CN103933036B - 2 Aryimidazoles simultaneously the acetamide derivative of [1,2 α] pyridine 3 prepare preventing and treating PTSD medicine in purposes - Google Patents
2 Aryimidazoles simultaneously the acetamide derivative of [1,2 α] pyridine 3 prepare preventing and treating PTSD medicine in purposes Download PDFInfo
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Abstract
The invention belongs to field of medicine and chemical technology, it is related to 2 Aryimidazoles simultaneously purposes of the acetamide derivative of [1,2 α] pyridine 3 in the medicine for preparing preventing and treating PTSD.In particular it relates to purposes of compound or pharmaceutically acceptable salt thereof of the TSPO parts for example shown in Formulas I in the medicine for preparing prevention and/or treatment and/or auxiliary treatment PTSD.Compound or pharmaceutically acceptable salt thereof of the TSPO parts for example shown in Formulas I can effectively prevent and/or treat and/or auxiliary treatment PTSD, can be used in the medicine for preparing prevention and/or treatment and/or auxiliary treatment PTSD.
Description
Technical field
The invention belongs to field of medicine and chemical technology, being related to 2- Aryimidazoles, simultaneously [1,2- α] pyridine-3-acetamide is being made
Purposes in standby preventing and treating PTSD medicine.
Background technology
In recent years, with global range, the accident such as serious natural calamity, serious infectious diseases prevalence, military conflict is not
Disconnected to occur, posttraumatic stress disorder (posttraumatic stress disorder, referred to as PTSD) turns into the harm mankind
The major disease of health.
PTSD refers to that individual delay after thundering threat or disaster is met with occurs and phrenoblabia lasting for a long time,
Clinical manifestation mainly includes pathologic reproduction, continuation alertness and increases and avoid.It is PTSD diagnostic criteria, pathogenesis, dynamic
From depression, anxiety disorder etc. it is different in terms of thing model.Clinically PTSD diagnostic criteria may be referred to Barlow,
D.H., V.M. (2006) writes, Yang Xia translations, abnormal psychology（Fourth edition）, China Light Industry Press（Such as
Page 167）.
Treatment PTSD fiest-tire medications are with 5-HT reuptake inhibitors at present（SSRIs）For the antidepressant of representative, the U.S.
FDA ratifies the Sertraline and Paxil for there was only SSRIs classes for treating PTSD medicine, regrettably, and these medicines are present
Efficient not high, action delay（More than 2-4 weeks）With adverse reaction it is serious the problems such as, limit its clinical practice, and state at present
Inside also not anti-PTSD medicine listing.
18KD indexing albumen（Translocator Protein,TSPO）It is predominantly located in intracerebral outside spongiocyte mitochondria
On film, by mediating neurosteroid synthesis regulation GABA energy nerve conductions, and hippocampus-hypothalamic-pituitary-adrenal can be suppressed
（HHPA）S function, regulation mood and stress reaction.Not yet systematically find there is clear and definite pass between TSPO and PTSD at present
System；Also the effect without the anti-PTSD of reported in literature TSPO parts.
The content of the invention
The present inventor passes through in-depth study and performing creative labour, finds TSPO parts（Such as YL-IPA08, its title
The compound 8 in table 1 is referred to structural formula）Acted on significant anti-PTSD.Disclose TSPO parts（Such as TSPO excitements
Agent or TSPO activator）Preparing the important value of preventing and treating PTSD medicines.Thus provide following inventions：
One aspect of the present invention is related to TSPO parts and is preparing prevention and/or treatment and/or auxiliary treatment PTSD medicine
Purposes in thing.Specifically, the TSPO parts are following Formulas I or the compound shown in Formula II.
Another aspect of the present invention be related to compound or pharmaceutically acceptable salt thereof shown in Formulas I prepare prevention and/or treatment and/
Or the purposes in auxiliary treatment PTSD medicine,
Wherein：
R1Selected from ethyl, propyl group, butyl and methoxyethyl；
R2Selected from benzyl, 2- picolyls, 3- picolyls, 4- picolyls, 2- morpholinyl ethyls and 3- morpholines third
Base；
R3、R4Separately it is selected from H, halogen, alkyl, substituted hydrocarbon radical, alkylene, substituted olefine base, phenyl, substitution
Phenyl, heteroaryl, substitution heteroaryl, C1-C6Alkoxy, C5-C10Aryloxy group, substituted aryloxy, C1-C6Alkylamino radical, C5-
C10Aryl amine, substituted aromatic amines base, two-(C1-C6Alkyl) amido, two-(C5-C10Aryl) amido, two-(substituted aryl) amidos,
C1-10Alkylacyloxy, C6-10Aryl acyloxy, C1-10Hydrocarbon amide groups, C6-10Aromatic amide, carboxyl, C1-10Hydrocarbon oxygen formoxyl, C6-10Virtue
Oxygen formoxyl, carbamyl, C1-10Hydroxylamine formoxyl or C6-10Arylamine formoxyl；Wherein, the hetero-aromatic ring is containing 1-3 choosing
From N, O or S heteroatomic monocyclic or polycyclic aromatic alkyl, the substituent in each group with substituent is selected from halogen
Element, hydroxyl, cyano group, nitro, C1-6Alkyl, C1-6Alkoxy, C1-6Alkylthio group, one or two or trihalogenated C1-6Alkyl, amino,
C1-6Alkylamino radical, C1-10Alkylacyloxy, C1-10Hydrocarbon amide groups, C6-10Aryl acyloxy and C6-10Aromatic amide.
According to the present invention, the pharmaceutical salts of compound of formula I can be acid-addition salts or the salt with alkali formation.The acid-addition salts
Can be inorganic acid salt, including but not limited to hydrochloride, sulfate, phosphate or hydrobromate etc.；Or acylate, including
But it is not limited to acetate, oxalates, sal limonis, gluconate, succinate, tartrate, tosilate, methanesulfonic acid
Salt, benzoate, lactate or maleate etc.；Compound of formula I and alkali forming salt can be alkali metal salts, including but not limit
In lithium salts, sodium salt or sylvite etc.；Or alkali salt, including but not limited to calcium salt or magnesium salts；Or organic alkali salt, including
But it is not limited to diethanolamine salt or choline salt etc.；Or chiral alkali salt, including but not limited to alkyl phenyl amine salt etc..
Purposes according to any one of the present invention, wherein, R3There are 1-2 substituent, and R3Positioned at imidazo [1,2-
A] pyridine ring 4-, 5-, 6- or 7- position；R4There are 1-3 substituent, and R4Positioned at the o- position, m- position or p- position of phenyl ring.
Purposes according to any one of the present invention, wherein, R3、R4It is each independently selected from F, Cl, Br, I, C1-C6Alkane
Base, C1-C3Alkoxyethyl and C1-C6Alkoxy；Specifically, R3、R4It is each independently selected from F, Cl, methyl, ethyl, methoxy
Base ethyl, methoxyl group and ethyoxyl.
Purposes according to any one of the present invention, it meets following（1）Extremely（4）In one or more：
(1)R1For ethyl or methoxyethyl；
(2)R2For benzyl, 2- picolyls, 3- picolyls, 4- picolyls or 2- morpholinyl ethyls；
(3)R3For 6- methyl or 7- methyl；
(4)R4For 4- chlorine, 3,4- dichloros, 4- methyl or 4- methoxyl groups.
Purposes according to any one of the present invention, wherein, the compound or pharmaceutically acceptable salt thereof is selected from the following institute of table 1
The compound or pharmaceutically acceptable salt thereof shown：
Table 1：The part of compounds or its officinal salt of the present invention
The preparation method of above-claimed cpd is referring to Publication No. CN102295642A（Application No. 201010209752.0）
Chinese patent application.The full content of the patent application is incorporated by reference into the present invention.
Another aspect of the invention is related to containing compound above described in any one and/or the medicine of its officinal salt
Purposes of the composition in the medicine for preparing prevention and/or treatment and/or auxiliary treatment PTSD.Described pharmaceutical composition may be used also
To include pharmaceutically acceptable carrier or auxiliary material.
The medicine is used for animal, is preferred for mammal, particularly people.Usual pharmaceutical composition of the present invention contains
0.1-90 weight % compound of formula I and/or its physiologically acceptable salt.Pharmaceutical composition can be according to side known in the art
It is prepared by method.When for this purpose, if it is desired, can be by compound of formula I or its officinal salt and one or more solids or liquid
Drug excipient and/or assistant agent are combined, be made can as people appropriate administration form or dosage form.
Compound of formula I or its officinal salt or pharmaceutical composition containing it can be administered in a unit, administration way
Footpath can be enteron aisle or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.Form of administration
For example tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, liposome, transdermal agent,
Buccal tablet, suppository, freeze drying powder injection etc..Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery systems.
In order to which unit dosage forms for administration is made into tablet, various carriers well known in the art can be widely used.Example on carrier is,
Such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, carbon
Sour calcium, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, ethanol, propyl alcohol,
Starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, lac, methyl
Cellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, for example dry starch, alginate, agar powder, laminaran,
Sodium acid carbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, second
Base cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat；Sorbefacient, for example
Quaternary ammonium salt, lauryl sodium sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, stearate, boric acid, liquid
Body paraffin, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric bag
Garment piece, or double-layer tablets and multilayer tablet.In order to which administration unit is made into pill, various loads well known in the art can be widely used
Body.Example on carrier is, such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil,
Polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive such as Arabic gum, bassora gum, gelatin, ethanol, honeybee
Honey, liquid sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methyl are fine
Tie up element, ethyl cellulose etc..In order to which administration unit is made into suppository, various carriers well known in the art can be widely used.Close
It is in the example of carrier, for example polyethylene glycol, lecithin, cocoa butter, higher alcohol, the ester of higher alcohol, gelatin, semi-synthetic glyceride
Deng.In order to which administration unit is made into capsule, active ingredient compound of formula I or its officinal salt are mixed with above-mentioned various carriers
Close, and thus obtained mixture is placed in hard obviously capsule or soft capsule.Also can by active ingredient compound of formula I or its
Microcapsules is made in officinal salt, is suspended in aqueous medium formation supensoid agent, and can also be fitted into hard shell capsules or injection is made should
With.In order to which administration unit is made into injection preparation, such as solution, emulsion, freeze drying powder injection and supensoid agent can use ability
The conventional all diluents in domain, for example, water, ethanol, polyethylene glycol, 1,3-PD, the isooctadecanol of ethoxylation, polyoxygenated
Isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can be to injection preparation
Middle addition appropriate sodium chloride, glucose or glycerine, further, it is also possible to add conventional cosolvent, buffer, pH adjusting agent
Deng.
In addition, if desired, can also be added into pharmaceutical preparation colouring agent, preservative, spices, flavouring, sweetener or
Other materials.
Term " composition " used herein means to include the product of each specified composition comprising specified amount, and directly
Or any product produced indirectly from the combination of each specified composition of specified amount.
Another aspect of the invention is related to a kind of prevention and/or treatment and/or auxiliary treatment PTSD method, including gives
The step of compound and/or its officinal salt or foregoing pharmaceutical composition before subject's effective dose described in any one
Suddenly.
The dosage of compound of formula I or its officinal salt depends on many factors, for example, to be prevented or treat disease
Property and the order of severity, sex, age, body weight and the individual reaction of patient or animal, particular compound used, administration way
Footpath and administration number of times etc..Above-mentioned dosage with ingle dose form or can be divided into several, and such as two, three or four dosage forms give
Medicine.
The actual dose level of each active component in pharmaceutical composition can be changed, can be had so as to the reactive compound amount of gained
Effect obtains required therapeutic response for specific patient, composition and administering mode.Dosage level must be according to particular compound
Activity, method of administration, the patient's condition and medical history of the order of severity for treating the patient's condition and patient to be treated are selected.But,
The way of this area is that the dosage of compound gradually increases since the level required less than therapeutic effect needed for obtaining
Dosage, until obtaining required effect.
When for above-mentioned treatment and/or prevention or other treatment and/or prevention when, treatment and/or prevention effective dose one
Planting compound can apply in a pure form, or (there is a situation where these forms with pharmaceutically acceptable ester or prodrug forms
Under) application.Or, the compound can be with the medicine containing the purpose compound with the acceptable excipient of one or more medicines
Compositions are administered.The compounds of this invention of word " prevention and/or therapeutically effective amount " refer to suitable for the prevention of any medical science and/
Or the compound of the sufficient amount of the reasonable effect for the treatment of/Hazard ratio treatment obstacle.It is to be understood that compound and composition is total
Consumption per day must be maked decision by attending physician in reliable medical judgment scope.For any specific patient, specifically control
Depending on treatment effective dose level must be according to many factors, the factor includes treated obstacle and the order of severity of the obstacle；
The activity of the particular compound used；The concrete composition used；The age of patient, body weight, general health, sex
And diet；Administration time, method of administration and the excretion rate of the particular compound used；Treat the duration；With being used
Particular compound is applied in combination or medicine used at the same time；And similar factor known to medical field.For example, this area is done
Method is, the dosage of compound is since the level required less than therapeutic effect needed for obtaining, gradually incremental dose, until
To required effect.It is, in general, that the dosage that compound of formula I is used for mammal particularly people can be between 0.001-
1000mg/kg body weight/days, such as between 0.01-100mg/kg body weight/days, such as between 0.01-10mg/kg body weight/days.
Term " subject " is preferably mammal, is more preferably people.
All documents recited in the present invention（Including patent document or non-patent literature）, their full content is by drawing
With being incorporated herein, and if implication expressed by these documents with it is of the invention inconsistent when, be defined by the statement of the present invention.This
Outside, the various terms and phrase that the present invention is used have well known to a person skilled in the art general sense, nonetheless, of the invention
Remain desirable to that these terms and phrase are described in more detail and explained at this, the term and phrase referred to contains if any with known
Justice is inconsistent, is defined by the implication that the present invention is stated.
In the present invention, term " halogen ", " halogen ", " Hal " or " halo " refers to fluorine, chlorine, bromine and iodine.
In the present invention, term " alkyl ", " alkenyl " and " alkynyl " has general sense well known in the art, and they are
The hydrocarbyl group of straight or branched, such as, but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group,
Pi-allyl, acrylic, propinyl etc., and described " alkyl ", " alkenyl " and " alkynyl " may be collectively referred to as " alkyl " or " chain
Alkyl ".In yet other embodiments, described " alkyl " refers to that alkyl includes alkyl group and cycloalkyl, special
It is not alkyl group such as C1-C6Alkyl.
In the present invention, term " substituted or unsubstituted C1-C6Alkyl " refer to specify number carbon atom substitution or
Unsubstituted alkyl group, the example includes but is not limited to：It is methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, new
Amyl group, hexyl.C1-C6Alkoxy or C1-C3Alkoxy can also do similar understanding.
The beneficial effect of invention
TSPO parts such as 2- Aryimidazoles simultaneously [1,2- α] pyridine-3-acetamide（Particularly compound YL-
IPA08）Can effectively prevent and/or treat and/or auxiliary treatment PTSD, can be used in prepare prevention and/or treatment and/or
Auxiliary treatment PTSD medicine.
Brief description of the drawings
Fig. 1：The foundation of conditioned fear.Determine the firmly time of the deadlock of the 1st day.Wherein, ordinate is the stiff firmly time
（Freezing time）；Ext, veh refer to regression training group respectively（Extinction, gavage gives distilled water）;Model control group
（Vehicle, gavage gives distilled water）.
Fig. 2：Fear, which disappears, trains.Determine the firmly time of the deadlock of the 2nd day.Wherein, ordinate is the stiff firmly time（Freezing
time）；Ext, veh refer to regression training group respectively（Extinction, gavage gives distilled water）;Model control group（Vehicle,
Gavage gives distilled water）.
Fig. 3：Conditioned fear, which disappears, keeps test.Fig. 3 A, 3B, 3C determine the 3rd respectively, the firmly time of the deadlock of 6,9 days.Data
Represented with Mean ± SEM,###P<0.001, compared with blank control group；$P<0.05, compared with model control group；*P<0.05, with
Regression training group compares；@P<0.05,@@P<0.01, compare with YL-IPA08 (0.3mg/kg, i.g.) group（n=10）.Wherein, indulge
Coordinate is the stiff firmly time（Freezing time）；Con, ext, veh refer to blank control group respectively（Control, gavage, which is given, steams
Distilled water）;Regression training group（Extinction, gavage gives distilled water）;Model control group（Vehicle, gavage, which is given, distills
Water）.
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 unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
Can be by the conventional products of acquisition purchased in market.
Embodiment 1：YL-IPA08 is to mouse posttraumatic stress disorder model（Of short duration electric shock model）Behaviouristics effect it is real
Test
First, experiment material：
1. experimental animal：
ICR mouse, male, SPF grades, original body mass 18-20g, purchased from the magnificent experimental animal Co., Ltd of dimension tonneau, license
Card：SCXK（Capital）2007-0001.
2. given the test agent：
YL-IPA08（I.e. compound 8, is synthesized by Poison ＆ Medicine Inst. of Military Medicial Sciences Academy, and preparation method is referring to public affairs
The number of opening is CN102295642A Chinese patent application；Purity 99%）；Positive drug Sertraline（Ser, purchased from Sigma companies）.
2nd, experimental method：
YL-IPA08 is to mouse posttraumatic stress disorder model（Of short duration electric shock model）Behaviouristics effect.
1. environment is adapted to：
It is soft daily to capture mouse 3 minutes, it is intended to reduce unrelated stress stimulation to follow-up within 7 days that adapt to environment
The influence of experimental implementation.In experimentation, it is ensured that the peace and quiet relatively of experimental situation.
2. training period：
Every mouse receives 15 foot shocks be interrupted, inevitability (0.8mA, is spaced 10s, continues 10s).Electric shock
Device is 20 × 10 × 10cm for having lid3Electric shock case, each case is connected by a main controller with microcomputer, the stainless steel in bottom portion
Grid（0.9cm intervals）Transmit unavoidable foot shock.
3. packet：
Blank control group；Model control group；Model+Sertraline (15mg/kg);Model+YL-IPA08 (0.03,0.1,
0.3mg/kg).Every group of mouse number refers to table 2-4.
4. administration：
Start administration from the 2nd day after training completion, administering mode is gavage（i.g.）, administered volume is 20mL/kg,
1 times/day.
5. behaviouristics is detected：
Bibliography：Li,Y.Murakami,M.Wang,K.Maeda,K.Matsumoto,“The effects of
chronic valproate and diazepam in a mouse model of posttraumatic stress
disorder,”Pharmacology Biochemistry and Behavior,vol.85,no.2,pp.324-31,2006.
1）Open field test：
After YL-IPA08 is administered 10 days, mouse is placed in 42cm × 42cm × 25cm prologue case, record mouse 5min
Interior standing number of times and across lattice numbers.Every mouse experiment is wiped to prologue case using 75% ethanol after finishing and thoroughly done
It is dry, it is to avoid the experiment on next mouse produces influence.It the results are shown in Table 2.
2）Deadlock lives behavioral value：
In ensuing 3 time-of-week, the 3rd day after electric shock, the 8th day, mouse was placed in the 15th day and once received electric shock
In case, but any stimulation is not given, record its total stiff firmly time.It the results are shown in Table 3.
3）Staircase tests：
YL-IPA08 is carried out after being administered 12 days.Experimental provision is the lucite case of a closing, inside there is 5 grades of 2.5cm height
Identical stair, stairway side wall highly keeps constant, so that animal has identical to stand distribution in all levels of stair.Give
After medicine 12 days, mouse is placed in the bottom of case, facing away from stair.Record 3min in staircase test number (using four limbs all stairs as
It is accurate) and standing number.It the results are shown in Table 4.
3rd, data statistics processing：
As a result withRepresent, one-way analysis of variance is carried out using the statistical softwares of GrphPad-Prism 4.0.
4th, experimental result：
As shown in following table 2-4.
Table 2：Influences of the YL-IPA08 to electric shock mouse prologue activity（10th day）
Note：As a result withRepresent.
Table 3：YL-IPA08 lives the influence of time to electric shock mouse deadlock
Note：As a result withRepresent；###P<0.001 is compared with blank control group,*P<0.05,**P<0.01 and mould
Type group compares.
Table 4：Influences of the YL-IPA08 to electric shock staircase test experiment（12nd day）
Note：As a result withRepresent；#P<0.05 is compared with blank control group,*P<0.05, compared with model group.
As a result show, give Environmental re-appearing repeatedly after mouse electric shock, obvious fear reaction occur, show as the stiff firmly time
Significantly extension；Cat ladder experimental result shows that the mouse stimulation unrelated to wound also shows obvious frightened performance after electric shock, but
Cat ladder number of times is not influenceed, and compound YL-IPA08 can significantly reverse above-mentioned behaviouristics to change, and not notable to prologue activity
Influence.
Embodiment 2：YL-IPA08 is to rat posttraumatic stress disorder model（time dependent
Sensitization, TDS) time dependence sensitization model）Behaviouristics effect experiment
First, experiment material：
1. experimental animal：
SD rats, male, SPF grades, original body mass 180-200g, purchased from the magnificent experimental animal Co., Ltd of dimension tonneau, license
Card：SCXK（Capital）2007-0001.
2. given the test agent：
YL-IPA08（I.e. compound 8, is synthesized by Poison ＆ Medicine Inst. of Military Medicial Sciences Academy, and preparation method is referring to public affairs
The number of opening is CN102295642A Chinese patent application；Purity 99%）；Positive drug Sertraline（Ser, purchased from Sigma companies）.
2nd, experimental method：
YL-IPA08 is to rat posttraumatic stress disorder model（Time dependent sensitization, TDS) when
Between dependence sensitization model）Behaviouristics effect.
1. environment is adapted to：
Within 7 days that adapt to environment, soft crawl rat 3 minutes, reduce unrelated stress stimulation to subsequent experimental daily
The influence of operation.In experimentation, it is ensured that experimental situation is relatively quiet.
2. the preparation of model：
Specific steps include：Rat fixes 2h（In the polyethylene fixed bin for being placed in cone, only tail can activity）Afterwards
Carry out forced swimming（Cylinder of swimming is 24 centimetres of radius, 50 centimetres of height）, the depth of water is the 2/3 of cylinder height, water temperature (24 DEG C),
Time is 20min.After recovering 15 minutes, until losing consciousness in aether pronarcosi.After 7 days in the same way again
Secondary carry out forced swimming.
3. packet：
Blank control group；Model control group；Model+Sertraline (15mg/kg);Model+YL-IPA08 (0.03,0.1,
0.3mg/kg).Every group of rat number refers to table 5-7.
4. administration：
Start administration from the 2nd day after training completion, administering mode is gavage（i.g.）, administered volume is 2mL/kg, 1
Times/day.
5. behaviouristics is detected：
Bibliography：
T.Takahashi,S.Morinobu,Y.Iwamoto,S.Yamawali,“Effect of paroxetine on
enhanced contextual fear induced by single prolonged stress in rats,”
Psychopharmacology,vol.189,no.2,pp.165-173,2006.
S.Yamamoto,S.Morinobu,S.Takei,M.Fuchikami,A.Matsuki,S.Yamawaki,et
al.,“Single prolonged stress:toward an animal model of posttraumatic stress
disorder,”Depression and Anxiety,vol.26,no.12,pp.1110-1117,2009.
1）Prologue activity：
YL-IPA08 is carried out after being administered 9 days.Begun using typical round, diameter 80cm, high 30cm, visual observations rat
5min active situation.Observation index climbs lattice and standing number of times including mainly level.Experiment is entered under conditions of low light illuminant
OK.It the results are shown in Table 5.
2）Deadlock lives behavioral value：
After YL-IPA08 is administered 11 days, rat is placed in electric shock device [by there is 60 × 21 × 30cm of lid3Cage
As the electric shock case of inevitability, each case is connected by a main controller with microcomputer, the stainless steel grid in bottom portion（1.5cm interval）
Transmit unavoidable foot shock] after 3min, give the foot shock 1 time (0.8mA, 4s) of inevitability.By rat after 24h
In the device for being again placed in receiving electric shock, detection it is stiff live behavioral duration（Refer to animal except breathing it is completely motionless when
Between）.It the results are shown in Table 6.
3）Rat elevated plus-maze test：
The stimulation unrelated to wound of TDS rats is observed using elevated plus-maze test to react.
YL-IPA08 carries out rat elevated plus-maze test after being administered 14 days.Plus maze device include two 50 ×
10cm relative open arms (open arms) and two the relative of 50 × 10 × 40cm close arm (closed arms), and closing arm top is
Unlimited.There is an one 10 × 10cm open portion in labyrinth center, labyrinth 50cm from the ground.Rat is placed in labyrinth center, head court opens
Arm, observer is apart from labyrinth center at least 1m.Rat enters open arms number of times and in the open arms holdup time point in record 5min respectively
Total degree is not accounted for（Into open arms and closing arm number of times sum）With the percentage of total time (in open arms and closing arm holdup time sum).
It the results are shown in Table 7.
3rd, data statistics processing：
As a result withRepresent, one-way analysis of variance is carried out using the statistical softwares of GrphPad-Prism 4.0.
4th, experimental result：
As shown in following table 5-7.
Table 5：Influences of the YL-IPA08 to the activity of TDS rats prologue（9th day）
Note：As a result withRepresent.
Table 6：YL-IPA08 lives the influence of time to TDS rats deadlock（12nd day）
Note：As a result withRepresent；###P<0.001 is compared with model group,**P<0.01,***P<0.001 and solvent
Group compares.
Table 7：YL-IPA08 is on the ethological influence of TDS rats Elevated plus-maze（14th day）
As a result withRepresent；##P<0.01 is compared with solvent group,*P<0.05,**P<0.01 is compared with model group.
As a result show, firmly the time significantly extends TDS rats deadlock, in elevated plus-maze test, the thorn unrelated to wound
Swash and also show obvious frightened behavior, and prologue activity is had no significant effect, and the performance of these behaviouristics can be by YL-
IPA08 is blocked.
The research of example 1 above -2 shows, on rat and mouse PTSD animal behavioral models, YL- of the present invention
IPA08 continuous gavages show the activity with significant anti-PTSD.
Embodiment 3：PK11195 antagonisms YL-IPA08 pharmacodynamic studies on rat Fear extinction models
First, experiment purpose：
By TSPO specific inhibition agents PK11195 can antagonism YL-IPA08 in rat Fear extinction models
On anti-PTSD effects, inquire into YL-IPA08 anti-PTSD effect whether is mediated by TSPO.
2nd, experiment material：
1. experimental animal：
SD rats：Male, SPF grades.
2. instrument：
Conditioned fear case (Med associates Inc Video Freeze SOF-843., USA).
3. medicine and processing：
Sertraline（Sertraline, Ser) and PK11195 be purchased from Sigma-Aldrich (St Louis, MO,
U.S.A.)；YL-IPA08（I.e. compound 8, is synthesized by Poison ＆ Medicine Inst. of Military Medicial Sciences Academy, and preparation method is referring to public affairs
The number of opening is CN102295642A Chinese patent application, and purity 99.96%, lot number is 100916）.Except PK11195 (0.1,3mg/
Kg) administering mode is intraperitoneal injection（i.p.）Outside, other medicines or solvent administering mode are gavage（i.g.）, administered volume is
2mL/kg, 1 times/day.Blank control group, model control group gavage give the solvent of respective volume.
3rd, experimental method：
Rat adapts to experimental situation 2 days before experiment, and then every rat is put into adaptation 3 days in conditioned fear case, daily
Once.
1. the foundation of conditioned fear：
Every group is 10, is, with a collection of animal, first to train and detect again.
Rat is respectively put into conditioned fear case, adapt to 2min after give again single-frequency voice signal (4.5KHZ,
70dB, 15s) adapt to 4 times（Sound interval 2min twice）, 6 inevitability foots using voice signal as prompting are then given again
Bottom is shocked by electricity (0.9mA, 5s), and sound terminates simultaneously with electric shock, and sound interval is 2min twice.Animal occurs frightened when being electrically shocked
Cry, startle, escape, occur flurried, escape or stiff vertical behavior when hearing auditory tone cues（Without other motion rows in addition to breathing
For）, and detect that its deadlock lives the time.Experiment terminates relief animal and stayed in conditioned fear case to put back to rearging cage feeding after 2min
Support.With 90% alcohol wipe bottom after experiment terminates every time, tank wall is wiped with wet cloth, to avoid residual smell big to subsequent experimental
The influence of mouse.
The training 2. fear disappears：
Every group is 10, is, with a collection of animal, first to train and detect again.
The animal for having built up conditioned fear is placed again into conditioned fear case after 24h, voice signal is given only 30 times,
Each 15s, sound interval is 1min twice.Frightened control group puts conditioned fear case at corresponding time point, without disappearing
Training（Do not give sonic stimulation）.
3. conditioned fear, which disappears, keeps test：
Every group is 10, is, with a collection of animal, first to train and detect again.
All rats respectively after frightened training of disappearing the 1st, 4,7 days rat is placed in training box, give 5 sound
Signal, each 15s, time interval is 10s, and the deadlock in detection 5min lives the time, and achievement is kept as disappearing.Time is shorter, table
Bright disappear keeps achievement better.
4th, experimental result：
1. the foundation of conditioned fear：
As shown in Figure 1（1st day）.
The training 2. fear disappears：
As shown in Figure 2（2nd day）.
3. conditioned fear, which disappears, keeps test
As shown in figs. 3 a-3 c.
As a result show, after YL-IPA08 (0.3mg/kg, p.o.) successive administration, at the 6th day, can significantly shorten within the 9th day
Deadlock caused by electric shock lives time lengthening, further confirms that YL-IPA08 has anti-PTSD activity on the mold, and TSPO is short of money
Anti-agent PK11195 (0.1 and 3mg/kg, i.p.) can block YL-IPA08 anti-PTSD to act on the 9th day completely at the 6th day, display
The anti-PTSD effects of YL-IPA08 are mediated by TSPO.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (2)
1.YL-IPA08 prepare prevention and/or treatment and/or auxiliary treatment posttraumatic stress disorder medicine purposes, it is described
YL-IPA08 structural formula is：
2. purposes according to claim 1, wherein, described pharmaceutical composition also includes pharmaceutically acceptable carrier or auxiliary
Material.
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