CN103254127B - Glycine reuptake inhibitor and application thereof - Google Patents
Glycine reuptake inhibitor and application thereof Download PDFInfo
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- CN103254127B CN103254127B CN201310204530.3A CN201310204530A CN103254127B CN 103254127 B CN103254127 B CN 103254127B CN 201310204530 A CN201310204530 A CN 201310204530A CN 103254127 B CN103254127 B CN 103254127B
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Abstract
The present invention relates to glycine reuptake inhibitor and application thereof, described glycine reuptake inhibitor is formula I, or its isomer, pharmacologically acceptable salts or solvate, wherein R1 is one or morely selected from following group: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group; R2 is selected from: hydrogen, C1-6 alkyl, C1-6 alkoxyl group, halo C1-6 alkyl and halo C1-6 alkoxyl group; R3 and R4 is selected from independently of one another: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group.Compound of the present invention is effective glycine reuptake inhibitor.
Description
Technical field
The present invention relates to glycine reuptake inhibitor and application thereof, this type of inhibitor such as can be used for treating schizophrenia.
Background technology
Schizophrenia (Schizophrenic disorder) is a kind of very serious mental disorder, lacks and contacts, there is illusion, vain hope and abnormal thinking, social function obvious damage with reality.Schizophrenia is a kind of global public health problem, and the total prevalence rate in its whole world (comprising China) is greatly about 0.8-1%.The schizoid onset peak age male sex is 18 ~ 25 years old, and women is then between 26 ~ 45 years old.But the patient even fallen ill old age children or teenager is also much.Severity and the clinical manifestations of different its symptoms of patient are different.Generally speaking, following three groups of symptoms can be summarized as: positive symptom (Positive symptoms), comprises illusion and vain hope, restless, paranoia, the disturbance of thought and dystropy; Negative symptoms (Negative Symptoms), comprises affective dullness, speaking scarcely,taciturn, interest blank, anhedonia and unsociable and eccentric unsocial; Recognition memory obstacle (CognitiveDeficits), comprising attention can not concentrate, and memory slump of disastrous proportions, incompetence is behavior according to plan.Can be there is above one group or all symptoms in a patient, these symptoms are usually relatively more serious, obviously affect work, the human communication of patient, or even personal lifestyle cooking.The catalogue for the treatment of of schizophrenia be mitigation symptoms, avoid recurrence, restore funcitons defect, promotes rehabilitation as much as possible, improves the quality of living.
The schizoid drug main of current clinical treatment is wanted to be divided into two classes: first-generation antipsychotic drug (Traditional antipsychotics).Such drug main will comprise selective dopamine D 2 receptor blocker, and typical medicine is Haloperidol and Chlorpromazine etc.This kind of medicine has certain therapeutic action to schizophrenia positive symptom, but to its negative symptoms and memory cognitive disorders without any curative effect.And such medicine can cause more serious untoward reaction, the outer side effect of such as cone, muscle rigidity, body weight increase etc.S-generation antipsychotic drug (atypical antipsychotic).This kind of medicine based on serotonin 5-HT2 receptor blocking agent and d2 dopamine receptor blocker, typical medicine as, Olanzepine, Risperidone, Aripiprazole, Quetiapine and Clozapine.S-generation atypia antipsychotic drug is close with first-generation antipsychotic drug to the therapeutic action of schizophrenia positive symptom, but has obviously less side effect, side effect as outer in cone.
The antipsychotic drug of current Clinical practice, especially s-generation atypia antipsychotic drug, have certain therapeutic action to schizophrenia positive symptom, can alleviate or eliminate the symptoms such as vain hope, illusion and the disturbance of thought.After acute symptom is eliminated, maintain the possibility using antipsychotics can reduce recurrence.But, nearly all clinical medicine to negative symptoms of schizophrenia and dysmnesia all without remarkable therapeutic action.The Aripiprazole (Aripiprazole) of nearest listing, according to clinical study results display, this medicine is to negative symptoms of schizophrenia or the therapeutic action that has to a certain degree, but its therapeutic action is still remarkable, needs clinical study to be investigated further.In addition, antipsychotic drug can cause obvious untoward reaction, as caused calmness, muscle rigidity, tremble and body weight increase.Meanwhile, these antipsychotics can cause tardive dyskinesia----a kind of not independently with the performance that the twisting motion obstacle of lip and tongue shrinkage or arm and leg is feature.Even if after drug withdrawal, tardive dyskinesia also can not disappear, and lacks effective remedy measures.
Schizoid recent prognosis (in 1 year) depends on the compliance of patient to treatment, if without maintenance drug therapy, the schizophrenia of 70% ~ 80% can recur and can again show effect in 12 months, maintains medication and this palindromia rate can be made to drop to about 30%.
Schizoid long-term prognosis is varied, and the patient of 1/3 can obtain the obviously improvement continued, and patient's state of an illness part of another 1/3 is improved, and is interrupted outbreak and has left over deformity, and remaining 1/3 conditions of patients is serious and have obvious deformity.The factor of prognosis bona then comprises that morbidity is anxious, age of onset is more late, premorbid has good social skill, and intolerance style or positive symptom schizophrenia patient.The factor of prognosis mala then comprise age of onset early, premorbid society or vocational skills poor, spiritedness Split disease Positive family history and hebephrenictype or Negative Schizophrenia.
CN101616592A discloses a kind of phentriazine ketone compound for improving glutamatergic synaptic responses, and it can be used for prevention and therapy brain insufficiency, the diseases such as such as multiple dementia, schizophrenia.CN101035760A discloses a kind of compound for strengthening glutamate receptor, and it can be used for treating schizophrenia.CN1535980A discloses new compound glycine transporter to inhibit activities, can be used for treating schizophrenia.
At present, the method having new treatment schizophrenia disease is still expected in this area.
Summary of the invention
The object of the present invention is to provide the glycine reuptake inhibitor of a class novelty and expect that it effectively can be used for the treatment of schizophrenia.The present invention is surprisingly found out that compound shown in formula I has effective glycine reuptake inhibition, the present invention is based on this and is accomplished.
In first aspect present invention, provide with compounds of Formula I,
Or its isomer, pharmacologically acceptable salts or solvate, wherein
R1 is one or morely selected from following group independently of one another: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group;
R2 is selected from: hydrogen, C1-6 alkyl, C1-6 alkoxyl group, halo C1-6 alkyl and halo C1-6 alkoxyl group;
R3 and R4 is selected from independently of one another: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group.
Compound according to a first aspect of the present invention, wherein R1 is selected from: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl group, halo C1-6 alkyl and halo C1-6 alkoxyl group.
Compound according to a first aspect of the present invention, wherein R2 is selected from: C1-6 alkyl and C1-6 alkoxyl group.
Compound according to a first aspect of the present invention, wherein R3 and R4 is selected from independently of one another: hydrogen, C1-6 alkyl, C1-6 alkoxyl group and hydroxyl.
Compound according to a first aspect of the present invention, wherein said C1-6 alkyl is C1-4 alkyl.
Compound according to a first aspect of the present invention, wherein said halogen (halo) is selected from fluorine, chlorine, bromine, iodine, preferred fluorine and chlorine.
Compound according to a first aspect of the present invention, it is be selected from following compound:
Second aspect present invention relates to the method preparing compound described in first aspect present invention.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention relates to the purposes of formula I in the medicine preparing glycine reuptake inhibitor described in any one of first aspect present invention.Fourth aspect present invention also relates to formula I described in any one of first aspect present invention for the preparation of the purposes treated and/or prevented in Mammals (comprising people) schizoid medicine.
Fifth aspect present invention relates to one in Mammals in need, treats and/or prevents Mammals (comprising people) schizoid method, and the method comprises to the formula I described in any one of first aspect present invention of administration treatment significant quantity in need.
Sixth aspect present invention relates to and is used for the treatment of and/or prevents Mammals (comprising people) schizoid pharmaceutical composition, this pharmaceutical composition comprises the formula I described in any one of first aspect present invention, and one or more optional pharmaceutically acceptable carriers or vehicle.
Seventh aspect present invention also relates to the formula I being used for the treatment of and/or preventing described in the schizoid any one of first aspect present invention of Mammals (comprising people).
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a second aspect of the present invention.
Formula I of the present invention can use with other active ingredient combinations, as long as it does not produce other detrimental actions, and such as anaphylaxis.
Active compound shown in formula I can be used as unique antipsychotic drug and uses, or can with one or more other antipsychotic drug conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.
Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.In the present invention, term " composition " can exchange with " pharmaceutical composition " and use.
Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al., J.Pharmaceutical Sciences, has been described in detail pharmacologically acceptable salts in 1977,66:1.Described salt, by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, is prepared at the final abstraction and purification process situ of the compounds of this invention or prepares separately.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, Basic nitrogen-containing groups can be quaternized with following material: elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halide as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to be formed the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid is as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt by make the compounds of this invention containing carboxylic moiety and suitable alkali reaction, in the final abstraction and purification process situ preparation of the compounds of this invention, the oxyhydroxide of the acceptable metallic cation of described alkali such as pharmacy, carbonate and supercarbonate, or ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to that positively charged ion based on basic metal or alkaline-earth metal is as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary ammonium and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the representative organic amines that can be used for being formed base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Formula I also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.
The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.
When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment and/or prevention.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.
The pharmaceutical carrier using those skilled in the art to be familiar with can be prepared into the pharmaceutical composition of the compounds of this invention containing effective dose.Therefore the present invention goes back the pharmaceutical composition of providing package containing the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.Described pharmaceutical composition can to become with solid or liquid form is for oral administration, for parental injection or for rectal administration by particular formulation especially.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, such as, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding injection water before the injection can use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose, and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and need, also containing disintegrating agent, as starch, agar, Lalgine or its salt, normally sodiun alginate, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, non-pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., the matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention by oral, rectum, parenteral, intestines, intravaginal, intraperitoneal, locally (as by powder, ointment or drops), mouth cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.
The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee the effect preventing microorganism.Also expect to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials in suspensoid.
In some cases, be the effect of prolong drug, expect absorption that is subcutaneous or intramuscular injection of drugs of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or its composition can by oral method or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and parenteral preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to the auxiliary material manufacturing tablet, capsule, Drug coating used is conventional auxiliary material, such as starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).Other auxiliary material, such as tensio-active agent is also had, lubricant, disintegrating agent, sanitas, correctives and pigment etc. containing in the preparation of the compounds of this invention.In tablet, capsule, Drug coating, injection and suppository containing the dosage of formula I be with unit dosage form in the compound gauge that exists calculate.In unit dosage form, the general content of formula I is 0.01-5000mg, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can accept vehicle or carrier such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least one inertia and mix: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agents is as paraffin; F) accelerator is absorbed as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, in described formulation, also buffer reagent can be comprised.
The solids composition of similar type uses excipients as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill can be prepared with the solid dosage of granule together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages optionally can contain opalizer, and its composition also can make its just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into microencapsulated form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form is except the inert diluent also can commonly used containing this area containing active ingredient beyond the region of objective existence, such as water or other solvents, the fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and sorbitan and their mixture.Oral compositions also can comprise auxiliary material except comprising inert diluent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
Composition for rectum or vagina administration is preferably suppository.Suppository is prepared by being mixed with suitable non-irritating excipient or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax by the compounds of this invention, they are at room temperature solid, but be then liquid under body temperature, therefore can melt in rectal cavity or vaginal canal and discharge active compound.
Compound of the present invention and composition thereof are also considered for topical.The dosage form giving the compounds of this invention for local comprises powder, sprays, ointment and inhalation.Aseptically by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposomal form administration.As known in the art, liposome obtains with phosphatide or other lipid materials usually.Liposome formed by the single or multiple lift aquation liquid crystal be scattered in water-bearing media.Any nontoxic, physiology that can form liposome can to accept and metabolizable lipid all can use.The present composition of liposomal form, except containing except the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide that is natural and that synthesize and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method forming liposome is well known in the art.See such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
Below the structure of exemplary compounds more of the present invention and the activity of glycine reuptake inhibition thereof are listed in, anti-glycine reuptake activity determination method wherein sees below test.These results show that the compounds of this invention is effective glycine reuptake inhibitor and can be used for treating schizophrenia.
Embodiment
Further illustrate the present invention below by concrete preparation embodiment and biological test example, but should be understood to, these embodiments and test example are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.
embodiment 1: prepare following formula: compound (Co.1)
Synthetic route is as follows:
Concrete steps:
Operation: by 10g compound 2 (N-Boc-L-α-amino-isovaleric acid, Laiyang City space occasion Chemical Engineering Technology research and development institute) be dissolved in methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er Chemical Co., Ltd.), reaction 30min, add 1.2ep piperidines, reaction terminates, filter, steam solvent, residue is dissolved in 20mL ethyl acetate, washes with rare HCl, then uses saturated NaHCO
3the aqueous solution is washed, and then with saturated common salt washing, dry, filter, precipitation obtains pale yellow oil (compound 3).
13g compound 3 is dissolved in methylene dichloride, is cooled to-5 DEG C.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and aqueous phase merge, and add 10mL water, wash by ethyl acetate, then use saturated Na
2cO
3solution adjusts pH to be about 10, with DCM extraction, dry, filters, desolventizing give light yellow oil (compound 4).
30ml THF is joined LiAlH
4in, have a large amount of bubble to produce, be cooled to-10 DEG C, slowly drip 5.6g compound 4, holding temperature, under 0 DEG C, after reaction terminates, adds shrend successively and goes out in 0 DEG C of downhill reaction system.Filter, filter cake THF washes, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, anhydrous magnesium sulfate drying, and filter, precipitation obtains oily product (compound 5).
By chloro-for 1.0g compound 6(2-6-methyl-Isonicotinic acid, Hangzhou Bang Hua Import and Export Co., Ltd.), 2.21g compound 7(2-(trifluoromethyl) phenylo boric acid, Shanghai one base Industrial Co., Ltd.) and, K
2cO
3, Pd (PPh
3) Cl
2join in reaction flask, use N
2protection, adds H successively
2o, DMF, be heated to 90 DEG C, and TLC follows the tracks of, after reaction terminates, filter, filter cake washes with water, and filtrate adds water, then uses ethyl acetate wash water phase, and aqueous phase hydrochloric acid furnishing is acid, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization obtains faint yellow solid (compound 8).
Be dissolved in 30mLTHF by 2.2g compound 8, add SOCl2,2 DMF catalysis, reflux 1 hour, is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC tracing detection, to reacting end, filters, steam solvent, residue is dissolved in 30mL ethyl acetate, use saturated Na
2cO
3the aqueous solution is washed, washing.Separate ethyl acetate, concentrated precipitation solid, filter and obtain white solid, drying obtains target compound 1(and Co.1).
Compound (Co.1) nuclear-magnetism H composes:
1H-NMR(CDCl
3):δ7.783～7.260(m，6H，Ar-H)，δ4.086(s，1H，N-H)，δ2.268(s，3H，Ar-CH
3)，δ2.489-2.343(t，6H，N-(CH
2)
3)，δ2.165-2.117(d，1H，N-CH)，Δ1.522-1.421(d，6H，(CH
2)
3)，δ0.965-0.948(d，6H，(CH
3)
2)，
embodiment 2: prepare following formula: compound (Co.2)
Synthetic route is as follows:
Operation: by 10g N-Boc-D-Isoleucine, Chengdu Ai Keda chemical reagent company limited) be dissolved in methylene dichloride, add methyl-chloroformate (Hunan De Jia biochemical technology company limited) and N-methylmorpholine (Nanjing Chemical Co., Ltd. of Oriental Pearl), reaction 60min, adds 1.2ep piperidines, reaction terminates, filter, steam solvent, residue is dissolved in 20mL ethyl acetate, wash with rare HCl, then use saturated NaHCO
3the aqueous solution is washed, and then with saturated common salt washing, dry, filter, precipitation obtains pale yellow oil (compound 3).
13g compound 3 is dissolved in methylene dichloride, is cooled to-5 DEG C.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and aqueous phase merge, and add 10mL water, wash by ethyl acetate, then use saturated Na
2cO
3solution adjusts pH to be about 10, with DCM extraction, dry, filters, desolventizing give light yellow oil (compound 4).
30ml THF is joined LiAlH
4in, have a large amount of bubble to produce, be cooled to-10 DEG C, slowly drip 5.6g compound 4, holding temperature, under 0 DEG C, after reaction terminates, adds shrend successively and goes out in 0 DEG C of downhill reaction system.Filter, filter cake THF washes, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, anhydrous magnesium sulfate drying, and filter, precipitation obtains oily product (compound 5).
By chloro-for 1.0g2-6-methyl-Isonicotinic acid (Hangzhou Bang Hua Import and Export Co., Ltd.), 2.5g2-(trifluoromethyl)-4-methyl-phenylo boric acid, and K
2cO
3, Pd (PPh
3) Cl
2join in reaction flask, use N
2protection, adds H successively
2o, DMF, be heated to 90 DEG C, and TLC follows the tracks of, after reaction terminates, filter, filter cake washes with water, and filtrate adds water, then uses ethyl acetate wash water phase, and aqueous phase hydrochloric acid furnishing is acid, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization obtains faint yellow solid (compound 8).
Be dissolved in 30mLTHF by 2.2g compound 8, add SOCl2,2 DMF catalysis, reflux 1 hour, is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC tracing detection, to reacting end, filters, steam solvent, residue is dissolved in 30mL ethyl acetate, use saturated Na
2cO
3the aqueous solution is washed, washing.Separate ethyl acetate, concentrated precipitation solid, filter and obtain white solid, drying obtains target compound Co.2.
Compound (Co.2) nuclear-magnetism H composes
1H-NMR(CDCl
3):δ8.0(s，1H)，δ7.01～7.96(m，6H)，δ3.81(d，1H)，δ2.35(s，3H)，δ2.24-2.58(t，6H)，δ1.522-1.421(d，6H)，δ0.965-0.948(d，6H)，δ1.29(s，2H)，δ0.96-1.06(m，6H)
embodiment 3: prepare following formula: compound (Co.3)
Synthetic route is as follows:
Operation: by 10g compound 2 (N-Boc-L-α-amino-isovaleric acid, Laiyang City space occasion Chemical Engineering Technology research and development institute) be dissolved in methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er Chemical Co., Ltd.), reaction 30min, add 1.2ep piperidines, reaction terminates, filter, steam solvent, residue is dissolved in 20mL ethyl acetate, washes with rare HCl, then uses saturated NaHCO
3the aqueous solution is washed, and then with saturated common salt washing, dry, filter, precipitation obtains pale yellow oil (compound 3).
13g compound 3 is dissolved in methylene dichloride, is cooled to-5 DEG C.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and aqueous phase merge, and add 10mL water, wash by ethyl acetate, then use saturated Na
2cO
3solution adjusts pH to be about 10, with DCM extraction, dry, filters, desolventizing give light yellow oil (compound 4).
30ml THF is joined LiAlH
4in, have a large amount of bubble to produce, be cooled to-10 DEG C, slowly drip 5.6g compound 4, holding temperature, under 0 DEG C, after reaction terminates, adds shrend successively and goes out in 0 DEG C of downhill reaction system.Filter, filter cake THF washes, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, anhydrous magnesium sulfate drying, and filter, precipitation obtains oily product (compound 5).
By chloro-for 1.0g compound 6(2-6-methyl-Isonicotinic acid, Hangzhou Bang Hua Import and Export Co., Ltd.), 2.4g4-hydroxy-2-methyl-phenylo boric acid, and K
2cO
3, Pd (PPh
3) Cl
2join in reaction flask, use N
2protection, adds H successively
2o, DMF, be heated to 90 DEG C, and TLC follows the tracks of, after reaction terminates, filter, filter cake washes with water, and filtrate adds water, then uses ethyl acetate wash water phase, and aqueous phase hydrochloric acid furnishing is acid, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization obtains faint yellow solid (compound 8).
Be dissolved in 30mLTHF by 2.2g compound 8, add SOCl2,2 DMF catalysis, reflux 1 hour, is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC tracing detection, to reacting end, filters, steam solvent, residue is dissolved in 30mL ethyl acetate, use saturated Na
2cO
3the aqueous solution is washed, washing.Separate ethyl acetate, concentrated precipitation solid, filter and obtain white solid, drying obtains target compound Co.3.
Compound (Co.3) nuclear-magnetism H composes
1H-NMR(CDCl
3):δ7.98.0(s，1H)，δ6.62～7.96(m，6H)，δ5.0(d，1H)，δ3.81(d，1H)，δ2.35-2.55(m，6H)，δ2.24-2.58(t，6H)，δ1.432-1.571(d，6H)，δ0.96-1.01(m，6H)
embodiment 4: prepare following formula: compound (Co.4)
Its synthetic route is as follows:
Operation: by 10g N-Boc-D-Threonine; Nantong Qi Hai Chemical Company) be dissolved in methylene dichloride; add methyl-chloroformate (Hunan De Jia biochemical technology company limited) and N-methylmorpholine (Nanjing Chemical Co., Ltd. of Oriental Pearl), reaction 60min, adds 1.2ep piperidines; reaction terminates; filter, steam solvent, residue is dissolved in 20mL ethyl acetate; wash with rare HCl, then use saturated NaHCO
3the aqueous solution is washed, and then with saturated common salt washing, dry, filter, precipitation obtains pale yellow oil (compound 3).
13g compound 3 is dissolved in methylene dichloride, is cooled to-5 DEG C.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and aqueous phase merge, and add 10mL water, wash by ethyl acetate, then use saturated Na
2cO
3solution adjusts pH to be about 10, with DCM extraction, dry, filters, desolventizing give light yellow oil (compound 4).
30ml THF is joined LiAlH
4in, have a large amount of bubble to produce, be cooled to-10 DEG C, slowly drip 5.6g compound 4, holding temperature, under 0 DEG C, after reaction terminates, adds shrend successively and goes out in 0 DEG C of downhill reaction system.Filter, filter cake THF washes, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, anhydrous magnesium sulfate drying, and filter, precipitation obtains oily product (compound 5).
By chloro-for 1.0g2-6-methyl-Isonicotinic acid (Hangzhou Bang Hua Import and Export Co., Ltd.), 2.1g2-trifluoromethylbenzene boronic acid, and K
2cO
3, Pd (PPh
3) Cl
2join in reaction flask, use N
2protection, adds H successively
2o, DMF, be heated to 90 DEG C, and TLC follows the tracks of, after reaction terminates, filter, filter cake washes with water, and filtrate adds water, then uses ethyl acetate wash water phase, and aqueous phase hydrochloric acid furnishing is acid, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization obtains faint yellow solid (compound 8).
Be dissolved in 30mLTHF by 2.2g compound 8, add SOCl2,2 DMF catalysis, reflux 1 hour, is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC tracing detection, to reacting end, filters, steam solvent, residue is dissolved in 30mL ethyl acetate, use saturated Na
2cO
3the aqueous solution is washed, washing.Separate ethyl acetate, concentrated precipitation solid, filter and obtain white solid, drying obtains target compound Co.4.
Compound (Co.4) nuclear-magnetism H composes
1H-NMR(CDCl
3):δ7.94.0(s，1H)，δ7.12～7.99(m，6H)，δ3.90(d，1H)，δ2.34-2.65(m，6H)，δ2.24(s，1H)，δ2.15-2.21(t，6H)，δ1.432-1.571(d，6H)，δ1.21-1.23(d，3H)
embodiment 5: prepare following formula: compound (Co.5)
Synthetic route is as follows:
Operation: by 10g compound 2 (L-N-Boc-2-amino-3-trifluoromethyl butanic acid, Laiyang City space occasion Chemical Engineering Technology research and development institute) be dissolved in methylene dichloride, add 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er Chemical Co., Ltd.), reaction 30min, add 1.2ep piperidines, reaction terminates, filter, steam solvent, residue is dissolved in 20mL ethyl acetate, washes with rare HCl, then uses saturated NaHCO
3the aqueous solution is washed, and then with saturated common salt washing, dry, filter, precipitation obtains pale yellow oil (compound 3).
13g compound 3 is dissolved in methylene dichloride, is cooled to-5 DEG C.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and aqueous phase merge, and add 10mL water, wash by ethyl acetate, then use saturated Na
2cO
3solution adjusts pH to be about 10, with DCM extraction, dry, filters, desolventizing give light yellow oil (compound 4).
30ml THF is joined LiAlH
4in, have a large amount of bubble to produce, be cooled to-10 DEG C, slowly drip 5.6g compound 4, holding temperature, under 0 DEG C, after reaction terminates, adds shrend successively and goes out in 0 DEG C of downhill reaction system.Filter, filter cake THF washes, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, anhydrous magnesium sulfate drying, and filter, precipitation obtains oily product (compound 5).
By chloro-for 1.0g compound 6(2-6-methyl-Isonicotinic acid, Hangzhou Bang Hua Import and Export Co., Ltd.), 2.4g5-methoxyl group-2-trifluoromethyl-phenylo boric acid, and K
2cO
3, Pd (PPh
3) Cl
2join in reaction flask, use N
2protection, adds H successively
2o, DMF, be heated to 90 DEG C, and TLC follows the tracks of, after reaction terminates, filter, filter cake washes with water, and filtrate adds water, then uses ethyl acetate wash water phase, and aqueous phase hydrochloric acid furnishing is acid, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization obtains faint yellow solid (compound 8).
Be dissolved in 30mLTHF by 2.2g compound 8, add SOCl2,2 DMF catalysis, reflux 1 hour, is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC tracing detection, to reacting end, filters, steam solvent, residue is dissolved in 30mL ethyl acetate, use saturated Na
2cO
3the aqueous solution is washed, washing.Separate ethyl acetate, concentrated precipitation solid, filter and obtain white solid, drying obtains target compound Co.5.
Compound (Co.5) nuclear-magnetism H composes
1H-NMR(CDCl
3):δ8.14(s，1H)，δ6.65～7.99(m，4H)，δ3.84(d，1H)，δ3.73(s，3H)，δ2.56(s，3H)，δ2.23-2.59(t，6H)，δ1.31-1.41(d，6H)，δ1.01-1.09(m，6H)
by biological test, preliminary assessment is carried out to the effect of drugs of synthesized compound:
Test example 1: test-compound is on the impact of normal rat spontaneous activity (LMA)
Testing animal used is adult Wistar male rats, body weight 180 ~ 250g, and 6/cage is raised, 12/12 little time/dark periodic adjustment, temperature 23 ± 1 DEG C of constant temperature, humidity 50 ~ 60%, ad lib is intake.After animal is bought from Experimental Animal Center, carry out after adaptability raises one week, all animals being divided into two groups at random:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: Experimental agents group, the test-compound Co.1:5.0 of rat respectively abdominal injection various dose, 10 and 30mg/kg, i.p., medicine ordinance is in 1%DMSO physiological saline.
Experiment adopts Shanghai Ji amount animal behavior video analytic system, and experimental situation keeps absolutely quiet, and when grabbing by animal and administration, action is soft, reduces the untoward reaction of mental status that outside stimulus brings to animal and mood as far as possible.Rat is in administration after 60 minutes, and be placed in by rat in spontaneous activity case, spontaneous activity case is placed among absolutely quiet environment.Spontaneous activity case is connected with recording instrumnet, record rat 30-60 minute active situation.Mensuration medicine or reference substance are on the impact of rat spontaneous activity.
Table 1. test-compound Co.1 is on the impact of normal rat spontaneous activity
Treatment mono-hour total distance (rice)
Vehicle 25.3±3.2
Olanzepine10mg/kg,i.p. 24.6±5.8
Test-compound Co.15mg/kg, i.p. 24.9 ± 6.2
Test-compound Co.110mg/kg, i.p. 22.4 ± 4.0
Test-compound Co.130mg/kg, i.p. 23.8 ± 5.2
Experimental result is expressed with mean ± s.e.means, Dunnett ' s t test.
Result: test-compound Co.1 does not all make significant difference (P > 0.05, Dunnett ' t test) to normal rat spontaneous activity, shows that compound is without excess sedation effect.Olanzepine on normal rat spontaneous activity also without impact.
Test example 2: test-compound is on the impact of PCP induced rat height spontaneous activity behavior
Testing animal used is adult Wistar male rats, body weight 180 ~ 250g, and 6/cage is raised, 12/12 little time/dark periodic adjustment, temperature 23 ± 1 DEG C of constant temperature, humidity 50 ~ 60%, ad lib is intake.After animal is bought from Experimental Animal Center, carry out after adaptability raises one week, all animals being divided into three groups at random:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: Experimental agents group, the test-compound Co.1:5 of rat respectively abdominal injection various dose, 10 and 30mg/kg, i.p., medicine ordinance is in 1%DMSO physiological saline;
3rd group: positive drug control group, rats by intraperitoneal injection Olanzepine(10mg/kg, i.p., medicine ordinance is in 1%DMSO physiological saline).
Experiment adopts Shanghai Ji amount animal behavior video analytic system, and experimental situation keeps absolutely quiet, and when grabbing by animal and administration, action is soft, reduces the untoward reaction of mental status that outside stimulus brings to animal and mood as far as possible.Rat to be transferred in a quiet laboratory from Animal House and to allow it adapt at least two hours.Subcutaneous injection PCP (5.0mg/kg, s.c.), or 1%DMSO physiological saline is in contrast.After 30 minutes, animal abdominal injection test-compound, or 1%DMSO physiological saline is in contrast, and be placed in by rat in spontaneous activity case, spontaneous activity case is placed among absolutely quiet environment.Spontaneous activity case is connected with recording instrumnet, record rat 30-60 minute active situation.Mensuration medicine or reference substance are on the impact of rat spontaneous activity.
Table 2. test-compound Co.1 is on the impact of the rat height spontaneous activity that PCP induces
Treatment LMA (one hour total distance (rice))
Vehicle+vehicle 28.9±6.5
PCP+vehicle 59.4±8.3**
PCP+Olanzepine10mg/kg,i.p. 32.1±5.2##
PCP+ test-compound Co.15mg/kg, i.p. 38.6 ± 7.1##
PCP+ test-compound Co.110mg/kg, i.p. 26.4 ± 4.0##
PCP+ test-compound Co.130mg/kg, i.p. 22.3 ± 3.4##
Experimental result is expressed with mean ± s.e.means, wherein * * P < 0.01, PCP group vs vehicle; ##P < 0.001, medication therapy groups vs PCP group, Dunnett ' s t test.
Experimental result: rats by intraperitoneal injection PCP significantly increases animal spontaneous activity (P < 0.01, Dunnett ' t test, compare with negative control group), test-compound Co.1(5,10 and 30mg/kg.i.p.) significantly suppress rat height spontaneous activity (the P < 0.01 induced by PCP, Dunnett ' t test, compares with PCP treatment group).Positive drug group Olanzepine significantly suppress the rat height spontaneous activity (P < 0.01, Dunnett ' t test, compare with PCP group) of PCP induction.Compared with positive drug Olanzepine, test-compound Co.1 is to the restraining effect of the rat height spontaneous activity that PCP induces stronger (P < 0.05, Dunnett ' t test, compare with Olanzepine/PCP group).
Conclusion: experimental result shows, test-compound Co.1 has the stronger rat height spontaneous activity restraining effect to PCP induction, and display, this compound has better antipsychotic positive symptom effect, and this effect is more excellent than Olanzepine.
Test example 3: test-compound Co.1 is on the impact of Amphetamine induced rat height crawler behavior
Testing animal used is adult Wistar male rats, body weight 180 ~ 250g, and 6/cage is raised, 12/12 little time/dark periodic adjustment, temperature 23 ± 1 DEG C of constant temperature, humidity 50 ~ 60%, ad lib is intake.After animal is bought from Experimental Animal Center, carry out after adaptability raises one week, all animals being divided into three groups at random:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: Experimental agents group, the test-compound Co.1:5 of rat respectively abdominal injection various dose, 10 and 30mg/kg, i.p., medicine ordinance is in 1%DMSO physiological saline;
3rd group: positive drug control group, rats by intraperitoneal injection Olanzepine(10mg/kg, i.p., medicine ordinance is in 1%DMSO physiological saline).
Experiment adopts Shanghai Ji amount animal behavior video analytic system, and experimental situation keeps absolutely quiet, and when grabbing by animal and administration, action is soft, reduces the untoward reaction of mental status that outside stimulus brings to animal and mood as far as possible.Rat to be transferred in a quiet laboratory from Animal House and to make it adapt at least two hours.Subcutaneous injection Amphetamine (1.0mg/kg, s.c.), or physiological saline is in contrast.After 30 minutes, animal oral administration of compound, or physiological saline is in contrast, and be placed in by rat in spontaneous activity case, spontaneous activity case is placed among absolutely quiet environment.Spontaneous activity case is connected with recording instrumnet, record rat 30-60 minute active situation.Mensuration medicine or reference substance are on the impact of rat spontaneous activity.
Table 3. test-compound Co.1 is on the impact of the rat height spontaneous activity that Amphetamine induces
Treatment LMA (one hour total distance (rice))
Vehicle+vehicle 25.6±4.5
AMP+vehicle 56.2±5.6**
AMP+Olanzepine10mg/kg,i.p. 38.4±3.9##
AMP+ test-compound Co.15mg/kg, i.p. 39.6 ± 6.0##
AMP+ test-compound Co.110mg/kg, i.p. 32.9 ± 6.8##
AMP+ test-compound Co.130mg/kg, i.p. 24.6 ± 4.6##
Experimental result is expressed with mean ± s.e.means, wherein * * P < 0.01, Amphetamine group vsvehicle; ##P < 0.001, medication therapy groups vs Amphetamine group, Dunnett ' s t test.
Experimental result: rats by intraperitoneal injection Amphetamine significantly increases animal spontaneous activity (P < 0.01, Dunnett ' t test, compare with negative control group), test-compound Co.1(5,10 and 30mg/kg.i.p.) significantly suppress rat height spontaneous activity (the P < 0.01 induced by Amphetamine, Dunnett ' ttest, compares with Amphetamine treatment group).Positive drug group Olanzepine significantly suppress the rat height spontaneous activity (P < 0.01, Dunnett ' t test, compare with Amphetamine control group) of Amphetamine induction.Compared with positive drug Olanzepine, test-compound Co.1 is to stronger (the P < 0.05 of the restraining effect of the rat height spontaneous activity that Amphetamine induces, Dunnett ' ttest, compares with Olanzepine/Amphetamine group).
Claims (9)
1. formula I,
Or its isomer, pharmacologically acceptable salts or solvate, wherein
R1 is one or morely selected from following group: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group; R2 is selected from: hydrogen, C1-6 alkyl, C1-6 alkoxyl group, halo C1-6 alkyl and halo C1-6 alkoxyl group;
R3 and R4 is selected from independently of one another: hydrogen, halogen, C1-6 alkyl, C1-6 alkoxyl group, nitro, cyano group, amino, hydroxyl, halo C1-6 alkyl and halo C1-6 alkoxyl group;
Wherein, described halogen is selected from fluorine, chlorine, bromine or iodine.
2. compound according to claim 1, wherein R1 is that one or two is selected from following group: halogen, hydroxyl, C1-6 alkyl, C1-6 alkoxyl group, halo C1-6 alkyl and halo C1-6 alkoxyl group.
3. compound according to claim 1, wherein R2 is selected from: C1-6 alkyl and C1-6 alkoxyl group.
4. compound according to claim 1, wherein R3 and R4 is selected from independently of one another: hydrogen, C1-6 alkyl, C1-6 alkoxyl group and hydroxyl.
5. compound according to claim 1, wherein said C1-6 alkyl is C1-4 alkyl.
6. compound according to claim 1, it is be selected from following compound:
7. a pharmaceutical composition, it comprises the formula I described in any one of claim 1-6, and one or more optional pharmaceutically acceptable carriers or vehicle.
8. the formula I described in any one of claim 1-6 is preparing the purposes in glycine reuptake inhibitor.
9. the formula I described in any one of claim 1-6 is for the preparation of the purposes treated and/or prevented in the schizoid medicine of Mammals.
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| CN1878551A (en) * | 2003-11-12 | 2006-12-13 | 默克公司 | 4-phenyl piperdine sulfonyl glycine transporter inhibitors |
| WO2007080159A2 (en) * | 2006-01-10 | 2007-07-19 | Glaxo Group Limited | Pyridine-, isoxazole, thiophenecarboxamide compounds having activity at the glycine transporter glyt1 and uses thereof |
| CN101014581A (en) * | 2004-08-02 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | Novel piperidine derivative for the treatment of depression |
| CN101356163A (en) * | 2005-01-06 | 2009-01-28 | 弗·哈夫曼-拉罗切有限公司 | Sulfanyl substituted phenyl methanones as glycine transporter 1 (GlyT-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| CN103096893A (en) * | 2010-06-04 | 2013-05-08 | 阿尔巴尼分子研究公司 | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
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| WO2003003009A1 (en) * | 2001-06-29 | 2003-01-09 | 7Tm Pharma A/S | Use of metal-ion chelates in validating biological molecules as drug targets in test animal models |
| CN1878551A (en) * | 2003-11-12 | 2006-12-13 | 默克公司 | 4-phenyl piperdine sulfonyl glycine transporter inhibitors |
| CN101014581A (en) * | 2004-08-02 | 2007-08-08 | 阿斯利康(瑞典)有限公司 | Novel piperidine derivative for the treatment of depression |
| CN101356163A (en) * | 2005-01-06 | 2009-01-28 | 弗·哈夫曼-拉罗切有限公司 | Sulfanyl substituted phenyl methanones as glycine transporter 1 (GlyT-1) inhibitors for the treatment of neurological and neuropsychiatric disorders |
| WO2007080159A2 (en) * | 2006-01-10 | 2007-07-19 | Glaxo Group Limited | Pyridine-, isoxazole, thiophenecarboxamide compounds having activity at the glycine transporter glyt1 and uses thereof |
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Address after: 102200, Beijing, Changping District, super road 37, Zhongguancun industrial pioneer park, building 4, 4 floor Patentee after: Beijing Harbin Medisan Science and Technology Co., Ltd. Patentee after: MEDISAN PHARMACEUTICAL CO., LTD. HARBIN Address before: 102200, Beijing, Changping District, super road 37, Zhongguancun industrial pioneer park, building 4, 4 floor Patentee before: Beijing Harbin Medisan Science and Technology Co., Ltd. Patentee before: Medisan Pharmaceutical Co., Ltd., Harbin |