CN107556206A - A kind of new 5 serotonin reuptake inhibitor class compound and preparation method thereof and application medically - Google Patents
A kind of new 5 serotonin reuptake inhibitor class compound and preparation method thereof and application medically Download PDFInfo
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Abstract
Application the present invention relates to a kind of new 5 serotonin reuptake inhibitor class compound and preparation method thereof and medically, specifically, the present invention relates to a kind of formula（I）Shown new 5 serotonin reuptake inhibitor class compound, its preparation method and the pharmaceutical composition containing the compound, as well as therapeutic agent, particularly prepare treat or prevent with monoamine transporter function controlling about disease medicine in application, its formula of（I）In each substituent definition it is identical with the definition in claims.
Description
Technical field
The invention belongs to medicinal chemistry arts, be related to new serotonin reuptake inhibitor class compound, preparation method,
Pharmaceutical composition containing the compound, and such compound are relevant with monoamine transporter function controlling in standby treatment or prevention
Disease medicine in purposes.
Background technology
Due to many reasons such as social pressures, unemployment, disease and poverty, suffer from emotional handicap such as major depressive disorder and table
Reveal the number of various depressive symptoms just in average annual growth.Depression is a kind of mondial serious problem of society today.For example,
In Japan, the incidence of depression is 5% or higher in a generation higher than 65 years old, and the depression hinders including major depression
Hinder.In this colony, part depression is relevant with phrenoblabia (mental disturbance), the phrenoblabia generation
Table and dull-witted and relevant neurosis infirmities of age.Many depressed patients show high relapse rate, and serious depression
The main reason for symptom is suicide and drug abuse (Nishimura Ken, " NIPPON RONEN IGAKUZASSHI ", the
Volume 33, the 503-504 pages (1996)).
Since the 1950s, tricyclics (such as imipramine, Desipramine, Ah rice have been had been developed that
For woods etc.), for suppressing monoamine-reuptake.They are frequently used for treatment and suffer from emotional handicap such as depression and major depressive disorder
Patient.However, these medicines have following side effect：Because dry, eyes obscure (hazy caused by anticholinergic activity
Eyes), dysuria, constipation, cognitive disorder etc.；It is cardiovascular secondary caused by α 1- adrenoceptor antagonists activity
Act on such as orthostatic hypotension, tachycardia；Side effect such as calm, body caused by histamine-H1 receptor antagonist activities
Increase etc. again.
Since 1980,5- serotonin reuptake inhibitors, including but not limited to Prozac, degree Lip river have been had been developed that
Xi Ting, Venlafaxine, Milnacipran, Citalopram, escitalopram, Fluvoxamine, Paxil and Sertraline, these inhibitor
With side effect such as cognitive disorder, sleep-disorder and excite (excerbation) anxiety and excitement.In addition, these inhibitor
Also there is other side effects such as Nausea and vomiting to digestive organs etc..
[because emotional handicap such as depressive symptom, depression etc. are the diseases that have serious strong psychalgalia, because of these
The problem of side effect and the new symptom that shows are very serious in emotional handicap treatment (Shioe Kunihiko, Kariya
Tetsuhiko, " SHINKEI SEISHINYAKURI ", volume 11, the 37-48 pages (1989)；Yamada
Mitsuhiko, UeshimaKunitoshi, " RINSHOU SEISHIN YAKURI ", volume 1, the 355-363 pages
(1998))。
Although the emotional handicap including depression and major depressive disorder is heterogeneous diseases, and the reason for these diseases still
It is not fully appreciated that, but monoamine energy central nervous system is different as caused by 5- hydroxytryptamines, norepinephrine and dopamine etc.
The reason for often and the abnormal and various stressor of various hormones and peptide is probably depression and various emotional handicaps (Kubota
Masaharu etc., " RINSHOU SEISHIN IGAKU ", volume 29, the 891-899 pages (2000)).Because these are former
Cause, although antidepressants such as tricyclic antidepressant and 5- serotonin reuptake inhibitors are used, these medicines are simultaneously
All depressive patients can not always be effectively treated.About 30% depressive patient is selected (primarily) first
Antidepressants it is unresponsive (Nelson, J.C etc., J.Clin.Psychiatry, 55, the 12-19 pages (1994)).And
And when being administered second or during the third antidepressants to these patients, about 10% there is symptom improvement in these patients
Insufficient result (Inoeu Takeshi, Koyama Tsukasa, " and RINSHOU SEISHIN IGAKU ", volume 38,
The 868-870 pages (1996)).These patients are referred to as Patients with Refractory Depression.
Sometimes, electric shock therapy be used to treat refractory depression, and the effect of this treatment has had been reported.It is but actual
On, the situation of many patients is not enhanced (Inoue Takeshi, Koyama Tsukasa, " RINSHOU SEISHIN
YAKURI ", volume 2, the 979-984 pages (1999)).In addition, participate in these patients using electric shock therapy and its family
The mental anguish of front yard experience is serious.
New therapy experiment includes the conjoint therapy having pointed out, and the conjoint therapy uses atypical psycholeptic medicine
Thing such as Olanzapine, this is a kind of for treating schizoid reagent (psycholeptic medicine), together with a kind of anti-suppression
Strongly fragrant medicine such as 5- serotonin reuptake inhibitors (EP0367141, WO98/11897, WO99/61027, WO99/62522,
US2002/0123490A1 etc.).But the medicine of commercially available atypical anti-psychotic has significant problem in terms of its security.
Such as Clozapine, Olanzapine and Quetiapine are put on weight and increase the risks of diabetes (Newcomer, J.W. are (by Aoba
Anri supervision translation), " RINSHOUSEISHIN YAKURI ", volume 5, the 911-925 pages (2002)；Haupt,
D.W. and Newcomer, J.W (by Fuji Yasuo and Misawa Fuminari translate), " RINSHOUSEISHIN
YAKURI ", volume 5, the 1063-1082 pages (2002)).In fact, occurred on by Olanzapine in Japan and
The urgent safety alarm of hyperglycemia, diabetic ketoacidosis and coma diabetic caused by Quetiapine, show for
The patient that suffers from diabetes and have for the patient of diabetes medical history, these medicines are by dosage contraindication.Risperidone is in high agent
Cause serum prolactin levels to increase under amount and produce the outer side effect of pyramidal tract.Ziprasidone is increased because the heart-QTC prolongs
The risk of serious heart murmur caused by long effect.In addition, Clozapine induce agranulocytosis, therefore its clinical practice by
(van Kammen, D.P. (are compiled) under Murasaki Mitsuroh supervision, " RINSHOU for strict limitation
SEISHINYAKURI ", volume 4, the 483-492 pages (2001)).
Therefore, it is necessary to available for the noval chemical compound for treating emotional handicap, particularly depression and major depressive disorder, the change
Compound is effective and will not cause the harmful side effect relevant with prior art compound.
The content of the invention：
The defects of in order to overcome prior art, the present invention provides one kind to be had for treating or preventing with monoamine transporter function controlling
The novel drugs of the disease of pass, compared with prior art, the semiduation significantly extends the medicine, and Oral availability significantly improves；Not simultaneously
The harmful side effect relevant with prior art compound can be caused.The present invention also provides the Preparation method and use of the medicine.
The present invention is achieved by the following technical solution.
On the one hand, the present invention provides a kind of compound shown in formula (I), its stereoisomer or can pharmaceutically received
Salt,
It is characterized in that:
N is 0 to 5 integer；
R1Selected from hydrogen, H, C1-C10Alkyl, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R2Selected from hydrogen, H, C1-C10Alkyl, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R3Selected from hydrogen, halogen, C1-C10Alkyl, C1-C10Alkenyl, C1-C10Alkoxy ,-O (CH2)mO(CHnXL)w, trifluoromethyl, two
Methyl fluoride, methyl fluoride, trifluoromethoxy, difluoro-methoxy, fluorine methoxyl group, wherein m be 1 to 10 integer, w be 1 to 10 it is whole
Number, n are 0 to 3 integer, and L is 0 to 3 integer, and X is halogen；
R4Selected from hydrogen, halogen, C1-C10Alkyl, C1-C10Alkenyl, C1-C10Alkoxy ,-O (CH2)mO(CHnXL)w, trifluoromethyl, two
Methyl fluoride, methyl fluoride, trifluoromethoxy, difluoro-methoxy, fluorine methoxyl group, wherein m be 1 to 10 integer, w be 1 to 10 it is whole
Number, n are 0 to 3 integer, and L is 0 to 3 integer, and X is halogen；
R1And R2For methyl when, R3And R4Can not be hydrogen simultaneously.
New serotonin reuptake inhibitor class compound provided by the invention, its stereoisomer or pharmaceutically can be with
The salt of receiving, wherein the compound is selected from one of following structure：
Second aspect of the present invention provides a kind of preparation method of compound shown in formula (I),
Wherein, R1、R1、R3And R4It is as defined above to state.
Another aspect, the present invention provide a kind of compound described in formula (I), its stereoisomer or can pharmaceutically connect
The salt received prepare be used for treat or prevent with monoamine transporter function controlling about disease medicine in purposes.
Another further aspect, the present invention also provide a kind of pharmaceutical composition, and the pharmaceutical composition includes the chemical combination described in formula (I)
Thing, its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary material；
Preferably, described pharmaceutical composition be tablet, suppository, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat agent,
The small pin of granule, dry powder doses, oral solution, injection, injection freeze-dried powder or big transfusion；
Preferably, the pharmaceutically acceptable auxiliary material includes following one or more：It is diluent, solubilizer, disintegrant, outstanding
Floating agent, lubricant, adhesive, filler, flavouring, sweetener, antioxidant, surfactant, preservative, coating agent and
Pigment.
Compared with prior art, the semiduation significantly extends the medicine of the present invention, and Oral availability significantly improves；It will not draw simultaneously
Play the harmful side effect relevant with prior art compound.The present invention also provides the Preparation method and use of the medicine.
Brief description of the drawings：
Hereinafter, embodiments of the invention are illustrated with reference to accompanying drawing：
Fig. 1 is compound I-7 pharmacokinetics collection of illustrative plates in Mice Body.
Embodiment：
The present invention is described in further detail with reference to embodiment, it should be understood that the scope of the present invention is non-to be only limitted to these realities
Apply the scope of example.
Embodiment 1：（S）-1-（3- fluorophenyls）- N, N- dimethyl -3-（Naphthalene -4- base epoxides）Propyl- 1- amine（Compound I-
1）Preparation
Compound I-1
Take（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine 10g, add stirring and dissolving in acetonitrile.Then add
Dimethyl suflfate 0.48g.Heating reflux reaction 6 hours.The activated carbon of overall accumulated amount 1% is added in reaction solution, backflow is decolourized
15min, filtering.Filtrate decompression is concentrated to dryness, and the residue obtains compound I-1 3.3g by HPLC piece-rate systems.
Embodiment 2：（S）- N, N- dimethyl -3-（Naphthalene -4- base epoxides）-1-（3-（Trifluoromethyl）Phenyl）Propyl- 1- amine（Change
Compound I-2）Preparation
Compound I-2
Take（S）-3-（Naphthalene -4- base epoxides）-1-（3-（Trifluoromethyl）Phenyl）Propyl- 1- amine 10.0g, add acetonitrile in stir it is molten
Solution.Then dimethyl suflfate 0.48g is added.Heating reflux reaction 6 hours.The activity of overall accumulated amount 1% is added in reaction solution
Charcoal, flow back decolouring 15min, filtering.Filtrate decompression is concentrated to dryness, and the residue obtains compound I-2 by HPLC piece-rate systems
4.5g。
Embodiment 3：（S）-3-（1- fluoronaphthalene -5- base epoxides）- N, N- dimethyl -1- phenyl-propane -1- amine（Compound I-
7）Preparation
Compound I-7
Prepare as described in Example 1, the difference is that will（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine is replaced
For（S）-3-（1- fluoronaphthalene -5- base epoxides）- 1- phenyl propyl- 1- amine.
Embodiment 4（S）-3-（1-（Trifluoromethyl）Naphthalene -4- base epoxides）- N, N- dimethyl -1-（3-（Trifluoromethyl）Benzene
Base）Propyl- 1- amine（Compound I-8）Preparation
Compound I-8
Prepare as described in Example 1, the difference is that will（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine is replaced
For（S）-3-（1-（Trifluoromethyl）Naphthalene -4- base epoxides）-1-（3-（Trifluoromethyl）Phenyl）Propyl- 1- amine.
Embodiment 5：（S）-3-（1-（Trifluoromethoxy）Naphthalene -5- base epoxides）The m- tolyl propyl-s of-N, N- dimethyl -1-
1- amine（Compound I-10）Preparation
Compound I-10
Prepare as described in Example 1, the difference is that will（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine is replaced
For（S）-3-（1-（Trifluoromethyl）Naphthalene -5- base epoxides）Tolyl propyl- 1- amine between -1-.
Embodiment 6：N- methyl-N-（（S）-3-（Naphthalene -4- base epoxides）- 1- phenyl propyls）Acetamide（Compound I-13）
Preparation
Compound I-13
Take（S）- N- methyl -3-（Naphthalene -4- base epoxides）- 1- phenyl propyl- 1- amine 10g, are dissolved with acetonitrile.Then acetic anhydride is added
2.48g.Heating reflux reaction 6 hours.The activated carbon of overall accumulated amount 1% is added in reaction solution, flow back decolouring 15min, filtering.
Filtrate decompression is concentrated to dryness, and the residue obtains compound I-13 5.6g by HPLC piece-rate systems.
Embodiment 7：N - （（S）-3-（Naphthalene -4- base epoxides）- 1- phenyl propyls）Acetamide（Compound I-14）Preparation
Compound I-14
Preparation method is with embodiment 1, by compound（S）- N- methyl -3-（Naphthalene -4- base epoxides）- 1- phenyl propyl- 1- amine replaces with
（S）-3-（Naphthalene -4- base epoxides）- 1- phenyl propyl- 1- amine.
Embodiment 8：N - （（S）-1-（3- methoxyphenyls）-3-（Naphthalene -4- base epoxides）Propyl group）Acetamide hydrochloride（Change
Compound I-17）Preparation
Compound I-17
Take（S）-1-（3- methoxyphenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine 10g, are dissolved with acetonitrile.Then acetic acid is added
Acid anhydride 2.48g.Heating reflux reaction 6 hours.The activated carbon of overall accumulated amount 1% is added in reaction solution, flow back decolouring 15min, mistake
Filter.Filtrate decompression is concentrated to dryness, and the residue obtains compound 5.0g by HPLC piece-rate systems.
The above-mentioned compound 5.0g that obtains is dissolved in the mixture of methanol and chloroform, it is then dense by 3.4 milliliters at room temperature
Hydrochloric acid is added in solution, is stirred 10 hours.It is concentrated to dryness.The residue obtains compound I-17 by HPLC piece-rate systems
1.6g。
Embodiment 9：（S）-3-（1- methyl naphthalene -5- base epoxides）- N, N- are double（Trifluoromethyl）-1-（3- methoxyphenyls）
Propyl- 1- amine（Compound I-23）Preparation
Compound I-23
Take（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine 10g, add stirring and dissolving in acetonitrile.Then add
It is double（Trifluoromethyl）Sulfuric ester 4.5g.Heating reflux reaction 6 hours.The activated carbon of overall accumulated amount 1% is added in reaction solution, is returned
Flow decolouring 15min, filtering.Filtrate decompression is concentrated to dryness, and the residue obtains compound I-23 3.3g by HPLC piece-rate systems.
Embodiment 10：（S）-3-（1-（3- methoxy propoxies）Naphthalene -5- base epoxides）- N, N- dimethyl -1- phenyl-propanes -
1- amine（Compound I-24）Preparation
Compound I-24
Preparation method is with embodiment 1, by compound（S）- N- methyl -3-（Naphthalene -4- base epoxides）- 1- phenyl propyl- 1- amine replaces with
（S）-3-（1-（3- methoxy propoxies）Naphthalene -5- base epoxides）- 1- phenyl propyl- 1- amine.
Embodiment 11：（S）-3-（1-（3- methoxy propoxies）Naphthalene -5- base epoxides）-1-（3-（3- methoxy propoxies）Benzene
Base）- N, N- are double（Trifluoromethyl）Propyl- 1- amine（Compound I-25）Preparation
Compound I-25
Preparation method is with embodiment 23, by compound（S）-1-（3- fluorophenyls）-3-（Naphthalene -4- base epoxides）Propyl- 1- amine replaces with
（S）-3-（1-（3- methoxy propoxies）Naphthalene -5- base epoxides）-1-（3-（3- methoxy propoxies）Phenyl）Propyl- 1- amine.
Embodiment 21：It is acute by the way that mouse vein is administered new serotonin reuptake inhibitor class compound
Toxotest
To test the acute toxicity of the compounds of this invention, following experiments are carried out.
1% hydroxypropyl methyl cellulose is selected into free compound I-1, I-2, I-7, I-8, I-10, I- with 200 milligrams
13rd, I-14, I-17, I-23, I-24 and I-25 composition group in a kind of mixture 5 ICR mouse be administereds (5 weeks greatly,
Male, the mouse that 20 grams ± 2 grams of body weight).Then the fatal rate after 2 weeks, body weight, symptom etc. are observed, to determine most
Small lethal dose (Minimum Lethal Dose, MLD, mg/Kg).The Dapoxetine hydrochloride used（Dapoxetine）As right
According to.As a result it is as shown in table 1.
Table 1：The acute toxic test result that mouse vein is administered new serotonin reuptake inhibitor class compound
| Compound | Minimum lethal dose（MLD, mg/Kg） |
| Dapoxetine | >600 |
| Compound I-1 | >600 |
| Compound I-2 | >600 |
| Compound I-7 | >600 |
| Compound I-8 | >600 |
| Compound I-10 | >600 |
| Compound I-13 | >600 |
| Compound I-14 | >600 |
| Compound I-17 | >600 |
| Compound I-23 | >600 |
| Compound I-24 | >600 |
| Compound I-25 | >600 |
The observation of survival rate, changes of weight, blood testing and middle toxicity syndrome proves to take new serotonin of the invention again
Uptake inhibitor class compound does not have toxicity.
Embodiment 22：Pharmacokinetic trial inside the compounds of this invention
Method：
By compound I-1, I-2, I-7, I-8, I-10, I-13, I-14, I-17, I-23, I-24 and I-25 respectively with 10g/L's
Concentration is dissolved in blank solution (30% PEG-400).
Experimental animal is male mice, 6 to 8 week old, 190-215 grams of body weight, purchased from Beijing Wei Litonghua experimental animals
Technology Co., Ltd..12 groups are randomly divided into based on mouse weight, every group of 3 animals.The dosage and approach of each group mouse are shown in
Table 2.
Table 2：The dosage and approach table of internal pharmacokinetic trial each group mouse
Before pharmacokinetic trial, by mouse fasting 16 hours.Then according to shown in table 2 through vein (1mL/kg；10mg/
Kg the compound of single dosage) is administered.The mode of the jugular puncture μ L of timed collection blood 200 upon administration are taken, wherein right
In the animal groups through intravenously administrable, 0,15 minute upon administration, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and
Collect blood within 24 hours.By blood sample collection in the sample cell with EDTA, immediately with 4000rpm centrifugation of blood samples at 4 DEG C
5 minutes, then blood plasma is transferred in another sample cell, is stored under -20 degrees Celsius.
The concentration for converting the compound 1 formed in the blood sample of each time point acquirement by test compound is detected, thus to sample
Product carry out pharmacokinetics inspection, and the method and instrument of use are as follows：
HPLC ：Shimadzu
MS：AB API4000Q
Pillar：Phenomenex Luna5μC18
Mobile phase：100% acetonitrile (3mM ammonium acetates) and 100% water (3mM ammonium acetates)
Quantitative approach：Internal standard method
Table 3：Pharmacokinetic trial result inside the compounds of this invention
NA ：Data do not obtain.
From data in table 3, compared to the half-life period of the intravenous administration of compound 1 itself, compound I-1, I-2, I-7
, I-23 and I-24 half-life period significantly extend.Wherein, compound I-7 long half time reaches nearly 30 hours, its pharmacokinetics
Collection of illustrative plates is shown in Fig. 1.
Claims (9)
1. formula（I）Shown serotonin reuptake inhibitor class compound, its stereoisomer or pharmaceutically acceptable
Salt,
It is characterized in that:
N is 0 to 5 integer
R1Selected from hydrogen, H, C1-C10Alkyl, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R2Selected from hydrogen, H, C1-C10Alkyl, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R3Selected from hydrogen, halogen, C1-C10Alkyl, C1-C10Alkenyl, C1-C10Alkoxy ,-O (CH2)mO(CHnXL)w, trifluoromethyl, two
Methyl fluoride, methyl fluoride, trifluoromethoxy, difluoro-methoxy, fluorine methoxyl group, wherein m be 1 to 10 integer, w be 1 to 10 it is whole
Number, n are 0 to 3 integer, and L is 0 to 3 integer, and X is halogen；
R4Selected from hydrogen, halogen, C1-C10Alkyl, C1-C10Alkenyl, C1-C10Alkoxy ,-O (CH2)mO(CHnXL)w, trifluoromethyl, two
Methyl fluoride, methyl fluoride, trifluoromethoxy, difluoro-methoxy, fluorine methoxyl group, wherein m be 1 to 10 integer, w be 1 to 10 it is whole
Number, n are 0 to 3 integer, and L is 0 to 3 integer, and X is halogen.
2. compound, its stereoisomer according to claim 1 or pharmaceutically acceptable salt, it is characterised in that
R1And R2For methyl when, R3And R4Can not be hydrogen simultaneously.
3. the formula according to claim 1 to 2（I）Shown compound, it is characterised in that pharmaceutically acceptable salt, choosing
From：Hydrochloride, hydrobromate, sulfate, disulfate, phosphate, nitrate, and acetate, oxalates, tartrate,
Succinate, malate, benzoate, embonate, alginate, mesylate, naphthalene sulfonate.
4. compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt, wherein described
Compound is selected from one of following structure：
。
5. the compound or its pharmaceutically acceptable salt according to any one of claim 1,2,4 are being prepared for controlling
Treat or prevent with monoamine transporter function controlling about disease medicine in purposes.
6. purposes according to claim 5, wherein the illness is selected from：Hypertension, depression, generalized-anxiety disorder, probably
It is afraid of disease, post traumatic stress syndrome, avoidance personality disease, premature ejaculation, eating disorder, obesity, chemical dependencies, cluster
It is headache, antimigraine, pain, alzheimer's disease, besetment and behavior disorder, panic disorder, memory disorders, Parkinson's, interior
Parasecretion, vasopasm, cerebellar ataxia, enterogastric diseases, schizoid negativity syndrome, premenstruum (premenstrua) synthesis
Sign, fibromyalgia syndrome, stress incontinence, tourette's syndrome, group hair addiction, kleptomania, impotence, notice do not collect
In hyperactivity disorder（ADHD）, it is chronic shake hair property antimigraine, headache（With vascular diseases）, Emotion Unstability, pathologic
Shout, sleep-disorder illness（Damping off）And shock.
7. according to the purposes described in claim 5 and 6, wherein the illness is selected from：It is depression, scatterbrained excessively anti-
Answer disease, besetment and behavior disorder, post-traumatic stress disorder, substance abuse disorders or sex dysfunction.
8. the purposes any one of claim 5 to 7, wherein the illness is premature ejaculation.
9. a kind of pharmaceutical composition, the pharmaceutical composition include compound according to any one of claim 1 to 3 or
Its pharmaceutically acceptable salt, and pharmaceutically acceptable auxiliary material；
Preferably, described pharmaceutical composition be tablet, suppository, dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet, capsule, sugar-coat agent,
The small pin of granule, dry powder doses, oral solution, injection, injection freeze-dried powder or big transfusion；
Preferably, the pharmaceutically acceptable auxiliary material includes following one or more：It is diluent, solubilizer, disintegrant, outstanding
Floating agent, lubricant, adhesive, filler, flavouring, sweetener, antioxidant, surfactant, preservative, coating agent and
Pigment.
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| CN1662246A (en) * | 2002-06-20 | 2005-08-31 | H.隆德贝克有限公司 | Combination therapy wherein a serotonin reuptake inhibitor is used |
| CN1845730A (en) * | 2003-09-04 | 2006-10-11 | H.隆德贝克有限公司 | The combination of a serotonin reuptake inhibitor and loxapine |
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Address after: Haijia Yunding 30803, No.2, Gaoxin 3rd road, high tech Zone, Xi'an City, Shaanxi Province Applicant after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: Haijia Yunding 30803, No.2, Gaoxin 3rd road, high tech Zone, Xi'an City, Shaanxi Province Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20180109 |