CN110003309A - Adjust the active compound of nmda receptor, its pharmaceutical composition and purposes - Google Patents

Adjust the active compound of nmda receptor, its pharmaceutical composition and purposes Download PDF

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CN110003309A
CN110003309A CN201910280399.6A CN201910280399A CN110003309A CN 110003309 A CN110003309 A CN 110003309A CN 201910280399 A CN201910280399 A CN 201910280399A CN 110003309 A CN110003309 A CN 110003309A
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threonyl
prolyl
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thiazolidine
carbonyl
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顾为
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Beijing Grand Pharmaceutical Technology Co Ltd
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Abstract

The invention belongs to field of medicine and chemical technology, it is related to adjusting the active compound of nmda receptor, its pharmaceutical composition and purposes.In particular it relates to Formulas I compound represented, its pharmaceutically acceptable salt or ester, its stereoisomer or its solvate.The invention further relates to the purposes of the pharmaceutical composition comprising compound of formula I and kit product and compound of formula I in preparation treatment and/or prevention of depression, anxiety disorder, cerebral apoplexy, Huntington's disease, Alzheimer disease, neuralgia or schizoid drug.NH2- P1-P2-P3-P4-COR Formulas I.

Description

Adjust the active compound of nmda receptor, its pharmaceutical composition and purposes
Technical field
The invention belongs to field of medicine and chemical technology, it is related to adjusting the active compound of nmda receptor, its pharmaceutical composition and use On the way.In particular it relates to have the compound and such compound of enhancing efficiency in the active adjusting of nmda receptor Purposes for the diseases such as preventing/treating depression and anxiety, anxiety, study and cognitive defect, neuropathic pain.
Background technique
The disease incidence of depression and harmfulness increasingly increase at present, but the therapeutic agent of depression fails to fully meet and faces Bed demand.The antidepressants listed are gone with selective serotonin (5-HT) reuptake inhibitor (SSRIs) and serotonin- Based on methylepinephrine reuptake inhibitor (SNRIs) class, these have to adjust serotonin as the antidepressants of core mechanism Many defects, including action is slow, adverse reaction is more, unresponsive patient (refractory depression patient) is more etc..Clinically to new The antidepressants of mechanism new feature have tight demand.
N-methyl-D-aspartate (NMDA) receptor plays a significant role in many maincenter activities, such as study, note Recall, emotion, cognition, the pain sensation etc..Nmda receptor excessive activation will lead to cerebral apoplexy, Huntington's disease, Alzheimer disease, nerve Bitterly, schizophrenia, depression etc. (NMDA receptors in nervous system Diseases.Neuropharmacology, 2013,74:69-75).
It is hot spot (the NMDA receptor of current medicament research and development circle using nmda receptor as the antidepressants of target spot Pathways as drug targets.Nature Neuroscience, 2002,5:1039-1042), including Esketamine (structural formula is as shown in following formula A) and Rapastinel (GLYX-13, structural formula is as shown in following formula B).Esketamine With Rapastinel quick acting, to refractory depression patient's response in terms of have stronger advantage.But Esketamine has additive, the induction dissociation risks such as disease and mania；Rapastinel cannot take orally, must in clinical application It must intravenously administrable.This severely limits the clinical applications of above compound.
Currently, being especially orally available drug it is still necessary to develop the new drug for nmda receptor.
Summary of the invention
The present inventor passes through in-depth study and creative labor, has obtained Formulas I compound represented.The present inventor is frightened It finds oddly, the compound of Formulas I or its pharmaceutically acceptable salt, solvate or their mixture are nmda receptors Agonist especially partial agonist, and there are the affinity of height with nmda receptor；It is reflected on animal model, it can be quick Effectively and enduringly prevent and treat the depression and anxiety state of animal pattern.
Thus provide following inventions:
One aspect of the present invention is related to Formulas I compound represented, its pharmaceutically acceptable salt or ester, its alloisomerism Body or its solvate,
NH2-P1-P2-P3-P4-COR
Formulas I
Wherein,
NH2- P1 is selected fromDotted line therein indicates and the connection site of P2；
P2 is selected fromWave therein Unrestrained line indicates and NH2The connection site of-P1, dotted line indicate and the connection site of P3；
P3 is selected fromWave therein Unrestrained line indicates to indicate and the connection site of P4 with the connection site of P2, dotted line；
Wherein, for P2 and P3,
R1Independently selected from C1-C5Alkyl andWherein R11、R12And R13Independently selected from H, halogen Element, nitro, C1-3Alkoxy and C1-3Alkyl, and n is 0,1,2 or 3；
P4-CO- is selected fromWave therein indicates and the connection site of P3, and dotted line is equal Indicate the connection site with R；
R is selected from OR2And NR3R4, wherein R2、R3And R4It is each independently selected from hydrogen, C1-C6Alkyl and following substituent group:
Dotted line therein indicates and the connection site of P4, R21、 R22And R23Independently selected from H, OH and OCH3, R31、R32And R33Independently selected from H and C1-C3Alkyl；
And when P2, P3 are simultaneouslyWhen, R2It is not C1-C6Alkyl and R3And R4It is not simultaneously hydrogen.
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, it is characterised in that any one in following (1) to (4) item:
(1)NH2- P1 isAnd P4-CO- is
(2)NH2- P1 isAnd P4-CO- is
(3)NH2- P1 isAnd P4-CO- isOr
(4)NH2- P1 isAnd P4-CO- is
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, it is characterised in that as follows the 1) any one into 9) item:
1) P2 isAnd P3 is
2) P2 isAnd P3 is
3) P2 isAnd P3 is
4) P2 isAnd P3 is
5) P2 isAnd P3 is
6) P2 isAnd P3 is
7) P2 isAnd P3 is
8) P2 isAnd P3 isOr
9)
P2 is selected fromAnd
P3 is selected from
Any one in the item of above-mentioned (1) to (4) can be with above-mentioned 1) to 9) any one in item combines.At this Invention some embodiments in, the compound of formula I, its pharmaceutically acceptable salt or ester, its stereoisomer or its Solvate works as NH2- P1 and P4-CO- is selected from any one in the item of above-mentioned (1) to (4), and P2 and P3 is selected from above-mentioned 1) any one into 9) item when, it will be appreciated by those skilled in the art that there is total 36 kinds of (4 × 9) specific embodiment party Formula, these are within the scope of the present invention.
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, wherein
R1Independently selected from C1-C5Alkyl, such as methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, tertiary fourth Base, amyl, 2- amyl, isopentyl or neopentyl；
Or
R1Independently selected fromSuch as phenyl or benzyl.
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, in which:
R is OR2, wherein R2Selected from hydrogen, C1-C6Alkyl (such as methyl, ethyl, propyl, isopropyl, normal-butyl, Zhong Ding Base, tert-butyl, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- hexyl or 3- hexyl) and following substituent group:
Dotted line therein indicates and the connection site of P4；
Or
R is selected from NR3R4, wherein R3And R4It is each independently selected from hydrogen, C1-C6Alkyl (such as it is methyl, ethyl, propyl, different Propyl, normal-butyl, sec-butyl, tert-butyl, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- hexyl or 3- hexyl) and with Lower substituent group:
Dotted line therein indicates and the connection site of P4；
And when P2, P3 are simultaneouslyWhen, R3And R4It is not simultaneously hydrogen.
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, wherein the compound of formula I is selected from following 1 compound represented of table.
Table 1: the embodiment of the present invention compound
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate, wherein the solvate is hydrate.
Another aspect of the present invention relates to a kind of pharmaceutical compositions, and it includes described in any one of a effective amount of present invention Compound of formula I, its pharmaceutically acceptable salt or ester, its stereoisomer or its solvate；
Optionally, described pharmaceutical composition also includes one or more of pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition in some embodiments of the present invention also includes to press down selected from serotonin reuptake Preparation, serotonin-norepinephrine reuptake inhibitor, Mirtazapine, Bupropion, vilazodone, in Vortioxetine It is one or more；
Preferably, the serotonin reuptake inhibitor is selected from Citalopram, Sertraline, Paxil and Prozac One of or it is a variety of；
Preferably, the serotonin-norepinephrine reuptake inhibitor be selected from Duloxetine, grammatical Racine, Remove one of first syntax Racine and Milnacipran or a variety of.
The pharmaceutical composition in some embodiments of the present invention also includes vertical selected from Benzodiazepines, card It is general mostly with one of Ding Taile or a variety of；
Preferably, the Benzodiazepines be selected from one of chlordiazepoxide, diazepam, Lorazepam and estazolam or It is a variety of.
Another aspect of the invention is related to a kind of kit product, and it includes the pharmaceutical preparation 1 of independent packaging and independent packagings Pharmaceutical preparation 2, in which:
The pharmaceutical preparation 1 includes compound of formula I described in any one of a effective amount of present invention, its is pharmaceutically acceptable Salt or ester, its stereoisomer or its solvate；
The pharmaceutical preparation 2 includes to be selected from serotonin reuptake inhibitor, serotonin-norepinephrine reuptake One of inhibitor, Mirtazapine, Bupropion, vilazodone, Vortioxetine or a variety of or described pharmaceutical preparation 2 include From one of Benzodiazepines, carisoprodol and Ding Taile or a variety of；
Optionally, the pharmaceutical preparation 1 and/or pharmaceutical preparation 2 are also comprising one or several kinds of pharmaceutically acceptable auxiliary Material；
Preferably, the serotonin reuptake inhibitor is selected from Citalopram, Sertraline, Paxil and Prozac One of or it is a variety of；
Preferably, the serotonin-norepinephrine reuptake inhibitor be selected from Duloxetine, grammatical Racine, Remove one of first syntax Racine and Milnacipran or a variety of；
Preferably, the Benzodiazepines be selected from one of chlordiazepoxide, diazepam, Lorazepam and estazolam or It is a variety of.
Another aspect of the invention is related to compound of formula I described in any one of present invention, its pharmaceutically acceptable salt Or ester, its stereoisomer or its solvate are in preparation treatment and/or prevention of depression, anxiety disorder, cerebral apoplexy, Heng Tingdunshi Purposes in disease, Alzheimer disease, neuralgia or schizoid drug.
Another aspect of the invention is related to compound of formula I described in any one of present invention, its pharmaceutically acceptable salt Or ester, its stereoisomer or its solvate adjust (such as up-regulation or downward) nmda receptor in preparation in vivo or in vitro Purposes in (such as human nmda receptor) active drug.
Another aspect of the invention be related to it is a kind for the treatment of and/or prevent strongly fragrant disease, anxiety disorder, cerebral apoplexy, Huntington's disease, Ah Alzheimer's disease, neuralgia or schizoid method, including given demand subject with it is a effective amount of the present invention in The step of described in any item compound of formula I, its pharmaceutically acceptable salt or ester, its stereoisomer or its solvate.
Another aspect of the invention is related to a kind of adjusting in vivo or in vitro (such as up-regulation or downward) nmda receptor (example Such as human nmda receptor) active method, including subject, mammalian cell or nmda receptor solution are given with a effective amount of Compound of formula I, its pharmaceutically acceptable salt or ester described in any one of invention, its stereoisomer or its solvate Step.
In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salt or ester, it is vertical Body isomers or its solvate are used for treatment and/or prevention of depression, anxiety disorder, cerebral apoplexy, Huntington's disease, A Er Ci Haimo disease, neuralgia or schizophrenia.
Compound of formula I, its pharmaceutically acceptable salt or the ester, its solid in some embodiments of the present invention Isomers or its solvate are used to adjust (such as up-regulation or lower) nmda receptor (such as people in vivo or in vitro Nmda receptor) activity.
Part term of the present invention is explained below.
In the present invention, term " C1-C6Alkyl " refers to the linear or branched alkyl group with 1-6 carbon atom, such as first Base, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- oneself Base, 3- hexyl etc.；C1-C5Alkyl and C1-C3Alkyl can also do similar understanding.
Term " metabolic stability " refers to that compound is entered in the form of proto-drug and steadily existed in this application In in vivo, it is not metabolized as the ability of other structures form.
Usual pharmaceutical composition of the present invention contains the type I compound of 0.1-90 weight % and/or its is physiologically acceptable Salt.Pharmaceutical composition can be prepared according to methods known in the art.When for this purpose, if it is desired, can be by type I compound And/or stereoisomer is made in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant and can be used as people's Administration form or dosage form appropriate.
Term " effective quantity ", which refers to, can realize in subject and treat, prevent, mitigate and/or alleviate disease of the present invention Or the dosage of illness.
Term " subject " can refer to patient or other receive the present composition to treat, prevent, mitigate and/or delay Solve the animal of disease or illness of the present invention, especially mammal, such as people, dog, monkey, ox, horse etc..
Term " disease and/or illness " refers to a kind of physical condition of the subject, the physical condition and institute of the present invention It states disease and/or illness is related.Term " pharmaceutically acceptable " refers in this application: compound or composition is in chemistry And/or in toxicology with constitute preparation other ingredients and/or with its prevention or treatment disease or illness the mankind or the food in one's mouth Newborn animal is compatible.
Term " subject " or " patient " include the mankind and mammal in this application.
Term " auxiliary material " refers to excipient or medium compound to be administered in this application comprising but not It is limited to diluent, disintegrating agent, precipitating inhibitor, surfactant, glidant, adhesive, lubricant, coating material etc..Auxiliary material It is described in " the Remington's Pharmaceutical Sciences " of E.W.Martin by generality.The example of auxiliary material Including but not limited to aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethylcellulose, Crospovidone, isostearic acid Glyceride, glycerin monostearate, hydroxy ethyl cellulose, hydroxy-methyl cellulose, two octadecyl ester of hydroxy stearic acid hydroxyl, hydroxyl Base propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose Deng.
Term " solvate " refer in this application by combination compound of formula I or its pharmaceutically acceptable salt and Solvent and the compound formed.It should be understood that treating compound of formula I used in disease or illness described herein Any solvate is once absorbed into subject although different property (including pharmacokinetic property) may be provided In, compound of formula I can be obtained, so that the use of any solvate of compound of formula I is covered in the use of compound of formula I respectively.
Term " hydrate " refers to that solvent is the situation of water in above-mentioned term " solvate ".
It is to be further understood that compound of formula I or its pharmaceutically acceptable salt can be separated with solvate form thereof, and because This any described solvate is all included in the scope of the present invention.For example, compound of formula I or its pharmaceutically acceptable salt can The solvation form formed in the form of unsolvated and with pharmaceutically acceptable solvent (such as, water, ethyl alcohol etc.) exists.
Term " pharmaceutically acceptable salt " refers to the relative nontoxic, inorganic acid or organic acid addition of the compounds of this invention Salt.For example, with reference to S.M.Berge et al. " Pharmaceutical Salts ", J.Pharm.Sci.1977,66,1-19.Its In, inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid etc.；Organic acids such as formic acid, acetic acid, acetyl second Acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4- hydroxyl Benzoyl)-benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, glucosulfone acid, 3- hydroxy-2-naphthoic acid, niacin, bar Not acid, pectinic acid, 3- phenylpropionic acid, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acid, itaconic acid, amidosulfonic acid, trifluoro methylsulphur Acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, Citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, rich horse Acid, maltonic acid, mandelic acid, ascorbic acid, glucoheptonic acid, phosphoglycerol, aspartic acid, sulfosalicylic acid etc..For example, can Use HCl (or hydrochloric acid), HBr (or hydrobromic acid solution), methanesulfonic acid, sulfuric acid, tartaric acid or fumaric acid and Formulas I compound represented Form pharmaceutically acceptable salt.
The compounds of this invention can be configured to pharmaceutical preparation, and the dosage form including being suitable for oral administration is suitable for parenteral note The dosage form (such as solution) for penetrating (such as intravenous injection, subcutaneous injection), dosage form (such as the conduct suitable for surface administration Ointment, patch or cream), and dosage form (such as suppository) suitable for rectally etc..
Depending on disease to be treated and patient and administration route, pharmaceutical preparation of the invention can be every with various dose Day primary or multiple dosing.Such as the daily dosage of the compounds of this invention can be oral administration about 0.1-10mg/kg weight.
The compound of the present invention, its pharmaceutically acceptable salt, its solvate or its N- oxide or medicine of the invention The dosage of compositions depends on many factors, such as the property and serious journey of the tumour to be treated or be assisted in the treatment of Gender, age, weight and the individual reaction of degree, patient or animal, particular compound used, administration route and administration number of times Deng.Above-mentioned dosage with single dose form or can be divided into several, such as two, three, four dosage forms for administration.
The actual dose of each active constituent is horizontal in changeable pharmaceutical composition of the present invention, so as to resulting reactive compound Amount effectively can obtain required therapeutic response for specific patient, composition and administration mode.Dosage level must be according to materialization Activity, administration route, the severity of the treated patient's condition and the patient's condition of patient to be treated and the medical history of object are closed to select. But the way of this field is, the dosage of compound is since less than obtaining required therapeutic effect and desired level, gradually Increase dosage, until obtaining required effect.
Compound according to the present invention can effectively prevent and/or treat various diseases or illness of the present invention.
Advantageous effect of the invention
The compound of Formulas I of the invention or its pharmaceutically acceptable salt, solvate or their mixture can be with For preventing/treating depression and/or anxiety disorder.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will Understand, the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is not specified in embodiment specific Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is It can be with conventional products that are commercially available.
The specific synthetic method of P2/P3 segment is as shown in following preparation example 1- preparation example 8.
Wherein, the synthetic route of preparation example 1-3 is schematically as follows:
The synthesis of preparation example 1:L- thiazolidinecarboxylic acid
The L-cysteine of 12.1g (0.1mol) is dissolved in 60ml hot water, the formalin of 10mL 36% is slowly poured into Solution is stood overnight after shaking up, and next day filtering is precipitated crystal, then recrystallizes to obtain needle-like white crystals 12.8g with second alcohol and water, Yield is 96.2%.
The synthesis of preparation example 2:L- thiazolidinecarboxylic acid methyl ester hydrochloride
L- thiazolidinecarboxylic acid 13.3g (0.1mol) is dissolved in 100ml anhydrous methanol, it is all molten to raw material to lead to hydrogen chloride gas Solution, continues the 2h or more that ventilates, and ventilation terminates to be stirred overnight.Next day evaporated under reduced pressure solvent, residue is dissolved with methanol to be evaporated again, weight Multiple 2 times to take away hydrogen chloride gas.Solvent evaporated obtains crude product, is recrystallized with methanol-diethyl ether, yield 91%.
The synthesis of preparation example 3:N- tertbutyloxycarbonyl-L- thiazolidinecarboxylic acid
Under ice bath, the L- thiazolidinecarboxylic acid of 0.10mol is dissolved in the sodium hydrate aqueous solution (0.10mol) of the 2N of 50mL, The acetone mixed solution of the t-butyloxycarbonylanhydride of 24.4g (0.11mol) and 50mL is slowly dropped under stirring, is finished, is continued Stir 2h.The water dilute reaction solution of 200mL is added, is extracted with ethyl acetate 3 times, uses ethyl acetate 80mL every time；It discards organic Phase.The salt acid for adjusting pH value that 1mol/L is used under water phase ice bath is 2, then is extracted with ethyl acetate 3 times, uses ethyl acetate every time 80mL；Merge organic phase, solvent is removed under reduced pressure after anhydrous sodium sulfate is dry, obtains white crystalline substance with petroleum ether and re-crystallizing in ethyl acetate Body, yield 88%.
The synthetic route of preparation example 4-5 is schematically as follows:
The synthesis of preparation example 4:2,2- dimethyl-L- thiazolidinecarboxylic acid methyl esters
3.5g L-cysteine methyl ester hydrochloride (20mmol) is mixed into reflux after ten minutes with 40ml acetone, is added 10ml methanol dissolves solid in system all, and after continuing reflux 0.5h, cooling crystallization, mother liquor concentrations continue crystallization, obtains nothing Color crystal 2,2- dimethyl-L- thiazolidinecarboxylic acid methyl ester hydrochloride, yield 94%.
The synthesis of preparation example 5:N- tertbutyloxycarbonyl -2,2- dimethyl-L- thiazolidinecarboxylic acid
2,2- dimethyl-L- thiazolidinecarboxylic acid methyl ester hydrochloride 4.03g (19mmol) and 1.92g triethylamine mixed dissolution are existed In 20ml methylene chloride, stirs lower instillation 4.15g (19mmol) t-butyloxycarbonylanhydride and be dissolved in 20ml methylene chloride Solution, room temperature reaction 3h after successively washed with 10% citric acid of 20ml, 20ml water, be dissolved in after being spin-dried in 25ml methanol, Be added 25ml 2N sodium hydrate aqueous solution, react at room temperature 4h, decompression as far as possible remove methanol, be diluted with water to 50ml, with 20ml × 3 ether washes away extra t-butyloxycarbonylanhydride, and it is 2 that the salt acid for adjusting pH value of 1mol/L is used under phase ice bath, has a large amount of whites solid Body is precipitated, and filtering washing obtains N- tertbutyloxycarbonyl -2,2- dimethyl-L- thiazolidinecarboxylic acid, yield 86%.
The synthesis of preparation example 6:2- alkyl substitution-L- thiazolidinecarboxylic acid methyl esters
Wherein, R is methyl, ethyl, isopropyl etc..
Synthetic route is schematically as follows:
Specific step is as follows:
By 3.5g L-cysteine methyl ester hydrochloride (20mmol), 1.96g potassium acetate (20mmol) stirring and dissolving in 60ml In the methanol of ice bath, 20mmol fatty aldehyde is dissolved in 20ml methanol, in instillation system, continues to post-process for stirring 5 hours.It is spin-dried for Solvent is distributed with saturated salt solution and methylene chloride, is spin-dried for after organic phase is dry, and colorless oil is obtained, and is 2- alkyl substitution- L- thiazolidinecarboxylic acid methyl esters, yield 92%-96%.
The synthesis of preparation example 7:2- phenyl-L- thiazolidinecarboxylic acid methyl esters
Synthetic route is schematically as follows:
Specific step is as follows:
2.4g L-cysteine is dissolved in 50ml ethyl alcohol, lower addition 2ml benzaldehyde is stirred at room temperature, it is small to continue stirring 6 When, there are a large amount of white solids to generate.Reaction solution filtering, the ethanol washing of solid 20ml × 3 are put into culture dish dry.Filter Liquid rotates out partial solvent to there is solid precipitation, filters after standing, washs, dry.2- phenyl-L- thiazolidinecarboxylic acid 4.0g is obtained, Yield 97%.
Obtained 4.0g 2- phenyl-L- thiazolidinecarboxylic acid is dissolved in 40ml methanol, 8ml thionyl chloride is added dropwise under ice bath, instead After should staying overnight, it is spin-dried for reaction solution, methylene chloride is added and is spin-dried for twice, obtaining faint yellow solid 5.0g, yield 96%.
The synthesis of preparation example 8:2- benzyl-L- thiazolidinecarboxylic acid methyl esters
Synthetic route is schematically as follows:
Specific step is as follows:
2.4g L-cysteine is dissolved in 50ml ethyl alcohol, lower addition 2ml phenylacetaldehyde is stirred at room temperature, it is small to continue stirring 6 When, there are a large amount of white solids to generate.Reaction solution filtering, the ethanol washing of solid 20ml × 3 are put into culture dish dry.Filter Liquid rotates out partial solvent to there is solid precipitation, filters after standing, washs, dry.2- benzyl-L- thiazolidinecarboxylic acid 4.4g is obtained, Yield 94%.
Obtained 4.4g 2- benzyl-L- thiazolidinecarboxylic acid is dissolved in 40ml methanol, 8ml thionyl chloride is added dropwise under ice bath, instead After should staying overnight, it is spin-dried for reaction solution, methylene chloride is added and is spin-dried for twice, obtaining white solid 5.5g, yield 95%.
Embodiment A-1: the preparation of compound A-1
Synthetic route is schematically as follows:
Specific step is as follows:
(1) synthesis of intermediate 1 (N- tertbutyloxycarbonyl-L- thiazolidinecarboxylic acid-L-PROLINE methyl esters):
L-PROLINE methyl ester hydrochloride 3.3g (20mmol) is dissolved in 100ml methylene chloride, under condition of ice bath, is added dropwise three Ethamine 2.0g (20mmol) is added 4.66g N- tertbutyloxycarbonyl-L- thiazolidinecarboxylic acid (20mmol), 1- hydroxy benzo after five minutes Triazole 2.7g (20mmol), 1- ethyl -3 (3- dimethyl propylamine) carbodiimide 3.8g (20mmol) stir lower nature and rise to room Temperature, contact plate monitoring reaction.After fully reacting, ethyl acetate and water dissolution, liquid separation, second is added in reaction solution rotary evaporation, concentrate Ethyl acetate layer is successively washed with aqueous citric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and anhydrous sodium sulfate is dry It is dry, it is condensed into colorless oil.Petroleum ether: ethyl acetate=1:1 column purification obtains colorless and transparent oily object 4.74g, yield 68.9%.1H-NMR(400MHz,DMSO-d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,- CH2),3.64(s,3H,-CH3),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2), 1.97-1.95(m,3H,-CH2),1.37(m,6H,-CH3,-CH3),1.15(m,3H,-CH3).M+1:344.1。
(2) synthesis of intermediate 2 (L- thiazolidinecarboxylic acid-L-PROLINE methyl ester hydrochloride):
4.74g intermediate 1 (13.7mmol) is dissolved in 30ml ethyl acetate, 10ml 4N HCl/ acetic acid second is added under ice bath Ester solution after fully reacting, is spin-dried for reaction solution, obtains white solid 3.73g, yield 96.1%.1H-NMR(400MHz,DMSO- d6),δppm:4.77(m,1H,-CH),4.43(m,1H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3),3.51(m, 2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,-CH2).M+1: 281.1。
(3) intermediate 3 (N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine-L- thiazolidinecarboxylic acid-L-PROLINE methyl esters) Synthesis:
2.2g intermediate 2 (7.8mmol) is dissolved in 40ml methylene chloride, triethylamine 0.78g is added under condition of ice bath After dissolution of raw material, N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine 2.15g (7.8mmol), 1- hydroxyl is added in (7.8mmol) Benzotriazole 1.05g (7.8mmol), 1- ethyl -3- (3- dimethyl propylamine) carbodiimide 1.5g (7.8mmol), is stirred overnight, Fully reacting back spin dry reaction liquid, concentrate ethyl acetate and water dissolution, liquid separation, ethyl acetate layer successively use citric acid water-soluble Liquid, saturated sodium bicarbonate solution, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, concentration.Petroleum ether: ethyl acetate= 1:1 column purification obtains white solid 2.09g, yield 53.6%.1H-NMR(400MHz,DMSO-d6),δppm:7.91(m, 1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,-CH),3.71(m,2H,-CH2),3.64(s,3H,-CH3), 3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2),1.97-1.95(m,3H,- CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:484.3。
(4) synthesis of intermediate 4 (N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine-L- thiazolidinecarboxylic acid-L-PROLINE):
2.09g intermediate 3 is dissolved in 20ml methanol, 20ml 2N sodium hydroxide solution is added at room temperature, after stirring 3 hours, Most of solvent is rotated out, is added 20ml water in residual reaction liquid, pH to 2-3 is adjusted with saturated citric acid solution under ice bath, adds Enter ethyl acetate 25ml*3 extraction, merge organic phase, anhydrous sodium sulfate is dry, is concentrated into white solid 2.03g, yield 100% 。1H-NMR(400MHz,DMSO-d6),δppm:7.91(m,1H,-NH),4.94(m,1H,-CH),4.52-4.23(m,3H,- CH),3.71(m,2H,-CH2),3.51(m,2H,-CH2),2.89-2.86(m,2H,-CH2),2.23-2.09(m,1H,-CH2), 1.97-1.95(m,3H,-CH2),1.37(m,9H,-CH3),1.12-1.01(m,13H,-CH3).M+1:470.3。
(5) (N- tertbutyloxycarbonyl-O- the tert-butyl-L-threonine-L- thiazolidinecarboxylic acid-L-PROLINE-L- Soviet Union ammonia of intermediate 5 Sour methyl esters) synthesis:
L-threonine methyl ester hydrochloride 0.35g (2mmol) is dissolved in 30ml methylene chloride, three second are added under condition of ice bath 1.0g intermediate 4 (2mmol) is added after five minutes in amine 0.21g (2mmol), I-hydroxybenzotriazole 0.28g (2mmol), 1- second Base -3 (3- dimethyl propylamine) carbodiimide 0.39g (2mmol), reaction nature are warmed to room temperature.After fully reacting, it is spin-dried for reacting Liquid, concentrate ethyl acetate and water dissolution, liquid separation, ethyl acetate layer successively use aqueous citric acid solution, saturated sodium bicarbonate molten Liquid, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, and concentration obtains white solid.Methylene chloride: methanol=40:1 column is pure Change, obtains white solid 890mg, yield 74.3%.1H-NMR (400MHz, DMSO-d6), δ ppm:7.94 (m, 1H ,-NH), 6.4 (m, 1H ,-NH), 5.05 (m, 1H ,-CH), 4.91 (m, 1H ,-CH), 4.56-4.54 (m, 2H ,-CH2),4.32(m,1H,-CH2), 4.24(m,1H,-CH2), 4.12 (m, 1H ,-CH2),3.72(m,2H,-CH2),3.60(s,3H,-CH3),3.50(m,1H,- CH2),2.91(m,1H,-CH2),2.17-1.86(m,5H,-CH2),1.37(s,9H,-CH3),1.21(m,1H,-CH3),1.11- 1.01(m,13H,-CH3).M+1:603.3。
(6) (N- tertbutyloxycarbonyl-O- the tert-butyl-L-threonine-L- thiazolidinecarboxylic acid-L-PROLINE-L- Soviet Union ammonia of intermediate 6 Sour amide) synthesis:
890mg intermediate 5 is dissolved in 3ml methanol, under ice bath, 10N ammonia/methanol solution 10ml is added, reacts 12 hours, It is spin-dried for reaction solution, obtains white solid 860mg.1H-NMR(400MHz,DMSO-d6), δ ppm:7.94 (m, 1H ,-NH), 7.18 (s, 2H,CO-NH2), 6.4 (m, 1H ,-NH), 5.04 (m, 1H ,-OH), 4.91 (t, 1H ,-CH, J=6.54Hz), 4.58-4.54 (m, 3H,-CH),4.32-4.25(m,2H,-CH),3.72(m,2H,-CH2),3.50(m,2H,-CH2),2.91(m,2H,-CH2), 2.15-1.86(m,4H,-CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+ 1:588.3
(7) synthesis of compound A-1:
Intermediate 6 is dissolved in 10ml ethyl acetate, under ice bath, 4N HCl/ ethyl acetate solution is added, reacts 6 hours, rotation Dry reaction liquid, obtaining white solid is final product 630mg.1H-NMR(400MHz,DMSO-d6),δppm:7.61(d,1H,CO- NH, J=8.16Hz), 7.05 (s, 2H, CO-NH2) 5.20 (d, 1H, OH, J=9.84Hz), 4.93 (t, 1H, OH, J= 7.84Hz),4.59-4.24(m,4H,CH),4.4(m,2H,CH2),3.8(m,2H,-CH2),3.6(m,2H,2-CH),3.0(m, 2H,-CH2),1.9-2.0(m,4H,-CH2),1.2(m,3H,-CH3),1.0(m,3H,-CH3), M+1:432.2.
Embodiment A-2 to A-20: the preparation of compound A-2 to A-20
The same A-1 of method, it is only necessary to be replaced corresponding P2/P3 segment.
A-2: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into uncle N- Butoxy carbonyl-O- tert-butyl-Serine, remaining operation are identical as A-1 synthesis；
A-3: the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate is replaced with into Serine methyl esters hydrochloric acid Salt, remaining operation are identical as A-1 synthesis；
A-4: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into uncle N- Butoxy carbonyl-O- tert-butyl-Serine, the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate replace with L- Serine methyl ester hydrochloride, remaining operation are identical as A-1 synthesis；
A-5: the raw material L-PROLINE methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into L- thiazolidinecarboxylic acid methyl esters salt Hydrochlorate, N- tertbutyloxycarbonyl-L- thiazolidinecarboxylic acid replace with N- tertbutyloxycarbonyl-L-PROLINE, remaining operation synthesizes phase with A-1 Together；
A-6: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into uncle N- Butoxy carbonyl-O- tert-butyl-Serine, remaining operation are identical as A-5 synthesis；
A-7: the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate is replaced with into Serine methyl esters hydrochloric acid Salt, remaining operation are identical as A-5 synthesis；
A-8: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into uncle N- Butoxy carbonyl-O- tert-butyl-Serine, the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate replace with L- Serine methyl ester hydrochloride, remaining operation are identical as A-5 synthesis；
A-9: the raw material L-PROLINE methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into L- thiazolidinecarboxylic acid methyl esters salt Hydrochlorate, remaining operation are identical as A-1 synthesis；
A-10: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into N- Tertbutyloxycarbonyl-O- tert-butyl-Serine, remaining operation are identical as A-9 synthesis；
A-11: the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate is replaced with into Serine methyl esters salt Hydrochlorate, remaining operation are identical as A-9 synthesis；
A-12: the raw material N- tertbutyloxycarbonyl-L- thiazolidinecarboxylic acid in 1 synthesis step of intermediate is replaced with into N- tertiary butyloxycarbonyl Base -2,2- dimethyl-L- thiazolidinecarboxylic acid, remaining operation are identical as A-1 synthesis；
A-13: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2,2- dimethyl-L- Thiazolidinecarboxylic acid methyl ester hydrochloride, remaining operation are identical as A-5 synthesis；
A-14: raw material N- tertbutyloxycarbonyl-O- tert-butyl-L-threonine in 3 synthesis step of intermediate is replaced with into N- Tertbutyloxycarbonyl-O- tert-butyl-Serine, remaining operation are identical as A-13 synthesis；
A-15: the raw material L-threonine methyl ester hydrochloride in 5 synthesis step of intermediate is replaced with into Serine methyl esters salt Hydrochlorate, remaining operation are identical as A-13 synthesis；
A-16: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2- methyl-L- thiazole Alkanoic acid methyl ester hydrochloride, remaining operation are identical as A-5 synthesis；
A-17: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2- ethyl-L- thiazole Alkanoic acid methyl ester hydrochloride, remaining operation are identical as A-5 synthesis；
A-18: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2- isopropyl-L- thiophene Oxazolidine acid methyl ester hydrochloride salt, remaining operation are identical as A-5 synthesis；
A-19: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2- benzyl-L- thiazole Alkanoic acid methyl ester hydrochloride, remaining operation are identical as A-5 synthesis；
A-20: the raw material L- thiazolidinecarboxylic acid methyl ester hydrochloride in 1 synthesis step of intermediate is replaced with into 2- phenyl-L- thiazole Alkanoic acid methyl ester hydrochloride, remaining operation are identical as A-5 synthesis.
Embodiment A-21 to A-24: the preparation of compound A-21 to A-24
The synthesis of compound A-21 to A-24 and compound A-1 are essentially identical, it is only necessary to accordingly be adjusted in following steps It is whole:
A-21: by intermediate 5 with the deprotection of 4N HCl/ ethyl acetate solution, compound A-21 is obtained.
A-22: being carried out ammonolysis for intermediate 5 with methylamine/methanol solution, then be deprotected with 4N HCl/ ethyl acetate solution, Obtain compound A-22.
A-23: replacing with L-threonine carbethoxy hydrochloride for L-threonine methyl ester hydrochloride, then by with compound A-1 Same synthesis path obtains compound A-23 with the deprotection of 4N HCl/ ethyl acetate solution in 5 step of intermediate.
A-24: replacing with L-threonine isopropyl ester hydrochloride for L-threonine methyl ester hydrochloride, then by with compound The same synthesis path of A-1 obtains compound A-24 with the deprotection of 4N HCl/ ethyl acetate solution in 5 step of intermediate.
The synthetic route of compound B-1 to B-9 is as follows:
Wherein,
R is successively selected from following 9 groups respectively:
Wherein, the synthetic route of intermediate b5 is similar with intermediate 5, in addition to by starting material N- tertbutyloxycarbonyl-thiazole Alkanoic acid replaces with N- tertbutyloxycarbonyl proline.
Embodiment B-1: the preparation of embodiment compound B-1
(1) 2.3g intermediate b5 (3.9mmol) is dissolved in 20ml methanol, is added with stirring 20ml 2N sodium hydroxide solution, Stirring 4 hours after fully reacting, rotates out most of solvent, 30ml water is added in residual solution, with saturated citric acid solution tune PH=2-3 is saved, ethyl acetate is added and extracts 3 times, uses ethyl acetate 20mL every time, merges organic phase, anhydrous sodium sulfate is dry, rotation It is dry, obtain 2.2g white solid intermediate b.
1H-NMR(400MHz,DMSO-d6),δppm:12.58(br,1H,CO-OH),7.6(m,1H,CO-NH),6.4(m, 1H,CO-NH),5.05(s,1H,-OH),4.63(m,1H,-CH),4.56-4.54(m,2H,-CH),4.32(m,1H,-CH), 4.24(m,1H,-CH),4.12(m,1H,-CH),3.42(m,4H,-CH2),2.91(m,4H,-CH2),2.17-1.86(m,4H,- CH2),1.37(s,9H,-CH3),1.21(m,3H,-CH3),1.11-1.01(m,12H,-CH3).M+1:571.3。
(2) 2.2g intermediate b6 (4mmol) is dissolved in 60ml methylene chloride, natural menthol 1.25g is added under ice bath (8mmol), 4-dimethylaminopyridine 0.54g (4.4mmol), dicyclohexylcarbodiimide 1.1g (5.2mmol) are stirred overnight, It is filtered after fully reacting, filtrate is successively washed with citric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, anhydrous Sodium sulphate is dry, is spin-dried for, and glass chromatography column purifying, methylene chloride: methanol=50:1 obtains white solid 1.5g, yield 53.5%. The white solid is dissolved in 20ml ethyl acetate, under ice bath, 6ml HCl/ ethyl acetate solution is added, reaction is spin-dried for after 4 hours Reaction solution obtains 1.2g compound B-1.
1H-NMR(400MHz,DMSO-d6),δppm:8.11(s,2H,-NH2),7.47(s,1H,CO-NH),5.17-5.14 (m,2H,-OH),4.61-4.30(m,5H,-CH),4.11-3.65(m,6H,CH),2.34-1.35(m,18H,-CH2),1.22- 0.83(m,16H,CH2,-CH3).M+1:553.4。
Embodiment B-2 to B-5: the preparation of compound B-2 to B-5
Step is a difference in that the natural menthol in step (2) replacing with (+) -2- camphane respectively with embodiment B-1 Compound B-2 to B-5 is made in alcohol, L- Oxiracetam, hydroxyethyltheophylline, Dyphylline respectively.
Embodiment B-6: the preparation of compound B-6
570mg intermediate b6 (1mmol) is dissolved in 60ml methylene chloride, amantadine 165mg is added under ice bath (1mmol), I-hydroxybenzotriazole 135mg (1mmol), 1- ethyl-(3- dimethyl propylamine) carbodiimide 200mg (1mmol), It is stirred overnight, is filtered after fully reacting, filtrate successively uses citric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution Washing, anhydrous sodium sulfate is dry, and be spin-dried for, methylene chloride: methanol=50:1 column purification obtains white solid 260mg, yield 36.2%.Product is dissolved in 20ml ethyl acetate, under ice bath, 6ml HCl/ ethyl acetate solution is added, reaction is spin-dried for anti-after 4 hours Liquid is answered, 200mg compound B-6 is obtained.
1H-NMR(400MHz,DMSO-d6),δppm:8.38(s,1H,CO-NH),8.11(s,2H,-NH2),7.47(s, 1H, CO-NH) 5.14 (s, 1H ,-OH), 4.61 (s, 1H ,-OH), 4.33-3.60 (m, 10H ,-CH ,-CH2),2.33-1.81(m, 8H,-CH2),1.80-1.71(m,6H,-CH2),1.59-1.55(m,4H,-CH2),1.32-1.22(m,7H,-CH2),1.10- 0.80(m,8H,-CH2,-CH3).M+1:576.4。
Embodiment B-7 to B-9: the preparation of compound B-7, B-8, B-9
Amantadine is replaced with Memantine, dopamine and 2- (7- methoxynaphthalene with embodiment B-6, only by step respectively Base -1-) ethamine, compound B-7, B-8 and B-9 are made respectively.
In addition, the structure of the compound by mass spectrum verifying preparation, as shown in Table 2 below；The compound structure of preparation Correctly.
Table 2: compound structure confirms (mass spectrum)
Number MS:(M+1) Number MS:(M+1)
A-1 432.2 A-2 418.2
A-3 418.2 A-4 404.2
A-5 432.2 A-6 418.2
A-7 418.2 A-8 404.2
A-9 450.1 A-10 436.1
A-11 436.1 A-12 460.2
A-13 460.2 A-14 446.2
A-15 446.2 A-16 446.2
A-17 460.2 A-18 474.2
A-19 522.2 A-20 508.2
A-21 447.1 A-22 446.2
A-23 461.2 A-24 475.2
B-1 553.4 B-2 551.3
B-3 555.3 B-4 621.3
B-5 635.3 B-6 576.4
B-7 548.3 B-8 549.3
B-9 598.3 GLYX-13 414.2
Experimental example 1: extracorporeal receptor Binding experiment
1. experiment purpose
It is control with GLYX-13 (Rapastinel), by ligand-receptor binding assay, studies test-compound to NMDA The affinity of receptor.
2. experimental method experimental method
(1) preparation of prefrontal cortex and hippocampus crude synaptosomes
After SD rat sacrificed by decapitation, it is rapidly separated out prefrontal cortex and hippocampus on ice, 10 times of volumes are added after weighing 50mM Tris-HCl buffer (50mM Tris-HCl, 5mMMgCl2·6H2O, 1mM EDTA, 0.5% (W/V) BSA, 1mM PMSF, 0.32M sucrose, pH 7.4), 1500 turns/min is homogenized 5 times, each 30s.Homogenate is centrifuged 10min through 1000 × g, takes Supernatant uses 40000 × g to be centrifuged 10min again, collects precipitating, and 10 times of volume Tris-HCl buffers are resuspended, 37 DEG C of incubations 10min, then finally the above buffer of obtained precipitating is resuspended with 40000 × g centrifugation 10min, -80 DEG C of preservations are standby after packing With.
(2) test medicine to rat crude synaptosomes with [3H]-MK-801 combine inhibit function detection
The 50 μ g of amount of rat crude synaptosomes albumen is sequentially added in all pipes.MK-801 is added in non-specific binding pipe (dizocilpine) 50 μ l of volume, reacts 15min in advance by final concentration of 100 μM.20 μ L respective concentrations pair are added in testing tube According to drug response 15min.Whole test tubes sequentially add tagged ligand [3H]-MK-801 volume 30 μ l, end level 10nM.With 50mM Tris-HCl buffer (50mM Tris-HCl, 5mM MgCl2·6H2O, 1mM EDTA, 0.5% (W/V) BSA, 0.1% NaN3, pH 7.4) and all reaction pipe volumes are supplied as 200 μ l.10min is reacted under 37 DEG C of reaction conditions.Prepare 49 type glass Fibrous filter membrane, while point sample.Filter membrane is put into bull cell harvestor, reaction system is through negative pressure leaching, then with ice-cold 50mM The washing of Tris-HCl buffer, each 10ml amount to 5 times.After pumping is dried, filter membrane addition 1ml flashing night is placed on shaking table shake 1.5h, next day, which is placed in liquid scintillation counter, measures radioactive intensity.
(3) detection of the test medicine to nmda receptor agonist activity energy in rat crude synaptosomes albumen
The 100 μ g of amount of rat crude synaptosomes albumen is sequentially added in all pipes.5,7 dichloros are added in non-specific binding pipe Kynurenic acid 50 μ l, final concentration of 10 μM.It is previously added 50 μM of glutamic acid in all test tubes, reacts 15min in advance.Test 20 μ L respective concentration control drugs are added in pipe, react 15min.The glycine of 1mM is added in maximum reaction tube.Whole test tubes according to Secondary addition tagged ligand [3H]-MK-801 volume 30 μ l, end level 10nM, react 15min.It is slow with 50mM Tris-HCl Fliud flushing (50mM Tris-HCl, 5mMMgCl2·6H2O, 1mM EDTA, 0.5% (W/V) BSA, 0.1%NaN3, pH 7.4) and it supplies All reaction pipe volumes are 500 μ l.15min is reacted under 37 DEG C of reaction conditions.Prepare 49 type glass fiber filters, same to time point Sample.Filter membrane is put into bull cell harvestor, reaction system is through negative pressure leaching, then with ice-cold 50mM Tris-HCl buffer Washing, each 10ml amount to 5 times.After pumping is dried, filter membrane addition 1ml flashing night is placed on shaking table and shakes 1.5h, and next day is placed on liquid sudden strain of a muscle Radioactive intensity is measured in calculating instrument.
(4) data statistics processing
Using GraphPad5.0 software analyzing and processing data, nonlinear fitting calculates its Competitive assays percentage.Wherein:
Inhibit percentage %=[(total binding cpm number-chemical feed pipe cpm number)/(total binding cpm number-non-specific pipe cpm number)] × 100%；
To inhibit percentage to carry out nonlinear fitting to the log concentration of test-compound, obtains competition inhibition curve and count Calculate IC50Value.
Maximum excitement efficiency=[(test -5,7 dichloro kynurenic acid cpm number of compound cpm number)/(1mM glycine cpm - 5,7 dichloro kynurenic acid cpm numbers of number)] × 100%.
Table 3: affinity and maximum exciting efficiency of the embodiment compound to nmda receptor
Experimental result shows that embodiment compound all has nmda receptor agonist activity, and maximum excitement efficiency is in 13%- Between 90%, belong to nmda receptor partial agonist.
Experimental example 2: animal pharmacodynamic experiment
Pharmacodynamic evaluation is carried out using rat forced swimming test.Experimental animal is SD rat, male, weight 150g- It 180g, SPF grades, buys rear adaptive feeding one week, carries out forced swim test, fasting 12h is needed before experiment.Embodiment compound Physiological saline solution is used, blank control group (physiological saline), positive controls (GLYX-13 tail vein injection group and fluorine are set up Western spit of fland gastric infusion group), embodiment compound administration group and GLYX-13 gastric infusion group；Every group of 8-10 rat.
Rat is placed in the glass jar of high 40cm, internal diameter 18cm, depth of water 23cm by experiment the previous day swims 15min, water temperature in advance 28℃.Rat is taken out after pre- trip, dry cloth is dried rear electric heater and dried, and rearging cage is put back to.1h gives before formal test Medicine carries out 5min swimming test after administration 1 hour, records in 5min and add up the dead time.Determine that motionless standard is that animal exists Stop struggling in water, is in floating state, only slight limb motion is to keep head to keep afloat.It the results are shown in Table 4, test number According to using 5.0 software of GraphPad Prism for statistical analysis, data are reduced compared with blank control group with the flotation time Ratio indicates that N/A represents the group experiment flotation time, and there was no significant difference compared with blank control group, and " -- " represents group experiment It does not carry out.
Table 4: the rat forced swimming test result of embodiment compound
Experimental result shows that the administration of control compound GLYX-13 tail vein is effective, and drug effect is still kept after 3 days； GLYX-13 gastric infusion is invalid；On the day of comparison medicine Prozac gastric infusion effectively, but drug effect cannot keep to next day；Multiple realities It is effective to apply a compound stomach-filling, and after drug effect can remain to next day to 3 days.
Although a specific embodiment of the invention has obtained detailed description, it will be understood to those of skill in the art that.Root According to all introductions having disclosed, those details can be carry out various modifications and be replaced, these change in guarantor of the invention Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (13)

1. Formulas I compound represented, its pharmaceutically acceptable salt or ester, its stereoisomer or its solvate,
NH2-P1-P2-P3-P4-COR
Formulas I
Wherein,
NH2- P1 is selected fromDotted line therein indicates and the connection site of P2；
P2 is selected fromWave therein Expression and NH2The connection site of-P1, dotted line indicate and the connection site of P3；
P3 is selected fromWave therein Indicate the connection site with P2, dotted line indicates and the connection site of P4；
Wherein, for P2 and P3,
R1Independently selected from C1-C5Alkyl andWherein R11、R12And R13Independently selected from H, halogen, C1-3 Alkoxy and C1-3Alkyl, and n is 0,1,2,3,4,5 or 6；
P4-CO- is selected fromWave therein indicates to indicate with the connection site of P3, dotted line With the connection site of R；
R is selected from OR2And NR3R4, wherein R2、R3And R4It is each independently selected from hydrogen, C1-C6Alkyl and following substituent group:
Dotted line therein indicates and the connection site of P4, R21、 R22And R23Independently selected from H, OH and OCH3, R31、R32And R33Independently selected from H and C1-C3Alkyl；
And when P2, P3 are simultaneouslyWhen, R2It is not C1-C6Alkyl and R3And R4It is not simultaneously hydrogen.
2. compound of formula I according to claim 1, its pharmaceutically acceptable salt or ester, its stereoisomer or its is molten Object is closed in agent, it is characterised in that any one in following (1) to (4) item:
(1)NH2- P1 isAnd P4-CO- is
(2)NH2- P1 isAnd P4-CO- is
(3)NH2- P1 isAnd P4-CO- isOr
(4)NH2- P1 isAnd P4-CO- is
3. according to claim 1 to compound of formula I described in any claim in 2, its pharmaceutically acceptable salt or ester, its Stereoisomer or its solvate, it is characterised in that as follows the 1) any one into 9) item:
1) P2 isAnd P3 is
2) P2 isAnd P3 is
3) P2 isAnd P3 is
4) P2 isAnd P3 is
5) P2 isAnd P3 is
6) P2 isAnd P3 is
7) P2 isAnd P3 is
8) P2 isAnd P3 isOr
9)
P2 is selected fromAnd
P3 is selected from
4. according to claim 1 to compound of formula I described in any claim in 3, its pharmaceutically acceptable salt or ester, its Stereoisomer or its solvate, wherein
R1Independently selected from C1-C5Alkyl, such as methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl, penta Base, 2- amyl, isopentyl or neopentyl；
Or
R1Independently selected fromSuch as phenyl or benzyl.
5. according to claim 1 to compound of formula I described in any claim in 4, its pharmaceutically acceptable salt or ester, its Stereoisomer or its solvate, in which:
R is OR2, wherein R2Selected from hydrogen, C1-C6Alkyl (such as methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, tertiary fourth Base, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- hexyl or 3- hexyl) and following substituent group:
Dotted line therein indicates and the connection site of P4；
Or
R is selected from NR3R4, wherein R3And R4It is each independently selected from hydrogen, C1-C6Alkyl (such as methyl, ethyl, propyl, isopropyl, Normal-butyl, sec-butyl, tert-butyl, amyl, 2- amyl, isopentyl, neopentyl, hexyl, 2- hexyl or 3- hexyl) and following substitution Base:
Dotted line therein indicates and the connection site of P4；
And when P2, P3 are simultaneouslyWhen, R3And R4It is not simultaneously hydrogen.
6. according to claim 1 to compound of formula I described in any claim in 5, its pharmaceutically acceptable salt or ester, its Stereoisomer or its solvate, wherein the compound of formula I is selected from:
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L- threonyl amine；
3- (L- seryl-)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L- threonyl amine；
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L- silk amide；
3- (L- seryl-)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L- silk amide；
3- (L- Threonyl-L- prolyl)-thiazolidine-(4R)-carbonyl-L- threonyl amine；
3- (L- seryl--L- prolyl)-thiazolidine-(4R)-carbonyl-L- threonyl amine；
3- (L- Threonyl-L- prolyl)-thiazolidine-(4R)-carbonyl-L- silk amide；
3- (L- seryl--L- prolyl)-thiazolidine-(4R)-carbonyl-L- silk amide；
3- (3-L- Threonyl-thiazolidine-(4R)-carbonyl -)-thiazolidine-(4R)-carbonyl-L- threonyl amine；
3- (3-L- seryl--thiazolidine-(4R)-carbonyl -)-thiazolidine-(4R)-carbonyl-L- threonyl amine；
3- (3-L- Threonyl-thiazolidine-(4R)-carbonyl -)-thiazolidine-(4R)-carbonyl-L- silk amide；
3- (L- Threonyl) -2,2- dimethylthiazole alkane-(4R)-oxycarbonyl-L-prolyl-L- threonyl amine；
3- (L- Threonyl-L- prolyl) -2,2- dimethylthiazole alkane-(4R)-carbonyl-L- threonyl amine；
3- (L- seryl--L- prolyl) -2,2- dimethylthiazole alkane-(4R)-carbonyl-L- threonyl amine；
3- (L- Threonyl-L- prolyl) -2,2- dimethylthiazole alkane-(4R)-carbonyl-L- silk amide；
- 4 (R)-carbonyl-L- threonyl amine of 3- (L- Threonyl-L- prolyl) -2- methyl thiazolium oxazolidine；
- 4 (R)-carbonyl-L- threonyl amine of 3- (L- Threonyl-L- prolyl) -2- ethyl thiazole alkane；
- 4 (R)-carbonyl-L- threonyl amine of 3- (L- Threonyl-L- prolyl) -2- isopropyl thiazolidine；
3- (L- Threonyl-L- prolyl) -2- substituted benzylthiazolidine -4 (R)-carbonyl-L- threonyl amine；
- 4 (R)-carbonyl-L- threonyl amine of 3- (L- Threonyl-L- prolyl) -2- phenyl thiazole alkane；
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L-threonine methyl esters；
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L- threonyl methylamine；
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L-threonine ethyl ester；
3- (L- Threonyl)-thiazolidine-(4R)-oxycarbonyl-L-prolyl-L-threonine isopropyl ester；
L- Threonyl-L- prolyl-L- prolyl-L- Threonyl-l-menthol ester；
L- Threonyl-L- prolyl-L- prolyl-L- Threonyl-(+) -2- barascamphor；
2- acetamido-pyrrolidones-(4S)-hydroxyl-L- Threonyl-L- prolyl-L- prolyl-L-threonine Ester；
7- ethyl-theophylline-beta-hydroxy-L- Threonyl-L- prolyl-L- prolyl-L-threonine ester；
7- propyl-theophylline-beta-hydroxy-L- Threonyl-L- prolyl-L- prolyl-L-threonine ester；
L- Threonyl-L- prolyl-L- prolyl-L- Threonyl-Memantine hydrochloride；
L- Threonyl-L- prolyl-L- prolyl-L- Threonyl-amantadine；
L- Threonyl-L- prolyl-L- prolyl-L- Threonyl-dopamine；With
1- ((2- (7- methoxyl group-naphthalene -1- base) ethyl) amino-L- Threonyl-L- prolyl-L- prolyl-L- Soviet Union ammonia Amide.
7. according to claim 1 to compound of formula I described in any claim in 6, its pharmaceutically acceptable salt or ester, its Stereoisomer or its solvate, wherein the solvate is hydrate.
8. a kind of pharmaceutical composition, it includes compound of formula I described in any claim in a effective amount of claim 1 to 7, Its pharmaceutically acceptable salt or ester, its stereoisomer or its solvate；
Optionally, described pharmaceutical composition also includes one or more of pharmaceutically acceptable auxiliary materials.
9. pharmaceutical composition according to claim 8 also includes selected from serotonin reuptake inhibitor, 5- hydroxyl color One of amine-norepinephrine reuptake inhibitor, Mirtazapine, Bupropion, vilazodone, Vortioxetine are a variety of；
Preferably, the serotonin reuptake inhibitor is in Citalopram, Sertraline, Paxil and Prozac It is one or more；
Preferably, the serotonin-norepinephrine reuptake inhibitor is selected from Duloxetine, grammatical Racine, goes first One of grammatical Racine and Milnacipran are a variety of.
10. pharmaceutical composition according to claim 8 also includes selected from Benzodiazepines, carisoprodol and Ding Taile One of or it is a variety of；
Preferably, the Benzodiazepines are selected from one of chlordiazepoxide, diazepam, Lorazepam and estazolam or more Kind.
11. a kind of kit product, it includes the pharmaceutical preparations 2 of the pharmaceutical preparation 1 of independent packaging and independent packaging, in which:
The pharmaceutical preparation 1 includes compound of formula I, its pharmacy described in any claim in a effective amount of claim 1 to 7 Upper acceptable salt or ester, its stereoisomer or its solvate；
The pharmaceutical preparation 2 includes to inhibit selected from serotonin reuptake inhibitor, serotonin-norepinephrine reuptake One of agent, Mirtazapine, Bupropion, vilazodone, Vortioxetine or a variety of or described pharmaceutical preparation 2 include from benzene One of diazepine, carisoprodol and Ding Taile or a variety of；
Optionally, the pharmaceutical preparation 1 and/or pharmaceutical preparation 2 are also comprising one or several kinds of pharmaceutically acceptable auxiliary materials；
Preferably, the serotonin reuptake inhibitor is in Citalopram, Sertraline, Paxil and Prozac It is one or more；
Preferably, the serotonin-norepinephrine reuptake inhibitor is selected from Duloxetine, grammatical Racine, goes first One of grammatical Racine and Milnacipran are a variety of；
Preferably, the Benzodiazepines are selected from one of chlordiazepoxide, diazepam, Lorazepam and estazolam or more Kind.
12. compound of formula I described in any claim, its pharmaceutically acceptable salt or ester in claim 1 to 7, it is vertical Body isomers or its solvate are in preparation treatment and/or prevention of depression, anxiety disorder, cerebral apoplexy, Huntington's disease, A Erci Purposes in the silent disease in sea, neuralgia or schizoid drug.
13. compound of formula I described in any claim, its pharmaceutically acceptable salt or ester in claim 1 to 7, it is vertical Body isomers or its solvate adjust (such as up-regulation or lower) nmda receptor (such as people in preparation in vivo or in vitro Nmda receptor) purposes in active drug.
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