralkyl, formoxyl, alkyl-carbonyl or the alkoxyalkyl carbonyl represented;
R
dRepresent heteroaryl;
This heteroaryl is optional independently to be selected from following substituent group replacement by following one or more; Halogen, hydroxyl, R ' R " N-, R ' R " N-alkyl, cyano group, nitro, trifluoromethyl, trifluoromethoxy, diazanyl, alkoxyl, cycloalkyloxy, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl and alkynyl;
Wherein, " independent separately is hydrogen or alkyl for R ' and R.
In one embodiment, R
aRepresent hydrogen, alkyl or aralkyl.In a further embodiment, R
aRepresent hydrogen or alkyl.In a concrete embodiment, R
aRepresent hydrogen.In another embodiment, R
aRepresent alkyl, as methyl or ethyl.In embodiment further, R
aRepresent aralkyl, as phenylalkyl, benzyl for example.
In a further embodiment, R
bRepresent hydrogen, alkyl, alkoxyl, aralkyl, formoxyl or alkyl-carbonyl.In embodiment further, R
bRepresent hydrogen, alkyl, formoxyl or alkyl-carbonyl.In a concrete embodiment, R
bRepresent hydrogen.In a further embodiment, R
bRepresent alkyl such as methyl or ethyl.In embodiment further, R
bRepresent aralkyl, as phenylalkyl, benzyl for example.In further embodiment, R
bRepresent formoxyl or alkyl-carbonyl, for example acetyl group.In embodiment further, R
bRepresentation alkoxy such as methoxyl group.
In embodiment further, R
cRepresent hydrogen or alkyl.In a concrete embodiment, R
cRepresent hydrogen.In further embodiment, R
cRepresent alkyl, as methyl.
In further embodiment, R
dRepresentative is selected from the heteroaryl of thiazolyl, pyridine radicals, pyrimidine radicals and pyrazinyl; This heteroaryl is optional to be replaced by one or more substituent group that independently is selected from halogen, diazanyl and alkoxyl.
In embodiment further, R
dThe optional substituted thiazolyl of representative.In further embodiment, R
dRepresent thiazolyl, for example thiazol-2-yl.In embodiment further, R
dRepresent halo-thiazolyl, chloro-thiazolyl for example is as 5-chloro-thiazol-2-yl.
In embodiment further, R
dThe optional substituted pyridine radicals of representative.In further embodiment, R
dRepresent pyridine radicals, for example pyridine-2-base or pyridin-3-yl.In embodiment further, R
dRepresent halogenated pyridyl, fluorine pyridine radicals for example is as 6-fluoro-pyridin-3-yl or 2-fluoro-pyridin-3-yl.In further embodiment, R
dRepresent the hydrazino pyridine base, for example 6-diazanyl-pyridin-3-yl.In further embodiment, R
dThe representation alkoxy pyridine radicals, methoxypyridine base for example is as 2-methoxyl group-pyridin-3-yl.
In embodiment further, R
dThe optional substituted pyrimidine radicals of representative.In further embodiment, R
dRepresent pyrimidine radicals, for example pyrimidine-5-base.In embodiment further, R
dRepresent the dialkoxy pyrimidine radicals, dimethoxypyridin base for example, as 2,4-dimethoxy-pyrimidine-5-base.
In embodiment further, R
dThe optional substituted pyrazinyl of representative.In further embodiment, R
dRepresent pyrazinyl, for example pyrazine-2-base.
In embodiment further, R
a, R
bAnd R
cIndependent separately hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl, alkoxyalkyl, formoxyl, alkyl-carbonyl or the alkoxyalkyl carbonyl represented.
In embodiment further, R
dRepresent heteroaryl; This heteroaryl is optional independently to be selected from following substituent group replacement by one or more; Halogen, hydroxyl, R ' R " N-, R ' R " N-alkyl, cyano group, nitro, trifluoromethyl, trifluoromethoxy, alkoxyl, cycloalkyloxy, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl and alkynyl; Wherein " independent separately is hydrogen or alkyl for R ' and R.
In a concrete embodiment, The compounds of this invention is;
C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-[6-fluoro-pyridin-3-yl]-phenyl)-1H-benzimidazole-5-yl]-methylamine;
C-[1-(3-[pyridine-2-yl]-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
1-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(6-diazanyl-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
N-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide;
N-[1-(3-pyridine-2-base-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide;
N-(1-[1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
Methyl-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dimethyl-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Benzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine;
Dibenzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine;
Methyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dimethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Ethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Diethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Benzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dibenzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
O-methyl-N-{1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-hydroxylamine;
N-{1-[3-thiazol-2-yl-phenyl]-1H-benzimidazole-5-ylmethyl }-Methanamide;
1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
Or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt.
In further concrete embodiment, The compounds of this invention is; 1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethanol; Or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt.
The combination in any of two kinds or more kinds of above-mentioned embodiments is regarded as within the scope of the present invention.
The substituent group definition
Halogen in the context of the invention is represented fluorine, chlorine, bromine or iodine.
In the context of the invention, alkyl is represented unit price hydrocarbon chain saturated, straight or branched.This hydrocarbon chain preferably contains one to six carbon atom (C
1-6-alkyl), comprises amyl group, isopentyl, neopentyl, tertiary pentyl, hexyl and isohesyl.In a preferred embodiment, alkyl is represented C
1-4-alkyl comprises butyl, isobutyl group, sec-butyl and the tert-butyl group.In another embodiment preferred of the present invention, alkyl is represented C
1-3-alkyl, it can be methyl, ethyl, propyl group or isopropyl especially.
In the context of the invention, alkenyl represents to contain the carbochain of one or more pair key, comprises two-alkene, three-alkene and many-alkene.In a preferred embodiment, alkenyl of the present invention contains two to six carbon atom (C
2-6-alkenyl), it comprises at least one two key.In a most preferred embodiment, alkenyl of the present invention is a vinyl; 1-acrylic or 2-acrylic; 1-butylene base, crotyl or 3-cyclobutenyl, or 1,3-butadiene base: 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, or 1, the 3-hexadienyl, or 1,3,5-hexatriene base.
In the context of the invention, alkynyl represents to contain one or more triple-linked carbochain, comprises two-alkynes, three-alkynes and many-alkynes.In a preferred embodiment, alkynyl of the present invention contains two to six carbon atom (C
2-6-alkynyl), comprise at least one triple bond.In its most preferred embodiment, alkynyl of the present invention is an acetenyl; 1-propinyl or 2-propynyl: ethyl acetylene base, 2-butyne base or 3-butynyl, or 1,3-diacetylene base; 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, or 1,3-pentadiine base; 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base or 5-hexin base, or 1,3-hexadiine base, or 1,3, oneself three alkynyls of 5-.
In the context of the invention, cycloalkyl is represented a kind of cyclic alkyl, preferably contains three to seven carbon atom (C
3-7-cycloalkyl), comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.
Alkoxyl is the O-alkyl, and alkyl wherein as defined above.
Cycloalkyloxy is the O-cycloalkyl, and cycloalkyl wherein as defined above.
Cycloalkyl-alkyl means aforesaid cycloalkyl and aforesaid alkyl, for example cyclopropyl methyl of anticipating promptly.
In the context of the invention, heteroaryl is represented aromatic monocyclic or bicyclic heterocyclic radical, and it contains one or more hetero atom in its ring structure.Preferred hetero atom comprises nitrogen (N), oxygen (O) and sulfur (S).
Preferred bicyclic heteroaryl of the present invention comprises aromatics 5-and 6-unit heterocycle monocyclic groups, for example includes but not limited to azoles base, different azoles base, thiazolyl, isothiazolyl, 1,2,4- di azoly, 1,2,4-thiadiazolyl group, 1,2,5- di azoly, 1,2, the 5-thiadiazolyl group, imidazole radicals, pyrrole radicals, pyrazolyl, furyl, thienyl, pyridine radicals, pyrimidine radicals, pyridazinyl or pyrazinyl.
Preferred bicyclic heteroaryl of the present invention for example includes but not limited to indolizine base, indyl, isoindolyl, indazolyl, benzofuranyl, benzo [b] thienyl, benzimidazolyl, benzoxazol base, benzothiazolyl, benzo [d] isothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl, pteridyl and indenyl.
Pharmaceutically acceptable salt
The compounds of this invention can any suitable expection administration form provide.The form that is fit to comprises that the pharmacy (being the physiology) of The compounds of this invention goes up acceptable salt and prodrug (predrug) or prodrug (prodrug) form.
The example of pharmaceutically acceptable addition salt class includes but not limited to: non-toxic inorganic and organic acid addition salt class, hydrochlorate for example, hydrobromate, nitrate, perchlorate phosphate, sulfate, formates, acetate, aconitate, Ascorbate, benzene sulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, Glu, glycollate, lactate, maleate, malonate, mandelate, mesylate, naphthalene-2-sulfonic acid salt, phthalate, Salicylate, sorbate, stearate, succinate, tartrate, toluene-right-sulfonate or the like.Such salt can form by the method for knowing in this area and describing.
Other acids is oxalic acid for example, and it may not be considered to be pharmaceutically acceptable, but can be used in the preparation of salt, and described salt can be used as intermediate product in obtaining The compounds of this invention and pharmaceutically-acceptable acid addition thereof.
The example of the pharmaceutically acceptable cation salt of The compounds of this invention includes but not limited to: contain the sodium salt of the The compounds of this invention of anionic group, potassium salt, calcium salt, magnesium salt, zinc salt, aluminum salt, lithium salts, choline salt, lysinate and ammonium salt etc.Such cation salt can form by the method for knowing in this area and describing.
In the context of the invention, " the salt " of nitrogen-containing compound also is considered to pharmaceutically acceptable salt.Preferably " salt " comprises alkyl- salt, cycloalkyl- salt and cycloalkyl-alkyl- salt.
The example of the prodrug of The compounds of this invention or prodrug form comprises the example of material appropriate drug precursor of the present invention, is included in adorned chemical compound on one or more reactions of parent compound or the deriveding group.Making us compound of interest especially is adorned chemical compound on carboxyl, hydroxyl or amino.The appropriate derivative example is ester or amide.
The compounds of this invention can solvable or insoluble form provide with pharmaceutically acceptable solvent such as water, ethanol etc.Soluble form can also comprise hydrated form, for example monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate etc.Usually, with regard to the object of the invention, think that soluble form is equal to insoluble form.
Stereoisomer
Those skilled in the art will recognize that The compounds of this invention can comprise one or more chiral centres, and the stereoisomer form that such chemical compound can be different-comprise that enantiomer, diastereomer and cis-trans isomer exist.
The present invention includes all such isomer and any mixture thereof, comprise racemic mixture.
Can use the method that is used to split optical isomer as known in the art, and be conspicuous those of ordinary skills.Such method comprises JJaques, and A.Collet and S.Wilen exist "
Enantiomer s.Racemates, and Resolutions", those methods of discussing among the John Wiley and Sons, New York (1981).
Optically active compound can also be by the optical activity feedstock production.
The N-oxide
In the context of the invention, the N-oxide is meant the oxidized derivatives of nitrogen-containing compound, for example can form the nitrogen-containing heterocycle compound of this N-oxide, and has one or more amino chemical compound.For example, the N-oxide that contains the chemical compound of pyridine radicals can be 1-oxygen base-pyridine-2 ,-3 or-the 4-radical derivative.
N-oxide of the present invention can make by the oxidation of corresponding nitrilo (nitrogen base), and this oxidation as in the presence of the acetic acid, uses conventional oxidant such as hydrogen peroxide to carry out in acid under the temperature that improves; Or at suitable solvent (for example dichloromethane, ethyl acetate or methyl acetate), or in the chloroform or dichloromethane that contain the coexistence of 3-chloroperoxybenzoic acid, by making with peracid such as peracetic acid reaction.
Labelled compound
The compounds of this invention can its labelling or the use of unlabelled form.In the context of the invention, this labelled compound has one or more atom, and described atom is had to be different from the atomic mass usually found at occurring in nature or the atomic mass of mass number or the atom of mass number and to replace.Described labelling can make the easy detection by quantitative of this chemical compound.
Labelled compound of the present invention can be used as diagnostic tool, radiotracer or the monitoring agent in the multiple diagnostic method, and can be used for the imaging of body inner recipient.
Labelled isomer of the present invention preferably comprises at least a radionuclide and serves as a mark.The radionuclide of emission positron is the use material standed for.In the context of the invention, radionuclide is preferably selected from
2H (deuterium),
3H (tritium),
13C,
14C,
131I,
125I,
123I and
18F.
The physical method that is used to detect labelled isomer of the present invention can be selected from positron emission tomography art (PET), single photon tomography computer tomography (SPECT), nuclear magnetic resonance spectroscopy method (MRS), nuclear magnetic resonance (MRI) and the axial x-ray tomography imaging of area of computer aided art (CAT) or their combination.
Preparation method
Chemical compound of the present invention can be by being used for the conventional method of chemosynthesis, for example described in an embodiment method preparation.The raw material that is used for the described method of the application is known, perhaps can be easily by conventional method by the chemical production that is available commercially.
Can also a kind of chemical compound of the present invention be changed into another kind of chemical compound of the present invention with conventional method.
The end-product of reaction described herein can pass through routine techniques, for example separates by extraction, crystallization, distillation, chromatograph etc.
The compounds of this invention can exist with the form of solvation and solvation not with pharmaceutically acceptable solvent such as water, ethanol etc.Usually, with regard to reaching the object of the invention, described solvation form is equivalent to not solvation form.
Biological activity
The compounds of this invention can be regulated GABA
AReceptor complex.Can be to them in conjunction with GABA
AReceptor complex, the ability that comprises its specific subunit is tested.
The compounds of this invention is GABA
AThe part of the benzodiazepine binding site on the receptor, therefore, it can be used for the treatment of and/or prevent central nervous system's various obstacles.Therefore, aspect further thinks that The compounds of this invention can be used for treating, prevent or alleviates GABA to the central nervous system
AThe adjusting of receptor complex has disease, obstacle or the disease of replying.
In a specific embodiment, The compounds of this invention is considered to can effectively treat, prevent or alleviate following obstacle;
Anxiety neurosis, as follow or do not follow the agoraphobia of the Panic disorder of agoraphobia, no Panic disorder medical history, to animal and other phobia, comprise the inductive anxiety neurosis of social phobia, obsessive idea and behavior disorder and generalization or material;
After stress disorders, the wound and acute stress disorder,
Sleep disorder;
Dysmnesia;
Neurosis;
Convulsibility obstacle, epilepsy, outbreak, convulsions, child's febrile convulsion;
Migraine;
Mood disorders;
Depression or bipolar disorder, melancholia, single ictal or recurrent severe melancholia, dysthymic disorder, bipolar disorder, I type two-phase mania, II type two-phase mania, cyclicity dysthymic disorder;
Mental disorder comprises schizophrenia;
The neural degeneration that causes by cerebrum ischemia;
The distractibility hyperkinetic syndrome;
Pain and nociception, for example neuropathic pain;
Vomiting comprises acute, tardy property and property vomiting, the particularly vomiting of being brought out by chemotherapy or radiotherapy in advance;
Motion sickness, operation back nausea and vomiting;
Eating disorders comprises nervous anorexia and bulimia nervosa;
Syndrome before the menstruation;
Neuralgia is as trigeminal neuralgia;
Muscle spasm or spasticity are as the spasticity in the paralytic patient;
Substance abuse or dependence effect comprise that ethanol gives up;
Cognitive disorder is as Alzheimer; And
Cerebrum ischemia, apoplexy, head trauma;
Tinnitus;
The circadian rhythm obstacle for example is subjected to the object of the effects of arrival time difference or shiftwork.
Preferably, consideration is used for the treatment of The compounds of this invention, prevent or alleviates anxiety neurosis, as follow or do not follow the agoraphobia of the Panic disorder of agoraphobia, no Panic disorder medical history, to animal and other phobia, comprise the inductive anxiety neurosis of social phobia, obsessive idea and behavior disorder and generality or material.
Further, The compounds of this invention can use as radioligand in mensuration, is used for detecting being incorporated into people GABA
AThe chemical compound of receptor.
The suitable dosage range of expection active pharmaceutical ingredient (API) is about 0.1 to about 1000mg API/ day at present, more preferably about 10 to about 500mg API/ days, most preferably about 30 to about 100mg API/ days, but depend on the indication, patient of definite administering mode, its form of medication, consideration and particularly related patient's body weight, and further, attending doctor or veterinary's preference and experience.
Preferred The compounds of this invention shows the biological activity of sub-micro mole and micro-molar range, promptly less than 1 to about 100 μ M.
Pharmaceutical composition
In one aspect of the method, the invention provides the novel pharmaceutical combination thing, it comprises the The compounds of this invention for the treatment of effective dose.
Although the form administration that the The compounds of this invention that is used for the treatment of can starting compound, but preferably with active component, randomly with the form of physiologically acceptable salt, introducing with one or more adjuvant, excipient, carrier, buffer agent, diluent and/or other conventional excipient substance becomes pharmaceutical composition.
In preferred embodiments, the invention provides pharmaceutical composition, it comprises The compounds of this invention or its pharmaceutically acceptable salt or derivant and one or more pharmaceutically acceptable carriers and therapeutic and/or preventative composition randomly known in the art with other and that use and mixes.This carrier must be " acceptable ", promptly with preparation in other composition compatible and can be harmful to its receiver.
Pharmaceutical composition of the present invention can be those pharmaceutical compositions that are suitable for oral, rectum, bronchus, nose, lung, part (comprising in the cheek and the Sublingual), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intra-arterial, the brain, intraocular injection or infusion) administration, or those are adapted to pass through the forms that suck or be blown into administration, comprise powder and liquid aerosol drug delivery or the pharmaceutical composition by the slow-released system administration.The example of suitable slow-released system comprises the semi-permeable substrate of the solid hydrophobic polymer that contains The compounds of this invention, and this substrate can be the formed article form, for example thin film or microcapsule.
Therefore chemical compound of the present invention can be made the form of pharmaceutical composition and unit dose thereof with adjuvant, carrier or the diluent of routine.Such form comprises solid, and the especially form and the liquid of tablet, filled capsules, powder and pill, especially the capsule of aqueous solution or non-aqueous solution, suspension, Emulsion, elixir and the above-mentioned form of filling, the suppository that all these forms all is used for is oral, be used for rectally and be used for parenteral sterile injectable solution.Such pharmaceutical composition and unit dosage form thereof can comprise conventional ratio conventional ingredient, contain or do not contain other reactive compound or composition, and such unit dosage form can contain the active component of any suitable effective amount suitable with expection application dose scope every day.
The compounds of this invention can various oral and parenteral dosage form administrations.For a person skilled in the art, it is evident that following dosage form can comprise The compounds of this invention or the The compounds of this invention pharmaceutically acceptable salt as active component.
For from the The compounds of this invention pharmaceutical compositions, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials that can also play diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binding agent, antiseptic, tablet disintegrant or coating material effect.
In powder agent, carrier is a fine-grained solids, and it mixes with the particulate active component.
In tablet, active component mixes in the proper ratio with the carrier with necessary binding capacity and is compressed into required shape and size.
Powder agent and tablet preferably contain 5% or 10% to about 70% reactive compound.Suitable carriers is magnesium carbonate, magnesium stearate, Pulvis Talci, sugar, lactose, pectin, dextrin, starch, gelatin, Tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melt wax, cocoa butter etc.Reactive compound and dosage form as the coating material of carrier desired to comprise in term " preparation ", and described coating material provides capsule, wherein contains or carrier-free active component suppressed by vector surrounds, and carrier combines with reactive compound thus.Similarly, also comprise cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be as the solid forms that is suitable for oral administration.
In order to prepare suppository, at first with low-melting wax, as the mixture melt of fatty glyceride or cocoa butter, by stirring active component is evenly dispersed in wherein then.In the suitable big or small mould of the homogeneous mixture impouring that will melt then, make its cooling and curing thus.
The compositions that is suitable for vagina administration can vaginal suppository, the form of tampon, ointment, gel, paste, foam or spray exists, and described compositions also contains suitable carriers known in the art except that containing active component.
Liquid preparation comprises solution, suspension and Emulsion, for example, and aqueous solution or water-propylene glycol solution.For example, the parenteral injection liquid preparation can be mixed with the solution of moisture Polyethylene Glycol.
Therefore, The compounds of this invention can be mixed with and be used for parenteral (for example injection, as inject or continuous infusion) preparation, and can provide with the unit dosage form of ampoule, pre-filled syringe, small size transfusion or with multi-dose container with the antiseptic that adds.Said composition can be taked the form of suspension, solution or the Emulsion of oiliness or aqueous carrier, and can contain the preparation composition, as suspending agent, stabilizing agent and/or dispersant.In addition, active component can be a powder type, and the aseptic separation by sterile solid or obtain by the solution lyophilizing is used for before use preparing with suitable carriers such as aseptic, pyrogen-free water.
The aqueous solution that is suitable for orally using can prepare by solubilization of active ingredient is also added suitable coloring agent, flavoring agent, stabilizing agent and thickening agent as required in water.
The water slurry that is suitable for orally using can prepare by the particulate active component being dispersed in contain in stickum, the water as natural or synthetic natural gum, resin, methylcellulose, sodium carboxymethyl cellulose or other known suspending agent.
Also comprise the solid form preparation of desiring before facing usefulness, to be converted into the liquid form preparation that is used for oral administration.Such liquid form comprises solution, suspension and Emulsion.Except that active component, such preparation can comprise coloring agent, flavoring agent, stabilizing agent, buffer agent, artificial and natural sweeting agent, dispersant, thickening agent, solubilizing agent etc.
In order to locally apply to epidermis, The compounds of this invention can be mixed with ointment, cream, or lotion, or transdermal patch.For example, ointment and cream can add suitable thickening and/or gellant is formulated with aqueous or oleaginous base.Lotion can be formulated with aqueous or oleaginous base, and also contain one or more emulsifying agents, stabilizing agent, dispersant, suspending agent, thickening agent or coloring agent usually.
Be suitable for that topical drug delivery composition is included in flavoured base in the oral cavity, be generally the lozenge that comprises active component in sucrose and acacin or the Tragacanth; The pastille (pastilles) that comprises active component at inert base, as gelatin and glycerol or sucrose and acacin; And the collutory that in suitable liquid-carrier, comprises active component.
Solution or suspension for example can be applied directly to nasal cavity with dropper, suction pipe or aerosol apparatus with conventional method.Said composition can single dose or the form of multiple dose provide.
Respiratory tract administration also can be realized by aerosol, wherein active component provides in pressurized package with suitable propellant, suitable propellant comprises chlorofluorocarbon (CFC) for example dichloro dichloromethane, Arcton 11 or dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.Aerosol also can suitably contain surfactant such as lecithin.The dosage of medicine can be by being equipped with metering valve control.
Perhaps, active component can provide by dry powder form, for example the mixture of powders of chemical compound in suitable powder substrate such as lactose, starch, starch derivatives such as hydroxypropyl emthylcellulose and polyvinylpyrrolidone (PVP).Aptly, dust carrier will form gel at nasal cavity.Powder composition can present by unit dosage form, for example with capsule or cartridge case (as the capsule or the cartridge case of gelatin) form, or can be by the inhaler blister package form of administration therefrom with powder.
Comprise intranasal compositions in the compositions of desiring to be used for respiratory tract administration, chemical compound has little particle diameter usually, for example is 5 microns or the littler order of magnitude.Such particle diameter can be by methods known in the art, for example obtain by micronization.
When needing, can use the compositions that is fit to provide the active component slow release.
Pharmaceutical preparation is preferably unit dosage form.In this class form, preparation is subdivided into the unit dose that contains an amount of active component.Unit dosage form can be the preparation of packing, and this packing contains the preparation of discrete amount, as tablet, the capsule of packing, and the powder in bottle or the ampoule.In addition, unit dosage form can be capsule, tablet, cachet or a lozenge itself, maybe can be the packaged form that is fit to any of these dosage form of quantity.
The tablet or the capsule that are used for oral administration are preferred compositions with the liquid and the continuous infusion liquid that are used for intravenously administrable.
About the more detailed data of preparation and medicine-feeding technology can (Maack PublishingCo.Easton finds on PA) at the Reminaton ' of latest edition s Pharmaceutical Sciences.
The treatment effective dose refers to the amount of active component, and it can improve symptom or condition of illness.Treatment effectiveness and toxicity, for example ED
50And LD
50Can in cell culture or laboratory animal, be measured by standard pharmacology program.But the dosage between therapeutic effect and the toxic action is than being therapeutic index and passing ratio LD
50/ ED
50Expression.Preferably show the pharmaceutical composition of big therapeutic index.
The dosage that gives certainly must be at age, body weight and the disease of the individuality of being treated, and route of administration, dosage form and dosage regimen, and the result of expectation and adjusting carefully, and definite dosage should be determined by the doctor certainly.
Actual dosage depends on the character and the order of severity of the disease for the treatment of, and within doctor's determination range, can be according to the present invention concrete condition the reaction of dosage is changed, to produce required therapeutic effect.Yet expection at present contains from about 0.1 to about 500mg, preferably from about 1 to about 100mg, more preferably the pharmaceutical composition from about active component of 1 to about 10mg/single dosage is suitable for therapeutic treatment.
Active component can every day one or several doses give.In some cases, can obtain gratifying result with the dosage that is low to moderate 0.1 μ g/ kilogram (intravenous) and 1 μ g/ kilogram (oral).Think that at present the upper limit of dosage range is about 10mg/ kilogram (intravenous) and 100mg/ kilogram (oral).Preferable range is from about 0.1 μ g/ kilogram to about 10mg/ kilogram/day (intravenous), and from about 1 μ g/ kilogram to about 100mg/ kilogram/day (oral).
Therapeutic Method
In one aspect of the method, the invention provides treatment, prevent or alleviate the disease that animal body alive comprises the people, the method for obstacle or disease, this disease wherein, obstacle or disease are for GABA among the central nervous system
AThe adjusting of receptor complex is replied, and this method comprise the work that these needs are arranged animal body, comprise the The compounds of this invention of human effective dose.
Expection at present, suitable dosage range is that every day 0.1 is to 1000mg, every day 10 is to 500mg, and particularly every day 30-100mg, depend on definite administering mode usually, form of medication, administration at indication, related patient and related patient's body weight, and further, doctor or veterinary's preference and experience.
Embodiment
Further specify the present invention with reference to the following example, but these embodiment have no intention to limit by any way the desired scope of the invention.
General rule: all relate to the reaction of air sensitive reagent or intermediate product and all carry out in nitrogen and anhydrous solvent.In post processor, use magnesium sulfate or sodium sulfate as desiccant and vapourisation under reduced pressure solvent.
Embodiment 1
3-nitro-4-(3-thiazol-2-yl-phenyl amino) benzoic acid
(15.0g, (14.0g is in anhydrous NMP (50ml) solution 79mmol) 127mmol) to be added to 3-thiazol-2-yl-phenyl amine with 4-fluoro-3-nitrobenzoic acid.The gained mixture stirs down in 90 ℃ and spends the night.Refrigerative reaction cake is suspended in water, filter out solid, wash with water, air-dry, the product that obtains expecting (22.5g, 83%).
3-nitro-4-(3-bromophenyl amine amino) benzoic acid
According to similar method, make by 4-fluoro-3-nitrobenzoic acid and 3-bromaniline.
[3-nitro-4-(3-thiazol-2-yl-phenyl amino)-phenyl]-methanol
In blanket of nitrogen, above-mentioned product is dissolved in anhydrous THF (150ml).Solution is cooled to 0 ℃, under agitation, dropwise adds the THF solution (132ml) of 1M borine-THF complex.Finish and add Hou, reactant mixture stirs at ambient temperature and spends the night.Vacuum is gone down and is desolventized, and residue distributes in water and dichloromethane.The organic layer dried over mgso, be evaporated to dried, the product that obtains expecting (23.3g, 77%).
[3-nitro-4-(3-bromophenyl amino) phenyl] methanol
According to similar method, make from 3-nitro-4-(3-bromophenyl amino) benzoic acid.
[3-amino-4-(3-thiazol-2-yl-phenyl amino) phenyl]-methanol
With hydrazine hydrate (11ml, 217mmol) and the Raney nickel of catalytic amount add to above-mentioned product (17.8g be in the solution of the mixture of THF 54.0mmol) (100ml) and ethanol (50ml).Reactant mixture stirs under environmental condition and spends the night, and filters by celite again.Filtrate is evaporated to dried, the product that obtains expecting (15.8g, 86%).
[3-amino-4-(3-bromophenyl amino) phenyl] methanol
According to similar method, make by [3-nitro-4-(3-bromophenyl amino) phenyl] methanol.
[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methanol
With triethyl orthoformate (18ml, 0.11mmol) and the p-methyl benzenesulfonic acid of catalytic amount add to above-mentioned product (15.8g be in anhydrous THF (100ml) solution 53.1mmol).Gained solution stirred 3 hours down in refluxing, and then went down to desolventize in vacuum.Residue distributes between aqueous sodium carbonate and ethyl acetate and methanol mixture.Organic layer concentrates in vacuum with dried over sodium sulfate, and concentrate carries out silica gel column chromatography, with dichloromethane and methanol mixture eluting, and the product that obtains expecting (6.5g, 40%).
[1-(3-bromophenyl)-1H-benzimidazole-5-yl]-methanol
According to similar method, make by [3-amino-4-(3-bromophenyl amino) phenyl] methanol.
2-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone
In 15 minutes and under stirring, with diethylazodicarboxylate (4.2g, 25.4mmol) dropwise add to by above-mentioned product (6.5g, 21.1mmol), phthalimide (3.7g, 25.4mmol) and the anhydrous THF of triphenylphosphine (in the ice-cold mixture of 15 (ml) solution.Continuous stirring 30 minutes.Then in vacuum, remove solvent.With ethyl acetate titration residue, leach the gained precipitate, air-dry with the ethyl acetate washing, the product that obtains expecting (7.5g, 81%).
2-[1-(3-bromo-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone
According to similar method, make by [1-(3-bromo-phenyl)-1H-benzimidazole-5-yl]-methanol.
2-{1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl]-ethyl }-iso-indoles-1, the 3-diketone
According to similar method, by 1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl]-ethanol makes.
C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine
(3.5ml, (7.5g is in dehydrated alcohol 17.2mmol) (100ml) suspension 68.7mmol) to add to above-mentioned product with hydrazine hydrate.Mixture stirred 1 hour down in refluxing, and placed under environmental condition then and spent the night.Vacuum is removed solvent, and the titration of residue water stays solid, makes it carry out silica gel column chromatography, and use dichloromethane and methanol (9: 1, V/V) as eluent.The product that obtains expecting is white crystal form solid (3.8g, 71%).99.7 ℃ of fusing points.
C-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine
According to similar method, by 2-[1-(3-(pyridin-3-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone makes, productive rate 26%.Fusing point 107-110 ℃.
C-[1-(3-[6-fluoro-pyridin-3-yl]-phenyl)-1H-benzimidazole-5-yl]-methyl amine
According to similar method, by 2-[1-(3-(6-fluoro-pyridin-3-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone makes, productive rate 25%.Fusing point 141-143 ℃.
C-[1-(3-pyridine-2-base-phenyl)-1H-benzimidazole-5-yl]-methyl amine
According to similar method, by 2-[1-(3-(pyridine-2-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone makes, productive rate 18%.Fusing point 224-229 ℃.
C-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-methyl amine
According to similar method, by 2-[1-(3-(pyrazine-2-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone makes, productive rate 22%.Fusing point 163-165 ℃.
1-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine
According to similar method, by 2-[1-[1-(3-(pyrazine-2-yl)-phenyl)-1H-benzimidazole-5-yl]-ethyl]-iso-indoles-1, the 3-diketone makes.[M+H]
+LC-ESI-HRMS show; 316.155Da. value of calculation 316.15622Da, de.-3.9ppm.
1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethylamine
According to similar method, by 2-{1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-iso-indoles-1, the 3-diketone makes, productive rate 10%.[M+H]
+LC-ESI-HRMS show; 315.1604Da.Calc, 315.160971Da, dev.-1.8ppm.
1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine
According to similar method, by 2-(1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl-ethyl)-iso-indoles-1, the 3-diketone makes, productive rate 15%.[M+H]
+LC-ESI-HRMS show; 333.1501Da. value of calculation 333.151549Da, dev.-4.3ppm.
The primary product of this reaction (24%) is 1-{1-[3-(6-diazanyl-pyridin-3-yl)-phenyl]-1H-benzimidazole-5 base }-ethylamine
1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine
According to similar method, by 2-{1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethyl }-iso-indoles-1, the 3-diketone makes
N-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide
With acetic anhydride (2.4ml 2.5mmol) drops to C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl under stirring]-(0.70g is in dichloromethane 2.3mmol) (30ml) suspension for methyl amine.After finishing dropping, continue to stir 30 minutes, reactant mixture saturated sodium bicarbonate aqueous solution washed twice washes with water 1 time.Use the dried over sodium sulfate organic facies, in vacuum, concentrate.The concentrate purification by silica gel column chromatography, with dichloromethane, methanol and ammonia (9: 1: 0.1, mixture eluting v/v/v).The product that obtains expecting (0.52g, 65%).156.4 ℃ of fusing points.
N-[1-(3-pyridine-2-base-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide
According to similar method, by C-[1-(3-[pyridine-2-yl]-phenyl)-1H-benzimidazole-5-yl] methyl amine makes (0.06g, 54%).[M+H]
+LC-ESI-HRMS show; 343.1544Da. value of calculation 343.155886Da, dev.-4.3ppm.
Embodiment 2
2-[1-(3-(pyridin-3-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone
In blanket of nitrogen, with 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1,3-diketone (1.10g, 2.54mmol), 3-pyridine boric acid (0.47g, 3.82mmol), potassium carbonate (1.06g, 7.63mmol), 1, ammediol (0.92ml, 12.72mmol) and the stirring 20 minutes that refluxes of the mixture that (0.1g) in the mixture of dimethoxy-ethane (20ml) and water (10ml), forms of two (triphenylphosphine) palladiums (II) of dichloro.Volatile material is removed in the cooling of gained mixture in vacuum.Product precipitates from residual solvent, filters, and washes with water, and is air-dry, obtains the 0.56g product.
2-[1-(3-(6-fluorine pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone
According to similar method, from 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1,3-diketone and (6-fluoro-3-pyridine) boric acid make.
2-{1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-ethyl }-iso-indoles-1, the 3-diketone
According to similar method, from 2-{1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-iso-indoles-1,3-diketone and 3-pyridine boric acid make.
2-(1-{1-(3-(6-fluorine pyridin-3-yl)-phenyl)-1H-benzimidazole-5-yl }-ethyl)-iso-indoles-1, the 3-diketone
According to similar method, by 2-{1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-iso-indoles-1,3-diketone and (6-fluoro-3-pyridine) boric acid make.
2-{1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl] ethyl }-iso-indoles-1, the 3-diketone
According to similar method, by 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl] ethyl }-iso-indoles-1,3-diketone and 5-pyrimidine boric acid make.
2-[1-(3-(pyridine-2-yl)-phenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1, the 3-diketone
To 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1,3-diketone (1.0g, 2.31mmol) anhydrous THF (20ml) solution in add 2-tributyl stannyl pyridine (0.82ml, 2.54mmol) and the tetrakis triphenylphosphine palladium (0) of catalytic amount (60mg), the gained mixture refluxes in blanket of nitrogen and stirred 3 days.Make the reactant mixture cessation reaction with ammonia, use ethyl acetate extraction.Use the dried over mgso organic extract, concentrate in a vacuum.Concentrate is used eluent ethyl acetate, the product that obtains expecting by silica gel.0.24g(24％)。
2-{1-(3-(pyrazine-2-yl)-phenyl)-1H-benzimidazole-5-ylmethyl }-iso-indoles-1, the 3-diketone
According to similar method, by 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]-iso-indoles-1,3-diketone and 2-tributyl stannyl pyrazine make.
2-{1-[1-(3-(pyrazine-2-yl)-phenyl)-1H-benzimidazole-5 base] ethyl }-iso-indoles-1, the 3-diketone
According to similar method, from 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl] ethyl }-iso-indoles-1,3-diketone and 2-tributyl stannyl pyrazine make.
Embodiment 3
1-[4-(3-bromo-phenyl amino)-3-nitro-phenyl] ethyl ketone
To 4-fluoro-3-nitro-acetophenone (165g, add in NMP 0.9mol) (350ml) solution 3-bromaniline (98ml, 0.9mol) and triethylamine (125.4ml, 0.9mol), reactant mixture stirred 6 hours in 80 ℃, followed in stirred overnight at room temperature.In the gained suspension impouring frozen water, leach precipitate, water and ether wash successively.Air-dry, the product that obtains expecting (262g, 87%).
1-{4-[3-(5-chloro-thiazol-2-yl)-phenyl amino]-3-nitro-phenyl }-ethyl ketone
According to similar method, make productive rate 76% by 4-fluoro-3-nitro-acetophenone and 3-thiazol-2-yl phenyl amine.
1-[3-amino-4-(3-bromo-phenyl amido)-phenyl] ethyl ketone
With 1-[4-(3-bromo-phenyl amino)-3-nitro-phenyl] (75g 0.22mol) is dissolved in THF (350ml) to ethyl ketone, uses Raney nickel as catalyst, carries out hydrogenation with standardization program, makes required diamidogen, need not to be further purified promptly to be used for next step.
1-{3-amino-4-[3-(5-chloro-thiazol-2-yl)-phenyl amino]-phenyl }-ethyl ketone
According to similar method, from 1-{4-[3-(5-chloro-thiazol-2-yl)-phenyl amino]-3-nitro-phenyl }-ethyl ketone makes.
1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl ketone
As described in embodiment 1, in the presence of p-methyl benzenesulfonic acid, with the THF solution-treated of triethyl orthoformate, from 1-[3-amino-4-(3-bromo-phenyl amino)-phenyl] (86.5g 0.28mol) makes ethyl ketone.
1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl ketone
According to similar method, from 1-{3-amino-4-[3-(5-chloro-thiazol-2-yl)-phenyl amino]-phenyl }-ethyl ketone makes.
1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethanol
With sodium borohydride (0.91g 23.9mmol) is added into 1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl-(6.3g, in methanol 17.8mmol) (75ml) solution, the gained mixture stirred 7 days under room temperature and blanket of nitrogen ethyl ketone.Reactant mixture dilutes with the water of 4 times of volumes, and uses ethyl acetate extraction.With salt water washing organic extract, use dried over mgso, evaporate in a vacuum, make the product (4.95g, 78%) of expectation.[M+H]
+LC-ESI-HRMS show; 356.035Da. value of calculation 356.062436Da, dev.3ppm.
1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethanol
According to similar method, from 1-{4-(3-bromo-phenyl amino)-3-nitro-phenyl }-ethyl ketone makes.
Embodiment 4
N-[1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-Methanamide
Make 1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl ketone (7.5g, 23.8mmol), Methanamide (9.5ml, 23.8mmol) and formic acid (22.4ml, mixture 595mmol) stirred 7 hours in 190 ℃.The refrigerative mixture of decant.Add saturated aqueous sodium carbonate and make the residue alkalization, use ethyl acetate extraction.Use the dried over mgso organic extract, in a vacuum evaporation.(9: 1: 0.1, mixture v/v/v) was from the silica gel eluting, the product that obtains expecting (60%) with dichloromethane, methanol and ammonia for concentrate.
N-(1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl } ethyl)-Methanamide
With 2-fluorine pyridine-3-boric acid (0.09g, 0.65mmol), two (triphenylphosphine) palladiums (II) of chlorination (5mg) and sodium carbonate (0.07g, 0.65mmol) add at dimethoxy-ethane, water and ethanol (4ml, 7: 3: the N-{1-[1-in mixture 2v/v/v) (3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-Methanamide (0.2g, 0.65mmol) in the solution, gained mixture microwave heating to 160 ℃ continues 4 minutes.Dilute refrigerative mixture with ethyl acetate, with water washing.Use dried over mgso, carry out column chromatography and handle, make the product (150mg, 67%) of expectation.[M+H]
+LC-ESI-HRMS show; 361.1451Da. value of calculation 361.146464Da, dev.-3.8ppm.
N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl } ethyl)-Methanamide
According to similar method, from N-{1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-Methanamide and 2-methoxypyridine-3-boric acid makes productive rate 77%.[M+H]
+LC-ESI-HRMS show; 373.1666Da. value of calculation 373.166451Da, dev.0.4ppm.
N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl } ethyl)-Methanamide
According to similar method, from N-{1-[1-(3-bromo-phenyl)-1H-benzimidazole-5-yl] ethyl }-Methanamide and 2,4-dimethoxypyridin-5 boric acid makes, productive rate 81%.[M+H]
+LC-ESI-HRMS show; 404.1729Da. value of calculation 404.172265Da, dev.1.6ppm.
1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl } ethylamine
Make N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl] ethyl-Methanamide (0.53g, hydrochloric acid 1.31mmol) (2,2ml, 6M) solution stirred 3 hours in 60 ℃.Ethyl acetate and aqueous sodium carbonate are added to quaternization in the refrigerative solution.Layer is separated organic layer dried over mgso, evaporation in a vacuum.(9: 1: 0.1, mixture v/v/v) was by silica gel eluting, the product that obtains expecting (0.12g, 25%) with dichloromethane, methanol and ammonia for concentrate.[M+H]
+LC-ESI-HRMS show; 376.1794Da. value of calculation 376.17735Da, dev.5.4ppm.
1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl } ethamine
According to similar method, by N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl ethyl)-Methanamide makes productive rate 31%.[M+H]
+LC-ESI-HRMS show; 345.1733Da.Calc 345.171536Da, dev.5.1ppm.
1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl } ethamine
According to similar method, by N-(1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl-ethyl)-Methanamide makes.
Embodiment 5
5-chloro-2-(3-nitro-phenyl)-thiazole
(28.2ml, (18.5g is 89.7mmol) in the solution of the mixture of chloroform (150ml) and dry DMF (40ml) 359mmol) slowly to be added into 2-(3-nitro-phenyl)-thiazole under stirring with sulfonic acid chloride.After interpolation was finished, the gained mixture stirred 3 hours down in refluxing.Refrigerative mixture concentrates down in decompression, and residue is in distributing in calcium chloride water (3M) and ethyl acetate.Wash organic layer with aqueous sodium carbonate, use dried over mgso, be evaporated to dried, the product that obtains expecting.20.6g(80％)。
3-thiazol-2-yl-phenyl amine
(20.0g, in THF 69.6mmol) (260ml) solution, (13.5ml is 278mmol) with Raney nickel (2g) to add the hydrazine monohydrate to 5-chloro-2-(3-nitro-phenyl)-thiazole.The gained mixture stirred under environmental condition 1 hour, filtered through celite.Filtrate is evaporated to dried, and filtrate is distributed in ethyl acetate and saturated aqueous sodium carbonate.Use the dried over sodium sulfate organic layer, in vacuum, concentrate.(1: 3, mixture v/v) was through the silica gel eluting, the product that obtains expecting (10.6g, 72%) with ethyl acetate and petroleum ether for concentrate.
Embodiment 6
General operation;
In dry DMF (the every donaxine 10-20ml) solution of amine, add the suitable alkylating agent of 1.1 equivalent triethylamines and 1.5 equivalents.The gained mixture is in stirring at room, and (TLC or LC-MS) exhausts fully until initial substance.Mixture is used ethyl acetate extraction with the water dilution of 4 times of volumes.Concentrated extract carries out column chromatography to be handled, and obtains required product.
By this operation, make following compounds:
From C-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl] methyl amine and iodomethane make
Methyl-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine and
Dimethyl-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine [fusing point; 235 ℃ (being hydrochlorate)].
From 1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl] ethylamine makes
Benzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5 base]-ethyl]-amine, [M+H]
+LC-ESI-HRMS show; 405.2069Da. value of calculation 405.207921Da, dev.-2.5ppm and
Dibenzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine.
By C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine makes
Methyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine and
Dimethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine, [M+H]
+LC-ESI-HRMS show; 335.1313Da. value of calculation 335.133042Da, dev.-5.2ppm.
Ethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine, fusing point; 224 ℃ (being hydrochlorate) and
Diethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine, fusing point; 152 ℃ (being hydrochlorate).
Benzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine
[M+H]
+LC-ESI-HRMS show; 397.1492Da. value of calculation 397.148692Da, dev.1.3ppm) and
Dibenzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine (fusing point; 126 ℃).
Embodiment 7
O-methyl-N-{1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-base ethyl]-azanol
To 1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl ketone O-methyl-oxime (description according to WO96/33191 makes) (0.88g, 2.57mmol) dichloromethane (10ml) solution in, add successively the pyridine borane complexes (0.87ml, 8.57mmol) and glacial acetic acid (2.5ml).Gained solution refluxes in blanket of nitrogen and stirred 4 days.(5ml 1M) adds in the refrigerative solution, connects to continue to stir 30 minutes, and the gained mixture concentrates in vacuum with hydrochloric acid.Concentrate distributes in ethyl acetate and sodium bicarbonate aqueous solution.Use the dried over sodium sulfate organic layer, (9: 1, mixture v/v) obtained the product of 27mg expectation through the silica gel eluting with ethyl acetate and methanol.[M+H]
+LC-ESI-HRMS show 345.1717Da. value of calculation 345.171536Da, dev.0.5ppm.
Embodiment 8
N-{1-[3-(thiazol-2-yl)-phenyl]-1H-benzimidazole-5-ylmethyl }-Methanamide
Make C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-(1.4g, formic acid 4.57mmol) (20ml) solution reflux and stirred 3 hours methyl amine.Mixture evaporates in vacuum.Residue distributes in ethyl acetate and saturated sodium bicarbonate aqueous solution.Use the dried over mgso organic layer, decompression concentrates down.Residue is by purification by silica gel column chromatography, and (9: 1, mixture v/v) was as eluent, the product 0.5g (33%) that obtains expecting to use dichloromethane and methanol.[M+H]
+LC-ESI-HRMS show; 335.095Da. value of calculation 335.096657Da, dev.-4.9ppm.
Embodiment 9
1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine
With 1-{1-[3-(5-chloro-the thiazol-2-yl)-phenyl under stirring]-1H-benzimidazole-5-yl }-ethanol (1.0g; 2.80mmol) dry toluene (60ml) and the suspension of THF (10ml) be cooled to 10 ℃; add 1 successively; 8-diazabicyclo [5.4.0] ten-carbon-7-alkene (0.5ml; 3.36mmol) and diphenyl phosphoryl azide (0.95g, 3.36mmol).Continue to stir 45 minutes at 10 ℃, heat up subsequently, mixture stirred 2 days down in refluxing.Refrigerative mixture concentrates in vacuum.Concentrate distributes in ethyl acetate and saturated aqueous sodium carbonate.Use the dried over mgso organic extract, decompression concentrates down, and (9: 1: 0.1, mixture v/v/v) washed through silica gel, the product that obtains expecting (0.75g, 70%) with dichloromethane, methanol and ammonia.[M+H]
+LC-ESI-HRMS show; 335.079Da. value of calculation 335.07842Da, dev.1.6ppm.
Embodiment 10
Described some amine of the foregoing description exists with racemic mixture.Its specific enantiomer can be by following general operation, with commercially available (R) that gets-and (S)-the 1-phenyl ethyl amine is that starting material makes.
By protecting optically pure 1-(4-fluorophenyl) ethylamine with the acetylation of acetic anhydride and the Nitrification of nitric acid.Products therefrom and the formylated 3-that suits are substituted the anionic reactive of aniline, obtain nitroaniline, and the latter then carries out hydrogenation and closed loop.
By this operation, can make following chemical compound
(R)-benzyl-{ 1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine and
(S)-benzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine.
(R)-1-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine and
(S)-1-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine.
(R)-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethylamine and
(S) 1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethylamine.
(R)-1-{1-[3-(6-diazanyl-pyridin-3-yl)-phenyl-1H-benzimidazole-5-base-ethylamine and
(S)-1-{1-[3-(6-diazanyl-pyridin-3-yl)-phenyl }-1H-benzimidazole-5-base-ethylamine.
(R)-1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl-1H-benzimidazole-5-base-ethylamine and
(S)-1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl }-1H-benzimidazole-5-base-ethylamine.
(R)-1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine and
(S)-1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine.
(R)-1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl-ethylamine and
(S)-1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine.
(R)-N-(1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl-ethyl) Methanamide and
(S)-N-(1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl) Methanamide
(R)-N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl-ethyl)-Methanamide and
(S)-N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide
(R)-N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl-ethyl)-Methanamide and
(S)-N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide
(R)-1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl-ethylamine and
(S)-1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine
(R)-1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl-ethylamine and
(S)-1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine
(R)-1-{1-[3-(2-fluoro-pyridine-5-yl)-phenyl]-1H-benzimidazole-5-yl-ethylamine and
(S)-1-{1-[3-(2-fluoro-pyridine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine.
Method of testing
Method of testing 1
3The H-flunitrazepam (
3H-FNM) bonded vitro inhibition effect
Optionally use
3H-flunitrazepam labelling GABA recognition site and benzodiazepine regulon.
The tissue preparation thing
Except as otherwise noted, be prepared in 0-4 ℃.To place from the cerebral cortex of male Wistar rat (150-200g) 20ml Tris-HCl (30mM, pH7.4) in, with Ultra-Turrax homogenizer homogenizing 5-10 second.Suspension centrifugal 15 minutes in 27,000 * g, pill is with buffer washing 3 times (in centrifugal 10 minutes of 27,000 * g).Pill after the washing homogenizes in the 20ml buffer, and water-bath (37 ℃) incubation 30 minutes, removing endogenous GABA, and then in 27,000 * g centrifugal 10 minutes.Then, pill homogenizes in buffer, in 27,000 * g centrifugal 10 minutes again.Final pill resuspending is in the 30ml buffer, and prepared product is freezing, is stored in-20 ℃.
Analyze
The film preparation thing is thawed, centrifugal 10 minutes with 27,000 * g in 2 ℃.Use the Ultra-Turrax homogenizer, with 20ml Tris-citrate (50mM, pH7.1) washing pill twice, and centrifugal 10 minutes in 27,000 * g.Final pill resuspending in 50mMTris-citrate (pH7.1, every g initially organize and use the 500ml buffer), is used for binding analysis then.The 0.5ml aliquot of tissue is added to 25 μ L tried solution and 25 μ L
3Among the H-FNM (1nM, final concentration), mix, in 2 ℃ of incubations 40 minutes.Use clonazepam (Clonazepam, 1 μ M, final concentration) to measure non-specific binding.After incubation is finished, add the 5ml ice-cold buffer, directly be poured onto on the Whatman GF/C glass fibre filter of suction attitude, wash with the 5ml ice-cold buffer immediately.With the radioactivity amount on the conventional liq scinticounting mensuration filter.Specificity is combined into total binding and deducts non-specific binding.
The result
Calculating IC
50Before, need to obtain earlier the specificity of 25-75% in conjunction with inhibitory action.
Test value is with IC
50(suppress 50%
3The bonded concentration (μ M) of being tried material of H-FNM specificity) provide.
Wherein,
C
oBe the specificity combination of check analysis group, and
C
xSpecificity combination for the analysis of experiments group.
(calculate be assumed under the normal quality effect kinetics carry out)
The result of the test of carrying out these experiments with some chemical compounds of the present invention is shown in following table 1.
Table 1
| Test-compound | External in conjunction with IC 50(μ m) |
| C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine. | 0.011 |
| N-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide. | 0.024 |
| N-{1-[3-(thiazol-2-yl)-phenyl]-1H-benzimidazole-5-ylmethyl }-Methanamide. | ? ?0.0048 |
Claims (11)
1. general formula (I) chemical compound,
Or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt,
Wherein
R
a, R
bAnd R
cIndependent separately hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl, alkynyl, hydroxyl, alkoxyl, alkoxyalkyl, aralkyl, formoxyl, alkyl-carbonyl or the alkoxyalkyl carbonyl represented;
R
dRepresent heteroaryl;
This heteroaryl is optional independently to be selected from following substituent group replacement by one or more; Halogen, hydroxyl, R ' R " N-, R ' R " N-alkyl, cyano group, nitro, trifluoromethyl, trifluoromethoxy, diazanyl, alkoxyl, cycloalkyloxy, alkyl, cycloalkyl, cycloalkyl-alkyl, thiazolinyl and alkynyl;
Wherein, " independent separately is hydrogen or alkyl for R ' and R.
2. the chemical compound of claim 1, wherein R
aRepresent hydrogen, alkyl or aralkyl.
3. claim 1 or 2 chemical compound, wherein R
bRepresent hydrogen, alkyl, alkoxyl, aralkyl, formoxyl or alkyl-carbonyl.
4. each chemical compound of claim 1 to 3, wherein R
cRepresent hydrogen or alkyl.
5. each chemical compound of claim 1 to 4, wherein R
dRepresentative is selected from the heteroaryl of thiazolyl, pyridine radicals, phonetic azoles base and pyrazinyl; This heteroaryl is optional to be replaced by one or more substituent group that independently is selected from halogen, diazanyl and alkoxyl.
6. claim 1 chemical compound, it is
C-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-[6-fluoro-pyridin-3-yl]-phenyl)-1H-benzimidazole-5-yl]-methylamine;
C-[1-(3-[pyridine-2-yl]-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
C-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-methyl amine;
1-[1-(3-pyrazine-2-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
1-{1-[3-(6-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(6-diazanyl-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-[1-(3-pyrimidine-5-base-phenyl)-1H-benzimidazole-5-yl]-ethylamine;
N-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide;
N-[1-(3-pyridine-2-base-phenyl)-1H-benzimidazole-5-ylmethyl]-acetamide;
N-(1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
N-(1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
N-(1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethyl)-Methanamide;
1-{1-[3-(2,4-dimethoxy-pyrimidine-5-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(2-methoxyl group-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
1-{1-[3-(2-fluoro-pyridin-3-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
Methyl-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dimethyl-[1-(3-pyridin-3-yl-phenyl)-1 H-benzimidazole-5-ylmethyl]-amine;
Benzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine;
Dibenzyl-1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-amine;
Methyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dimethyl-[1-(3-thiazol-2-yl-phenyl)-1 H-benzimidazole-5-ylmethyl]-amine;
Ethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Diethyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Benzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
Dibenzyl-[1-(3-thiazol-2-yl-phenyl)-1H-benzimidazole-5-ylmethyl]-amine;
O-methyl-N-{1-[1-(3-pyridin-3-yl-phenyl)-1H-benzimidazole-5-yl]-ethyl }-hydroxylamine;
N-{1-[3-thiazol-2-yl-phenyl]-1H-benzimidazole-5-ylmethyl }-Methanamide;
1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzimidazole-5-yl }-ethylamine;
Or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt.
7. pharmaceutical composition, it comprises each the chemical compound of claim 1 to 6 for the treatment of effective dose, or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt, and at least a pharmaceutically acceptable carrier, excipient or diluent.
8. each chemical compound of claim 1 to 6, or any mixture of its N-oxide, any its isomer or its isomer, or its pharmaceutically acceptable salt is used to prepare the purposes of medicine.
9. the purposes of claim 8 is used to prepare treatment, prevention or releasing mammal, comprises the pharmaceutical composition of human diseases, obstacle or disease, and described disease, obstacle or disease are to central nervous system's GABA
AThe adjusting of receptor complex is replied.
10. the purposes of claim 9, wherein this disease, obstacle or disease be anxiety neurosis, follow or do not follow the agoraphobia of the Panic disorder of agoraphobia, no Panic disorder medical history, to animal and the inductive anxiety neurosis of other phobia, social phobia, obsessive idea and behavior disorder, generalization or material; Stress disorders, after the wound and acute stress disorder, sleep disorder, dysmnesia, neurosis, the convulsibility obstacle, epilepsy, outbreak, faint from fear, child's febrile convulsion, migraine, mood disorders, depression or bipolar disorder, the melancholia, single ictal or recurrent severe melancholia, the dysthymic disorder, bipolar disorder, I type two-phase mania, II type two-phase mania, the cyclicity dysthymic disorder, mental disorder, comprise schizophrenia, the neural degeneration that causes by cerebrum ischemia, the distractibility hyperkinetic syndrome, pain, nociception, neuropathic pain, vomiting, acute, tardy property and property vomiting in advance, the particularly vomiting of bringing out by chemotherapy or radiotherapy, motion sickness, feel sick in the operation back, vomiting, eating disorders, nervous anorexia, bulimia nervosa, syndrome before the menstruation, neuralgia, trigeminal neuralgia, muscle spasm, spasticity, as the spasticity in the paralytic patient, substance abuse or dependence effect, ethanol is given up, cognitive disorder, Alzheimer, cerebrum ischemia, apoplexy, head trauma, ear toot or the circadian rhythm obstacle, for example be subjected to the object of the effects of arrival time difference or shiftwork.
11. treat, prevent or alleviate the animal body of work, comprise the method for people's disease, obstacle or disease, this obstacle, disease or disease are to central nervous system's GABA
AThe adjusting of receptor complex is replied, this method comprises each the chemical compound of claim 1 to 6 of the animal body treatment effective dose of this work that these needs are arranged, or any mixture of its N-oxide, any its isomer or its isomer, or the step of its pharmaceutically acceptable salt.
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| AR (1) | AR053578A1 (en) |
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| WO2019037161A1 (en) * | 2017-08-24 | 2019-02-28 | 重庆沃肯精细化工有限公司 | Method for synthesizing key clofazimine intermediate n-(4-chlorphenyl)-1,2-phenylenediamine |
-
2006
- 2006-04-07 CN CNA2006800082378A patent/CN101141958A/en active Pending
- 2006-04-07 BR BRPI0609417-1A patent/BRPI0609417A2/en not_active IP Right Cessation
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| WO2019037161A1 (en) * | 2017-08-24 | 2019-02-28 | 重庆沃肯精细化工有限公司 | Method for synthesizing key clofazimine intermediate n-(4-chlorphenyl)-1,2-phenylenediamine |
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