CN102548407A - The use of metabotropic glutamate receptor potentiators for reducing nicotine dependence - Google Patents
The use of metabotropic glutamate receptor potentiators for reducing nicotine dependence Download PDFInfo
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Abstract
Methods of using potentiators of glutamate receptors for reducing nicotine usage, reducing the urge to smoke or chew tobacco or inducing the cessation of smoking are described.
Description
Technical field
The present invention relates to glutamate receptor reinforcing agent and the purposes in treatment thereof.More specifically, the present invention relates to the glutamate receptor reinforcing agent is reducing the use of nicotine, reducing the impulsion of smoking or chewing tobacco and is inducing the purposes that stops in the smoking.
Background technology
Glutamic acid is excitatory neurotransmitter main in the central nervous system, to the acceptor of two kinds of main types, i.e. and ionotropic acceptor and close metabotropic receptor.Parent's metabotropic glutamate receptor is a g protein coupled receptor, and it regulates the presynaptic release (presynaptic release) of being replied (postsynaptic responses) and glutamic acid, GABA and 5-HT the postsynaptic of glutamic acid.Identified the close metabotropic glutamate receptor of eight kinds of hypotypes, and it has been divided into the acceptor of I group (mGluR1 and mGluR5), II group (mGluR2 and mGluR3) and III group (mGluR4, mGluR6, mGluR7 and mGluR8).
The mGluR (mGluR2 and mGluR3) of II group thus suppress adenyl cyclase (adenylate cyclase) and mainly be involved in the presynaptic inhibition of release of glutamic acid and GABA through the Gi/o coupling.The mGlur2 expression of receptor (comprises preceding cingulum (anterior cingulate) and preceding fronto-orbital area (prefrontal orbital area) in corticocerebral zone of dispersion; Limbic forebrain (limbic forebrain) (comprising amygdaloid nucleus (amygdala) and hippocampus)) in; And less degree be expressed in ventral tegmental area (VTA) and the volt nuclear (NAc).The expression of mGlurR3 is variation more usually, and mGluR3 also is expressed in the neuroglia, and mGluR3 is considered in neuroglia, play the effect of regulating glutamic acid release and GABAergic neuron.The mGlur2 acceptor is positioned at the outer site of cynapse of neuron tip, plays the effect of autoreceptor at this mGlur2 acceptor, thereby under high glutamic acid condition (hyper-glutamatergic conditions), suppresses the release of glutamic acid.
Glutamic acid is considered to the main effect of performance in the adjusting of nicotine award (reward) and smoking recurrence (relapse to smoking).The nicotine increase spreads all over the transmission of the glutamic acid mediation in reward of brain loop (brain reward circuits).For example, the nicotine activation is positioned at the excitability nACh acceptor of glutamic acid serotonergic neuron tip, and said glutamic acid serotonergic neuron projects on middle limbic brain dopamine (DA) neuron the VTA from brain stem (LDT/PPT).The DA neuron projects to the shell of NAc again.In rat, the taking certainly of nicotine increase DA in the shell of NAc release and what shown is that nonselective mGlur2/3 receptor stimulating agent preferentially reduces the release of DA in the shell of NAc, and the blocking-up of mGlur2/3 has increased the DA in the NAc shell.Non-selective mGlur2/3 activator has also reduced the reinstatement (recurrence) of the behavior of the searching nicotine that the taking certainly of nicotine (self-administration), nicotine award and clue induce in rat, the while not significance increase the weight of the reward of brain defective relevant with nicotine withdrawal.
Summary of the invention
The positive allosteric modulators of mGlur2 (mGluR2PAMs) plays a role in the site away from the glutamic acid binding site on the mGlur2 acceptor and strengthens the activation to the glutamic acid binding site.Therefore, such reagent is only in the descend effect of low glutamic acid of the condition of the cynapse extracellular glutamate level that raises.Therefore; Thereby we think mGlur2 PAM that the application describes will with endogenous glutamic acid harmonious play a role reduce dopamine in the shell of NAc release and reduce nicotine from taking, simultaneously not significance increase the weight of the reward of brain defective relevant with nicotine withdrawal.Further think; In human body; Thereby mGlur2 PAMs will play a role weaken to the glutamic acid of nicotine reply, reduce tobacco use, reduce the nicotine award and to the consumption of cigarette; And alleviate smoking clue (smoking cues) and smoking are replied through the glutamic acid of (smoking lapses), do not hinder normal glutamic acid can transmit or increase the weight of nicotine withdrawal symptoms (nicotine withdrawal symptoms) simultaneously.
Therefore, conceived the method that reduces the use of nicotine or alleviate nicotine withdrawal symptoms, having comprised: to the mGluR2 PAM of experimenter's drug treatment effective dose that these needs are arranged.
More specifically, conceived following method, wherein mGluR2 PAM is selected from following compound: 7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4] oxadiazole-5-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-5-[3-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-5-yl]-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-5-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
7-chloro-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-chloro-2-(4-benzyl chloride base)-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
7-methyl-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-benzyl chloride base)-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
5-[5-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-3-yl]-7-methyl-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S, 4S)-1-(2,5-diaza-two ring [2.2.1] heptan-2-yl) methyl]-[1,2,4] oxadiazole-3-yls }-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
7-chloro-5-[5-(3,3-dimethyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone, or
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1; 2; 4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone, or the officinal salt of any aforesaid compound, active metabolite, intermediate or derivative, hydrate or solvate.
Still more specifically, conceived when attempting to reduce the experimenter, through the experimenter being used the described compound of the application to reduce smoking, reduce chewing tobacco and to alleviate the method for the experience of nicotine withdrawal symptoms usually to the dependence of tobacco.
Conceive the pharmaceutical composition that is used for the described method of the application, comprised at least a pharmaceutically acceptable carrier of the described compound of the application or excipient.
Also conceived officinal salt, active metabolite, intermediate or derivative, hydrate or the solvate of the described compound of the application or such compound, it can be used as medicine.
Officinal salt, active metabolite, intermediate or derivative, hydrate or the solvate of the described compound of the application or such compound can be used for preparing and is used to alleviate nicotine withdrawal symptoms or reduces the medicine that tobacco is used.
Embodiment:
mGluR2?PAMs：
The mGlur2PAMs that is conceived and its active metabolite, intermediate or derivative be used to weaken to nicotine reply, reduce the nicotine award and to the consumption of cigarette; Be described among disclosed International Patent Application WO 2006020879, WO2007021309, WO2007095024, WO2007115077, WO2008100715 and the WO2008130853; Or among U.S. publication application US20070021606A1, US20090069340A1, US20070032469A1, US20080227794A1, US20070275966A1, US20080125431A1, US20080306088A1 and the US20080306077A1, its entirety is introduced among the application as a reference.
Although being described in any mGlur2 PAM in above-mentioned any patent application will alleviate the glutamic acid of smoking clue and smoking fault is replied; Simultaneously do not hinder normal glutamic acid can transmit or increase the weight of nicotine withdrawal symptoms; And will promote to stop smoking, be selected from following compound yet conceived especially:
7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4] oxadiazole-5-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-5-[3-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-5-yl]-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-5-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone,
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
7-chloro-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-chloro-2-(4-benzyl chloride base)-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
7-methyl-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-benzyl chloride base)-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
5-[5-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-3-yl]-7-methyl-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S, 4S)-1-(2,5-diaza-two ring [2.2.1] heptan-2-yl) methyl]-[1,2,4] oxadiazole-3-yls }-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
7-chloro-5-[5-(3,3-dimethyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone, or
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone,
Or therefore the officinal salt, active metabolite, intermediate, derivative, hydrate or the solvate that are described in any above-claimed cpd among US20080306088A1 or the US20080306077A1 will have concrete practicality.
Effect:
The validity of mGlur2PAMs can be estimated through following method, for example through randomized, double-blind study, double dummy technique, placebo method and activating agent counter point, parallel-group, the human experimentation chamber research in masculinity and femininity healthy, that seek treatment is grown up the smoker, carried out.Other method of estimating validity dawn that will be known to those skilled in the art.
Validity can be explained in the following manner; For example, through smoking cessation, through alleviating withrawal symptom and craving for tobacco (for example through Minnesota State nicotine withdrawal scale (revised edition) (Minnesota Nicotine Withdrawal Scale-Revised) and the brief questionnaire of QSU (QSU-Brief Questionnaire on smoking urges) that smoking is got excited is assessed) during prolonging before the smoking recurrence or through subjectivity.
Other effect can be used for estimating validity, positivity and the negativity mood of for example using positivity and negativity mood scale to measure; Use the depressive symptom of stream accent center with the SDS assessment; Pierre Bei Geer State-Anxiety Trait Inventory is executed in use; Or utilize: 1) estimate vision probe task, with 2 to the notice bias of outstanding clue) measure the anxiety level of the reactive assessment of clue of smoking in the body being compared the reactive task of clue of the subjective craving for tobacco of reacting and producing with achromatic stimulus.
Effective dose
Although think that the treatment effective dose will depend on that the experimenter that treated and such dosage can be confirmed by those skilled in the art in reality, it has been generally acknowledged that from the dosage of the described mGluR2PAM of the application of about 1 microgram to about 40 micrograms to comprise the treatment effective dose.
More specifically, think and comprise the treatment effective dose from about 1 milligram of dosage to the about 20 milligrams described mGluR2PAM of the application.
Usually; Suitable dosage regimen, the specific interval between the dosage of each administration mGluR2 PAM and the every kind of active agent administration will depend on that the experimenter who is treated, the given activity reagent that carries out administration and nicotine use or the essence and the severity of the illness of being treated.More specifically, think that the dosage of the described mGluR2 PAM of the application will be administered once every day.Usually, the dosage of mGluR2PAM will be with the form administration of the composition that contains at least a pharmaceutically acceptable carrier or excipient.
Composition
The composition intention comprises mGluR2PAM or officinal salt and pharmaceutically suitable carrier, and the preparation of optional other compositions.Be pharmaceutical compositions, inertia, pharmaceutically suitable carrier can be solid or liquid.For example; Can composition be made into following form through methods known in the art; For example tablet, capsule, water or oil solution, supensoid agent, emulsion, cream, ointment, gel, nasal mist, suppository, divided powder or aerosol or the spray (nebulisers) that is used to breathe, and be used for outer (comprising intravenous, intramuscular or infusion) sterile water or oil solution or the supensoid agent that uses of stomach and intestine or do not have bacterial emulsion.
The composition of liquid form comprises solution, supensoid agent and emulsion.Sterile water or the water-propylene glycol solution conduct that can mention reactive compound are suitable for the instance of the liquid preparation of parenteral.Fluid composition also can be built in the solution in the moisture polyglycol solution.The aqueous solution that is used for oral administration can be through being dissolved in the water active component and preparing according to the suitable colouring agent of required adding, flavor enhancement, stabilizing agent and thickener.The aqueous suspension that is used for orally using can be scattered in water through the active component with segmentation and cohesive material prepares such as natural synthetic natural gum, resin, methylcellulose, sodium carboxymethylcellulose and the known suspending agent of other medicines formulation art.
But the composition of solid form comprises powder, tablet dispersible granule, capsule, cachet agent and suppository.Solid carrier can also can play the material of thinner, flavor enhancement, solubilizer, lubricant, suspending agent, adhesive or tablet disintegrant effect for one or more; It also can be coating material.
In powder, carrier can be finely-divided solid, and it forms mixture with the segmentation active component.In tablet, active component mixes with the carrier with necessary bond property with suitable ratio and is pressed into required shape and size.
Be the preparation suppository composition, be scattered in wherein at first with the mixture melt of low melt wax such as fatty glyceride and cocoa butter, and with the mode of active component through for example stirring.Uniform homogeneous blend injection with fusing makes things convenient for the mould of size and makes its cooling and curing then.
Suitable carriers is magnesium carbonate, dolomol, talcum, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter or the like.
The term group compound also is intended to comprise mGluR2 PAM active component and preparation as the coating material of carrier, the capsule that said carrier provides active component (having or do not have other carrier) suppressed by vector (therefore relevant with active component) wherein to be sealed.Similarly, also comprise the cachet agent.
Pharmaceutical composition can be the form of unit metering.In such form, composition is divided into the UD of the active component that contains suitable amount.The form of unit metering can be packaged preparation, and said packing contains the preparation of the amount of separation, for example, and box-packed tablet, capsule and the powder in phial (vials) and ampoule.The form of unit metering also can be capsule, cachet agent or tablet self, or it can be the form of any these packings of right quantity.The method for preparing formulation is disclosed in for example Remington ' s Pharmaceutical ScienceS, Mack Publishing Company, and Easton, guest sunset Fan Niya state, the 15th edition, in 1975.
Composition can be made into to be used for the form of any suitable way and mode administration.Pharmaceutically suitable carrier or thinner comprise be used for being suitable for oral, rectum, intranasal, part (comprise and contain clothes and hypogloeeis), vagina or stomach and intestine outer (comprise in subcutaneous, intramuscular, intravenous, intracutaneous, the sheath, exterior dura, peritonaeum is interior, intrathoracic, the ventricles of the brain interior and through being injected to the joint) those of the preparation of administration.Preparation can be easily provides and can prepare through the known method of any drug world with the form of UD.
Claims (8)
1. reduce the use of nicotine or alleviate the method for nicotine withdrawal symptoms, comprising: to the mGluR2 PAM of experimenter's drug treatment effective dose that these needs are arranged.
2. the method for claim 1, wherein said mGluR2 PAM is selected from following compound:
7-methyl-5-(3-piperazine-1-ylmethyl-[1,2,4] oxadiazole-5-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-5-[3-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-5-yl]-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-(3-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-5-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2,3-dihydro-iso-indoles-1-ketone;
7-chloro-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-chloro-2-(4-benzyl chloride base)-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
7-methyl-5-(5-piperazine-1-ylmethyl-[1,2,4] oxadiazole-3-yls)-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-(4-benzyl chloride base)-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-xylylenimine-1-ketone;
5-[5-(2,5-diaza-two ring [2.2.1] heptan-2-ylmethyl)-[1,2,4] oxadiazole-3-yl]-7-methyl-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazine-1-ylmethyl-[and 1,2,4] oxadiazole-3-yls)-2,3-dihydro-iso-indoles-1-ketone;
2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S, 4S)-1-(2,5-diaza-two ring [2.2.1] heptan-2-yl) methyl]-[1,2,4] oxadiazole-3-yls }-7-methyl-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-xylylenimine-1-ketone;
7-chloro-5-[5-(3,3-dimethyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoro-methoxybenzyl)-2,3-xylylenimine-1-ketone;
7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-iso-indoles-1-ketone;
2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone, or
2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazine-1-base-ethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-iso-indoles-1-ketone,
Or the officinal salt of any aforesaid compound, hydrate or solvate.
3. as claimed in claim method 1 or 2, it is used to reduce smoking.
4. as claimed in claim method 1 or 2, it is used to reduce chewing tobacco.
5. according to claim 1 or claim 2 method is used to alleviate nicotine withdrawal symptoms.
6. pharmaceutical composition comprises compound as claimed in claim 2 and at least a pharmaceutically acceptable carrier or excipient.
7. compound as claimed in claim 2, it is as medicine.
8. compound as claimed in claim 2 is used for alleviating nicotine withdrawal symptoms or reduces the purposes of the medicine that tobacco uses in preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21847809P | 2009-06-19 | 2009-06-19 | |
| US61/218,478 | 2009-06-19 | ||
| PCT/US2010/038802 WO2010148074A1 (en) | 2009-06-19 | 2010-06-16 | The use of metabotropic glutamate receptor potentiators for reducing nicotine dependence |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102548407A true CN102548407A (en) | 2012-07-04 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800271376A Pending CN102548407A (en) | 2009-06-19 | 2010-06-16 | The use of metabotropic glutamate receptor potentiators for reducing nicotine dependence |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2442649A4 (en) |
| JP (1) | JP2012530710A (en) |
| CN (1) | CN102548407A (en) |
| WO (1) | WO2010148074A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11161838B2 (en) | 2018-11-13 | 2021-11-02 | Incyte Corporation | Heterocyclic derivatives as PI3K inhibitors |
| WO2020102198A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
| WO2020102216A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Substituted heterocyclic derivatives as pi3k inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0420719D0 (en) * | 2004-09-17 | 2004-10-20 | Addex Pharmaceuticals Sa | Novel allosteric modulators |
| TW200911255A (en) * | 2007-06-07 | 2009-03-16 | Astrazeneca Ab | Metabotropic glutamate receptor oxadiazole ligands and their use as potentiators-841 |
-
2010
- 2010-06-16 WO PCT/US2010/038802 patent/WO2010148074A1/en active Application Filing
- 2010-06-16 JP JP2012516235A patent/JP2012530710A/en active Pending
- 2010-06-16 EP EP10790110A patent/EP2442649A4/en not_active Withdrawn
- 2010-06-16 CN CN2010800271376A patent/CN102548407A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010148074A1 (en) | 2010-12-23 |
| JP2012530710A (en) | 2012-12-06 |
| EP2442649A4 (en) | 2013-04-03 |
| EP2442649A1 (en) | 2012-04-25 |
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Application publication date: 20120704 |