CN1989109A - 2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels - Google Patents
2-amino benzimidazole derivatives and their use as modulators of small-conductance calcium-activated potassium channels Download PDFInfo
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- CN1989109A CN1989109A CNA2005800241825A CN200580024182A CN1989109A CN 1989109 A CN1989109 A CN 1989109A CN A2005800241825 A CNA2005800241825 A CN A2005800241825A CN 200580024182 A CN200580024182 A CN 200580024182A CN 1989109 A CN1989109 A CN 1989109A
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Abstract
This invention relates to novel 2-amino benzimidazole derivatives useful as modulators of small-conductance calcium-activated potassium channels (SK channels). In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.
Description
Technical field
The present invention relates to can be used as the new 2-amino-benzene benzimidazole derivative of small-conductance calcium-activated potassium channels (SK passage) conditioning agent.
Others of the present invention also relate to the purposes of these compounds in methods of treatment and the pharmaceutical composition that contains The compounds of this invention.
Background technology
Three kinds of hypotype: SK1, SK2 and the SK3 (using the genome nomenclature to be equivalent to KCNN1-3) of small-conductance calcium-activated potassium channels (SK passage) have been cloned.The activity of these passages is by free intracellular calcium concentration ([Ca
2+]
i) by determining with passage constitutive character bonded calmodulin.The SK passage is by [the Ca in the physiological range
2+]
iRegulate accurately, as [Ca
2+]
iClose during up to about 0.1 μ M, but as [Ca
2+]
iActivated fully when being 1 μ M.Because potassium is had selectivity, the membrane potential of unlatching or activatory SK passage pair cell has the hyperpolarization influence.SK passage wide expression is in nervus centralis.The distribution of SK1 and SK2 demonstrates the plyability of height, and demonstrates the highest expression level in neocortex (neocortical), edge and the hippocampus of mouse brain.On the contrary, the SK3 passage basal ganglion, thalamus and brain stem monoamine serotonergic neuron for example nucleus raphes dorsalis, locus coeruleus (locuscoeruleus) and veutro back of the body lid district demonstrate high expression level (people such as Sailer. " three kinds of low electricity are led Ca in mouse brain
2+The SKl of-activated potassium channels subunit, distribution (the Comparativeimmunohistochemical distribution of three small-conductanceCa of relative immunity histological chemistry of SK2 and SK3
2+-activated potassium channel subunits, SK1, SK2, and SK3 inmouse brain), Mol.Cell.Neurosci.2004,26,458-469).The SK passage also is present in several peripheral nerve-cells, comprises skeletal muscle, glandular cell, liver cell and T-lymphocyte.
The hyperpolarizing action of activation SK passage has vital role opening of control excitable cell aspect (firing) pattern and the excitability.SK channel inhibitor for example apamin and dicentrine Methobromide has been proved and can have improved excitability, can reduce electrical activity and open agent 1-EBIO.Ca at the irrelevant passage of process and current potential
2+Influx is in the extremely sensitive non membrane potential, and activation SK passage will improve motivating force, and the blocker of SK passage has unpolarizing, thereby has offset the motivating force to calcium.
Getting in touch [Ca based on the SK passage
2+]
iWith the vital role in the membrane potential, the SK passage makes us interested target when becoming the exploitation novel treatment.
WO03/094861 (Icagen Inc) has described bisbenzimidazole and relevant compound is used as potassium channel modulating agents.
Summary about SK passage and SK channel modulators can be referring to Liegeois, J.-F. wait the people: " adjusting of small-conductance calcium-activated potassium (SK) passage: the new challenge in pharmaceutical chemistry field (Modulation of small conductance calcium-activated potassium (SK) channel:a new challenge in medicinal chemistry) ", CurrentMedicinal Chemistry, 2003,10,625-647.
Known SK channel modulators often all is macromolecular cpd or peptide class (apamin, scyllatoxin, tubocurarine, dequalinium chloride, UCL1684) or renders a service not high (1-EBIO, Riluzole) therefore, still needs to have the compound of optimizing pharmacological property.Specifically, need a class to have optionally part strongly, for example the SK3 channel modulators.
Summary of the invention
Aspect its first, the invention provides the 2-amino-benzene benzimidazole derivative of formula I:
Or any mixture or its pharmacologically acceptable salt of its isomer or its isomer arbitrarily,
R wherein
1, R
2, R
3, R
4And R
5Be defined as follows.
Aspect its second, the invention provides pharmaceutical composition, it contains the The compounds of this invention for the treatment of significant quantity or any mixture or its pharmacologically acceptable salt of its isomer or its isomer arbitrarily, and at least a pharmaceutically acceptable carrier, excipient or thinner.
Further, the invention provides The compounds of this invention or arbitrarily any mixture or its pharmacologically acceptable salt of its isomer or its isomer be used for the treatment of in preparation, the purposes in the pharmaceutical composition of prevention or releasing mammal, the disease that comprises the people or obstacle or illness, described disease or obstacle or illness are replied for the adjusting of SK passage.
In yet another aspect, the present invention relates to treat, prevent or alleviate animal body alive, comprise people's the disease or the method for obstacle or illness, described disease or obstacle or illness are replied for the adjusting of SK passage, and described method comprises to the The compounds of this invention of the moving object administering therapeutic significant quantity that these needs are arranged or its isomer or any mixture of its isomer or the step of its pharmacologically acceptable salt arbitrarily.
According to following detailed and embodiment, other purpose of the present invention will be conspicuous to those skilled in the art.
Detailed Description Of The Invention
2-amino-benzene benzimidazole derivative
Aspect its first, the invention provides the 2-amino-benzene benzimidazole derivative of formula I:
Or any mixture or its pharmacologically acceptable salt of its isomer or its isomer arbitrarily,
Wherein
R
1The expression hydrogen or alkyl;
R
2Expression hydrogen, alkyl or alkoxyl group;
R
3Expression is selected from the following cyclic group that contains:
Wherein m is 0,1 or 2;
N is 0,1,2,3 or 4;
And R wherein
3Ring optionally independently of one another independently be selected from following substituting group and replace by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group;
R
4And R
5Be independently from each other:
Hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group.
In a specific embodiments, R
1The expression hydrogen or alkyl;
R
2Expression hydrogen, alkyl or alkoxyl group;
R
3Expression is selected from the following cyclic group that contains:
Wherein m is 0,1 or 2;
N is 0,1,2,3 or 4;
And R wherein
3Aromatic group optionally independently of one another independently be selected from following substituting group and replace by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group;
R
4And R
5Be independently from each other:
Hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group.
In one embodiment, R
1Expression hydrogen.
In second embodiment, R
2Expression hydrogen.
In another embodiment, R
3Expression 1,2,3,4-tetrahydrochysene-naphthyl, wherein this ring is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.In a specific embodiment, R
3Expression by alkyl replace 1,2,3,4-tetrahydrochysene-naphthyl, 2-methyl isophthalic acid for example, 2,3,4-tetrahydrochysene-naphthalene-1-base or 4-methyl isophthalic acid, 2,3,4-tetrahydrochysene-naphthalene-1-base.In another embodiment, R
3Expression by alkyl replace twice 1,2,3,4-tetrahydrochysene-naphthyl, for example 5,7-dimethyl-1,2,3,4-tetrahydrochysene-naphthalene-1-base.
In another embodiment, R
3Expression 1,2,3,4-tetrahydrochysene-naphthyl, wherein aromatic portion is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.In a specific embodiment, R
3Expression 1,2,3,4-tetrahydrochysene-naphthyl, for example 1,2,3,4-tetrahydrochysene-naphthalene-1-base.In another embodiment, R
3Expression by halogen replace 1,2,3,4-tetrahydrochysene-naphthyl, 7-halo-1,2,3 for example, 4-tetrahydrochysene-naphthalene-1-base be as 7-fluoro-1,2,3,4-tetrahydrochysene-naphthalene-1-base or 7-chloro-1,2,3,4-tetrahydrochysene-naphthalene-1-base.
In another embodiment, R
3The expression indanyl, wherein aromatic portion is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.In a specific embodiment, R
3Expression indanyl, for example indane-1-base or indane-2-base.In another embodiment, R
3The indanyl that expression is replaced by halogen, for example 5-halo-indane-1-base is as 5-bromo-indane-1-base, 5-chloro-indane-1-base or 5-fluoro-indane-1-base.
In another embodiment, R
3Expression 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, wherein this ring is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.In a specific embodiment, R
3Expression 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, for example 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta-5-base.
In another embodiment, R
3Expression
Wherein two benzyl rings are chosen wantonly independently of one another and independently are selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.In a specific embodiment, R
3Expression diphenyl methyl (below be called diphenyl-methyl).In another embodiment, R
3Expression 2, the 2-diphenyl-ethyl, in another embodiment, R
3Expression 3, the 3-diphenyl propyl.
In another embodiment, R
3Expression
Wherein two benzyl rings are optional independently of one another by one or more halogens, for example chlorine or fluorine replacement.In a specific embodiment, R
3Expression 4-halogenated diphenyl methyl (4-halobenzhydryl), for example 4-chlorobenzhydryl.In another embodiment, R
3Expression 4,4 '-dihalo diphenyl-methyl, for example 4,4 '-difluorodiphenyl methyl.In another embodiment, R
3Expression 2, two (4-halogenophenyl) ethyls of 2-, for example 2, two (4-chloro-phenyl-) ethyls or 2 of 2-, two (4-fluorophenyl) ethyls of 2-.
In another embodiment, n is 0,1 or 2.In one embodiment, n is 0.In second embodiment, n is 1.In the 3rd embodiment, n is 2.
In another embodiment, m is 0.In second embodiment, m is 1.In the 3rd embodiment, m is 2.
In another embodiment, R
4And R
5Expression hydrogen.In another embodiment, R
4Expression hydrogen, R simultaneously
5The expression alkyl is methyl for example.In another embodiment, R
4The expression alkyl is methyl for example, simultaneously R
5The expression alkyl is methyl for example.In another embodiment, R
4Expression hydrogen, R simultaneously
5The expression halogen is fluorine for example.In another embodiment, R
4Expression trifluoromethyl, R simultaneously
5The expression trifluoromethyl.
In another embodiment, formula I compound is by R on the 5-position of benzoglyoxaline ring
4Or R
5One of replace, simultaneously on the 6-position of benzoglyoxaline ring by R
4Or R
5In another replacement benzimidizole derivatives.In another embodiment, formula I compound is by R on the 5-position of benzoglyoxaline ring
4Or R
5One of replace, simultaneously on the 7-position of benzoglyoxaline ring by R
4Or R
5In the benzimidizole derivatives of another replacement.
In a specific embodiment, compound of the present invention is
N-(benzimidazolyl-2 radicals-yl)-2,2-diphenyl-ethyl amine;
N-(benzimidazolyl-2 radicals-yl)-2, two (4-fluorophenyl) ethylamines of 2-;
N-(benzimidazolyl-2 radicals-yl)-2, two (4-chloro-phenyl-) ethylamines of 2-;
N-(benzimidazolyl-2 radicals-yl)-3,3-diphenyl propyl amine;
N-(benzimidazolyl-2 radicals-yl)-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-2-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-fluoro-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-chloro-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-bromo-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(the benzhydryl amine of benzimidazolyl-2 radicals-yl);
N-(benzimidazolyl-2 radicals-yl)-4-chlorobenzhydryl amine;
N-(benzimidazolyl-2 radicals-yl)-4,4 '-dichloro benzhydryl amine;
N-(benzimidazolyl-2 radicals-yl)-4,4 '-difluorodiphenyl methylamine;
N-(benzimidazolyl-2 radicals-yl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base amine;
(R)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(S)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-the 2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-the 4-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-[5, two (trifluoromethyl) benzimidazolyl-2 radicals-yl of 7-]-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(R)-and N-(5-tolimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(R)-and N-(5,6-dimethylbenzimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(5-fluorobenzene and imidazoles-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-7-chloro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-7-fluoro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
Or its pharmacologically acceptable salt.
The arbitrary combination of two or more above-mentioned embodiments is considered as falling within the scope of the invention.
The substituting group definition
In the context of the invention, halogen is represented fluorine, chlorine, bromine or iodine.
In the context of the invention, alkyl is represented unit price saturated straight chain or side chain hydrocarbon chain.This hydrocarbon chain preferably contains 1-6 carbon atom (C
1-6-alkyl), comprise amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.In a preferred embodiment, alkyl is represented C
1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.In another preferred embodiment of the present invention, alkyl is represented C
1-3-alkyl, particularly methyl, ethyl, propyl group or sec.-propyl.
Alkoxyl group is the O-alkyl, and wherein the alkyl definition is the same.
Pharmacologically 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 physiology) of The compounds of this invention goes up acceptable salt and prodrug forms.
The example of pharmaceutically acceptable additive salt includes but not limited to: the inorganic and organic acid addition salt of nontoxicity is hydrochloride for example, hydrobromate, nitrate, perchlorate, phosphoric acid salt, vitriol, formate, acetate, aconitate, ascorbate salt, benzene sulfonate, benzoate, cinnamate, Citrate trianion, embonate, enanthate, fumarate, glutaminate, glycollate, lactic acid salt, maleate, malonate, mandelate, mesylate, naphthalene-2-sulfonic acid salt, phthalate, salicylate, sorbate, stearate, succinate, tartrate, tosilate etc.Above-mentioned salt can form by method well known and that describe.
The example of the pharmaceutically acceptable cationic salts of The compounds of this invention includes but not limited to: sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, aluminium salt, lithium salts, choline salt, lysine salt and the ammonium salt etc. that contain the The compounds of this invention of anionic group.Such positively charged ion salt can form by method well known and that describe.
In the context of the invention, " the salt " of nitrogenous compound also is considered to pharmacologically acceptable salt.Preferably " salt " comprises alkyl- salt, cycloalkyl- salt and cycloalkylalkyl- salt.
The example of the prodrug of The compounds of this invention (pre-or prodrug) form comprises the prodrug that material of the present invention is suitable, is included in adorned compound on one or more reactions of parent compound or the deriveding group.Making us compound of interest especially is adorned compound on carboxyl, hydroxyl or amino.The appropriate derivative example is ester or acid amides.
The compounds of this invention can solvable or insoluble form provide with acceptable solvent such as water, ethanol etc.Soluble form can also comprise hydrated form, for example monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate etc.Generally with regard to the object of the invention, think that soluble form is equal to insoluble form.
Steric isomer
It should be appreciated by those skilled in the art that The compounds of this invention can comprise one or more chiral centres, therefore described compound can exist by isomeric forms.
In addition, The compounds of this invention can (+) and the enantiomer and the racemic form (±) of (-) form exist.The racemoid of these isomer and independent isomer itself thereof fall within the scope of the invention.
The present invention includes all these isomer and any mixture thereof, comprise racemic mixture.
Racemic form can adopt known method and technology to split into optical antipode.A kind of method of separating isomerism salt is to use optical activity acid, and with alkaline purification to disengage the optical activity amine compound.The another kind of method that racemic modification is split into optical antipode is based on the chromatography on the optical activity matrix.Therefore, for example can racemic compound of the present invention be split into their optical antipode by fractional crystallization d-or 1-(tartrate, mandelate or camsilate) salt.
The compounds of this invention can also split by the following method: make The compounds of this invention and optically active activating carboxy acid as forming the diastereomer acid amides by (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) dextrocamphoric acid deutero-carboxylic acid reaction, perhaps make the reaction of The compounds of this invention and optically active chloro-formic ester or analogue form the diastereomer carbamate.
Other method that is used to split optical isomer is known in the art.These class methods comprise Jaques J, ColletA ， ﹠amp; Wilen S exists "
Enantiomers.Racemates, and Resolutions", the method for describing among the John Wiley and Sons, New York (1981).
Optically active compound can also be obtained by the optical activity feedstock production.
Tagged compound
The compounds of this invention can its mark or the use of unlabelled form.In the context of the invention, this tagged compound has one or more atomic mass or the atomic mass of total mass number or atom institute metathetical atoms of total mass number that are different from the common discovery of occurring in nature that had.Described mark can make this compound by easy detection by quantitative.
Tagged compound of the present invention can also can be used for the imaging of body inner recipient as diagnostic tool, radiotracer or the monitoring agent in the various diagnostic methods.
Labelled isomer of the present invention preferably contains 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.
The preparation method
The compounds of this invention can be by for example preparation of the method described in the embodiment of ordinary method of chemosynthesis.The raw material that is used for the described method of the application is known, perhaps also can be obtained by the chemical production that is available commercially by ordinary method easily.
Can also use ordinary method that a kind of compound of the present invention is changed into another kind of compound of the present invention.
The end product of reaction described herein can for example separate by extraction, crystallization, distillation, chromatogram etc. by routine techniques.
Biological activity
Can test the ability of the external adjusting of The compounds of this invention SK passage.According to as people such as Str b k: " the low electricity of expressing in the HEK293 cell is led Ca
+The pharmacological characteristic of the K passage of-sensitization is described (Pharmacological characterization ofsmall-conductance Ca
2+-actiVated Kchannels expressed in HEK293cells) "; British Journal of Pharmacology (2000) 129; the described patch clamp technique of 991-999, can come the measurement function adjusting by measuring to change by compound inductive SK electric current.According to such measuring method, can record the effectiveness of appointed compound, for example with K for blocker/inhibitor
iOr IC
50Value and to the EC of opener/activator
50The form of value.Can obtain the class likelihood data by the passage in various clones by other patch clamp structure and endogenous expression.
In one embodiment, The compounds of this invention demonstrates the SK3 selectivity that is better than SK1 and SK2.In another embodiment, The compounds of this invention is SK passage positive modulators, for example SK3 passage positive modulators.In another embodiment, The compounds of this invention is negative conditioning agent, for example the negative conditioning agent of SK3 passage.In a specific embodiment, The compounds of this invention is the SK channel blocker.SK3 channel blocker for example.
Based on observed activity in the patch clamp test, think that The compounds of this invention can be used for treating, prevention or releasing mammal, the disease that comprises the people or obstacle or illness, described disease, obstacle or illness are replied regulating the SK passage.
In a specific embodiment, think that The compounds of this invention can be used for treatment, prevention or alleviation: petit mal, the loss of memory increases the weight of, Alzheimer, stenocardia, irregular pulse, asthma, anxiety, ataxia, attention deficit, bald head, bipolar disorder, the bladder superexcitation, bladder flows out and blocks, cystospasm, cerebral tumor, cerebrum ischemia, chronic obstructive pulmonary disease, cancer, cardiovascular disorder, cognition dysfunction, colitis, constipation, twitch, coronary vasospasm, coronary heart disease, cystic fibrosis, dull-witted, depressed, type ii diabetes, dysmenorrhoea, epilepsy, gastrointestinal dysfunction, the gastroesophageal reflux obstacle, the not enough obstacle of gastrointestinal movement, the gastrointestinal peristalsis deficiency, hearing disability (loss), hyperinsulinemia, hypertension, immunosuppression, inflammatory bowel, inflammatory pain, intermittent claudication, irritable bowel syndrome, ischemic, ischemic heart disease, the study defective, male erectile dysfunction, manic type depression, lethe, migraine, affective disorder, motor neurone disease, myokymia (myokymia), tetanic property myotrophy imbalance, tetanic property myodystrophy, narcolepsy, neuropathic pain, pain, Parkinson's disease, POLYCYSTIC KIDNEY DISEASE, postoperative ileus, premature labor, psychosis, mental disorder, ephrosis, Reynaud ' s disease, rhinorrhea, secretory diarrhea, epileptic seizures (seizure), Sjorgren ' s syndrome, sleep apnea, spasticity, somnopathy, apoplexy, traumatic brain injury, trigeminal neuralgia, the urinary incontinence, the urogenital obstacle, vascular spasm, visual loss (loss) and xerostomia.
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 this depends on the body weight of the form of concrete administering mode, administration, the indication of being considered, object and particularly related object and attending doctor or animal doctor's preference and experience.
Preferred The compounds of this invention demonstrates the biological activity of sub-micro mole and micro-molar range, promptly less than 1 to about 100 μ M.
Pharmaceutical composition
In yet another aspect, the invention provides the novel pharmaceutical combination thing, wherein contain the The compounds of this invention for the treatment of significant quantity.
Although the form administration that the The compounds of this invention that is used for the treatment of can starting compound is preferably randomly introduced activeconstituents with one or more assistant agents, vehicle, carrier, buffer reagent, thinner and/or other conventional medicine auxiliary material with the form of acceptable salt on its physiology with pharmaceutical compositions.
In preferred embodiments, the invention provides pharmaceutical composition, wherein contain The compounds of this invention or its pharmacologically acceptable salt or derivative and one or more pharmaceutically acceptable carrier and optional known in the art and used other therapeutic and/or preventative composition.Described carrier must be " acceptable ", promptly with preparation in other composition compatible and can be harmful to its recipient.
Pharmaceutical composition of the present invention can be the pharmaceutical composition that is suitable for oral, rectum, segmental bronchus, nose, lung, part (comprising in the cheek and the hypogloeeis), transdermal, vagina or non-enteron aisle (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, or be adapted to pass through the form that sucks or be blown into administration, comprise powder and liquid aerosol or the pharmaceutical composition by the slow-released system administration.Suitable slow-released system example comprises the semi-permeable matrix of the solid hydrophobic polymkeric substance that contains The compounds of this invention, and this matrix can be the formed article form, for example film or micro-capsule.
Therefore The compounds of this invention can be made pharmaceutical composition and unit dosage form thereof with assistant agent, carrier or the thinner of routine.Such form comprises solid especially tablet, filling capsule, powder and pill, with the capsule of liquid especially aqueous pharmaceutical or non-aqueous solution agent, suspensoid, emulsion, elixir and the above-mentioned form of filling, that all these forms all can be used for is oral, the suppository and the agent of non-enteron aisle sterile injectable solution of rectal administration.Such pharmaceutical composition and unit dosage form thereof can comprise the conventional ingredient of conventional ratio, the active compound that contains or do not conform to other or composition, and such unit dosage form can contain and the suitable any suitable effective amount of actives of expection application dose scope every day.
The compounds of this invention can various oral and non-parenteral dosage forms administrations.For a person skilled in the art, it is evident that following formulation can contain the pharmacologically acceptable salt of The compounds of this invention or The compounds of this invention as activeconstituents.
In order to prepare pharmaceutical composition by The compounds of this invention, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials that have thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material effect simultaneously.
In powder, carrier is and segmentation active ingredient blended finely-divided solid.
In tablet, activeconstituents is mixed in the proper ratio with the carrier with essential bonding force, be pressed into required shape and size then.
Powder and tablet preferably contain 5% or 10% to about 70% active compound.Suitable carrier is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Term " preparation " be meant contain active compound with as the formulation of the coating material of capsular carrier is provided, in this formulation, contain or carrier-free activeconstituents suppressed by vector surrounds, combine with carrier thus.Similarly, also comprise cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be as the solid forms that is fit to oral administration.
In order to prepare suppository, at first, by stirring activeconstituents is evenly dispersed in wherein then the mixture melt of low melt wax such as glycerin fatty acid ester or theobroma oil.In the mould of the suitable size of the uniform mixture impouring that will melt then, make its cooling and curing.
The composition that is fit to vagina administration can vaginal suppository, tampon, ointment, gelifying agent, paste, foam or spray form exist, and except that containing activeconstituents, also contains appropriate carrier known in the art in the described composition.
Liquid preparation comprises solution, suspensoid and emulsion, for example aqueous pharmaceutical or water-propylene glycol solution agent.For example, non-enteron aisle injecting fluid preparation can be mixed with the solution of moisture polyoxyethylene glycol.
Therefore, The compounds of this invention can be mixed with the preparation that is used for parenterai administration (for example injection is as injecting or continuous infusion), and provide with the unit dosage form or the multi-dose container form of the sanitas that adds with ampoule, pre-filled syringe, small volume transfusion.Said composition can be taked suspensoid, solution or the emulsion form of oiliness or aqueous carrier, and can contain various preparation compositions such as suspension agent, stablizer and/or dispersion agent.In addition, activeconstituents can also be a powder type, and it is prepared itself and suitable carrier such as aseptic, pyrogen-free water before use by sterile solid being carried out aseptic separation or obtaining by the solution freeze-drying.
The aqueous pharmaceutical that is fit to orally use can by with solubilization of active ingredient in water, and add suitable tinting material, seasonings, stablizer and thickening material as required and prepare.
The water suspension that is fit to orally use can be dispersed in the water that contains viscous substance such as natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or known other suspending agent and prepares by segmenting active ingredient.
Comprise that also plan was converted into the solid form preparation of the liquid form preparation of oral administration before facing usefulness.Such liquid form comprises solution, suspensoid and emulsion.Except that active ingredient, this class preparation can contain tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent etc.
For topical application to epidermis, The compounds of this invention can be mixed with ointment, creme or lotion or transdermal patch.For example, can suit water-based or oleaginous base adds suitable thickening material and/or jelling agent is formulated of ointment and creme.Lotion water-based or the oleaginous base preparation that can suit, and also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material usually.
Being adapted at topical drug delivery composition in the oral cavity is included in flavoured base, normally contains the lozenge of activeconstituents in sucrose and kordofan gum or the tragacanth gum; The pastille (pastilles) that in inert base such as gelatin and glycerine or sucrose and kordofan gum, contains activeconstituents; And the mouth wash shua that in the appropriate liquid carrier, contains activeconstituents.
Solution or suspensoid for example can be applied directly to nasal cavity with dropper, suction pipe or atomizer with ordinary method.Described composition can single dose or the multiple doses form provide.
Respiratory tract administration also can be realized by aerosol, wherein activeconstituents is provided in the pressurized package with suitable propelling agent, suitable propelling agent comprises chlorofluorocarbon (CFC) for example Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Aerosol also can suitably contain tensio-active agent such as Yelkin TTS.The dosage of medicine can be controlled by being equipped with metering valve.
Perhaps, activeconstituents also can provide by dry powder form, and for example compound is in suitable powder matrix such as the powdered mixture form in lactose, starch, starch derivative such as Vltra tears and the polyvinylpyrrolidone (PVP).Aptly, powder carrier is formed 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, and perhaps can be by the sucker Blister Package form of administration therefrom with powder.
Comprise in the intranasal compositions that at the composition that is intended for use respiratory tract administration compound has little particle diameter usually, for example is 5 microns or the littler order of magnitude.Such particle diameter can for example obtain by micronization by methods known in the art.
When needing, can use and be fit to composition that activeconstituents is slowly disengaged.
Pharmaceutical preparation is preferably unit dosage form.According to this form, preparation is subdivided into the unitary dose that contains an amount of active ingredient.Unit dosage form can be a packaged preparation, and this packing contains the preparation of discrete magnitude such as package troche, capsule, and the powder in bottle or the ampoule.In addition, unit dosage form can also be capsule, tablet, cachet or a lozenge itself, or any packaged form of these formulations of proper amt.
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 detail file of preparation and medicine-feeding technology can (Maack Publishing Co.Easton finds on PA) at the Reminaton ' of latest edition sPharmaceutical Sciences.
The treatment effective dose refers to the absorption of active ingredient that can improve symptom or illness.Treatment effectiveness and toxic reaction be ED for example
50And LD
50Can in cell culture or laboratory animal, be measured by standard pharmacology program.Dosage between result of treatment and the toxic action can ratio LD than being therapeutic index
50/ ED
50Expression.The pharmaceutical composition that preferably has big therapeutic index.
The dosage of using certainly must be at the result of age, body weight and the illness of the individuality of being treated and route of administration, dosage form and dosage regimen and expectation and careful the adjustment, and definite dosage should be determined by the doctor certainly.
Actual dose depends on the character and the severity of the disease for the treatment of, and within doctor's determination range, it can be according to the present invention concrete situation the reaction of dosage is changed and changes, to obtain required result of treatment.Yet the pharmaceutical composition that expection at present contains 0.1 to about 500mg, preferably about 1 to about 100mg, more preferably from about 1 to about 10mg the activeconstituents/single dose of having an appointment is suitable for therapeutic treatment.
Activeconstituents every day can the administration potion or several doses.In some cases, the dosage that is low to moderate 0.1 μ g/kg (intravenously) and 1 μ g/kg (oral) can obtain gratifying result.Think that at present the upper limit of dosage range is about 10mg/kg (intravenously) and 100mg/kg (oral).Preferable range is about 0.1 μ g/kg to about 10mg/kg/ day (intravenously), and from about 1 μ g/kg about 100mg/kg/ day (oral) extremely.
Methods of treatment
In yet another aspect, the invention provides the method for treatment, prevention or alleviation animal body, the disease that comprises the people, obstacle or illness alive, described disease, obstacle or illness are replied regulating the SK passage, and described method comprises to the animal body of the work that these needs are arranged, comprises that the people uses the The compounds of this invention of significant quantity.
At present expection appropriate dosage scope be every day 0.1-1000mg, every day 10-500mg, particularly every day 30-100mg, this depend on usually definite administering mode, form of medication, administration at indication, related patient and related patient's body weight and responsible doctor or animal doctor's preference and experience.
Embodiment
The present invention is further specified with reference to following embodiment, but these embodiment and not meaning that by any way are construed as limiting the present invention for required protection scope.
General rule: shown in step represent to be used to prepare the general step of The compounds of this invention.Used abbreviation is as follows:
Ac: ethanoyl
DMSO: methyl-sulphoxide
Et: ethyl
Mp: fusing point
MW: microwave
Rt: room temperature
THF: tetrahydrofuran (THF)
Steps A
2-chloro benzimidazole and required amine (be commercially available or by step B preparation) are suspended in the acetonitrile in the airtight bottle, use microwave (MW) radiation heating, continue 15-30 minute to 150-200 ℃.After being cooled to room temperature, leach the solid that precipitation is separated out, by CH
3CN/MeOH mixture recrystallization obtains the required product into HCl salt.Perhaps, the precipitation of reaction mixture is passed through column chromatography or preparation property LCMS purifying, obtain replacing the amino benzoglyoxaline of 2-as the required N-of parent compound.
As the example of steps A, (benzimidazolyl-2 radicals-yl)-2, the preparation of two (4-chloro-phenyl-) ethylamines of 2-is shown in scheme 1 for N-.
(scheme 1)
Step B
In the MeOH of ketone or aldehyde solution, add O-methyl hydroxylamine hydrochloride, at room temperature stir simultaneously and spend the night.Add entry, mixture extracts with EtOAc.Organic phase drying (the MgSO that merges
4), filter and vacuum concentration.This crude product oxime is dissolved in the dry THF, dropwise adds the THF solution of borine.At N
2After stirring 30 minutes under the room temperature, reaction mixture is heated to 60 ℃, stirs and spends the night postcooling to room temperature.Add the 1M NaOH aqueous solution, mixture heated 1 hour down at 60 ℃.Add NaHCO
3The aqueous solution, solution extracts with EtOAc.Organic phase drying (the MgSO that merges
4), filtration and vacuum concentration obtain required amine, and it is according to use as described in steps A.This amine is not purified can be used or by using behind the column chromatography purifying.
As the example of step B, 2, the preparation of two (4-chloro-phenyl-) ethylamines of 2-is shown in scheme 2.
(scheme 2)
Step C
CH to amino benzoglyoxaline of 2-and corresponding aldehyde
3The AcOH that adds sodium triacetoxy borohydride and catalytic amount in the CN solution.Reaction mixture is by 100 ℃ of MW radiation heatings 30 minutes.Add NaHCO
3The aqueous solution, mixture stirs the back and extracts with EtOAc.Organic phase drying (the MgSO that merges
4), filter, by preparation property LCMS purifying, obtain replacing the amino benzoglyoxaline of 2-behind the vacuum concentration as the required N-of parent compound.
As the example of step C, (benzimidazolyl-2 radicals-yl)-2, the preparation of 2-diphenyl-ethyl amine is shown in scheme 3 for N-.
(scheme 3)
Step D
Isocyanic ester (by with corresponding amine and thiophosgene prepared in reaction) and the mixture of phenylenediamine in the exsiccant methylene dichloride that is suitably replaced at room temperature stirred spend the night, be evaporated to dried.Then resulting thiocarbamide is passed through for example column chromatography purifying, perhaps further react as crude product.Then, this thiocarbamide is dissolved among the THF, adds for example dicyclohexylcarbodiimide (DCC) of coupling reagent, under reflux temperature, stir and spend the night.Add NaHCO
3The aqueous solution, solution extracts with EtOAc.Organic phase drying (the MgSO that merges
4), filtration and vacuum concentration obtain the amino benzoglyoxaline of crude product 2-, and it is next by column chromatography or preparation property LCMS purifying.
As the example of step D, N-[5, two (trifluoromethyl) benzimidazolyl-2 radicals-yl of 7-]-1,2,3, the preparation of 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE is shown in scheme 4.
(scheme 4)
Embodiment 1
N-(benzimidazolyl-2 radicals-yl)-2,2-diphenyl-ethyl amine
Title compound is by the amino benzoglyoxaline and 2 of 2-, and the 2-diphenyl acetaldehyde is by step C or by 2-chloro benzimidazole and 2,2-diphenyl-ethyl amine prepares by steps A.For the latter, crude product is passed through to use the EtOAc/MeOH recrystallization purifying, and separation obtains HCl salt (white solid, mp 153.5-154.5 ℃).MS(ES
+)m/z?314([M+1]
+，100)。
1NMR(DMSO-d6)δ4.14(m，2H)，4.39(t，1H)，7.18-7.44(m，14H)，9.00(m，1H)，12.7(br?s，1H)。
Embodiment 2
N-(benzimidazolyl-2 radicals-yl)-2, two (4-fluorophenyl) ethylamines of 2-
Title compound is by 2-chloro benzimidazole and 2, and two (4-fluorophenyl) ethylamines of 2-(by 2, two (4-fluorophenyl) acetaldehyde of 2-prepare by step B) prepare by steps A (20 minutes, 170 ℃).Product separates by preparation property LCMS, obtains the title compound (white solid, mp 155-157 ℃) into free alkali.MS(ES
+)m/z?350([M+1]
+，100)。
1NMR(DMSO-d6)δ3.90(m，2H)，4.46(t，1H)，6.50(m，1H)，6.80-6.90(m，2H)，7.07-7.18(m，6H)，7.35-7.42(m，4H)，10.5(s，1H)。
Embodiment 3
N-(benzimidazolyl-2 radicals-yl)-2, two (4-chloro-phenyl-) ethylamines of 2-
Title compound is by 2-chloro benzimidazole and 2, and two (4-chloro-phenyl-) ethylamines of 2-(by 2, two (4-chloro-phenyl-) acetaldehyde of 2-prepare by step B) prepare by steps A (20 minutes, 170 ℃).Product separates by preparation property LCMS, obtains the title compound (white solid, mp 189-190 ℃) into free alkali.MS(ES
+)m/z?382([M+1]
+，100)。
1NMR(DMSO-d6)δ3.91(m，2H)，4.47(t，1H)，6.52(m，1H)，6.81-6.90(m，2H)，7.06-7.18(m，2H)，7.33-7.36(m，8H)，10.6(s，1H)。
Embodiment 4
N-(benzimidazolyl-2 radicals-yl)-3,3-diphenyl propyl amine
Title compound is by 2-chloro benzimidazole and 3, and 3-diphenyl propyl amine prepares by steps A.In reaction mixture, add rare HCl aqueous solution and CH
2Cl
2By CH
2Cl
2The phase filtering separation obtains throw out, obtains the title compound (mp136.5-137.5 ℃) into the respective pure form of HCl salt.MS(ES
+)m/z?328([M+1]
+，100)。
1NMR(DMSO-d6)δ2.43(m，2H)，3.28(m，2H)，4.15(t，1H)，7.15-7.35(m，14H)，9.00(m，1H)，12.7(br?s，1H)。
Embodiment 5
N-(benzimidazolyl-2 radicals-yl)-indanyl amine
Title compound is prepared by steps A (15 minutes, 200 ℃) by 2-chloro benzimidazole and racemize 1-aminoidan.Product separates by preparation property LCMS, obtains the title compound (white solid, mp 195.5-197 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?250([M+1]
+，100)。
1NMR(DMSO-d6)δ1.90(m，1H)，2.55(m，1H)，2.83(m，1H)，2.95(m，1H)，5.36(m，1H)，6.82-6.97(m，3H)，7.11-7.31(m，6H)，10.70(s，1H)。
Embodiment 6
N-(benzimidazolyl-2 radicals-yl)-2-indanyl amine
Title compound is prepared by steps A (15 minutes, 150 ℃) by 2-chloro benzimidazole and 2-aminoidan.Product separates by preparation property LCMS, obtains the title compound (white solid, mp 246-249 ℃) into free alkali.MS(ES
+)m/z?250([M+1]
+，100)。
1NMR(DMSO-d6)δ2.91(dd，2H)，3.29(dd，2H)，4.35(m，1H)，6.80-6.92(m，3H)，7.10-7.17(m，4H)，7.22-7.25(m，2H)，10.60(s，1H)。
Embodiment 7
N-(benzimidazolyl-2 radicals-yl)-5-fluoro-1-indanyl amine
Title compound is prepared by steps A (30 minutes, 170 ℃) by 2-chloro benzimidazole and racemize 1-amino-5-bromine indane (being prepared by 5-fluoro-1-indone by step B).Product separates by preparation property LCMS, obtains the title compound (white solid, mp 207-208 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?268([M+1]
+，100)。
1NMR(DMSO-d6)δ1.93(m，1H)，2.55(m，1H)，2.82(m，1H)，2.97(m，1H)，5.32(m，1H)，6.80-6.99(m，4H)，7.05-7.15(m，3H)，7.26-7.30(m，1H)，10.7(s，1H)。
Embodiment 8
N-(benzimidazolyl-2 radicals-yl)-5-chloro-1-indanyl amine
Title compound is prepared by steps A (30 minutes, 170 ℃) by 2-chloro benzimidazole and racemize 1-amino-5-chlorine indane (being prepared by 5-chloro-1-indone by step B).Product separates by preparation property LCMS, obtains the title compound (white solid, mp 242-243 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?284([M+1]
+，100)。
1NMR(DMSO-d6)δ1.92(m，1H)，2.55(m，1H)，2.83(m，1H)，2.95(m，1H)，5.32(m，1H)，6.81-6.97(m，3H)，7.10-7.21(m，3H)，7.26-7.33 (m，2H)，10.8(s，1H)。
Embodiment 9
N-(benzimidazolyl-2 radicals-yl)-5-bromo-1-indanyl amine
Title compound is prepared by steps A (30 minutes, 170 ℃) by 2-chloro benzimidazole and racemize 1-amino-5-bromine indane (being prepared by 5-bromo-1-indone by step B).Product separates by preparation property LCMS, obtains the title compound (white solid, mp 242-243 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?328([M+1]
+，100)。
1NMR(DMSO-d6)δ1.92(m，1H)，2.50(m，1H)，2.83(m，1H)，2.95(m，1H)，5.35(m，1H)，6.82-7.02(m，3H)，7.12-7.35(m，4H)，7.46(s，1H)，10.7(s，1H)。
Embodiment 10
N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-naphthyl (naphtyl) amine
Title compound is by 2-chloro benzimidazole and racemize 1,2,3, and 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE prepares by steps A (10 minutes, 170 ℃, then 15 minutes, 200 ℃).Product is separated by preparation property LCMS by crude product mixture, obtains the title compound (white solid, mp 230-234 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?264([M+1]
+，100)。
1NMR(DMSO-d6)δ1.73-1.82(m，1H)，1.85-1.96(m，2H)，2.01-2.09(m，1H)，2.70-2.85(m，2H)，5.04(m，1H)，7.01-7.05(m，2H)，7.12-7.28(m，5H)，7.33-7.37(m，1H)，8.05(br?s，1H)。
Embodiment 11
N-(the benzhydryl amine of benzimidazolyl-2 radicals-yl)
Title compound is prepared by steps A by 2-chloro benzimidazole and benzhydryl amine.Product separates by preparation property LCMS, obtains the title compound (white solid, mp255-258 ℃) into free alkali.MS(ES
+)m/z?300([M+1]
+，100)。
1NMR(DMSO-d6)δ6.20(d，1H)，6.75-7.65(m，15H)，10.5(s，1H)。
Embodiment 12
N-(benzimidazolyl-2 radicals-yl)-4-chlorobenzhydryl amine
Title compound is prepared by steps A by 2-chloro benzimidazole and 4-chlorobenzhydryl amine HCl.Product separates by preparation property LCMS, obtains the title compound (white solid, mp 180-184 ℃) into free alkali.MS(ES
+)m/z?334([M+1]
+，100)。
1NMR(DMSO-d6)δ6.18(d，1H)，6.80-6.90(m，2H)，7.08-7.14(m，2H)，7.20-7.40(m，9H)，7.66(d，1H)，10.6(s，1H)。
Embodiment 13
N-(benzimidazolyl-2 radicals-yl)-4,4 '-dichloro benzhydryl amine
Title compound is by 2-chloro benzimidazole and 4, and 4 '-dichloro benzhydryl amine (by 4,4 '-dichloro benzophenone prepares by step B) prepares by steps A.Product separates by preparation property LCMS, obtains the title compound (white solid, mp 176-180 ℃) into free alkali.MS(ES
+)m/z?368([M+1]
+，100)。
1NMR(DMSO-d6)δ6.19(d，1H)，6.82-6.90(m，2H)，7.10-7.16(m，2H)，7.40(s，8H)，7.69(d，1H)，10.6(s，1H)。
Embodiment 14
N-(benzimidazolyl-2 radicals-yl)-4,4 '-difluorodiphenyl methylamine
Title compound is by 2-chloro benzimidazole and 4, and 4 '-difluorodiphenyl methylamine (by 4,4 '-dichloro benzophenone prepares by step B) prepares by steps A.Product separates by preparation property LCMS, obtains the title compound (white solid, mp 241-243 ℃) into free alkali.MS(ES
+)m/z?336([M+1]
+，100)。
1NMR(DMSO-d6)δ6.20(d，1H)，6.80-6.91(m，2H)，7.09-7.20(m，6H)，7.38-7.43(m，4H)，7.69(d，1H)，10.6(s，1H)。
Embodiment 15
N-(benzimidazolyl-2 radicals-yl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base amine
Title compound is by 2-chloro benzimidazole and racemize 6,7,8, and 9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base amine (by step B by 1-benzosuberone (benzosuberone) preparation) prepares by steps A (reflux in toluene 2 days).Product is separated by preparation property LCMS by crude product mixture, obtains the title compound (white solid, mp 203-205 ℃) into free alkali and mixture of enantiomers.MS(ES
+)m/z?278([M+1]
+，100)。
1NMR(DMSO-d6)δ1.28-1.39(m，1H)，1.65-2.02(m，5H)，2.83-2.97(m，2H)，5.03(t，1H)，6.77-6.89(m，2H)，7.05-7.29(m，7H)，10.6(s，1H)。
Embodiment 16
(R)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and (R)-1,2,3, and 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE prepares by steps A (40 minutes, 170 ℃).Wash with acetonitrile after leaching product, obtain title compound (white solid, mp 264-265 ℃) into HCl salt.MS(ES
+)m/z?264([M+1]
+，100)。
Embodiment 17
(S)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and (S)-1,2,3, and 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE prepares by steps A (reflux in toluene 2 days).Product adds HCl by preparation property LCMS purifying, separates obtaining HCl salt (white solid, mp 257-258 ℃).MS(ES
+)m/z264([M+1]
+，100)。
Embodiment 18
N-(benzimidazolyl-2 radicals-yl)-the 2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and 2-methyl isophthalic acid, and 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE (by step B by 2-methyl isophthalic acid-Tetralone an intermediate of Sertraline preparation) prepares by steps A.Product separates by column chromatography, obtains the title compound (white solid, mp 256-257 ℃) into free alkali and stereoisomer mixture.MS(ES
+)m/z?278([M+1]
+，100)。
Embodiment 19
N-(benzimidazolyl-2 radicals-yl)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and 5, and 7-dimethyl-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE (by 5,7-dimethyl-1-Tetralone an intermediate of Sertraline prepares by step B) pass through steps A (60 minutes, 170 ℃, then 20 minutes, 200 ℃) and prepare.Product obtains the title compound (white solid, mp 250-252 ℃) into free alkali and mixture of enantiomers by recrystallization purifying.MS(ES
+)m/z?292([M+1]
+，100)。
Embodiment 20
N-(benzimidazolyl-2 radicals-yl)-the 4-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and 4-methyl isophthalic acid, and 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE (by step B by 4-methyl isophthalic acid-Tetralone an intermediate of Sertraline preparation) prepares by steps A.Product separates by recrystallization, obtains the title compound (white solid, 276 ℃ of mp) into HCl salt and stereoisomer mixture.MS(ES
+)m/z?278([M+1]
+，100)。
Embodiment 21
N-[5, two (trifluoromethyl) benzimidazolyl-2 radicals-yl of 7-]-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 3, two (trifluoromethyl)-1 of 5-, and 2-diaminobenzene and 1-isothiocyanato (isothiocyanato)-1,2,3, the 4-naphthane prepares by step D.Title compound separates by column chromatography, obtains its free alkali and mixture of enantiomers form (solid decomposes＞240 ℃).MS(ES
+)m/z?400([M+1]
+，100)。
Embodiment 22
(R)-and N-(5-tolimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 3,4-diaminotoluene and (R)-1-isothiocyanato-1,2,3, and the 4-naphthane prepares by step D.Title compound separates by column chromatography, obtains its free alkali form (white solid, mp 91-93 ℃).MS(ES
+)m/z?278([M+1]
+，100)。
Embodiment 23
(R)-and N-(5,6-dimethylbenzimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 4,5-dimethyl phenylene diamine and (R)-1-isothiocyanato-1,2,3, and the 4-naphthane prepares by step D.Title compound separates by column chromatography, obtains its free alkali form (solid, mp 121-124 ℃).MS(ES
+)m/z?292([M+1]
+，100)。
Embodiment 24
N-(5-fluorobenzene and imidazoles-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 4-fluorobenzene diamines and 1-isothiocyanato-1,2,3, and the 4-naphthane prepares by step D.Title compound separates by column chromatography, obtains its free alkali and mixture of enantiomers form (solid, mp 220-221 ℃).MS(ES
+)m/z?282([M+1]
+，100)。
Embodiment 25
N-(benzimidazolyl-2 radicals-yl)-7-chloro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and 7-chloro-1,2,3, and 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE (being prepared by 7-chloro-1-Tetralone an intermediate of Sertraline by step B) prepares by steps A.Product obtains the title compound (white solid) into free alkali and mixture of enantiomers by preparation property LCMS purifying.MS(ES
+)m/z?298([M+1]
+，100)。
1NMR(DMSO-d6)δ1.72-1.95(m，3H)，2.02-2.09(m，1H)，2.67-2.80(m，2H)，5.00(m，1H)，6.82-7.18(m，8H)，10.6(s，1H)。
Embodiment 26
N-(benzimidazolyl-2 radicals-yl)-7-fluoro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE
Title compound is by 2-chloro benzimidazole and 7-fluoro-1,2,3, and 4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE (being prepared by 7-fluoro-1-Tetralone an intermediate of Sertraline by step B) prepares by steps A.Product obtains the title compound (white solid, 181 ℃ of mp) into free alkali and mixture of enantiomers by the column chromatography purifying.MS(ES
+)m/z?282([M+1]
+，100)。
Claims (14)
1. the 2-amino-benzene benzimidazole derivative of formula I:
Or any mixture or its pharmacologically acceptable salt of its isomer or its isomer arbitrarily,
Wherein
R
1The expression hydrogen or alkyl;
R
2Expression hydrogen, alkyl or alkoxyl group;
R
3Expression is selected from the following cyclic group that contains:
Wherein m is 0,1 or 2;
N is 0,1,2,3 or 4;
And R wherein
3Ring optionally independently of one another independently be selected from following substituting group and replace by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group;
R
4And R
5Be independently from each other:
Hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and alkoxyl group.
2. the compound of claim 1, wherein R
1Expression hydrogen.
3. claim 1 or 2 compound, wherein R
2Expression hydrogen.
4. each compound, wherein R among the claim 1-3
3Expression 1,2,3,4-tetrahydrochysene-naphthyl, wherein this ring is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.
5. each compound, wherein R among the claim 1-3
3The expression indanyl, wherein aromatic portion is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.
6. each compound, wherein R among the claim 1-3
3Expression 6,7,8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, wherein this ring is optional independently is selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.
7. each compound, wherein R among the claim 1-3
3Expression
Wherein two benzyl rings are chosen wantonly independently of one another and independently are selected from by one or more: the substituting group in halogen, trifluoromethyl, trifluoromethoxy, cyano group, alkyl and the alkoxyl group replaces.
8. each compound, wherein R among the claim 1-7
4And R
5Expression hydrogen.
9. the compound of claim 1, it is:
N-(benzimidazolyl-2 radicals-yl)-2,2-diphenyl-ethyl amine;
N-(benzimidazolyl-2 radicals-yl)-2, two (4-fluorophenyl) ethylamines of 2-;
N-(benzimidazolyl-2 radicals-yl)-2, two (4-chloro-phenyl-) ethylamines of 2-;
N-(benzimidazolyl-2 radicals-yl)-3,3-diphenyl propyl amine;
N-(benzimidazolyl-2 radicals-yl)-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-2-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-fluoro-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-chloro-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-5-bromo-1-indanyl amine;
N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(the benzhydryl amine of benzimidazolyl-2 radicals-yl);
N-(benzimidazolyl-2 radicals-yl)-4-chlorobenzhydryl amine;
N-(benzimidazolyl-2 radicals-yl)-4,4 '-dichloro benzhydryl amine;
N-(benzimidazolyl-2 radicals-yl)-4,4 '-difluorodiphenyl methylamine;
N-(benzimidazolyl-2 radicals-yl)-6,7,8,9-tetrahydrochysene-5H-benzocyclohepta alkene-5-base amine;
(R)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(S)-and N-(benzimidazolyl-2 radicals-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-the 2-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-5,7-dimethyl-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-the 4-methyl isophthalic acid, 2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-[5, two (trifluoromethyl) benzimidazolyl-2 radicals-yl of 7-]-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(R)-and N-(5-tolimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
(R)-and N-(5,6-dimethylbenzimidazole-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(5-fluorobenzene and imidazoles-2-yl)-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-7-chloro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
N-(benzimidazolyl-2 radicals-yl)-7-fluoro-1,2,3,4-tetrahydrochysene-1-ALPHA-NAPHTHYL AMINE;
Or its pharmacologically acceptable salt.
10. pharmaceutical composition, it contains among the claim 1-9 that treats significant quantity each compound or any mixture or its pharmacologically acceptable salt and at least a pharmaceutically acceptable carrier, excipient or the thinner of its isomer or its isomer arbitrarily.
11. each compound or any mixture or the purposes of its pharmacologically acceptable salt in the preparation medicine of its isomer or its isomer arbitrarily among the claim 1-9.
12. according to the purposes of claim 11, be used to prepare treatment, prevention or releasing mammal, comprise the pharmaceutical composition of people's disease or obstacle or illness, described disease, obstacle or illness are replied regulating the SK passage.
13. according to the purposes of claim 12, wherein said have the disease of replying to regulating the SK passage, obstacle or illness are: petit mal, the loss of memory increases the weight of, Alzheimer, stenocardia, irregular pulse, asthma, anxiety, ataxia, attention deficit, bald head, bipolar disorder, the bladder superexcitation, bladder flows out and blocks, cystospasm, cerebral tumor, cerebrum ischemia, chronic obstructive pulmonary disease, cancer, cardiovascular disorder, cognition dysfunction, colitis, constipation, twitch, coronary vasospasm, coronary heart disease, cystic fibrosis, dull-witted, depressed, type ii diabetes, dysmenorrhoea, epilepsy, gastrointestinal dysfunction, the gastroesophageal reflux obstacle, the not enough obstacle of gastrointestinal movement, the gastrointestinal peristalsis deficiency, hearing disability, hyperinsulinemia, hypertension, immunosuppression, inflammatory bowel, inflammatory pain, intermittent claudication, irritable bowel syndrome, ischemic, ischemic heart disease, the study defective, male erectile dysfunction, manic type depression, lethe, migraine, affective disorder, motor neurone disease, myokymia, tetanic property myotrophy imbalance, tetanic property myodystrophy, narcolepsy, neuropathic pain, pain, Parkinson's disease, POLYCYSTIC KIDNEY DISEASE, postoperative ileus, premature labor, psychosis, mental disorder, ephrosis, Reynaud ' s disease, rhinorrhea, secretory diarrhea, epileptic seizures, Sjorgren ' s syndrome, sleep apnea, spasticity, somnopathy, apoplexy, traumatic brain injury, trigeminal neuralgia, the urinary incontinence, the urogenital obstacle, vascular spasm, visual loss or xerostomia.
14. the animal body of treatment, prevention or the work alleviated, comprise the method for human disease or obstacle or illness, described disease, obstacle or illness are replied regulating the SK passage, described method comprise to the animal body administering therapeutic significant quantity of the work that these needs are arranged according to claim 1-9 in each compound or its isomer or any mixture of its isomer or the step of its pharmacologically acceptable salt arbitrarily.
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| CN106467476A (en) * | 2016-09-04 | 2017-03-01 | 王际菊 | A kind of synthetic method of left-handed amine compound |
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| CN106467476A (en) * | 2016-09-04 | 2017-03-01 | 王际菊 | A kind of synthetic method of left-handed amine compound |
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