CN101090895A - Aryl sulphonamide modulators - Google Patents

Aryl sulphonamide modulators Download PDF

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CN101090895A
CN101090895A CNA2005800452309A CN200580045230A CN101090895A CN 101090895 A CN101090895 A CN 101090895A CN A2005800452309 A CNA2005800452309 A CN A2005800452309A CN 200580045230 A CN200580045230 A CN 200580045230A CN 101090895 A CN101090895 A CN 101090895A
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phenyl
enantiomorph
benzsulfamide
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迪安·布朗
弗朗西斯·M·麦克拉伦
托马斯·R·辛普森
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Abstract

Compounds of Formula I: wherein R<1>, R<2>, R<3>, R<4>, R<5> Ar1 and X are as described in the specification, pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially for treatment of conditions associated with reductions in nicotinic transmission.

Description

Aryl sulphonamide modulators
Technical field
The present invention relates to compound or its pharmacy acceptable salt, prepare their method, comprise their pharmaceutical composition and their purposes in treatment.The invention particularly relates to the positive modulators (positive modulator) of nAChR, this positive modulators has the ability that increases nicotinic receptor agonists usefulness.
Background technology
Cholinergic receptor usually combines with endogenous neurotransmitter vagusstoff (ACh), triggers the unlatching of ionic channel thus.Based on the agonist activity of muscarine and nicotine, the ACh acceptor in the mammalian central nervous system can be divided into muscarine (mAChR) hypotype and nicotine (nAChR) hypotype respectively.NAChR is the ligand-gated ion channel that contains 5 subunits.,, be divided into two groups based on their aminoacid sequence with the member of nAChR subunit gene family; One group contains so-called β subunit, and second group contains alpha subunit.Three kinds of alpha subunits, α 7, α 8 and α 9 have demonstrated when single expression and can form functional receptor, suppose that therefore they can form high oligomeric five poly-acceptors (homooligomeric pentameric receptors).
Developed the allosteric transformation condition model (allosteric transition statemodel) of nAChR, it relates to dormant state, state of activation and " desensitization " close passage state at least, and this is that acceptor becomes to the insensitive process of agonist.Different nAChR parts can be stablized the conformational state of their preferential bonded acceptors.For example, agonist ACh and (-)-nicotine are stablized state of activation and desensitization state respectively.
The activity change of nAChR is involved in the numerous disease.In these diseases some, for example myasthenia gravis is relevant with the active reduction of nicotine transmission with ADNFLE (frontal lobe epilepsy at night of autosomal dominant inheritance), and reason is that acceptor reduced number or desensitization increase.Suppose that also the minimizing of nAChR can mediate the cognitive defect (cognitive deficits) that arrives seen in Alzheimer's for example (Alzheimer ' s disease) and the schizophrenia diseases such as (schizophrenia).
Effect from the nicotine of tobacco is mediated by nAChR also, and because the effect of nicotine is an acceptor of stablize the desensitization state, thus the activity of nAChR increase can minimizing to the serious hope of smoking.
Be proposed to be used in treatment with nACHrs bonded compound and related to the disease that cholinergic function reduces, for example Alzheimer's in a large number; cognitive disorder or attention disorders (cognitive orattention disorders); attention deficit companion hyperkinetic syndrome (Attention Deficit HyperactivityDisorder); anxiety disorder (anxiety); dysthymia disorders (depression); (smoking cessation) given up in smoking; neuroprotective (neuroprotection); schizophrenia; analgesia (analgesia); Tourette's syndrome (Tourette ' s syndrome) and Parkinson's disease (Parkinson ' s disease).
But it is problematic using the nicotinic receptor agonists that acts on same loci with ACh to treat, and this is because ACh not only activates, and blocks receptor active by the process that comprises desensitization and noncompetitive retardance (uncompetitive blockade).And the activation of prolongation may be induced long-term inactivation.Therefore, the expectation agonist that can reduce activity and improve active ACh
Usually on nAChR, special concern be on the alpha 7 nicotinic acceptor, desensitization has limited the acting duration of the agonist of using.
Summary of the invention
We have found that some compound can increase the usefulness of agonist on nAChR (nAChR).Compound with this effect is those compounds of formula I:
Figure A20058004523000061
Wherein:
Ar 1Be selected from aryl or heteroaryl, wherein aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl,  azoles base, thiazolyl, pyrryl, pyridyl, pyrazinyl, pyrimidyl or quinolyl;
R 3, R 4And R 5Be independently selected from hydrogen, C when occurring at every turn 1-4Alkyl and C 1-4Alkoxyl group;
X is selected from the part of formula II, III, IV, V, VI or VII
Figure A20058004523000062
Figure A20058004523000071
R 1And R 2Be independently selected from when occurring at every turn hydrogen, halogen ,-C 1-6Alkyl ,-C 1-6Alkoxyl group ,-C 2-6Thiazolinyl ,-C 2-6Alkynyl, C 3-8Cycloalkyl ,-CN ,-NO 2,-CF 3,-CONR 3R 4,-S (O) nR 3, wherein n be 0,1 or 2 ,-NR 3R 4,-CH 2NR 3R 4,-OR 3,-CH 2OR 3Or-CO 2R 3, R wherein 3And R 4Be independently selected from hydrogen or C when occurring at every turn 1-4Alkyl.
The present invention also comprises the interior hydrolyzable precursor of steric isomer, enantiomorph, body and the pharmacy acceptable salt of formula I compound, the pharmaceutical composition and the preparation that contain them, use they or they is united the method for using treatment disease and illness with other treatment active compound or material separately, be used to prepare their method and intermediate, they are as the purposes of medicine, they preparation in the medicine purposes and they be used to diagnose purposes with analysis purposes.
Compound of the present invention is a positive modulators, and it reduces relevant illness for treatment and nicotine transmission and may be particularly useful.In treatment was provided with, these compounds can recover to communicate by letter between normal neurone, and did not influence activated temporarily distribute (temporal profile of activation).In addition, using different with the prolongation of agonist is that positive modulators does not expect to produce the long-term deactivation of acceptor.
One aspect of the present invention comprises compound and steric isomer, enantiomorph, the interior hydrolyzable precursor of body and the pharmacy acceptable salt of formula I:
Figure A20058004523000072
Wherein:
Ar 1Be selected from aryl or heteroaryl, wherein aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl,  azoles base, thiazolyl, pyrryl, pyridyl, pyrazinyl, pyrimidyl or quinolyl;
R 3, R 4And R 5Be independently selected from hydrogen, C when occurring at every turn 1-4Alkyl and C 1-4Alkoxyl group;
X is selected from the part of formula II, III, IV, V, VI or VII
R 1And R 2Be independently selected from when occurring at every turn hydrogen, halogen ,-C 1-6Alkyl ,-C 1-6Alkoxyl group ,-C 2-6Thiazolinyl ,-C 2-6Alkynyl, C 3-8Cycloalkyl ,-CN ,-NO 2,-CF 3,-CONR 3R 4,-S (O) nR 3, wherein n be 0,1 or 2 ,-NR 3R 4,-CH 2NR 3R 4,-OR 3,-CH 2OR 3Or-CO 2R 3, R wherein 3And R 4Be independently selected from hydrogen or C when occurring at every turn 1-4Alkyl.
The embodiment of this aspect of the present invention comprises compound and steric isomer, enantiomorph, the interior hydrolyzable precursor of body and the pharmacy acceptable salt of formula I, wherein:
Ar 1Be phenyl or pyridyl;
R 3, R 4And R 5Be independently selected from hydrogen, C when occurring at every turn 1-4Alkyl and C 1-4Alkoxyl group;
X is selected from the part of formula II, III, IV, V, VI or VII
Figure A20058004523000082
R 1And R 2Be independently selected from hydrogen or halogen when occurring at every turn.
The most concrete compound of the present invention be the application described those.
On the other hand, the invention provides treatment or prevention of psychotic disorders (psychotic disorders), amentia disease (intellectual impairment disorders) or wherein the adjusting of alpha 7 nicotinic acceptor be the useful disease or the method for illness, this method comprises positive modulators or its diastereomer, enantiomorph or the pharmacy acceptable salt of the I of formula as mentioned above of drug treatment significant quantity.
The concrete aspect of the inventive method is the method for the following disease of treatment: Alzheimer's, deficiency of learning ability (learning deficit), cognitive defect, attention deficit (attention deficit), the loss of memory (memoty loss), Lu Yi body dementia (Lewy Body Dementia), attention deficit companion hyperkinetic syndrome, anxiety disorder, psychotic disorder, mania (mania), manic depression of sex (manic depression), Parkinson's disease, Huntington's disease (Huntington ' s disease), Tourette's syndrome, the neurodegenerative disease (neurodegenerative disorder) that wherein has the cholinergic synapse disappearance, jet lag (jetlag), nicotine addiction (nicotine addiction), pain (pain), ulcerative colitis (ulcerativecolitis) or irritable bowel syndrome (irritable bowel syndrome).
Methods of treatment of the present invention comprises the positive modulators of administration as unique active substance, regulates the activity of endogenous nicotinic receptor agonists (for example vagusstoff or choline) thus, perhaps with positive modulators and nicotinic receptor agonists administration together.
In the specific form of the present invention aspect this, methods of treatment comprises with described alpha 7 nicotinic receptor modulators of the application and alpha 7 nicotinic receptor stimulant treats.The example of suitable alpha 7 nicotinic receptor stimulant is (-)-spiral shell [1-azabicyclic [2.2.2.] octane-3,5 '- azoles alkane]-2 '-ketone.Combine other alpha 7 nicotinic receptor stimulant that is used for the treatment of is described among international open WO 96/06098, WO 97/30998 and the WO 99/03859 with positive modulators of the present invention.
Another aspect of the present invention comprises the method for preparation I compound.
Positive modulators of the present invention has the following advantages: their toxicity is lower, and is more effective, and action time is longer, has the activity of wider scope, more potent, produces side effect still less, easier absorption or have other useful pharmacological properties.
Acid salt also within the scope of the invention.This salt comprises the salt of mineral acid, for example hydrochloride and hydrobromate; With the salt that forms with organic acid for example formate, acetate, maleate, benzoate, tartrate and fumarate.The acid salt of formula I compound can form by one or more Equivalent reactions that make free alkali or salt, its enantiomorph or shielded derivative and appropriate acid.Reaction can be in insoluble solvent of salt or medium or the soluble solvent of salt (for example water, two  alkane, ethanol, tetrahydrofuran (THF) or ether, or the mixture of solvent) in carry out, these solvents can be removed by vacuum or lyophilize.Reaction can be the metathesis process or can carry out on ion exchange resin.
The compound of formula I exists with the form of tautomer or enantiomorph, and all these within the scope of the present invention.Can use routine techniques for example fractional crystallization or chirality HPLC, isolate various optical isomers by the racemic mixture of separating compound.Alternatively, independent enantiomorph can prepare under the reaction conditions that can not cause racemization by suitable optically-active raw material.
Another aspect of the present invention relates to pharmaceutical composition, and it is used for the treatment of or prevents the application illness or disease mentioned, that the dysfunction of nAChR neurotransmission causes among the preferred mankind of Mammals.This pharmaceutical composition comprises compound, its enantiomorph or its pharmacy acceptable salt (treat or prevent this disease or illness effective) and the pharmaceutically acceptable carrier of the formula I that treats significant quantity.
Another aspect of the present invention is a pharmaceutical composition, and it comprises compound or its diastereomer, enantiomorph or the pharmacy acceptable salt of the described formula I of the application, and at least a pharmaceutically acceptable diluent or carrier.
Particularly, this aspect of the present invention provides a kind of pharmaceutical composition, and it comprises and preferably is less than 80 weight %, more preferably less than the The compounds of this invention of 50 weight %, and is mixed with pharmaceutically acceptable diluent or carrier.
The example of thinner and carrier is:
-for tablet and lozenge: lactose, starch, talcum, stearic acid;
-for capsule: tartrate or lactose;
-for injection liquid: water, alcohol, glycerol, vegetables oil;
-for suppository: natural or hardened is oily or wax.
The another pharmaceutical composition of the present invention also comprises nicotinic receptor agonists.
Another aspect of the present invention provides the method for pharmaceutical compositions, and it comprises with the composition in the ordinary method bonding composition.
Another aspect of the present invention is the purposes that compound, its enantiomorph or its pharmacy acceptable salt of formula I is used to prepare medicine.
The compound that concrete aspect of the present invention is the described formula I of the application or its diastereomer, enantiomorph or the pharmacy acceptable salt purposes in the preparation medicine, this medicine is used for the treatment of or prevention of psychotic disorders, the amentia disease, wherein the adjusting of alpha 7 nicotinic acceptor is useful human diseases or illness, comprises Alzheimer's, deficiency of learning ability, cognitive defect, attention deficit, the loss of memory, Lu Yi body dementia, attention deficit companion hyperkinetic syndrome, anxiety disorder, psychotic disorder, mania, manic depression of sex, Parkinson's disease, Huntington's disease, Tourette's syndrome, the neurodegenerative disease that wherein has the cholinergic synapse disappearance, jet lag, nicotine addiction, pain, ulcerative colitis or irritable bowel syndrome.
Particularly, this aspect of the present invention is the purposes of The compounds of this invention in the preparation medicine, this medicine is used to prepare treatment or prevention reduces relevant illness or reduces relevant illness with nAChR density with the nAChR transmission, these illnesss can be a kind of of mentioned disease of the application or illness, and described treatment comprises the described medicine that patient's administration is comprised the The compounds of this invention for the treatment of significant quantity.
Should be appreciated that this purposes comprises medication preparation, this medicine comprises as the positive modulators of regulating the active unique active substance of endogenous nicotinic receptor agonists; Or preparation comprises the medicine of positive modulators and nicotinic receptor agonists.Therefore, this purposes is used to prepare medicine that comprises positive modulators and the medicine that also comprises nicotinic receptor agonists.
In the specific form of the present invention aspect this, medicine or pharmaceutical composition comprise described alpha 7 nicotinic receptor modulators of the application and alpha 7 nicotinic receptor stimulant.The example of suitable alpha 7 nicotinic receptor stimulant is (-)-spiral shell [1-azabicyclic [2.2.2.] octane-3,5 '- azoles alkane]-2 '-ketone.Combine other alpha 7 nicotinic receptor stimulant that is used for the treatment of is described among international open WO 96/06098, WO97/30998 and the WO 99/03859 with positive modulators of the present invention.
Another aspect of the present invention is the illness that especially caused by the dysfunction of nAChR neurotransmission among the mankind of treatment or mentioned, the Mammals of prevention the application or the method for disease.
The specific form of this aspect of the present invention provides, the method of the disease that treatment is relevant with nicotine transmission reduction, by the positive modulators to the nicotinic receptor agonists of patient's administration of this treatment of needs medical treatment significant quantity, described positive modulators can increase the usefulness of described nicotinic receptor agonists.
At above-mentioned composition, in purposes and the method, the amount of used formula I compound changes along with used compound, administering mode and desired therapeutic certainly.But in general, when during to the per daily dose administration compound of the present invention of about 20mg, will obtaining satisfied result with every kilogram of about 0.1mg of the weight of animals, described per daily dose can be divided into the every day of 1 to 4 time broken dose or to continue the form administration of release.For the male sex, total per daily dose is at 5mg to 1, and in the scope of 400mg, more specifically in the scope of 10mg to 100mg, and the unit dosage form that is suitable for oral administration comprises 2mg to 1,400mg compound and be mixed with solid or liquid pharmaceutical carriers or thinner.
In composition of the present invention, purposes and method, the compound of formula I, the form of the medical article that its enantiomorph and pharmacy acceptable salt thereof can be used with administration in the intestines or administered parenterally is used separately, or uses with the composition forms that comprises other pharmacologically active agent.For example, the composition that comprises other forms of pharmacologically active agents can comprise positive modulators compound and the nicotinic receptor agonists of formula I.
Therefore, the present invention includes and contain positive modulators as the composition of unique active substance with comprise the composition of positive modulators and nicotinic receptor agonists, this active substance is regulated for example activity of vagusstoff or choline of endogenous nicotinic receptor agonists.Therefore, the described pharmaceutical composition that comprises the positive modulators of nicotinic receptor agonists can comprise nicotinic receptor agonists in addition.
Disease that these aspects of the present invention are useful and examples of disorders comprise psychotic disorder, mania and manic depression of sex, anxiety disorder, Alzheimer's, deficiency of learning ability, cognitive defect, attention deficit, the loss of memory, Lu Yi body dementia, attention deficit companion hyperkinetic syndrome, Parkinson's disease, Huntington's disease, Tourette's syndrome, jet lag and nicotine addiction (comprising owing to being exposed to the nicotine addiction that the product that contains Nicotine causes).
Should be appreciated that, for regulating for example effect of vagusstoff or choline of endogenous nicotinic receptor agonists, or for regulating the effect of exogenous nicotinic receptor agonists, but administration positive modulators of the present invention.
Experimental technique
The activity of compound of the present invention can be measured in following test:
(a) Xenopus ovocyte (Xenopus oocyte) electric current record
The Xenopus ovocyte provides the powerful measure of assess proteins function, and this protein is meant the subunit of thinking ligand-gated ion channel.Injection is by the RNA that transcribes of cDNA of the suitable receptor subunits of coding, or injection promotor downstream is equipped with the cDNA of encoding sequence, all cause (for example functional ligand-gated ion channel occurring on the ovocyte surface, referring to Boulter et al. (1987) Proc.Natl.Acad.Sci.U.S.A.84,7763-7767).
Therefore, the technology that a kind of suitable evaluation nicotine usefulness improves is, according to the two electrode voltage clamps records (two-electrodevoltage-clamp recording) from the Xenopus ovocyte of cRNA express alpha 7-nAChR.
Can use 0.15% tricaine anaesthetize Xenopus laevis flogs (Xenopus I, Kalamazoo, MI).Ovocyte is separated to OR2 solution (82mM NaCl, 2.5mM KCl, 5mM HEPES, 1.5mM NaH 2PO 4, 1mM MgCl 2, 0.1mM EDTA; PH7.4).By on the platform with 1Hz vibration, containing among the 25mL OR2 of 0.2% collagenase 1A (Sigma) and cultivating twice 60 minutes, make ovocyte remove vesicle (defolliculated), and it can be kept at Leibovitz ' sL-15 substratum (50 μ g/ml gentamicins (gentomycin), 10 units/ml penicillin and 10 μ g/ml Streptomycin sulphates) in.About 5ng cRNA was expelled in each ovocyte in second day.
Ovocyte is placed external record solution, and it is by 90mM NaCl, 1mM KCl, 1mMMgCl 2, 1mM BaCl 25mM HEPES, pH7.4 forms.Can use ovocyte clamped amplifier (Oocyte Clamp amplifier) (OC 725C for example; Warner Instrument, Hamden CT) carries out two electrode voltage clamp records.With being filled with 3M KCl, tip resistance is that two electrodes of 1-2M Ω are pegged ovocyte.When membrane potential is being lower than-current potential of the 20mV (Ba in bathing solution ++Replaced C a ++The time, the negative value of static membrane potential is less) become when stablizing opening entry.Clamp membrane potential at-80mV.The speed recording solution continous pouring ovocyte that has or do not have vagusstoff with 5mL/min.
The current amplitude of mensuration from the baseline to the peak.By for example use GraphPad Prism (GrapbPadSoftware, Inc., San Diego, CA) with data fitting to logical equatiion, can estimate EC 50Value, maximum efficiency and Hill slope.
The increase of the agonist usefulness of being drawn by positive modulators can be calculated by following dual mode:
(1) as the enhancing per-cent (precent potentiation) of current amplitude, this per-cent is defined as 100 (Im-Ic)/Ic, and wherein Im is the current amplitude when having conditioning agent, and Ic is the electric current when not having conditioning agent.
(2) as the enhancing per-cent of " area under the curve " of agonist trace, it is the integration of net current to the time.Area under the curve is the common expression (commonrepresentation) of passing the total ion current of passage.
(b) Ca ++Flow imaging
Measuring the active another kind of means of conditioning agent is to the Ca by nAChR α 7 acceptors in the clone of transient expression nAChR α 7 acceptors ++Flow imaging.
The cell (for example neurone of HEK-293 cell or process cell cultures) of express alpha 7 acceptors is cultured to fusion in 96 orifice plates, and loads fluo-3--fluorescence calconcarboxylic acid.In order to screen the activity that α 7 regulates, place fluorescence imaging to read plate device (FLIPR) 96 orifice plates, and test compound is applied in all holes simultaneously with α 7 agonists.Receptor activation is measured by the calcium influx that enters cell, and described calcium current comes quantitatively by the increase of each hole fluorescence intensity of being write down simultaneously by FLIPR.Regulating effect shows as the increase of fluorescence when only using agonist induction.Similarly, in order to test nAChR α 7 agonist activities, test compound and α 7 conditioning agents are applied to all holes together simultaneously.Receptor activation is measured by the calcium influx that enters cell, and described calcium current comes quantitatively by the increase of each hole fluorescence intensity.The agonist effect is determined by the increase of fluorescence when only inducing with conditioning agent.
Can be prepared as follows neurone through cell cultures.From the female mouse of gestation, sterilely take out the Sprague-Dawley rat fetal (E-18) of 18 ages in days, it is put to death, remove the volume cortex of decerebrate, peel off meninx, the cortex of cleaning is put into cold HBSS.Hippocampal tissue just cuts off hippocampus from cortex if desired, is placed on then among the cold HBSS.The mechanical dispersion tissue, washing once is resuspended in and is added with glutamine, microbiotic, Repone K, Regular Insulin, Transferrins,iron complexes, selenium and 5% heat-inactivated foetal calf serum (FBS in HBSS (200g is at 4 ℃ of washing 30min); Do not contain intracellular toxin) the Sato substratum in, and be layered in each hole of 24 orifice plates (being coated with poly-L-Lysine (poly-L-lysine)).Slide glass (glass cover slips) can be contained in described hole, and it also is coated with PLL.At 37 ℃, CO 2This plate of incubation in the incubator.After 24 hours, remove substratum, add fresh substratum, make cell growth at least 11 days again, feed supplement when needing.
When measuring from the baseline to the peak from the vagusstoff (30 μ M) at lower concentration, compound of the present invention causes base current to increase by 1 times (enhancement of 100%), and this shows that their expections have useful therapeutic activity.At Ca 2+When applying compound of the present invention during flow imaging is measured, they also increase Ca ++Stream.With the Ca that only causes with agonist ++Stream increases to be compared, any Ca that is caused by compound of the present invention ++Stream increases (measuring) and all shows in the fluorescence intensity unit, their expections have useful therapeutic activity.
Compound of the present invention has the following advantages: their toxicity is lower, and is more effective, and action time is longer, has the activity of wider scope, more potent, produces side effect still less, easier absorption or have other useful pharmacological properties.
General experimentation
By the described embodiment of the application the present invention is described, but the invention is not restricted to this, in the description of embodiment,, use following term, abbreviation and condition if when using and not, illustrate in addition:
Use commercial reagents, and be not further purified.
The application uses following abbreviation: aq., the aqueous solution; Atm, normal atmosphere; BOC, 1, the 1-dimethyl ethoxycarbonyl; DCM, methylene dichloride; DMF, N, dinethylformamide; DMSO, methyl-sulphoxide; EtOH, ethanol; Et2O, ether; EtOAc, ethyl acetate; H, hour (s); HPLC, high pressure liquid chromatography; HOBT, I-hydroxybenzotriazole; MeOH, methyl alcohol; Min, minute; MS, mass spectrum; NMR, nucleus magnetic resonance; Psi, pound/square inch; RT, room temperature; Sat., saturated; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran (THF).
Temperature with degree centigrade (℃) provide; Unless otherwise indicated, operate in room temperature or envrionment temperature (18-25 ℃).
Through anhydrous sodium sulphate or anhydrous magnesium sulfate drying organic solvent; Use rotary evaporation in decompression (4.5-30mm Hg), 60 ℃ bath temperature is carried out the evaporation of solvent at the most.
Unless otherwise noted, chromatogram is meant silica gel flash column chromatography (flash column chromatographyon silica gel); The solvent mixture composition provides with volume percent or volume ratio.
When providing, the NMR data are the δ value forms (in respect to the part per million (ppm) as interior target tetramethylsilane) at the main detection proton of 300MHz mensuration.
Fusing point is uncorrected.
Use Hewlett Packard 5988A or MicroMass Quattro-1 MassSpectrometer record mass spectrum, and be reported as parent molecule ionic m/z.Room temperature is meant 20-25 ℃.
Unless otherwise indicated, the described reaction of the application usually about 1 to about 3 normal atmosphere, is preferably carried out under environmental stress (about 1 normal atmosphere).
Unless otherwise indicated, be reflected at inert atmosphere, preferably carry out at nitrogen.Standard technique be can use, compound of the present invention and intermediate from their reaction mixture, separated.
As used in this application, unless otherwise noted, " C 1-6Alkyl " comprise methyl, ethyl, n-propyl, normal-butyl, sec.-propyl, isobutyl-, the tertiary butyl, sec-butyl etc., C 3-8Moieties can be straight chain, branching or cyclic, for example cyclopropyl or cyclobutyl.
As used in this application, unless otherwise noted, " C 2-4Thiazolinyl " include but not limited to 1-propenyl, 2-propenyl, 1-butylene base, crotyl and 3-butenyl.
As used in this application, unless otherwise noted, " C 2-4Alkynyl " include but not limited to ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base and 3-butynyl.
Used " halogen " of the application is meant fluorine, chlorine, bromine or iodine.
Embodiment
Usually prepare compound of the present invention by the method described in the embodiment 1 to 5.In described all methods of the application, when needing, can use protecting group protection hydroxyl, amino or other reactive group, as understood by one of ordinary skill in the art.
Embodiment 1
4-[3-(2,4,6-trimethylammonium-phenyl)-4,5-dihydro-different  azoles-5-yl]-benzsulfamide
Figure A20058004523000151
With Three methyl Benzene formonitrile HCN-N-oxide compound 1a of stirring (0.200g, 1.23mmol) and the chloroformic solution reflux 18h of 4-vinyl-benzsulfamide 1b.Concentration residue, and with chromatogram (SiO 2, CHCl 3/ MeOH, the MeOH solution of gradient 0 to 10%) purifying, obtain title compound, be solid (0.030,7%): 1H NMR (300MHz, CDCl 3, 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), and 3.03-3.11 (br m, 1H), 3.63-3.72 (br m, 1H), 4.86 (br s, 2H), 5.80-5.85 (br ms, 1H), 6.88 (s, 2H), 7.57 (d, 2H, J=7.2Hz), 7.95 (d, 2H, J=7.2Hz) .APCI (m+1), m/z=345.LC/MS=2.38.
Embodiment 2
2-chloro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide
With Three methyl Benzene formonitrile HCN-N-oxide compound 1a of stirring (0.073g, 0.33mmol) and 2-chloro-4-ethynyl-benzsulfamide 2b (0.034g, chloroformic solution reflux 18h 0.33mmol).Concentration residue, and with chromatogram (SiO 2, EtOAc/Hex, the EtOAc solution of gradient 0 to 20%) and purifying, obtain title compound, be solid (0.037,28%): 1H NMR (300MHz, CDCl 3, 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 5.18 (br s, 2H), 6.62 (s, 1H), 6.97 (s, 2H), 7.85 (d, 1H, J=8.0Hz), 8.02 (s, 1H), 8.23 (d, 1H, J=8.0Hz) .APCI (m+1), m/z=377.LC/MS=2.71.
Preparation 2-chloro-4-ethynyl-benzsulfamide 2b
Figure A20058004523000162
To the 2-chloro-4-bromo-benzsulfamide 2d (1.02g that stirs, 3.77mmol) and trimethyl silane acetylene (0.55g, 5.66mmol) triethylamine (24mL) solution in add cuprous iodide (I) (0.028g, 0.14mmol) and four (triphenylphosphinyl) palladium (0) (0.063g, 0.05mmol).Mixture is heated 18h at 80 ℃.Enriched mixture, and ether joined in the resistates.Filter out the solid of acquisition.Add MeOH (100mL) and K to this solid 2CO 3(8.66mmol), reactant is stirred 18h.The concentration response thing, and with it at CHCl 3And H 2Distribute between the O.The sedimentary brown solid of filtered and recycled, and directly use, and be not further purified.
Embodiment 3
3-fluoro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide
Figure A20058004523000163
Use 3-chloro-4-ethynyl-benzsulfamide 3b, prepare embodiment 3 in the mode that is similar to embodiment 2.With chromatogram (CH 2Cl 2, SiO 2) isolate this material, then at preparation HPLC (acetonitrile/H 2The O gradient) purifying once more on obtains title compound, is white solid (0.012g, 6%): 1H NMR (300MHz, CDCl 3, 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 5.00 (br s, 2H), 6.78 (d, J=4.2Hz), 1H), 6.96 (s, 1H), 7.77 (d, 1H, J=11.0Hz), 7.85 (s, J=8.4Hz, 1H), 8.19-8.24 (m, 1H) .APCI (m+1), m/z=361.LC/MS=2.42.
Embodiment 4
4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide
Figure A20058004523000172
Use 4-ethynyl-benzsulfamide 4b, prepare embodiment 4 in the mode that is similar to embodiment 2.With chromatogram (EtOAc/ hexane 20/80, SiO 2) isolate this material, obtain title compound, be white solid (0.011g, 8%): 1H NMR (300MHz, CDCl 3, 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 4.86 (br s, 2H), 6.59 (s, 1H), 6.96 (s, 2H), 7.95 (d, J=8.4Hz, 2H), 8.06 (d, J=8.4Hz, 2H) .APCI (m+1), m/z=343.LC/MS=2.60.
Embodiment 5
2-fluoro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide
Figure A20058004523000181
Use 4-ethynyl-benzsulfamide 5b, prepare embodiment 5 in the mode that is similar to embodiment 2.With chromatogram (EtOAc/ hexane 20/80, SiO 2) isolate this material, obtain title compound, be white solid (0.091g, 30%): 1H NMR (300MHz, CDCl 3, 300K) δ 2.18 (s, 6H), 2.33 (s, 3H), 5.10 (br s, 2H), 6.60 (s, 1H), 6.96 (s, 2H), 7.68-7.73 (br m, 2H), 8.03 (app t, J=7.5Hz, 1H) .APCI (m+1), m/z=361.LC/MS=2.65.
Can use and be substantially similar to the compound that the step described in the previous embodiment prepares embodiment 6 and 7.
Embodiment 6
4-[3-(2,4,6-trimethylammonium-phenyl)-[1,2,4]  diazole-5-yl]-benzsulfamide
Figure A20058004523000182
Embodiment 7
4-[3-(4-methoxyl group-2,3-dimethyl-phenyl)-4,5-dihydro-different  azoles-5-yl]-benzsulfamide

Claims (16)

1. hydrolyzable precursor and pharmacy acceptable salt in the compound of formula I and steric isomer thereof, enantiomorph, the body,
Figure A2005800452300002C1
Wherein:
Ar 1Be selected from aryl or heteroaryl, wherein aryl is selected from phenyl or naphthyl, and heteroaryl is selected from furyl, thienyl, imidazolyl,  azoles base, thiazolyl, pyrryl, pyridyl, pyrazinyl, pyrimidyl or quinolyl;
R 3, R 4And R 5Be independently selected from hydrogen, C when occurring at every turn 1-4Alkyl and C 1-4Alkoxyl group;
X is selected from the part of formula II, III, IV, V, VI or VII
Figure A2005800452300002C2
R 1And R 2Be independently selected from when occurring at every turn hydrogen, halogen ,-C 1-6Alkyl ,-C 1-6Alkoxyl group ,-C 2-6Thiazolinyl ,-C 2-6Alkynyl, C 3-8Cycloalkyl ,-CN ,-NO 2,-CF 3,-CONR 3R 4,-S (O) nR 3, wherein n be 0,1 or 2 ,-NR 3R 4,-CH 2NR 3R 4,-OR 3,-CH 2OR 3Or-CO 2R 3, R wherein 3And R 4Be independently selected from hydrogen or C when occurring at every turn 1-4Alkyl.
2. hydrolyzable precursor and pharmacy acceptable salt in the compound of claim 1 and steric isomer thereof, enantiomorph, the body, wherein:
Ar 1Be phenyl or pyridyl;
R 3, R 4And R 5Be independently selected from hydrogen, C when occurring at every turn 1-4Alkyl and C 1-4Alkoxyl group;
X is selected from the part of formula II, III, IV, V, VI or VII
Figure A2005800452300003C1
R 1And R 2Be independently selected from hydrogen or halogen when occurring at every turn.
3. hydrolyzable precursor and pharmacy acceptable salt in the compound of claim 1 and steric isomer thereof, enantiomorph, the body, described compound is selected from:
4-[3-(2,4,6-trimethylammonium-phenyl)-4,5-dihydro-different  azoles-5-yl]-benzsulfamide;
2-chloro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide;
3-fluoro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide;
4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide;
2-fluoro-4-[3-(2,4,6-trimethylammonium-phenyl)-different  azoles-5-yl]-benzsulfamide;
4-[3-(2,4,6-trimethylammonium-phenyl)-[1,2,4]  diazole-5-yl]-benzsulfamide and
4-[3-(4-methoxyl group-2,3-dimethyl-phenyl)-4,5-dihydro-different  azoles-5-yl]-benzsulfamide.
4. treatment or to prevent the wherein adjusting of alpha 7 nicotinic acceptor be the useful disease or the method for illness, this method comprise hydrolyzable precursor and pharmacy acceptable salt in the compound of the claim 1 of patient's drug treatment significant quantity of suffering from described disease or illness and steric isomer thereof, enantiomorph, the body.
5. the method for claim 4, wherein said disease or illness are anxiety disorder, schizophrenia, mania or manic depression of sex.
6. treat or prevent the method for neurological disorder, mental disorder or amentia disease, it comprises compound and steric isomer, enantiomorph, the interior hydrolyzable precursor of body and the pharmacy acceptable salt of the claim 1 of drug treatment significant quantity.
7. the method for claim 6, wherein said disease are Alzheimer's, deficiency of learning ability, cognitive defect, attention deficit, the loss of memory, attention deficit companion hyperkinetic syndrome, Parkinson's disease, Huntington's disease, Tourette's syndrome, wherein have neurodegenerative disease, jet lag, nicotine addiction, one-tenth addiction, pain or a ulcerative colitis of cholinergic synapse disappearance.
8. the method for inducing smoking to give up, this method comprise compound and steric isomer, enantiomorph, the interior hydrolyzable precursor of body and the pharmacy acceptable salt of the claim 1 of effective dosage.
9. pharmaceutical composition comprises hydrolyzable precursor and pharmacy acceptable salt in the compound of claim 1 and steric isomer thereof, enantiomorph, the body, and pharmaceutically acceptable thinner, lubricant or carrier.
10. treating or prevent the wherein activation of alpha 7 nicotinic acceptor is the useful disease or the method for illness, and this method comprises the pharmaceutical composition to the claim 9 of patient's drug treatment significant quantity of suffering from described disease or illness.
11. the method for claim 10, wherein said disease or illness are anxiety disorder, schizophrenia, mania or manic depression of sex.
12. the method for treatment or prevention neurological disorder, mental disorder or amentia disease, it comprises the pharmaceutical composition of the claim 9 of drug treatment significant quantity.
13. the method for claim 12, wherein said disease are Alzheimer's, deficiency of learning ability, cognitive defect, attention deficit, the loss of memory, attention deficit companion hyperkinetic syndrome, Parkinson's disease, Huntington's disease, Tourette's syndrome, wherein have neurodegenerative disease, jet lag, nicotine addiction, one-tenth addiction, pain or a ulcerative colitis of cholinergic synapse disappearance.
14. the method for inducing smoking to give up, this method comprises the pharmaceutical composition of the claim 9 of effective dosage.
15. the compound of claim 1, its enantiomorph or its pharmacy acceptable salt purposes in the preparation medicine, this medicine is used for the treatment of or prevents the wherein activation of alpha 7 nicotinic acceptor is useful human diseases or illness, is selected from neurological disorder, mental disorder, the amentia disease, Alzheimer's, deficiency of learning ability, cognitive defect, attention deficit, the loss of memory, attention deficit companion hyperkinetic syndrome, anxiety disorder, schizophrenia, mania or manic depression of sex, Parkinson's disease, Huntington's disease, Tourette's syndrome or the neurodegenerative disease that wherein exists cholinergic synapse to lack.
16. the purposes of the compound of claim 1 in the preparation medicine, this medicine is used for the treatment of or prevents jet lag, pain or ulcerative colitis, or be used to be convenient to smoking and give up or treat nicotine addiction or become addiction, comprise owing to be exposed to nicotine addiction or the one-tenth addiction that the product that contains Nicotine causes.
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