CN107556209A - A kind of new melatonin class compound and preparation method thereof and application medically - Google Patents
A kind of new melatonin class compound and preparation method thereof and application medically Download PDFInfo
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- CN107556209A CN107556209A CN201610499532.3A CN201610499532A CN107556209A CN 107556209 A CN107556209 A CN 107556209A CN 201610499532 A CN201610499532 A CN 201610499532A CN 107556209 A CN107556209 A CN 107556209A
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Abstract
Application the present invention relates to a kind of new melatonin class compound and preparation method thereof and medically, specifically, the present invention relates to a kind of formula（I）Shown new melatonin class compound, its preparation method and the pharmaceutical composition containing the compound, as well as therapeutic agent, the particularly application in the medicine for the treatment of depression or periventricular leukomalacia is prepared, its formula of（I）In each substituent definition it is identical with the definition in claims.
Description
Technical field
The present invention relates to a kind of melatonin class compound and its pharmaceutically acceptable salt of non-toxic, preparation method, containing it
Pharmaceutical composition and clinically purposes, the particularly treatment for depression.
Background technology
The destruction of circadian rhythm mode has been considered as one of Etiology factor in depression Pathological Physiology, and
The disorder of this endogenous rhythm is exactly the feature of abnormal feeling change, therefore the normalization of such rhythm and pace of moving things damage has been identified as resisting
The New Set of depression medication effect.
Epiphysin is a kind of endogenous neural hormone, is only secreted and produced by pineal anterior pituitary at night, and acted on
It is present in hypothalamus SCN (SCN) melatonin receptors in concentration, participates in reconciling the circadian rhythm and pace of moving things of mammal,
It is time defender inside well-known, corrects the biological clock adjusted by outside day-night cycle.However, because epiphysin exists
The selectivity for the acceptor for having Metabolism rate in vivo and causing its half-life period shorter and being located to it in SCN is poor, causes its use
It is restricted in the treatment of circadian rhythm disorder disease.Therefore, to overcome these defects of epiphysin, researcher sets
A series of epiphysin analogs are counted.Molecular model research shows that the indole ring of epiphysin is the structure bit of its catabolism inactivation
Point, therefore indole ring turns into the desired site of isostere modification.The agomelatine that Servier companies develop as takes off black
Biological (electronics) the isostere analog of the naphthalene of element, it instead of indole ring with naphthalene core, it is had more metabolic stability compared with epiphysin.
Agomelatine is the selectivity and specific agonist of a hypothalamus melatonin receptors, while has weak 5-HT acceptors concurrently again
Competitive antagonism activity, the new pharmacology for showing a kind of MASSA (melatonin agonist and selective 5-HT antagonists) are special
Property.It can simulate the effect of epiphysin, have unique mode of action again, be that treatment circadian rhythm disorders disease (is such as slept
Obstacle/depression) great future drug candidate.
Although tricyclic antidepressant is uncomfortable to major depressive disorder, generally existing problem of resistance in can effectively treating
Most patients are closed to use.And new class selectivity 5-HT reuptaking inhibitors (SRIs) have preferably compared with tricyclic drugs
Tolerance, it has also become most popular antidepressant, but such medicine has specific side effect again, especially influences
Sexual function, therefore its compliance reduces, and evidence suggests, SRIs is effective to mild to moderate depression, and to pole major depressive disorder
The effect of it is not good enough.Agomelatine is then effective to all types of depression, and few side effects.Nearest one is random, right
Show according to clinical test, this product 25mgd is for the effect for the treatment of major depressive disorder and bipolar disorder patient and SRI pas
Luo Xiting is close, and this product has more preferable tolerance than traditional antidepressant.Agomelatine as the whole world it is first take off it is black
Hormone receptor MT1 and MT2 activator class antidepressants find that after being administered orally allergic, oral cavity can be caused under therapeutic dose
Ulcer and nausea, the adverse reaction such as have a stomach upset, it is easy to cause the repulsion psychology of patient, be unfavorable for medication.To reduce it
Adverse reaction, a kind of new melatonin class compound of exploitation is very necessary.
The content of the invention：
The defects of in order to overcome prior art, the present invention, which provides, a kind of to be used to treat the new of depression or periventricular leukomalacia
Medicine, compared with prior art, the semiduation significantly extends the medicine, and Oral availability significantly improves；Simultaneously will not cause with it is existing
The relevant harmful side effect of technical compound.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,
（I）
It is characterized in that:
N is 0 to 5 integer；
R1It is selected from, wherein R4For hydrogen, methyl, trifluoromethyl, difluoromethyl, methyl fluoride, m be 1 to 10 it is whole
Number；
R2Selected from H, methyl, ethyl, propyl group, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane
Acyl group, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R3Selected from H, methyl, ethyl, propyl group, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane
Acyl group, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
（HLX)mFor pharmaceutically acceptable any acid, X represents acid group, and L is 1-4 integer, and m is 0-3 integer.
When m is 0, the melatonin class compound is free alkali form.
New melatonin class compound provided by the invention, its stereoisomer or pharmaceutically acceptable salt, wherein institute
State compound and be 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、R2、R3, L, m and n represent it is as described above.
Another aspect, the present invention provide a kind of compound described in formula (I), its stereoisomer or can pharmaceutically connect
The salt received is preparing the purposes in being used to treat the medicine of depression or periventricular leukomalacia.
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-3 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：N - （（2-（3- methoxy propoxies）Naphthalene -8- bases）Ethyl）Acetamide（Compound I-1）Preparation
Compound I-1
Take（2-（3- methoxy propoxies）Naphthalene -8- bases）Methylamine 10.0g, dissolved with acetonitrile 100ml.Then acetic anhydride is added
6.48g.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-1 5.6g by HPLC piece-rate systems.
Embodiment 2：N - （（2-（3-（Trifluoromethyl）Propoxyl group）Naphthalene -8- bases）Ethyl）Acetamide（Compound I-2）'s
Prepare
Compound I-2
Take（2-（3-（Trifluoromethyl）Propoxyl group）Naphthalene -8- bases）Methylamine 10.0g, dissolved with acetonitrile 100ml.Then acetic anhydride is added
6.48g.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-2 5.0g by HPLC piece-rate systems.
Embodiment 3：（2-（3- methoxy propoxies）Naphthalene -8- bases）- N, N- dimethyl amine（Compound I-3）Preparation
Compound I-3
Take（2-（3- methoxy propoxies）Naphthalene -8- bases）Methylamine 10.0g, add acetonitrile 100ml stirring and dissolvings.Then sulfuric acid is added
Dimethyl ester 5.7g.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-3 4.5g by HPLC piece-rate systems.
Embodiment 4： N - （（2-（3-（Trifluoromethyl）Propoxyl group）Naphthalene -8- bases）Methyl）- 2,2,2- trifluoroacetamides
（Compound I-4）Preparation
Compound I-4
Prepare as described in Example 1, the difference is that acetic anhydride is replaced with into TFAA.
Embodiment 5：N - （（2-（3- methoxy propoxies）Naphthalene -8- bases）Methyl）Acetamide hydrochloride（Compound I-5）
Preparation
Compound I-5
Compound I-1 5.0g are dissolved in the mixture of methanol and chloroform, then at room temperature added 3.4 milliliters of concentrated hydrochloric acids
In solution, stir 10 hours.It is concentrated to dryness.The residue obtains compound I-5 1.2g by HPLC piece-rate systems.
Embodiment 6：N - （（2-（3-（Trifluoromethyl）Propoxyl group）Naphthalene -8- bases）Methyl）Three fluoro- N-（Trifluoromethyl）First
Amine（Compound I-6）Preparation
Compound I-6
Prepare as described in Example 3, the difference is that dimethyl suflfate is replaced with double（Trifluoromethyl）Sulfuric ester.
Embodiment 7：Pass through the acute toxic test that mouse vein is administered new melatonin class compound
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-3, I-4, I-5, I-6 with 200 milligrams
A kind of mixture in the group of composition 5 ICR mouse is administered (5 weeks big, male, the mouse that 20 grams ± 2 grams of body weight
).Then the fatal rate after 2 weeks, body weight, symptom etc. are observed, with determine minimum lethal dose (Minimum Lethal Dose,
MLD, mg/Kg).The agomelatine used（Agomelatine）As control.As a result it is as shown in table 1.
Table 1;
| Compound | Minimum lethal dose（MLD, mg/Kg） |
| Agomelatine | >600 |
| Compound I-1 | >600 |
| Compound I-2 | >600 |
| Compound I-3 | >600 |
| Compound I-4 | >600 |
| Compound I-5 | >600 |
| Compound I-6 | >600 |
The observation of survival rate, changes of weight, blood testing and middle toxicity syndrome proves to take the new melatonin class of the present invention
Compound does not have toxicity.
Embodiment 22：Pharmacokinetic trial inside the compounds of this invention
Method：
Compound I-1, I-2, I-3, I-4, I-5, I-6 are dissolved in blank solution (30% PEG- with 10g/L concentration respectively
400) in.
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..7 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：
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, it is thus right
Sample carries 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
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-3
Half-life period significantly extend.Wherein, compound I-3 long half time reaches nearly 30 hours, and its pharmacokinetics collection of illustrative plates is shown in Fig. 1.
Claims (7)
1. formula（I）Shown melatonin class compound, its stereoisomer or pharmaceutically acceptable salt,
（I）
It is characterized in that:
N is 0 to 5 integer；
R1It is selected from, wherein R4For hydrogen, methyl, trifluoromethyl, difluoromethyl, methyl fluoride, m be 1 to 10 it is whole
Number；
R2Selected from H, methyl, ethyl, propyl group, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
R3Selected from H, methyl, ethyl, propyl group, trifluoroacetyl group, difluoro acetyl group, acetyl fluoride base, ethylsulfonyl, C2-C10Alkane acyl
Base, C2-C10Enoyl-, C2-C10Alkoxy acyl, aryl C2-C10Alkanoyl；
（HLX)mFor pharmaceutically acceptable any acid, X represents acid group, and L is 1-4 integer, and m is 0-3 integer.
2. compound shown in formula I according to claim 1, it is characterised in that when m is 0, the melatonin class chemical combination
Thing is free alkali form.
3. compound shown in formula I according to claim 1, it is characterised in that pharmaceutically acceptable salt, be selected from：Hydrochloric acid
Salt, hydrobromate, sulfate, disulfate, phosphate, nitrate, and acetate, oxalates, tartrate, butanedioic acid
Salt, 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. compound shown in formula I according to claim 1, it is characterised in that compound shown in formula I include it is a kind of or
The composition of a variety of pharmaceutically acceptable carriers, excipient or diluent.
6. compound or pharmaceutical composition any one of claim 1-5, it is characterised in that described compound or medicine
Purposes of the compositions in for depression or periventricular leukomalacia related drugs.
7. compound or pharmaceutical composition any one of claim 1-5, it is characterised in that described compound or medicine
Compositions are used to treat depression or periventricular leukomalacia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610499532.3A CN107556209A (en) | 2016-06-30 | 2016-06-30 | A kind of new melatonin class compound and preparation method thereof and application medically |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610499532.3A CN107556209A (en) | 2016-06-30 | 2016-06-30 | A kind of new melatonin class compound and preparation method thereof and application medically |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230742A (en) * | 2014-08-14 | 2014-12-24 | 广东东阳光药业有限公司 | Naphthalene derivatives and application of naphthalene derivatives to medicine |
| CN104292125A (en) * | 2014-08-14 | 2015-01-21 | 广东东阳光药业有限公司 | Naphthalene derivatives and application thereof in drugs |
| CN104619346A (en) * | 2012-09-11 | 2015-05-13 | 法国施维雅药厂 | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. |
-
2016
- 2016-06-30 CN CN201610499532.3A patent/CN107556209A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104619346A (en) * | 2012-09-11 | 2015-05-13 | 法国施维雅药厂 | Stabilised amorphous form of agomelatine, a process for its preparation and pharmaceutical compositions containing it. |
| CN104230742A (en) * | 2014-08-14 | 2014-12-24 | 广东东阳光药业有限公司 | Naphthalene derivatives and application of naphthalene derivatives to medicine |
| CN104292125A (en) * | 2014-08-14 | 2015-01-21 | 广东东阳光药业有限公司 | Naphthalene derivatives and application thereof in drugs |
Non-Patent Citations (2)
| Title |
|---|
| MOHAMED ETTAOUSSI等: "Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I)", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| STN COLUMBUS: "RN 1529264-21-8等", 《REGISTRY》 * |
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Address after: 2hao Haijia Yunding 30803, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: 2hao Haijia Yunding 30803, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20180109 |