CN103254127A - Glycine-reuptake inhibitor and application thereof - Google Patents
Glycine-reuptake inhibitor and application thereof Download PDFInfo
- Publication number
- CN103254127A CN103254127A CN2013102045303A CN201310204530A CN103254127A CN 103254127 A CN103254127 A CN 103254127A CN 2013102045303 A CN2013102045303 A CN 2013102045303A CN 201310204530 A CN201310204530 A CN 201310204530A CN 103254127 A CN103254127 A CN 103254127A
- Authority
- CN
- China
- Prior art keywords
- compound
- alkyl
- halo
- alkoxyl group
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention relates to a glycine-reuptake inhibitor and an application thereof. The glycine-reuptake inhibitor is a compound as shown in a formula I, or an isomer, a pharmaceutically acceptable salt or solvate of the compound as shown in the formula I, wherein R1 is one or more of the following groups: hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitryl, cyanogroup, amino, hydroxyl, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; R2 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy; each of R3 and R4 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, nitryl, cyanogroup, amino, hydroxyl, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy. The compound disclosed by the invention is an efficient glycine-reuptake inhibitor.
Description
Technical field
The present invention relates to glycine reuptake inhibitor and application thereof, this type of inhibitor for example can be used for treating schizophrenia.
Background technology
Schizophrenia (Schizophrenic disorder) is a kind of very serious mental disorder, lacks with reality to contact, and has illusion, vain hope and abnormal thinking, the social function obvious damage.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 the women is then between 26～45 years old.But the patient in children or teenager even morbidity in old age is also much.Severity and the clinical manifestation form of different its symptoms of patient have nothing in common with each other.Generally speaking, can be summarized as following three groups of symptoms: positive symptom (Positive symptoms), comprise 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 (Cognitive Deficits) comprises that attention can not concentrate, the memory slump of disastrous proportions, and incompetence is behavior according to plan.A patient can exist above one group or all symptoms, and these symptoms are usually relatively more serious, obviously influence patient's work, human communication, or even the personal lifestyle cooking.The catalogue for the treatment of of schizophrenia be mitigation symptoms, avoid the recurrence, the restore funcitons defective is promoted rehabilitation as much as possible, improves the quality of living.
Treating schizoid drug main at present clinically wants to be divided into two classes: first-generation antischizophrinic thing (traditional antipsychotics).Such drug main will comprise the selective dopamine D 2 receptor blocker, and typical medicine is Haloperidol and Chlorpromazine etc.This class medicine has certain therapeutic action to the schizophrenia positive symptom, but to its negative symptoms and the memory cognitive disorders without any curative effect.And such medicine can cause than serious adverse effects, such as the outer side effect of cone, muscle rigidity, weight increase etc.S-generation antischizophrinic thing (atypical antipsychotic).This class medicine is 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 antischizophrinic thing is close with first-generation antischizophrinic thing to the therapeutic action of schizophrenia positive symptom, but has obviously less side effect, as the outer side effect of cone.
The antischizophrinic thing of present clinical use, especially s-generation atypia antischizophrinic thing has certain therapeutic action to the schizophrenia positive symptom, can alleviate or eliminate symptoms such as vain hope, illusion and the disturbance of thought.After acute symptom is eliminated, keep the possibility of using antipsychotics can reduce recurrence.But nearly all clinical medicine does not all have remarkable therapeutic action to negative symptoms of schizophrenia and dysmnesia.Recently the Aripiprazole (Aripiprazole) of listing shows according to the clinical study result, and this medicine is to negative symptoms of schizophrenia or have to a certain degree therapeutic action, but its therapeutic action is still not remarkable, remains clinical study further to be investigated.In addition, the antischizophrinic thing can cause tangible untoward reaction, as causing calmness, muscle rigidity, trembling and weight increase.Simultaneously, these antipsychotics can cause tardive dyskinesia----a kind of be not the performance of feature with the twisting motion obstacle of lip and tongue shrinkage or arm and shank independently.Even after the drug withdrawal, tardive dyskinesia also can not disappear, and lacks therapy measure.
Schizoid recent prognosis (in 1 year) depends on that patient is to the compliance for the treatment of, if without maintenance drug therapy, 70%～80% schizophrenia can recur in 12 months and can show effect again, keeps medication this palindromia rate is dropped to about 30%.
Schizoid long-term prognosis is varied, and 1/3 patient can obtain obviously and lasting improvement, and patient's state of an illness of 1/3 is partly improved in addition, and is interrupted outbreak and has left over deformity, and remaining 1/3 conditions of patients seriously has obvious deformity.Prognosis bona's factor comprises that then morbidity is anxious, age of onset is later, 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 are poor, the positive family history of spiritedness Split disease and hebephrenictype or negative schizophreniac.
CN101616592A discloses a kind of for the phentriazine ketone compound that improves glutamatergic synaptic responses, and it can be used for prevention and treatment brain insufficiency, for example diseases such as multiple dementia, schizophrenia.CN101035760A discloses a kind of for the compound that strengthens glutamate receptor, and it can be used for treating schizophrenia.CN1535980A discloses has the new compound that suppresses active to glycine transporter, can be used for treating schizophrenia.
At present, the method for new treatment schizophrenia disease is still expected to have 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 can effectively be used for the treatment of schizophrenia.The present invention is surprisingly found out that compound shown in the formula I has effective glycine reuptake inhibition, the present invention is based on this and is accomplished.
In first aspect present invention, provide with the following formula I compound,
Or its isomer, pharmacologically acceptable salts or solvate, wherein
R1 is one or more following groups that are 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;
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 are 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.
According to the compound of first aspect 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.
According to the compound of first aspect present invention, wherein R2 is selected from: C1-6 alkyl and C1-6 alkoxyl group.
According to the compound of first aspect present invention, wherein R3 and R4 are selected from independently of one another: hydrogen, C1-6 alkyl, C1-6 alkoxyl group and hydroxyl.
According to the compound of first aspect present invention, wherein said C1-6 alkyl is the C1-4 alkyl.
According to the compound of first aspect present invention, wherein said halogen (halo) is selected from fluorine, chlorine, bromine, iodine, preferred fluorine and chlorine.
According to the compound of first aspect present invention, it is to be selected from following compound:
Second aspect present invention relates to the method for preparing the described compound of first aspect present invention.
Third aspect present invention relates to a kind of pharmaceutical composition, and it comprises each described formula I compound of first aspect present invention, and optional one or more pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention relates to the purposes of each described formula I compound of first aspect present invention in the medicine of preparation glycine reuptake inhibitor.Fourth aspect present invention also relates to each described formula I compound of first aspect present invention for the preparation of the purposes that treats and/or prevents in the schizoid medicine of Mammals (comprising the people).
Fifth aspect present invention relates to a kind of schizoid method of Mammals (comprising the people) that treats and/or prevents in the Mammals of needs is arranged, this method comprises each the described formula I compound of first aspect present invention to the administration treatment significant quantity that needs are arranged.
Sixth aspect present invention relates to and is used for the treatment of and/or prevents the schizoid pharmaceutical composition of Mammals (comprising the people), this pharmaceutical composition comprises each described formula I compound of first aspect present invention, and optional one or more pharmaceutically acceptable carriers or vehicle.
Seventh aspect present invention also relates to and is used for the treatment of and/or prevents each described formula I compound of the schizoid first aspect present invention of Mammals (comprising the people).
Arbitrary embodiment of either side of the present invention can make up with other embodiment, as long as they contradiction can not occur.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they contradiction can not occur.
Below the invention will be further described.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this more detailed description and interpretation to be made in these terms and phrase, the term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
In the method for synthetic compound of formula i of the present invention, the various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the document known method, or can buy by commerce.Used intermediate, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge in the above reaction scheme.Perhaps, those skilled in the art also can synthesize other formula I compound that the present invention does not specifically enumerate according to the second aspect present invention method.
Formula I compound of the present invention can be used in combination with other activeconstituents, as long as it does not produce other detrimental actions, for example anaphylaxis.
Active compound shown in the formula I of the present invention can be used as unique antischizophrinic thing and uses, and perhaps can unite use with one or more other antischizophrinic things.Combination therapy realizes by each being treated component while, order or separating administration.
Term used herein " composition " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying 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 in reliable medical judgment scope, is suitable for not occurring with human the contact with zootic tissue excessive toxicity, stimulation, anaphylaxis etc., and with rational effect/risk than the salt that matches.Pharmacologically acceptable salts is well known in the art.For example, S.M.Berge, et al., J.Pharmaceutical Sciences describes in detail pharmacologically acceptable salts among 1977, the 66:1.Described salt can be by free alkali functionality and the appropriate organic reaction that makes The compounds of this invention, in final separation and purge process made acid-stable in situ or the preparation separately of The compounds of this invention.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, the 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, the 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, alkaline nitrogen-containing group can be quaternized with following material: the muriate of elementary alkyl halide such as methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; The muriate of long-chain halogenide such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide such 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 form the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid such as oxalic acid, toxilic acid, succsinic acid and citric acid.
Base addition salt can contain carboxylic moiety and suitable alkali reaction by what make The compounds of this invention, final separation and purge process made acid-stable in situ at The compounds of this invention, described alkali is oxyhydroxide, carbonate and the supercarbonate of the acceptable metallic cation of pharmacy for example, perhaps ammonia or organic primary amine, secondary amine or tertiary amine.
Pharmacologically acceptable salts includes but not limited to based on the positively charged ion of basic metal or alkaline-earth metal such 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 representative organic amines that can be used for forming base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Formula I compound of the present invention also comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester, formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, solvate and ester can also form solvate, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges described activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of pharmacy acceptable solvent such as water, ethanol etc.
The active compound amount of gained can change the actual dose level of each activeconstituents in the pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response at concrete patient, composition and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result for the treatment of requires, up to obtaining required effect.
When being used for above-mentioned treat and/or prevent or when other treatment and/or prevention, a kind of The compounds of this invention that treats and/or prevents significant quantity can be used with pure form, perhaps uses with the acceptable ester of pharmacy or prodrug forms (under the situation that has these forms).Perhaps, described compound can be accepted the pharmaceutical composition administration of vehicle to contain this purpose compound and one or more medicines.The The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to that the reasonable effect/risk of any therapeutic treatment and/or prevention is than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that The compounds of this invention and composition must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to multiple factor, and described factor comprises the severity of the obstacle for the treatment of and this obstacle; The activity of the particular compound that adopts; The concrete composition that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with the particular compound that adopts; And the known similar factor of medical field.For example, the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result for the treatment of requires, up to obtaining required effect.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example between 0.01～100mg/kg body weight/day, for example between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.
The pharmaceutical carrier that uses those skilled in the art to be familiar with can be prepared into the pharmaceutical composition of the The compounds of this invention that contains effective dosage.Therefore the present invention also provides the pharmaceutical composition that comprises with one or more nontoxic drug acceptable carriers The compounds of this invention formulated together.That described pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, for the parenteral injection or for rectal administration.
Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding injection water before injection can use immediately).Carrier comprises in the described pharmaceutical composition: the tackiness agent that oral preparations uses is (as starch, corn normally, 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), and if desired, also contain disintegrating agent, as starch, agar, Lalgine or its salt, sodiun alginate normally, 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 that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention can by in oral, rectum, parenteral, the intestines, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouth cheek give the mankind and other Mammalss, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The composition that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes 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 such 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 agents and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.Also expectation comprises isotonic agent, for example carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin can reach the prolongation absorption of injectable drug form.
Also can contain suspension agent except the active ingredient beyond the region of objective existence in the suspensoid, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or the intramuscularly medicine.This can realize by the crystal of use 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.Perhaps, the delay of the medicament forms of parenteral admin absorb by with this medicine dissolution in or be suspended in the oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-poly-glycollide (polylactide-polyglycolide).Can drug releasing rate be controlled according to the character of medicine with ratio with the concrete polymkeric substance that adopts of polymkeric substance.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering with bacterial filter or sterilizing by the disinfectant that mixes the aseptic solid composite form, and described solids composition can face with before being dissolved or dispersed in sterilized water or other sterile injectable medium.
The compounds of this invention or its composition can be with oral methods or parenteral administration modes.Oral administration can be tablet, capsule, Drug coating, and the enteron aisle external application preparation has injection and suppository etc.These preparations prepare according to method appreciated by those skilled in the art.Be the auxiliary material of conventional usefulness in order to make tablet, capsule, the used auxiliary material of Drug coating, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, the solvent that liquid dosage form is used such as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).Contain and also have other auxiliary material in the preparation of The compounds of this invention, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, Drug coating, injection and suppository is that the compound amount that exists in unit dosage form is calculated.The general content of formula I compound of the present invention is 0.01-5000mg in unit dosage form, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the present invention's solid dosage for oral administration that can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Lin Suanergai and/or following material with the medicine of at least a inertia and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.Under the situation of capsule, tablet and pill, also can comprise buffer reagent in the described formulation.
The solids composition of similar type uses vehicle for example lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and the hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can prepare with dressing and shell material such as enteric coating material and known other clothing materials of field of medicine preparations.These solid dosages can be chosen wantonly and contain opalizer, and it is formed and also can make it just or preferentially optional with the delayed mode release of active ingredients at certain position of enteron aisle.The example of operable embedding composition comprises polymer substance and wax class.If be fit to, active compound also can be made into the micro-capsule 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 also can contain this area inert diluent commonly used except containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be 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 the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material except comprising inert diluent, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by for example theobroma oil, polyoxyethylene glycol or suppository wax mix to prepare with The compounds of this invention and suitable non-irritating excipient or carrier, they at room temperature are solid, therefore but next at body temperature is liquid, can melt in rectal cavity or vaginal canal and discharges active compound.
Compound of the present invention and composition thereof are also considered for topical.Dosage form for the topical administration The compounds of this invention comprises powder, sprays, ointment and inhalation.Under aseptic condition with active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution also are considered within the scope of the present invention.
The compounds of this invention also can the liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in the water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stablizer, sanitas, vehicle etc. except containing The compounds of this invention.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
Below the activity of the structure of exemplary compounds more of the present invention and glycine reuptake inhibition thereof is listed in, the test that sees below of anti-glycine reuptake activity determination method wherein.These results show that The compounds of this invention is effective glycine reuptake inhibitor and can be used for treating schizophrenia.
Embodiment
Further specify the present invention below by concrete preparation embodiment and biological test example, still, should be understood to, these embodiment and test example are only used for the more detailed usefulness that specifically describes, and should not be construed as for limiting the present invention in any form.
The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Though for realizing that the employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Embodiment 1: preparation following formula: compound (Co.1)
Synthetic route is as follows:
Concrete steps:
Operation: with 10g compound 2 (N-Boc-L-Xie Ansuan, Laiyang City space occasion chemical industry technical research institute) is dissolved in the methylene dichloride, adds 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er chemical industry company limited), reaction 30min, add the 1.2ep piperidines, reaction finishes, and filters, steam solvent, residue is dissolved in the 20mL ethyl acetate, washes with rare HCl, uses saturated NaHCO then
3The aqueous solution is washed, and with the saturated common salt washing, drying is filtered then, and precipitation obtains faint yellow oily thing (compound 3).
13g compound 3 is dissolved in the methylene dichloride, is cooled to-5 ℃.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and water merge, and add 10mL water, wash with ethyl acetate, use saturated Na again
2CO
3It is about 10 that solution is transferred pH, and with the DCM extraction, drying is filtered, and desolventizing gets light yellow oil (compound 4).
30ml THF is joined LiAlH
4In, there are a large amount of bubbles to produce, be cooled to-10 ℃, slow Dropwise 5 .6g compound 4, holding temperature is under 0 ℃, and reaction adds water cancellation after finishing successively in 0 ℃ of downhill reaction system.Filter, filter cake is washed with THF, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, and anhydrous magnesium sulfate drying filters, and precipitation obtains oily product (compound 5).
With 1.0g compound 6(2-chloro-6-methyl-4-pyridine carboxylic acid, import and export company limited of Hangzhou nation), 2.21g compound 7(2-(trifluoromethyl) phenylo boric acid, Shanghai one basic Industrial Co., Ltd.), K
2CO
3, Pd (PPh
3) Cl
2Join in the reaction flask, use N
2Protection adds H successively
2O, DMF is heated to 90 ℃, and TLC follows the tracks of, after reaction finishes, filter, filter cake washes with water, and filtrate adds water, uses ethyl acetate wash water phase again, water hydrochloric acid furnishing acidity, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization gets faint yellow solid (compound 8).
2.2g compound 8 is dissolved among the 30mLTHF, adds SOCl2,2 DMF catalysis, reflux 1 hour is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC follows the tracks of to detect to reacting and finishes, and filters, steam solvent, residue is dissolved in the 30mL ethyl acetate,, use saturated Na
2CO
3The aqueous solution is washed, washing.Tell ethyl acetate, concentrate and separate out solid, filter and obtain white solid, it is Co.1 that drying obtains target compound 1().
Compound (Co.1) nuclear-magnetism H spectrum:
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: preparation following formula: compound (Co.2)
Synthetic route is as follows:
Operation: with 10g N-Boc-D-Isoleucine, Chengdu Ai Keda chemical reagent company limited) is dissolved in the methylene dichloride, add methyl-chloroformate (the Hunan moral is praised biochemical technology company limited) and N-methylmorpholine (chemical industry company limited of Nanjing Oriental Pearl), reaction 60min adds the 1.2ep piperidines, reaction finishes, filter, steam solvent, residue is dissolved in the 20mL ethyl acetate, wash with rare HCl, use saturated NaHCO then
3The aqueous solution is washed, and with the saturated common salt washing, drying is filtered then, and precipitation obtains faint yellow oily thing (compound 3).
13g compound 3 is dissolved in the methylene dichloride, is cooled to-5 ℃.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and water merge, and add 10mL water, wash with ethyl acetate, use saturated Na again
2CO
3It is about 10 that solution is transferred pH, and with the DCM extraction, drying is filtered, and desolventizing gets light yellow oil (compound 4).
30ml THF is joined LiAlH
4In, there are a large amount of bubbles to produce, be cooled to-10 ℃, slow Dropwise 5 .6g compound 4, holding temperature is under 0 ℃, and reaction adds water cancellation after finishing successively in 0 ℃ of downhill reaction system.Filter, filter cake is washed with THF, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, and anhydrous magnesium sulfate drying filters, and precipitation obtains oily product (compound 5).
With 1.0g2-chloro-6-methyl-4-pyridine carboxylic acid (import and export company limited of Hangzhou nation), 2.5g2-(trifluoromethyl)-4-methyl-phenylo boric acid, and K
2CO
3, Pd (PPh
3) Cl
2Join in the reaction flask, use N
2Protection adds H successively
2O, DMF is heated to 90 ℃, and TLC follows the tracks of, after reaction finishes, filter, filter cake washes with water, and filtrate adds water, uses ethyl acetate wash water phase again, water hydrochloric acid furnishing acidity, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization gets faint yellow solid (compound 8).
2.2g compound 8 is dissolved among the 30mLTHF, adds SOCl2,2 DMF catalysis, reflux 1 hour is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC follows the tracks of to detect to reacting and finishes, and filters, steam solvent, residue is dissolved in the 30mL ethyl acetate,, use saturated Na
2CO
3The aqueous solution is washed, washing.Tell ethyl acetate, concentrate and separate out solid, filter and obtain white solid, drying obtains target compound Co.2.
Compound (Co.2) nuclear-magnetism H spectrum
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: preparation following formula: compound (Co.3)
Synthetic route is as follows:
Operation: with 10g compound 2 (N-Boc-L-Xie Ansuan, Laiyang City space occasion chemical industry technical research institute) is dissolved in the methylene dichloride, adds 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er chemical industry company limited), reaction 30min, add the 1.2ep piperidines, reaction finishes, and filters, steam solvent, residue is dissolved in the 20mL ethyl acetate, washes with rare HCl, uses saturated NaHCO then
3The aqueous solution is washed, and with the saturated common salt washing, drying is filtered then, and precipitation obtains faint yellow oily thing (compound 3).
13g compound 3 is dissolved in the methylene dichloride, is cooled to-5 ℃.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and water merge, and add 10mL water, wash with ethyl acetate, use saturated Na again
2CO
3It is about 10 that solution is transferred pH, and with the DCM extraction, drying is filtered, and desolventizing gets light yellow oil (compound 4).
30ml THF is joined LiAlH
4In, there are a large amount of bubbles to produce, be cooled to-10 ℃, slow Dropwise 5 .6g compound 4, holding temperature is under 0 ℃, and reaction adds water cancellation after finishing successively in 0 ℃ of downhill reaction system.Filter, filter cake is washed with THF, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, and anhydrous magnesium sulfate drying filters, and precipitation obtains oily product (compound 5).
With 1.0g compound 6(2-chloro-6-methyl-4-pyridine carboxylic acid, import and export company limited of Hangzhou nation), 2.4g4-hydroxy-2-methyl-phenylo boric acid, and K
2CO
3, Pd (PPh
3) Cl
2Join in the reaction flask, use N
2Protection adds H successively
2O, DMF is heated to 90 ℃, and TLC follows the tracks of, after reaction finishes, filter, filter cake washes with water, and filtrate adds water, uses ethyl acetate wash water phase again, water hydrochloric acid furnishing acidity, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization gets faint yellow solid (compound 8).
2.2g compound 8 is dissolved among the 30mLTHF, adds SOCl2,2 DMF catalysis, reflux 1 hour is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC follows the tracks of to detect to reacting and finishes, and filters, steam solvent, residue is dissolved in the 30mL ethyl acetate,, use saturated Na
2CO
3The aqueous solution is washed, washing.Tell ethyl acetate, concentrate and separate out solid, filter and obtain white solid, drying obtains target compound Co.3.
Compound (Co.3) nuclear-magnetism H spectrum
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: preparation following formula: compound (Co.4)
Its synthetic route is as follows:
Operation: with 10g N-Boc-D-Threonine; extra large chemical company limited is opened in Nantong) be dissolved in the methylene dichloride; add methyl-chloroformate (the Hunan moral is praised biochemical technology company limited) and N-methylmorpholine (chemical industry company limited of Nanjing Oriental Pearl), reaction 60min adds the 1.2ep piperidines; reaction finishes; filter, steam solvent, residue is dissolved in the 20mL ethyl acetate; wash with rare HCl, use saturated NaHCO then
3The aqueous solution is washed, and with the saturated common salt washing, drying is filtered then, and precipitation obtains faint yellow oily thing (compound 3).
13g compound 3 is dissolved in the methylene dichloride, is cooled to-5 ℃.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and water merge, and add 10mL water, wash with ethyl acetate, use saturated Na again
2CO
3It is about 10 that solution is transferred pH, and with the DCM extraction, drying is filtered, and desolventizing gets light yellow oil (compound 4).
30ml THF is joined LiAlH
4In, there are a large amount of bubbles to produce, be cooled to-10 ℃, slow Dropwise 5 .6g compound 4, holding temperature is under 0 ℃, and reaction adds water cancellation after finishing successively in 0 ℃ of downhill reaction system.Filter, filter cake is washed with THF, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, and anhydrous magnesium sulfate drying filters, and precipitation obtains oily product (compound 5).
With 1.0g2-chloro-6-methyl-4-pyridine carboxylic acid (import and export company limited of Hangzhou nation), 2.1g2-trifluoromethyl phenylo boric acid, and K
2CO
3, Pd (PPh
3) Cl
2Join in the reaction flask, use N
2Protection adds H successively
2O, DMF is heated to 90 ℃, and TLC follows the tracks of, after reaction finishes, filter, filter cake washes with water, and filtrate adds water, uses ethyl acetate wash water phase again, water hydrochloric acid furnishing acidity, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization gets faint yellow solid (compound 8).
2.2g compound 8 is dissolved among the 30mLTHF, adds SOCl2,2 DMF catalysis, reflux 1 hour is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC follows the tracks of to detect to reacting and finishes, and filters, steam solvent, residue is dissolved in the 30mL ethyl acetate,, use saturated Na
2CO
3The aqueous solution is washed, washing.Tell ethyl acetate, concentrate and separate out solid, filter and obtain white solid, drying obtains target compound Co.4.
Compound (Co.4) nuclear-magnetism H spectrum
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: preparation following formula: compound (Co.5)
Synthetic route is as follows:
Operation: with 10g compound 2 (L-N-Boc-2-amino-3-trifluoromethyl butanic acid, Laiyang City space occasion chemical industry technical research institute) is dissolved in the methylene dichloride, adds 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine (Chongqing Wo Ken Fine Chemical Co., Ltd) and N, N-diisopropylethylamine (Shanghai Ling Er chemical industry company limited), reaction 30min, add the 1.2ep piperidines, reaction finishes, and filters, steam solvent, residue is dissolved in the 20mL ethyl acetate, washes with rare HCl, uses saturated NaHCO then
3The aqueous solution is washed, and with the saturated common salt washing, drying is filtered then, and precipitation obtains faint yellow oily thing (compound 3).
13g compound 3 is dissolved in the methylene dichloride, is cooled to-5 ℃.Slowly add trifluoroacetic acid, be placed to room temperature, steam solvent, residue and water merge, and add 10mL water, wash with ethyl acetate, use saturated Na again
2CO
3It is about 10 that solution is transferred pH, and with the DCM extraction, drying is filtered, and desolventizing gets light yellow oil (compound 4).
30ml THF is joined LiAlH
4In, there are a large amount of bubbles to produce, be cooled to-10 ℃, slow Dropwise 5 .6g compound 4, holding temperature is under 0 ℃, and reaction adds water cancellation after finishing successively in 0 ℃ of downhill reaction system.Filter, filter cake is washed with THF, and mother liquor steams solvent, and residue is dissolved in ethyl acetate, and anhydrous magnesium sulfate drying filters, and precipitation obtains oily product (compound 5).
With 1.0g compound 6(2-chloro-6-methyl-4-pyridine carboxylic acid, import and export company limited of Hangzhou nation), 2.4g5-methoxyl group-2-trifluoromethyl-phenylo boric acid, and K
2CO
3, Pd (PPh
3) Cl
2Join in the reaction flask, use N
2Protection adds H successively
2O, DMF is heated to 90 ℃, and TLC follows the tracks of, after reaction finishes, filter, filter cake washes with water, and filtrate adds water, uses ethyl acetate wash water phase again, water hydrochloric acid furnishing acidity, separate out yellow solid, filter, obtain yellow solid, ethyl alcohol recrystallization gets faint yellow solid (compound 8).
2.2g compound 8 is dissolved among the 30mLTHF, adds SOCl2,2 DMF catalysis, reflux 1 hour is down to 5 degree, add compound 5 and triethylamine, rise to room temperature reaction 30min, TLC follows the tracks of to detect to reacting and finishes, and filters, steam solvent, residue is dissolved in the 30mL ethyl acetate,, use saturated Na
2CO
3The aqueous solution is washed, washing.Tell ethyl acetate, concentrate and separate out solid, filter and obtain white solid, drying obtains target compound Co.5.
Compound (Co.5) nuclear-magnetism H spectrum
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 the effect of drugs of institute's synthetic compound is carried out preliminary assessment:
Test example 1: test-compound is to the influence of normal rat spontaneous activity (LMA)
Testing used animal is the adult Wistar male rat, and body weight 180～250g, 6/cage raise, 12/12 little time/dark periodic adjustment, 23 ± 1 ℃ of constant temperature of temperature, humidity 50～60%, ad lib water inlet.After animal is bought from Experimental Animal Center, carry out all animals being divided into two groups at random after adaptability raises a week:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: experiment medicine group, rat is the test-compound Co.1:5.0 of abdominal injection various dose respectively, and 10 and 30mg/kg, i.p., medicine are disposed in the 1%DMSO physiological saline.
Shanghai lucky amount animal behavior video analytic system is adopted in experiment, and it is absolutely quiet that experimental situation keeps, and when grabbing by animal and administration, action is soft, reduces mental status that outside stimulus brings to animal and the untoward reaction of mood as far as possible.Rat, places rat in the spontaneous activity case after 60 minutes in administration, and the spontaneous activity case places among the absolutely quiet environment.The spontaneous activity case is connected with recording instrumnet, 30-60 minute active situation of record rat.Measure medicine or reference substance to the influence of rat spontaneous activity.
The influence of the normal rat spontaneous activity of table 1. test-compound Co.1
One hour total distance (rice) of Treatment
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.
The result: test-compound Co.1 is, and normal rat spontaneous activity does not all make significant difference (P＞0.05, Dunnett ' t test), shows that compound does not have excessive sedative effect.Olanzepine is, and normal rat spontaneous activity does not also have influence.
Test example 2: test-compound is induced the influence of the high spontaneous activity behavior of rat to PCP
Testing used animal is the adult Wistar male rat, and body weight 180～250g, 6/cage raise, 12/12 little time/dark periodic adjustment, 23 ± 1 ℃ of constant temperature of temperature, humidity 50～60%, ad lib water inlet.After animal is bought from Experimental Animal Center, carry out all animals being divided into three groups at random after adaptability raises a week:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: experiment medicine group, rat is the test-compound Co.1:5 of abdominal injection various dose respectively, and 10 and 30mg/kg, i.p., medicine are disposed in the 1%DMSO physiological saline;
The 3rd group: the positive drug control group, rats by intraperitoneal injection Olanzepine(10mg/kg, i.p., medicine are disposed at 1%DMSO physiological saline).
Shanghai lucky amount animal behavior video analytic system is adopted in experiment, and it is absolutely quiet that experimental situation keeps, and when grabbing by animal and administration, action is soft, reduces mental status that outside stimulus brings to animal and the untoward reaction of mood as far as possible.Rat is transferred in the quiet laboratory and allows it adapt at least two hours from Animal House.(5.0mg/kg, s.c.), or 1%DMSO physiological saline in contrast for subcutaneous injection PCP.After 30 minutes, animal abdominal injection test-compound, or 1%DMSO physiological saline is in contrast, and rat is placed in the spontaneous activity case, and the spontaneous activity case places among the absolutely quiet environment.The spontaneous activity case is connected with recording instrumnet, 30-60 minute active situation of record rat.Measure medicine or reference substance to the influence of rat spontaneous activity.
The influence of the high spontaneous activity of rat that the PCP of table 2. test-compound Co.1 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, * * P＜0.01 wherein, PCP group vs vehicle; ##P＜0.001, medication therapy groups vs PCP group, Dunnett ' s t test.
Experimental result: rats by intraperitoneal injection PCP has significantly increased 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 suppressed the high spontaneous activity of rat (P＜0.01 of being induced by PCP, Dunnett ' t test compares with the PCP treatment group).Positive drug group Olanzepine has significantly suppressed the high spontaneous activity of rat that PCP induces (P＜0.01, Dunnett ' t test compare with the PCP group).Olanzepine compares with positive drug, the restraining effect of the high spontaneous activity of rat that the PCP of test-compound Co.1 induces stronger (P＜0.05, Dunnett ' t test compare with the Olanzepine/PCP group).
Conclusion: experimental result shows, test-compound Co.1 has the stronger high spontaneous activity restraining effect of rat that PCP is induced, and shows that this compound has preferable antipsychotic positive symptom effect, and this effect is more excellent than Olanzepine.
Test example 3: the Amphetamine of test-compound Co.1 induces the influence of the high crawler behavior of rat
Testing used animal is the adult Wistar male rat, and body weight 180～250g, 6/cage raise, 12/12 little time/dark periodic adjustment, 23 ± 1 ℃ of constant temperature of temperature, humidity 50～60%, ad lib water inlet.After animal is bought from Experimental Animal Center, carry out all animals being divided into three groups at random after adaptability raises a week:
First group: negative control group, abdominal injection 1%DMSO physiological saline (2ml/kg, i.p.);
Second group: experiment medicine group, rat is the test-compound Co.1:5 of abdominal injection various dose respectively, and 10 and 30mg/kg, i.p., medicine are disposed in the 1%DMSO physiological saline;
The 3rd group: the positive drug control group, rats by intraperitoneal injection Olanzepine(10mg/kg, i.p., medicine are disposed at 1%DMSO physiological saline).
Shanghai lucky amount animal behavior video analytic system is adopted in experiment, and it is absolutely quiet that experimental situation keeps, and when grabbing by animal and administration, action is soft, reduces mental status that outside stimulus brings to animal and the untoward reaction of mood as far as possible.Rat is transferred in the quiet laboratory and makes it adapt at least two hours from Animal House.(1.0mg/kg, s.c.), or physiological saline in contrast for subcutaneous injection Amphetamine.After 30 minutes, the animal oral administration of compound, or physiological saline is in contrast, and rat is placed in the spontaneous activity case, and the spontaneous activity case places among the absolutely quiet environment.The spontaneous activity case is connected with recording instrumnet, 30-60 minute active situation of record rat.Measure medicine or reference substance to the influence of rat spontaneous activity.
The influence of the high spontaneous activity of rat that the Amphetamine of table 3. test-compound Co.1 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, * * P＜0.01 wherein, Amphetamine group vs vehicle; ##P＜0.001, medication therapy groups vs Amphetamine group, Dunnett ' s t test.
Experimental result: rats by intraperitoneal injection Amphetamine has significantly increased 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 suppressed the high spontaneous activity of rat (P＜0.01 of being induced by Amphetamine, Dunnett ' ttest compares with the Amphetamine treatment group).Positive drug group Olanzepine has significantly suppressed the high spontaneous activity of rat that Amphetamine induces (P＜0.01, Dunnett ' t test compare with the Amphetamine control group).Olanzepine compares with positive drug, the restraining effect of the high spontaneous activity of rat that the Amphetamine of test-compound Co.1 induces stronger (P＜0.05, Dunnett ' ttest compare with the Olanzepine/Amphetamine group).
Claims (10)
1. formula I compound,
Or its isomer, pharmacologically acceptable salts or solvate, wherein
R1 is one or more following groups that are selected from: 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 are 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.
2. according to the compound of 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. according to the compound of claim 1, wherein R2 is selected from: C1-6 alkyl and C1-6 alkoxyl group.
4. according to any one described compound of claim 1-3, wherein R3 and R4 are selected from independently of one another: hydrogen, C1-6 alkyl, C1-6 alkoxyl group and hydroxyl.
5. according to any one described compound of claim 1-3, wherein said halogen is selected from fluorine, chlorine, bromine, iodine, preferred fluorine and chlorine, and the described halogen of described halo is selected from fluorine, chlorine, bromine, iodine, preferred fluorine and chlorine.
6. according to any one described compound of claim 1-3, wherein said C1-6 alkyl is the C1-4 alkyl.
7. according to the compound of claim 1, it is to be selected from following compound:
8. pharmaceutical composition, it comprises each described formula I compound of claim 1-7, and optional one or more pharmaceutically acceptable carriers or vehicle.
9. the purposes of each described formula I compound of claim 1-7 in preparation glycine reuptake inhibitor.
10. each described formula I compound of claim 1-7 is for the preparation of the purposes that treats and/or prevents in the schizoid medicine of Mammals (comprising the people).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310204530.3A CN103254127B (en) | 2013-05-28 | 2013-05-28 | Glycine reuptake inhibitor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310204530.3A CN103254127B (en) | 2013-05-28 | 2013-05-28 | Glycine reuptake inhibitor and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103254127A true CN103254127A (en) | 2013-08-21 |
| CN103254127B CN103254127B (en) | 2015-08-19 |
Family
ID=48958395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310204530.3A Active CN103254127B (en) | 2013-05-28 | 2013-05-28 | Glycine reuptake inhibitor and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103254127B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
-
2013
- 2013-05-28 CN CN201310204530.3A patent/CN103254127B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103254127B (en) | 2015-08-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2449996C2 (en) | COMPOUNDS AND METHODS FOR INHIBITING Bcl PROTEIN INTERACTION WITH BINDING PARTNERS | |
| CN101528716B (en) | Compounds and methods for inhibiting the interaction of BCL proteins with binding partners | |
| CN100406011C (en) | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient | |
| KR102559354B1 (en) | dementia treatment | |
| CN107223125B (en) | SGC stimulant | |
| CN102743380A (en) | Compounds, formulations, and methods for treating or preventing rosacea | |
| KR20090021169A (en) | Compositions of r(+) and s(-) pramipexole and methods of using the same | |
| CN107847499A (en) | The method for treating nerve degenerative diseases | |
| EP0944621B1 (en) | 2-imidazolinylaminoindole compounds useful as alpha-2 adrenoceptor agonists | |
| EP2298296A1 (en) | Composition and method for treating cognitive impairments in down syndrome subjects | |
| CN101374807B (en) | Compounds and methods for inhibiting the interaction of BCL proteins with binding partners | |
| JP2001506600A (en) | Guanidinyl heterocyclic compounds useful as α-2 adrenergic receptor agonists | |
| CA3148939A1 (en) | Compositions and methods for the treatment of estrogen-dependent disorders | |
| RU2468015C2 (en) | Polymorphic forms of deferasirox (icl670a) | |
| BRPI0712483A2 (en) | 6-Methoxy-8- [4-1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline hydrochloric acid salts | |
| CN102746292A (en) | Cyclized berberine derivatives, preparation method and uses thereof | |
| JP2001506601A (en) | 2-imidazolinylaminobenzoxazole compounds useful as α-2 adrenergic receptor agonists | |
| BRPI0713107A2 (en) | 6-Methoxy-8- [4- (1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline siccinate salts, and crystalline forms thereof | |
| CN103254127B (en) | Glycine reuptake inhibitor and application thereof | |
| CN102260253A (en) | Benzo[5,6]cycloheptyl[1,2-b]pyridine derivatives and preparation method thereof, and pharmaceutical composition and application thereof in anaphylactic disease resistance | |
| CN109180670A (en) | Imino group thiadiazine dioxide derivative and application thereof | |
| US20170196883A1 (en) | Derivatives of 7-fluoro-8-chloro-5h-dibenzo [b,e,] [1,4] diazepine and use thereof | |
| JP2023528896A (en) | Use of phosphodiesterase 10 inhibitors for the treatment of Tourette's syndrome | |
| BRPI0713101A2 (en) | 6-methoxy-8- [4- (1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline crystalline forms | |
| CN101433536A (en) | Therapeutic compositions containing amlodipine niacin and losartan medicament |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
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 |