CN103772220A - Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof - Google Patents
Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof Download PDFInfo
- Publication number
- CN103772220A CN103772220A CN201310646191.4A CN201310646191A CN103772220A CN 103772220 A CN103772220 A CN 103772220A CN 201310646191 A CN201310646191 A CN 201310646191A CN 103772220 A CN103772220 A CN 103772220A
- Authority
- CN
- China
- Prior art keywords
- medicine
- ethyl
- dimethylamino
- hexalin
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and an application thereof. The derivative is good in medicine activity, and can be used for greatly prolonging the half life of a medicine, prolonging the time of the medicine staying in a human body and increasing the concentration of the medicine in blood, so that a better curative effect can be achieved. The half life of the medicine is greatly prolonged, so that the active concentration of the medicine can be kept in blood for a longer time, and the dosage of the medicine can be reduced while the curative effect is maintained under a dosage limited treatment condition. According to the derivative, adverse metabolism problems of the medicine can be solved, the medicine toxicity can be reduced, and the toxic and side effects in the administration process can be reduced.
Description
Technical field
The present invention relates to a kind of derivative and application thereof of compound, belong to technical field of pharmaceuticals.
Background technology
Major depressive disorder (MDD), is often called depression, is a kind of mental disorder, and major depressive disorder can disable and make people's function undesired.According to World Health Organization prediction, to the year two thousand thirty dysthymia disorders will become disabled major cause.Be characterized in that emotional change and other symptoms interference people work, sleep, learn, have a meal and enjoy happy movable ability.In people's life cycle, can often recur dysthymia disorders, some people may only stand 1 dysthymia disorders and occur.Other S&Ss of MDD comprise daily routines forfeiture interest; body weight or be suitable for noticeable change; insomnia or hypersomnia (drowsiness); restless/walking (psychomotor agitation); tired increasing; sense of guilt or valueless sense, thought is slow or attention is impaired and suicide purpose or suicide idea etc., is not that all people that have dysthymia disorders stand identical symptom.Venlafaxine is serotonin-NRI class thymoleptic, is to be released the medicine that is used for the treatment of major depressive disorder and generalized anxiety disorder disease of now being produced by Pfizer company in 1993 by Wyeth.Its chemical name is: 1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] hexalin.The multinomial relatively research of Venlafaxine curative effect all thinks that this medicine Cure of depression is evident in efficacy, this medicine is mainly by block the re-uptake of NE and 5-HT simultaneously, thereby rising NE and 5-HT concentration are brought into play dual antidepressant effect, there are some researches show, this medicine can make normal people's attention concentrate, memory, fast reaction speed, improve intelligence, and main drive parameter and a series of psychomotor are all had no significant effect, but affect vigilance.For depressive patients, after general medication 1-2 week can there is obvious antidepressant effect in (also having in 4 days).Due in the time using Venlafaxine to treat, conventionally strengthen dosage in order to reach result for the treatment of, cause producing a lot of poor metabolism problems, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, thereby can produce more side effect to human body in therapeutic process, use the common adverse reactions that can make patient produce in venlafaxine process to have: gastrointestinal discomfort is as felt sick, dry, apocleisis, constipation and vomiting, central nervous system is abnormal as dizzy, drowsiness, dreamland is strange, insomnia and nervous, visual abnormality, yawn, perspiration and sexual function are abnormal as impotence, abnormal and the sexual desire reduction of ejaculation.Accidental untoward reaction is: unable, inflatable, tremble, exciting, diarrhoea and rhinitis.
Summary of the invention
The object of the invention is to overcome defect of the prior art, 1-[2-dimethylamino-1-(4-p-methoxy-phenyl is provided) ethyl] new derivatives and the application thereof of hexalin, the pharmaceutical activity of described derivative is good, the bad metabolic problems that can solve medicine simultaneously, the toxic side effect in medication process is little.
The present invention is achieved by the following technical programs.
1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] new derivatives of hexalin, there is the following chemical structure general formula:
R in formula
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
Above-mentioned 1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] new derivatives of hexalin, wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19in one or several is fluorine.
Above-mentioned 1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] new derivatives of hexalin, wherein, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19in one or several is deuterium.
Above-mentioned 1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] application of new derivatives of hexalin, the application of described derivative in the medicine of preparing Cure of depression and anxiety disorder disease.
1-[2-dimethylamino-1-(4-p-methoxy-phenyl of the present invention) ethyl] new derivatives of hexalin can be used as the activeconstituents of the medicine of Cure of depression and anxiety disorder disease, in this medicine, also can contain described derivative and pharmaceutically acceptable carrier or the figuration body of significant quantity, make the formulation that is applicable to use.Drug delivery system can be albumin bound type injection liquid, liposome, powder pin, nanoparticle and cyclodextrin inclusion compound etc., form of administration can be injection liquid, also can be solid dosage or semisolid dosage form, as being injection, tablet, wafer, pill, powder or granule etc.
1-[2-dimethylamino-1-(4-p-methoxy-phenyl of the present invention) ethyl] new derivatives of hexalin can be made into the pharmaceutically acceptable salt that is suitable as medicine, the pharmaceutically acceptable salt that is suitable as medicine refers to the salt that is suitable as medicine that derivative of the present invention and acid or alkali form, and comprises inorganic salt and organic salt.The preferred salt of one class is derivative of the present invention and the sour salt forming.The acid that is applicable to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, benzene methanesulfonic acid and Phenylsulfonic acid; And the acidic amino acid such as aspartic acid, L-glutamic acid.
1-[2-dimethylamino-1-(4-p-methoxy-phenyl of the present invention) ethyl] new derivatives of hexalin is compared with Venlafaxine of the prior art, and tool has the following advantages:
(1) better efficacy of derivative of the present invention, it can increase the transformation period of medicine greatly, the time that prolong drug is detained at human body Inner, improves the concentration of blood Chinese traditional medicine simultaneously, thereby reaches better curative effect.
(2) the drug use dosage of derivative of the present invention is less, thereby can eliminate the bad metabolic problems of medicine, because the transformation period of medicine greatly increases and makes medicine can keep for more time active concentration in blood, make under the treatment condition that has dose limitation, the using dosage that can reduce medicine in keeping curative effect, reduces drug toxicity.
(3) toxicity of derivative of the present invention, side effect are still less, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, eliminate the bad metabolic problems of medicine, greatly reduced toxicity and other side effects of medicine.
Embodiment
By specific embodiment, the specific embodiment of the present invention is described in further detail below.
Embodiment 1
Preparation 1-[2-dimethylamino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin.
The preparation of the derivative of the present invention three-step reaction that comprises condensation, reduces and methylate:
Reaction equation is as follows:
Preparation process is as follows:
(1) condensation reaction preparation (1-hydroxy-cyclohexyl)-(4 – Trifluoromethoxyphen-l) acetonitrile (1-1):
Under anhydrous and oxygen-free argon shield; the sodium hydroxide of hydrogen sulfate-tetra-n-butyl ammonium and 2mol/L is added successively in (4-Trifluoromethoxyphen-l) acetonitrile; 0 ℃ and stir under reaction keep 30min; then at 0-5 ℃, in 10min, pimelinketone is joined in this mixture; reaction mixture is warming up to room temperature vigorous stirring 1h; white depositions is filtered; wash with water and hexane wash-out, obtaining required product (1-hydroxy-cyclohexyl)-(4 – Trifluoromethoxyphen-l) acetonitrile (1-1) is white solid.(4-Trifluoromethoxyphen-l) acetonitrile and pimelinketone, the mole ratio of sodium hydroxide and hydrogen sulfate-tetra-n-butyl ammonium is 1 ︰ 1-1.2 ︰ 1.2-1.3 ︰ 0.1.
(2) reduction reaction is prepared 1-[2-amino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin (1-2).
Under anhydrous and oxygen-free hydrogen shield; in the methanol solution of (4-Trifluoromethoxyphen-l) acetonitrile, add nickel catalyzator; reaction mixture is warming up to room temperature vigorous stirring 1-4h; by white depositions filtering and concentrating, thick product obtains product 1-[2-amino-1-(4-Trifluoromethoxyphen-l through purification by silica gel column chromatography)-ethyl]-hexalin (1-2).The mole ratio of (4-Trifluoromethoxyphen-l) acetonitrile and nickel catalyzator is 1 ︰ 0.1-0.2.1 molar (4-Trifluoromethoxyphen-l) acetonitrile uses the methyl alcohol of 2-5L.
(3) methylation reaction is prepared 1-[2-dimethylamino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin.
Under anhydrous and oxygen-free argon shield, methyl iodide and salt of wormwood are at room temperature joined to 1-[2-amino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin is in the solution of anhydrous tetrahydro furan, at room temperature stir 20h, reaction mixture is diluted with tetrahydrofuran (THF), filter, by filtrate vacuum concentration, add again 3-amino-1-propyl alcohol (1mL), mixture is cooled to room temperature after stirring reaction 4h at 170 ℃, dilute with water, and be extracted with ethyl acetate, by the organic layer salt water washing merging, dry also concentrating under reduced pressure, thick product obtains target product 1-[2-dimethylamino-1-(4-Trifluoromethoxyphen-l through purification by silica gel column chromatography)-ethyl]-hexalin.1-[2-amino-1-(4-Trifluoromethoxyphen-l)-ethyl] mole ratio of-hexalin and methyl iodide and salt of wormwood is 1 ︰ 6-7 ︰ 3-4.1 molar 1-[2-amino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin uses the tetrahydrofuran (THF) of 2-5L, 3-amino-1-propyl alcohol of 0.2-0.3L and the salt solution of 2-5L.
Embodiment 2
Preparation 1-[2-dimethylamino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin-d6.
Preparation method, with embodiment 1, replaces with methyl iodide-d3 by the methyl iodide in embodiment 1.
Embodiment 3
Preparation 1-[2-bis-(trifluoromethyl) amino-1-(4-Trifluoromethoxyphen-l)-ethyl]-hexalin.
Preparation method, with embodiment 1, replaces with iodo trifluoromethane by the methyl iodide in embodiment 1.
Here description of the invention and application is illustrative, not wants scope of the present invention to limit in the above-described embodiments, and therefore, the present invention is not subject to the restriction of the present embodiment, and the technical scheme that any employing equivalence replacement obtains is all in the scope of protection of the invention.
Claims (4)
1.1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] new derivatives of hexalin, it is characterized in that thering is the following chemical structure general formula:
R in formula
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
2. 1-[2-dimethylamino-1-(4-p-methoxy-phenyl as claimed in claim 1) ethyl] new derivatives of hexalin, it is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19in one or several is fluorine.
3. 1-[2-dimethylamino-1-(4-p-methoxy-phenyl as claimed in claim 1) ethyl] new derivatives of hexalin, it is characterized in that R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14r
15, R
16, R
17, R
18, R
19in one or several is deuterium.
4. the 1-[2-dimethylamino-1-(4-p-methoxy-phenyl as described in any one in claim 1-3) ethyl] application of new derivatives of hexalin, it is characterized in that the application of described derivative in the medicine of preparing Cure of depression and anxiety disorder disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310646191.4A CN103772220A (en) | 2013-12-03 | 2013-12-03 | Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310646191.4A CN103772220A (en) | 2013-12-03 | 2013-12-03 | Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103772220A true CN103772220A (en) | 2014-05-07 |
Family
ID=50565049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310646191.4A Pending CN103772220A (en) | 2013-12-03 | 2013-12-03 | Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103772220A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020022662A1 (en) * | 1999-06-15 | 2002-02-21 | American Home Products Corporation | Enantiomers of O-desmethyl venlafaxine |
| CN101336226A (en) * | 2005-12-01 | 2008-12-31 | 奥斯拜客斯制药有限公司 | Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity |
| CN101663263A (en) * | 2007-02-21 | 2010-03-03 | 塞普拉柯公司 | Solid forms comprising (-) o-desmethylvenlafaxine and uses thereof |
| WO2012070025A1 (en) * | 2010-11-26 | 2012-05-31 | Cadila Pharmaceuticals Ltd | Process for the preparation of agomelatine |
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
| WO2013028639A1 (en) * | 2011-08-19 | 2013-02-28 | The Trustees Of Princeton University | C-halogen bond formation |
-
2013
- 2013-12-03 CN CN201310646191.4A patent/CN103772220A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020022662A1 (en) * | 1999-06-15 | 2002-02-21 | American Home Products Corporation | Enantiomers of O-desmethyl venlafaxine |
| CN101336226A (en) * | 2005-12-01 | 2008-12-31 | 奥斯拜客斯制药有限公司 | Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity |
| CN101663263A (en) * | 2007-02-21 | 2010-03-03 | 塞普拉柯公司 | Solid forms comprising (-) o-desmethylvenlafaxine and uses thereof |
| WO2012070025A1 (en) * | 2010-11-26 | 2012-05-31 | Cadila Pharmaceuticals Ltd | Process for the preparation of agomelatine |
| WO2013028639A1 (en) * | 2011-08-19 | 2013-02-28 | The Trustees Of Princeton University | C-halogen bond formation |
| CN102675101A (en) * | 2012-05-16 | 2012-09-19 | 王蕾 | Preparation method of 2-(4-haloethyl) phenyl-2-methyl propionic ester and synthesis method of bilastine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2019394956A1 (en) | Methods of treating neurological and psychiatric disorders | |
| EP1466889B1 (en) | O-Desmethylvenlafaxine succinate | |
| JPS61277618A (en) | Remedy for autism | |
| JP2015535290A (en) | 7,8-Dihydroxyflavone and 7,8-substituted flavone derivatives, compositions and methods related thereto | |
| US20210315859A1 (en) | Methods of treating neurological and psychiatric disorders | |
| US10239848B2 (en) | Cyclohexenyl compounds, compositions comprising them and uses thereof | |
| US11332475B2 (en) | Optically active pyranochromenyl phenol derivative and pharmaceutical composition comprising same | |
| JP2005535584A5 (en) | ||
| CN104231013B (en) | A kind of gastrodine Glehnilae and preparation method thereof and application | |
| CN104523589A (en) | Oral suspension type medicine composition containing agomelatine | |
| CN101270074A (en) | Method for preparing high purity mitiglinide calcium | |
| CN111960972A (en) | Preparation process and application of taurine magnesium salt and taurine magnesium complex | |
| CN103772220A (en) | Novel derivative of 1-[2-dimethylamino-1-(4-methoxyphenyl) ethyl] cyclohexanol and application thereof | |
| CN103724281A (en) | Novel derivative of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propyl and application of novel derivative | |
| CN115141161A (en) | Crystal form A of pramipexole xinafoate and preparation method thereof | |
| CN103724198A (en) | Novel derivative of dimethyl fumarate and application of novel derivative | |
| RU2015117412A (en) | IMPROVED METHOD FOR OBTAINING VINCRISTINE INTEGRATED IN LIPOSOMES FOR THERAPEUTIC USE | |
| CN103819471A (en) | Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof | |
| CN105693813A (en) | Preparation and medical application of glycyrrhizic acid berberine coupling compound | |
| TWI735652B (en) | Co-crystal and/or eutectic crystal of kojic acid, compositions comprising the same, and uses thereof | |
| CN106176740B (en) | The medical usage of the anti-habituation of corydalmine | |
| CN110339201B (en) | Application of polygala tenuifolia saponin B | |
| US20200085849A1 (en) | Methods and compositions for improving sleep | |
| WO2021115372A1 (en) | Vortioxetine prodrug and use thereof | |
| KR100923434B1 (en) | Sibutramine thioctate, process for preparing the same and pharmaceutical composition including the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140507 |