CN100455560C - Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use - Google Patents
Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use Download PDFInfo
- Publication number
- CN100455560C CN100455560C CNB2004100462825A CN200410046282A CN100455560C CN 100455560 C CN100455560 C CN 100455560C CN B2004100462825 A CNB2004100462825 A CN B2004100462825A CN 200410046282 A CN200410046282 A CN 200410046282A CN 100455560 C CN100455560 C CN 100455560C
- Authority
- CN
- China
- Prior art keywords
- venlafaxine
- prodrug
- cyclohexyl
- ethyl
- dimethylin
- 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.)
- Active
Links
Abstract
The present invention discloses a prodrug which comprises long chain fatty acyl and substitutes venlafaxine. The prodrug comprises a compound of which the structure is disclosed in a general formula 1, and a medicinal salt or aqua compound, wherein R1 represents hydrogen, straight chain or branch chain alkyl, or acyl or trifluoromethyl containing 1 to 6 carbon; R2 represents straight chain or branch chain carbon acyl containing 8 to 18 carbon; star represents a chiral center. The present invention also discloses a preparation method of the prodrug and the application of the prodrug for preventing and curing central nervous system diseases. The half life of the prodrug provided by the present invention approaches to or exceeds 10 hours. Compared with venlafaxine, the prodrug has the advantage of excellent long-acting effects.
Description
Affiliated technical field
The present invention relates to the Venlafaxine prodrug (I) that a class contains the long-chain fat acyl substituted; comprise one group of new medical compounds and can be used as medicinal salt or hydrate; the pharmaceutical composition that also relates to the prodrug that contains effective dosage; and the preparation method of this its prodrug, and this prodrug and the composition application in preventing and treating disease such as central nervous system.
Background technology
Venlafaxine (Venlafaxine) is the medicine that has inhibition of 5-HT reuptake and norepinephrine reuptake inhibition dual function concurrently of clinical application, is mainly used in the control of dysthymia disorders.Usefulness is strong or similar with Fourth Ring class thymoleptic (TCAs) than three rings, to MAOI unrestraint effect, there is not avidity with acceptors such as cholinergic, histaminergic, adrenergics, so the not untoward reactions such as calmness, dry, constipation, uroschesis and blurring of vision relevant with these acceptors.Venlafaxine is lower than TCAs greatly to the untoward reaction of central nervous system, and cardiovascular systems is not had obvious influence.Prior art shows in addition, and Venlafaxine also can be used for treating diseases such as anxiety disorder, attention-deficient obstacle, pain, alcoholism and irritable bowel syndrome.
Venlafaxine is a kind of phenylethylamine class thymoleptic of new texture.Its structural formula is suc as formula shown in the II, has an asymmetric carbon atoms in the molecular structure, exists in the mode of racemization.Confirm through hydrobromic monocrystalline X-ray analysis and chromatic dispersion technology, the absolute configuration of (+) enantiomorph of Venlafaxine be the S type (yardley etc., J Med Chem, 1990,33:2899).
Receptor, agonist Racemic isoproterenol cAMP (cAMP) concentration that can raise therefore in preclinical test, is utilized the minimizing that cAMP discharges and is caused that the beta-receptor downward modulation is used for estimating the effect of thymoleptic.Experimentation on animals finds, Venlafaxine no matter short-term or long term administration can both reduce the release of cAMP, thereby causes the downward modulation effect of beta-receptor, but TCA needs long-term prescription that this effect just be arranged.Because this beta-receptor is the hypothesis of downward modulation fast, thereby proposed Venlafaxine and may have the characteristics more rapid-action than other thymoleptic of present use.Clinical control studies show that patient takes Venlafaxine after one week, tangible antidepressant effect can occur.
Prior art discloses (Pang cloud dawn, the tribute swallow that oozes. the pharmacology of Venlafaxine and clinical application [J]. Chinese Journal of New Drugs and Clinical Remedies, 2000,19 (5): 342-344), after Venlafaxine is oral, there is first pass effect, only 12.6% enters the body circulation, by the P450 enzymes metabolism, main metabolites is the O-ODV with pharmacologically active in liver.The transformation period of Venlafaxine only is 4 hours.So the action time of Venlafaxine is short, needs administration 2-3 time every day.This makes this medicine be used to treat neural psychosis and is restricted that patient needs frequent medication, has increased new psychological burden.For reaching long-acting purpose, once studied the prolonged action preparation of slow release abroad from the technology of pharmaceutics angle.U.S. Wyeth (Wyeth-Ayerst) has developed 1 day 1 time oral prolonged action preparation (Efexor XR), and respectively at 1997 and 1999 in Britain, the U.S. and Argentina's listing.This prolonged action preparation is a kind of slow delivery formulations (Qi Xuedan that contains Venlafaxine; Tu Shuzi; Wang Qiujuan. the progress [J] of treatment dysthymia disorders medicine. Chinese Journal of New Drugs; 2003; 12 (10): 810-816); the Venlafaxine prodrug that contains the long-chain fat acyl group with the present invention is compared, and the long-acting principle that it reached is different fully.
Summary of the invention
The object of the present invention is to provide a kind of new long-acting Venlafaxine prodrug.
New long-acting Venlafaxine prodrug provided by the invention is the Venlafaxine that contains the long-chain fat acyl substituted, its structure shown in general formula I compound and can be used as medicinal salt or hydrate, among the formula I, R
1Represent hydrogen, contain straight or branched alkyl or the acyl group or the trifluoromethyl of 1 to 6 carbon; R
2Representative contains the straight or branched carbonyl acyl group of 8 to 18 carbon; * represent chiral centre, comprise R, S and RS (racemic modification) configuration of compound.
Among the present invention, new compound is that tert-hydroxyl in the Venlafaxine structure and longer chain fatty acid are with the new ester of the formed class of covalent bonds.Be specifically as follows: sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; N-nonanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Capric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Undecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl, lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl, tridecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Tetradecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Hexadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Margaric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; R-(-)-lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; S-(+)-lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; 2-methyl lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl, and the formed pharmaceutically useful salt of these esters, example hydrochloric acid salt, hydrobromate, phosphoric acid salt, Citrate trianion, maleate.
Experimental verification is compared with Venlafaxine, and the advantage that compound of the present invention and pharmaceutical salts thereof are outstanding is to demonstrate excellent long-acting.
Another object of the present invention is to provide preparation to contain the method for the Venlafaxine compound of long-chain fat acyl substituted.
This method is to be raw material with R, S or RS-Venlafaxine, adds dewatering agent and catalyzer, prepares ester with the long-chain fat carboxylic acid reaction.At dewatering agent described in the preparation process for being selected from carbon imide class reagent such as dicyclohexyl carbon imide (DCC), 1-dimethylamino-propyl-3-ethyl carbon imide (EDC) or di-isopropyl carbon imide etc.; Described catalyzer is for being selected from acylation reaction catalyst such as dimethylamino pyridine (DMAP), 2 or pyridine etc.
A further object of the present invention is to provide one or more pharmaceutical compositions that contain Venlafaxine prodrug and pharmaceutically acceptable carrier or vehicle.
Another purpose of the present invention is to provide the purposes of the medicine of described long-acting Venlafaxine prodrug in neural psychosis of preparation control especially dysthymia disorders and anxiety disorder relative disease.
Embodiment
The present invention at first provides has the novel Venlafaxine compound that contains the long-chain fat acyl substituted shown in the general formula I:
In the formula,
The configuration of chiral centre (*) can be R, S or RS (racemic modification); R
1Represent hydrogen, contain the straight or branched alkyl of 1 to 6 carbon or acyl group, trifluoromethyl; R
2Representative contains the straight or branched carbonyl acyl group of 8 to 18 carbon.
Concrete these compounds can be sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; N-nonanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Capric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Undecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl, lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl, tridecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Tetradecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Hexadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Margaric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-pentadecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; R-(-)-octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; S-(+)-octadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl; Lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; R-(-)-lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; S-(+)-lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl; 2-methyl lauric acid 1-[2-(dimethylin)-1-(4-Trifluoromethoxyphen-l)-ethyl] cyclohexyl etc.
As prodrug of the present invention, comprise that also these compounds can be used as medicinal salt or hydrate.Organic or inorganic hydrochlorates such as example hydrochloric acid salt, hydrobromate, phosphoric acid salt, maleate, Citrate trianion.
In order to prepare the compound described in the general formula I of the present invention, the present invention includes, with Venlafaxine and longer chain fatty acid, in suitable solvent and under the effect of dewatering agent and catalyzer, to reflux temperature, carry out esterification in room temperature.Specifically, can directly use longer chain fatty acid, perhaps longer chain fatty acid be prepared the form that becomes active ester or carboxylic acid halides.Venlafaxine is that free alkali or preparation become metal oxide.Suitable solvent comprises acetone, tetrahydrofuran (THF), and dioxane, dimethyl formamide, methyl-sulphoxide, pyridine, trimethylpyridine and halogenated alkane etc., halogenated alkane is selected from methylene dichloride, trichloromethane and ethylene dichloride etc.Dewatering agent is selected from various carbon imide such as dicyclohexyl carbon imide (DCC), 1-dimethylamino-propyl-3-ethyl carbon imide (EDC) or di-isopropyl carbon imide (DCC) etc.Catalyzer is selected from acylation catalyst commonly used, as dimethylamino pyridine (DMAP), 2 or pyridine etc.
The preparation of chirality Venlafaxine can be according to Yardley etc., J Med Chem, 1990,33 (10): the method preparation that 2899-2905 describes.Also can optically active stage enantiomer separation be obtained by other disassemble technique of this area routine.
The preparation of The compounds of this invention pharmacologically acceptable salt is the free alkali that adopts compound, carries out with inorganic or the direct salt-forming reaction of organic acid.Inorganic or organic acid can be selected from hydrochloric acid, Hydrogen bromide, phosphoric acid, citric acid, toxilic acid etc.
The invention still further relates to the pharmaceutical composition that obtains as the described compound of general formula I and pharmaceutically acceptable carrier or vehicle co-production that will contain medicine effective dose.Use pharmaceutical carrier well known to those skilled in the art can make the pharmaceutical composition of the The compounds of this invention that contains effective dose.
About the purposes research of known Venlafaxine, U.S. Patent number 5530013 (Husbands etc.) discloses Venlafaxine and the purposes of relevant new compound in inducing cognitive enhancing the thereof; U.S. Patent number 5043466 (Shepard etc.) discloses the preparation and the antidepressant effect thereof of sulfo-Venlafaxine; Open racemization Venlafaxine of U.S. Patent number 4535186 (Husbands etc.) and meta-bolites thereof; European patent number 0639374A3 (Rudolph) discloses Venlafaxine and the purposes of derivative in treatment obesity, anxiety, anxiety and attention-deficient thereof; Chinese patent application number 02808112.9 (breathe out Field, etc.) discloses salt, composition, formulation and the usage of new O-ODV; Chinese patent publication number CN1399626A has disclosed the ether of o-desmethyl venlafaxine and the method for treatment central nervous system disease thereof.(Zhao Yu, Chen Jie, Li Kuiluan, the pharmacology of Venlafaxine and clinical application such as Zhao Yu.The medicine Leader, 2001,20 (5): reported at antidepressant, neurasthenia, anxiety disorder, women's premenstrual syndrome, childhood hyperkinetic syndrome etc. that 315) result of treatment is all arranged.Zhang Yan flies to wait (Zhang Yanfei, Zhang Jianliang.The tired comparative study that occurs together of Venlafaxine and clomipramine treatment dysthymia disorders.The pharmacoepidemiology magazine, 2003,12 (3): 117-9) reported the tired curative effect of treatment.Lu Rongzhuan reports the (clinical application of novel antidepressant Wan Lafaxin.The Tianjin pharmacy, 2002,14 (4): 14-16) use purposes such as this medicine treatment dysthymia disorders, anxiety disorder, schizophrenia, hyperkinetic syndrome, abstinence from alcohol.
The Venlafaxine long chain fatty acid ester of formula of the present invention (I) and pharmacologically acceptable salt and hydrate, be on the basis of original medicine, to have increased long-acting group, slowly decompose the former medicine Venlafaxine of generation in vivo after taking and bring into play drug effect, reached long-acting purpose, but do not change the biological activity of former medicine, can be used for the biology and the pharmacological activity of Venlafaxine known in the art and salt thereof in theory.Specifically, these compounds can be used for treatment or suppress central nervous system disease, comprise depression, fibromyalgia, anxiety, Phobias, phobia, post-traumatic stress disorder, premenstrual dysphoria (being also referred to as premenstrual syndrome), social anxiety disorder, extensive anxiety disorder, autism, schizophrenia, fat, anorexia nervosa, bulimia nervosa, Cocaine and alcohol addiction, sexual dysfunction, marginal personality's disease, chronic fatigue syndrome, the urinary incontinence, pain, the Reynolds syndrome, the attention-deficient obstacle, with or without hyperkinetic syndrome etc.
The present invention also comprises prodrug is used for the preferred people of Mammals, treat, prevent, suppress or alleviate the method for above listed disease, this method comprises that the Mammals for the treatment of to needs provides the medicine of the present invention of medicine effective dose, comprises prodrug and its pharmaceutical composition.
When compound of the present invention and salt thereof or composition were provided, described using method is meant directly used the precursor substance that can form the Venlafaxine of dose therapeutically effective in vivo among the present invention.
Medicine effective dose comprises the dosage that alleviation or prophylactic effect can be provided described disease.The compounds of this invention is a prodrug, and its long-chain ester based meeting contacts with enzyme in vivo and decomposes, and the result produces the parent compound Venlafaxine.
The external medicine of healthy people's whole blood shows that for experiment the transformation period of The compounds of this invention is approaching or surpass 10 hours, all is longer than Venlafaxine 4 hours; And the long half time that generates Venlafaxine after the metabolism was in 20 hours.The optical isomer of The compounds of this invention and equal significant prolongation of the transformation period of corresponding racemic modification.Illustrate that Venlafaxine is very remarkable through the transformation period prolongation of transformation period after the prodrugization and generation Venlafaxine, reached the long lasting intended purposes of prodrug.
The compounds of this invention or its composition can be with oral methods or the medications of parenteral road.Oral medication can be tablet, pill, powdered mixture, capsule, Drug coating, solution, emulsion, dispersion agent, injection and suppository or other suitable form.These preparations are according to the known method preparation of those skilled in the art.In order to make tablet, capsule, the used auxiliary material of Drug coating is the auxiliary agent of conventional usefulness, starch for example, gelatin, gum arabic, masonry, polyoxyethylene glycol, the used solvent of liquid dosage form is water for example, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.Containing in the preparation of The compounds of this invention also can have other auxiliary agent, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives, pigment etc.
The invention will be further described below with reference to embodiment, but do not limit the scope of the invention.
The determining instrument that uses in embodiment and the experiment is, fusing point is with RY-1 type electric heating fusing point instrument, and thermometer reading is not calibrated, and NMR (Nuclear Magnetic Resonance) spectrum is with JNM-ECA-400 type nuclear magnetic resonance analyser, and mass spectrum is with Zabspec type mass spectrograph.Elemental analyser is a Carlo Erba1106 type elemental analyser.Polarimeter is a PE-243B type polarimeter.
Embodiment 1: prepare sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B1)
In the 100ml eggplant-shape bottle, adding Venlafaxine 0.50g (1.59mmo]) and sad 0.46g (3.19mmol), after anhydrous methylene chloride 15ml dissolving, stir in ice bath.Add N, the solution that N-dicyclohexyl carbimide 0.69g (3.34mmol) and anhydrous methylene chloride 5ml form, generate white precipitate gradually, the ice bath reaction added N after 2 hours, and N-Dimethylamino pyridine 0.1g is as catalyzer, after removing ice bath, stirring at room 24 hours, TLC (methylene dichloride: methyl alcohol 15: 1 adds 2 of ammoniacal liquor) detects demonstration and reacts completely.Remove by filter white precipitate N, after the N-dicyclohexylurea (DCU), solution extracts with 5% aqueous citric acid solution (25ml * 3), with saturated sodium-chloride water solution (30ml * 3) extraction, dichloromethane solution was added anhydrous magnesium sulfate drying after 6 hours again, filter, the evaporate to dryness methylene dichloride, obtain off-white color solid 0.51g, this product is B1, productive rate 79.6%.Solid is dissolved in the anhydrous diethyl ether, the cooling of external application frozen water, the diethyl ether solution of dropping hydrogenchloride has a large amount of white hydrochloride salts precipitations.It is extremely neutral with the anhydrous diethyl ether washing to filter the back, with ethanol and ether solvent recrystallization, mp142-144 ℃.
1H-NMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.96-3.93 (dd, 1H, J=3.4Hz, J=10.9Hz, CH), 3.78 (s, 3H, CH
3O), 2.93-2.13 (tt, 2H, J=3.4Hz, J=10.9Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.30-0.87 (m, 23H, cyclohexyl, (CH
2)
5CH
3).MS (FAB) m/z:404.3 (M
+), 260.2 (M
+-OCO (CH
2)
5CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 68.23 9.62 3.18
Measured value (%) 68.51 9.87 3.02
Embodiment 2: preparation n-nonanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B2)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and n-nonanoic acid 0.56g (3.54mmol) reaction, used halogenated alkane solvent is a trichloromethane, and dewatering agent is 1-dimethylamino-propyl-3-ethyl carbon imide, and catalyzer is a 2.Get white solid (B2) 0.43g, productive rate 64.9%.Make hydrochloride by similar approach, mp136-138 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.6Hz, Ph-H), 6.84 (d, 2H, J=8.6Hz, Ph-H), 3.96-3.93 (dd, 1H, J=3.1Hz, J=10.7Hz, CH), 3.78 (s, 3H, CH
3O), 2.96-2.14 (tt, 2H, J=3.1Hz, J=10.7Hz, CH
2N), 2.26 (t, 2H, COCH
2), 2.15 (s, 6H, N (CH
3)
2), 1.61-0.86 (m, 25H, cyclohexyl, (CH
2)
6CH
3).MS (FAB) m/z:418.3 (M
+), 260.1 (M
+-OCO (CH
2)
6CH
2), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 68.77 9.77 3.08
Measured value (%) 68.99 10.09 2.92
Embodiment 3: preparation capric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B3)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and capric acid 0.55g (3.19mmol) reaction, solvent for use is an ethylene dichloride, and dewatering agent is DCC, and catalyzer is DMAP.Get off-white color solid (B3) 0.32g, productive rate 49.5%.Make hydrochloride by well-established law, mp150-152 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.96-3.94 (dd, 1H, J=3.4Hz, J=10.9Hz, CH), 3.78 (s, 3H, CH
3O), 2.96-2.14 (tt, 2H, J=3.4Hz, J=10.9Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.14 (s, 6H, N (CH
3)
2), 1.59-0.86 (m, 27H, cyclohexyl, (CH
2)
7CH
3).MS (FAB) m/z:432.4 (M
+), 260.2 (M
+-OCO (CH
2)
7CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 69.28 9.90 2.99
Measured value (%) 69.25 10.37 2.69
Embodiment 4: preparation undeeanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B4)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and undeeanoic acid 0.60g (3.22mmol) reaction, get off-white color solid (B4) 0.43g, productive rate 59.9%.Make hydrochloride by well-established law, mp114-116 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.4Hz, Ph-H), 6.83 (d, 2H, J=8.4Hz, Ph-H), 3.94-3.91 (dd, 1H, J=3.4Hz, J=11Hz, CH), 3.78 (s, 3H, CH
3O), 2.90-2.12 (tt, 2H, J=3.4Hz, J=11Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.12 (s, 6H, N (CH
3)
2), 1.60-0.86 (m, 29H, cyclohexyl, (CH
2)
8CH
3).MS (FAB) m/z:446.3 (M
+), 260.1 (M
+-OCO (CH
2)
8CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 69.75 10.03 2.91
Measured value (%) 69.52 10.46 2.77
Embodiment 5: preparation laurostearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B5)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and laurostearic acid 0.64g (3.19mmol) reaction, get light yellow solid (B5) 0.59g, productive rate 80.6%.Make hydrochloride by well-established law, mp105-107 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.95-3.93 (dd, 1H, J=3.4Hz, J=10.7Hz, CH), 3.78 (s, 3H, CH
3O), 2.94-2.13 (tt, 2H, J=3.4Hz, J=10.7Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.60-0.86 (m, 31H, cyclohexyl, (CH
2)
9CH
3).MS (FAB) m/z:460.3 (M
+), 260.1 (M
+-OCO (CH
2)
9CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 70.20 10.16 2.82
Measured value (%) 70.32 10.48 2.79
Embodiment 6: preparation tridecylic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B6)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and tridecylic acid 0.69g (3.22mmol) reaction, get white solid (B6) 0.50g, productive rate 66.5%.Make hydrochloride by well-established law, mp108-111 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.4Hz, Ph-H), 6.83 (d, 2H, J=8.4Hz, Ph-H), 3.95-3.93 (dd, 1H, J=3.0Hz, J=10.6Hz, CH), 3.78 (s, 3H, CH
3O), 2.94-2.13 (tt, 2H, J=3.0Hz, J=10.6Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.60-0.86 (m, 33H, cyclohexyl, (CH
2)
10CH
3).MS (FAB) m/z:474.3 (M
+), 260.1 (M
+-OCO (CH
2)
10CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 70.63 10.27 2.75
Measured value (%) 71.33 10.74 2.59
Embodiment 7: preparation TETRADECONIC ACID 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B7)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and TETRADECONIC ACID 0.73g (3.19mmol) reaction, get white solid (B7) 0.45g, productive rate 58.1%.Make hydrochloride by well-established law, mp108-110 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.6Hz, Ph-H), 6.83 (d, 2H, J=8.6Hz, Ph-H), 3.95-3.93 (dd, 1H, J=3.6Hz, J=10.9Hz, CH), 3.78 (s, 3H, CH
3O), 2.92-2.13 (tt, 2H, J=3.6Hz, J=10.9Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.58-0.86 (m, 35H, cyclohexyl, (CH
2)
11CH
3).MS (FAB) m/z:488.4 (M
+), 260.1 (M
+-OCO (CH
2)
11CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 71.02 10.38 2.67
Measured value (%) 71.01 10.70 2.51
Embodiment 8: preparation pentadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B8)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and pentadecanoic acid 0.78g (3.22mmol) reaction, get light yellow solid (B8) 0.72g, productive rate 90.4%.Make hydrochloride by well-established law, mp107-109 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.97-3.95 (dd, 1H, J=3.4Hz, J=10.9Hz, CH), 3.78 (s, 3H, CH
3O), 2.98-2.15 (tt, 2H, J=3.4Hz, J=10.9Hz, CH
2N), 2.26 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.59-0.86 (m, 37H, cyclohexyl, (CH
2)
12CH
3).MS (FAB) m/z:502.4 (M
+), 260.2 (M
+-OCO (CH
2)
12CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 71.40 10.49 2.60
Measured value (%) 71.25 10.72 2.51
Embodiment 9: preparation palmitic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B9)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and palmitic acid 0.82g (3.19mmol) reaction, get light yellow solid (B9) 0.69g, productive rate 84.3%.Make hydrochloride by well-established law, mp120-122 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.93-3.92 (dd, 1H, J=3.3Hz, J=10.9Hz, CH), 3.78 (s, 3H, CH
3O), 2.92-2.13 (tt, 2H, J=3.3Hz, J=10.9Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.13 (s, 6H, N (CH
3)
2), 1.60-0.86 (m, 39H, cyclohexyl, (CH
2)
13CH
3).MS (FAB) m/z:516.5 (M
+), 260.2 (M
+-OCO (CH
2)
13CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 71.77 10.59 2.54
Measured value (%) 71.87 10.78 2.42
Embodiment 10: preparation stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B10)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and stearic acid 0.91g (3.20mmol) reaction, get yellow solid (B10) 0.56g, productive rate 64.9%.Make hydrochloride by well-established law, mp112-114 ℃.
1HNMR (CDCl
3) δ (ppm): 7.16 (d, 2H, J=8.7Hz, Ph-H), 6.83 (d, 2H, J=8.7Hz, Ph-H), 3.94-3.93 (dd, 1H, J=3.7Hz, J=11Hz, CH), 3.78 (s, 3H, CH
3O), 2.92-2.12 (tt, 2H, J=3.7Hz, J=11Hz, CH
2N), 2.25 (t, 2H, COCH
2), 2.12 (s, 6H, N (CH
3)
2), 1.59-0.86 (m, 41H, cyclohexyl, (CH
2)
15CH
3).MS (FAB) m/z:544.4 (M
+), 260.2 (M
+-OCO (CH
2)
15CH
3), 58 (CH
2N (CH
3)
2, base peak).
Ultimate analysis: C H N
Theoretical value (%) 72.11 10.68 2.47
Measured value (%) 72.02 10.89 2.29
Embodiment 11: preparation 2-methyl lauric acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (B11)
The same B1 of synthetic method.Get Venlafaxine 0.50g (1.59mmol) and 2-methyl lauric acid 0.94g (3.20mmol) reaction, get yellow solid (B11).Make hydrochloride by well-established law.
1HNMR (CDCl
3) δ (ppm): 7.19 (d, 2H, J=8.7Hz, Ph-H), 6.78 (d, 2H, J=8.7Hz, Ph-H), 3.94-3.93 (dd, 1H, J=3.7Hz, J=11Hz, CH), 3.73 (s, 3H, CH
3O), 2.92-2.12 (tt, 2H, J=3.7Hz, J=11Hz, CH
2N), 2.21 (1H, COCH), 2.12 (s, 6H, N (CH
3)
2), 1.59-0.86 (m, 34H, cyclohexyl, aliphatic chain).MS(FAB)m/z：473.3(M
+)。
Embodiment 12: preparation stearic acid 1-[2-(dimethylin)-1-(4-acetoxyl group phenyl)-ethyl] cyclohexyl (B12)
The same B1 of synthetic method.Get 1-[2-(dimethylin)-1-(4-acetoxyl group phenyl)-ethyl] hexalin 0.55g (1.59mmol) and stearic acid 0.91g (3.20mmol) reaction, get yellow solid (B12).Make hydrochloride by well-established law.
1HNMR (CDCl
3) δ (ppm): 7.17 (d, 2H, J=8.7Hz, Ph-H), 6.81 (d, 2H, J=8.7Hz, Ph-H), 3.94-3.93 (dd, 1H, J=3.7Hz, J=11Hz, CH), 2.92-2.12 (tt, 2H, J=3.7Hz, J=11Hz, CH
2N), 2.38 (s, 3H, CH
3COO), 2.25 (t, 2H, COCH
2), 2.10 (s, 6H, N (CH
3)
2), 1.60-0.83 (m, 41H, cyclohexyl, (CH
2)
15CH
3).MS(FAB)m/z：571.4(M
+)。
Embodiment 13: prepare left-handed sad 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C1)
Get left-handed Venlafaxine 0.04g (0.14mmol) and sad 0.04g (0.28mmol) adds in the 10ml eggplant-shape bottle, after anhydrous methylene chloride 1.5ml dissolving, stir in ice bath.Add N, the solution that N-dicyclohexyl carbimide 0.06g (0.29mmol) and anhydrous methylene chloride 0.5ml make, generate white precipitate gradually, the ice bath reaction is after 2 hours, add N, N-Dimethylamino pyridine 0.01g is as catalyzer, remove ice bath after, stirring at room 24 hours, TLC (methylene dichloride: methyl alcohol 8: 1) detect demonstration and react completely.Remove by filter N, the N-dicyclohexylurea (DCU), with the preparation Thin-layer separation, developping agent is a methylene dichloride: methyl alcohol 8: 1, scrape and get afterwards with methylene dichloride: 8: 1 wash-outs of methyl alcohol get white solid (C1) 0.02g, productive rate 34.5% behind the evaporate to dryness.Make hydrochloride by well-established law, Rf=0.36.The sad Venlafaxine ester of racemization Rf=0.37.[α]
25 D-8.51°(c1.14，95％EtOH)。
Embodiment 14: the preparation sad 1-[2-of dextrorotation (dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C2)
Get dextrorotation Venlafaxine 0.04g (0.14mmol) and sad 0.04g (0.28mmol) adds in the 10ml eggplant-shape bottle, after anhydrous methylene chloride 1.5ml dissolving, stir in ice bath.Add N, the solution that N-dicyclohexyl carbimide 0.06g (0.29mmol) and anhydrous methylene chloride 0.5ml make, generate white precipitate gradually, the ice bath reaction is after 2 hours, add N, N-Dimethylamino pyridine 0.01g is as catalyzer, remove ice bath after, stirring at room 24 hours, TLC (methylene dichloride: methyl alcohol 8: 1) detect demonstration and react completely.Remove by filter N, the N-dicyclohexylurea (DCU), with the preparation Thin-layer separation, developping agent is a methylene dichloride: methyl alcohol 8: 1, scrape and get afterwards with methylene dichloride: 8: 1 wash-outs of methyl alcohol get white solid (C2) 0.02g, productive rate 34.5% behind the evaporate to dryness.Make hydrochloride by well-established law, Rf=0.37.The sad Venlafaxine ester of racemization Rf=0.37.[α]
25 D+8.68°(c0.76，95％EtOH)。
Embodiment 15: prepare left-handed laurostearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C3)
The same C1 of synthetic method.Get left-handed Venlafaxine 0.04g (0.14mmol) and laurostearic acid 0.06g (0.30mmol) reaction, get white solid (C3) 0.03g, productive rate 45.3%.Make hydrochloride by well-established law, Rf=0.45.[α]
25 D-8.33°(c0.84，95％EtOH)。
Embodiment 16: preparation dextrorotation laurostearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C4)
The same C2 of synthetic method.Get dextrorotation Venlafaxine 0.04g (0.14mmol) and laurostearic acid 0.06g (0.30mmol) reaction, get white solid (C4) 0.03g, productive rate 45.3%.Make hydrochloride by well-established law, Rf=0.45.Racemization laurostearic acid Venlafaxine ester Rf=0.45.[α]
25 D+8.74°(c0.95，95％EtOH)。
Embodiment 17: prepare left-handed pentadecanoic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C5)
The same C1 of synthetic method.Get left-handed Venlafaxine 0.04g (0.14mmol) and pentadecanoic acid 0.07g (0.29mmol) reaction, get white solid (C5) 0.04g, productive rate 52.3%.Make hydrochloride by well-established law, Rf=0.64.Racemization pentadecanoic acid Venlafaxine ester Rf=0.62.[α]
25 D-7.94°(c0.63，95％EtOH)。
Embodiment 18: the preparation sad 1-[2-of dextrorotation pentadecanoic acid (dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C6)
The same C2 of synthetic method.Get dextrorotation Venlafaxine 0.04g (0.14mmol) and pentadecanoic acid 0.07g (0.29mmol) reaction, get white solid (C6) 0.04g, productive rate 52.3%.Make hydrochloride by well-established law, Rf=0.62.Racemization pentadecanoic acid Venlafaxine ester Rf=0.62.[α]
25 D+8.52°(c0.54，95％EtOH)。
Embodiment 19: prepare left-handed stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C7)
The same C1 of synthetic method.Get left-handed Venlafaxine 0.04g (0.14mmol) and stearic acid 0.08g (0.28mmol) reaction, get white solid (C7) 0.04g, productive rate 51.0%.Make hydrochloride by well-established law, Rf=0.40.Racemization stearic acid Venlafaxine ester Rf=0.40.[α]
25 D-8.71°(c0.31，95％EtOH)。
Embodiment 20: preparation dextrorotation stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl (C8)
The same C2 of synthetic method.Get dextrorotation Venlafaxine 0.04g (0.14mmol) and stearic acid 0.08g (0.28mmol) reaction, get white solid (C8) 0.04g, productive rate 51.0%.Make hydrochloride by well-established law, Rf=0.40.Racemization stearic acid Venlafaxine ester Rf=0.40.[α]
25 D+8.125°(c0.48，95％EtOH)。
Experimental example 1: external prodrug transformation period test
Healthy people's whole blood is taken from blood bank of affiliated hospital of Military Medical Science Institute, and physiological saline is purchased in Beijing company limited of Double-Crane Pharmaceutical Co., Ltd.Amount of samples is the 5mg/10ml whole blood.In 10ml tool plug test tube, compound is taken by weighing 5mg respectively respectively be dissolved in 1ml physiological saline, add the 10ml whole blood, place 37 ℃ of thermostat containers to hatch.Respectively at 0,15 minute, 30 minutes, 1h, 2h, 4h, 8h, 16h and 32h respectively get the 1ml whole blood, with the centrifugal 2min of 15000r/min, get 200 μ l blood plasma, add dehydrated alcohol to 1ml,, after the disposable filter filtration, carry out efficient liquid phase chromatographic analysis with the centrifugal 2min of 15000r/min.High-efficient liquid phase chromatogram condition: the instrument model is HP 1100 high performance liquid chromatographs; Pillar is ZORBAX Eclipse VDB-C8,4.6 * 150mm, 5 μ m; Moving phase is 0.1M ammonium acetate buffer (transferring PH=6 with the 5%NaOH aqueous solution): water: acetonitrile=5: 5: 90; Flow velocity 1ml/min; Detect wavelength 229nm, reference wavelength: 350nm.Adopt the 3p87 software processes of Chinese mathematics pharmacology association establishment,, and calculate the transformation period according to the minimum principle preference pattern of Akaike ' s information criterion (AIC).
Experimental result is shown in Table 1, and shows that prodrug and whole blood hatched 0-32 hour, its transformation period all near or surpass 10 hours, be longer than Venlafaxine; And B5, B8, B10, C5, C6, C7 and C8 generate the transformation period of Venlafaxine all greater than 20h.
The transformation period of table 1 prodrug and generation Venlafaxine thereof (hour)
The ND representative is not calculated.
Experimental example 2: mouse toxicity experiment
Carry out according to the known conventional toxicity test method of this area professional.Animal is selected the 18-22g healthy mice for use, and grouping is observed 10 every group.The hydrochloride that is subjected to the reagent thing is dissolved in the physiological saline, is mixed with certain density solution.Route of administration is an oral administration gavage.The result shows, compares with contrast medicine Venlafaxine, and the The compounds of this invention acute toxicity does not have significant difference.
Claims (10)
1. the Venlafaxine prodrug that contains the long-chain fat acyl substituted is for having stearic acid 1-[2-(dimethylin)-1-(4-the p-methoxy-phenyl)-ethyl of opticity] cyclohexyl.
2. the Venlafaxine prodrug that contains the long-chain fat acyl substituted as claimed in claim 1 is characterized in that, is left-handed stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl.
3. the Venlafaxine prodrug that contains the long-chain fat acyl substituted as claimed in claim 1 is characterized in that, is dextrorotation stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl.
4. contain right and require the Venlafaxine prodrug of 1 to 3 arbitrary described long-chain fat acyl substituted and the pharmaceutical composition of pharmaceutically acceptable carrier or vehicle.
5. preparation method who contains the Venlafaxine prodrug of long-chain fat acyl substituted is to be raw material with R or S Venlafaxine, adds dewatering agent dicyclohexyl carbon imide and catalyzer dimethylamino pyridine, obtains with the stearic acid prepared in reaction.
6. according to the described preparation method of claim 5, it is characterized in that, carry out following operation: get left-handed or dextrorotation Venlafaxine 0.14mmol and stearic acid 0.28mmol add in the eggplant-shape bottle, after anhydrous methylene chloride 1.5ml dissolving, stir in ice bath; Add N, the solution that N-dicyclohexyl carbimide 0.29mmol and anhydrous methylene chloride 0.5ml make generates white precipitate gradually, and the ice bath reaction added N after 2 hours, and N-Dimethylamino pyridine 0.01g is as catalyzer, remove ice bath after, stirring at room 24 hours; Remove by filter N, the N-dicyclohexylurea (DCU), with methylene dichloride: methyl alcohol is that developping agent carries out Thin-layer separation at 8: 1, scrapes and gets the back with methylene dichloride: 8: 1 wash-outs of methyl alcohol, behind the evaporate to dryness white solid is left-handed or dextrorotation stearic acid 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl)-ethyl] cyclohexyl.
7. the arbitrary described application that contains on the Venlafaxine prodrug of long-chain fat acyl substituted and medicinal compositions is prevented and treated the mammalian central nervous system disease in preparation the prodrug thereof of claim 1 to 3.
8. as application as described in the claim 7, it is characterized in that described central nervous system disease is selected from following one or more: dysthymia disorders; Anxiety disorder; Phobias; Post-traumatic stress disorder; The attention-deficient obstacle, with or without hyperkinetic syndrome; The urinary incontinence; Schizophrenia; Alcohol addiction; Premenstrual dysphoria and autism.
9. application as claimed in claim 7 is characterized in that described central nervous system disease is a pain.
10. the application of claim 7 is characterized in that, described central nervous system disease is anorexia nervosa, bulimia nervosa or chronic fatigue syndrome.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100462825A CN100455560C (en) | 2004-06-09 | 2004-06-09 | Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100462825A CN100455560C (en) | 2004-06-09 | 2004-06-09 | Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1706813A CN1706813A (en) | 2005-12-14 |
| CN100455560C true CN100455560C (en) | 2009-01-28 |
Family
ID=35580946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100462825A Active CN100455560C (en) | 2004-06-09 | 2004-06-09 | Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100455560C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012041013A1 (en) * | 2010-10-01 | 2012-04-05 | Shan Dong Luye Pharmaceutical Co., Ltd. | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods for preparing the same and use of the same |
Families Citing this family (51)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1955159B (en) | 2005-06-17 | 2010-11-24 | 山东绿叶制药有限公司 | Composite for blocking 5-hydroxytryptamine and norepinephrine reabsorbed, its preparation method and its use |
| US9303038B2 (en) | 2011-09-06 | 2016-04-05 | Cellix Bio Private Limited | Compositions and methods for the treatment of epilepsy and neurological diseases |
| AU2013257742A1 (en) | 2012-05-07 | 2014-11-27 | Cellixbio Private Limited | Compositions and methods for treatment of neuromuscular disorders and neurodegenerative disorders |
| CN104350041A (en) | 2012-05-07 | 2015-02-11 | 塞利克斯比奥私人有限公司 | Compositions and methods for the treatment of neurological disorders |
| WO2013167990A1 (en) * | 2012-05-07 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of depression |
| US9403826B2 (en) | 2012-05-08 | 2016-08-02 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammatory disorders |
| WO2013168023A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for treatment of parkinson's disease |
| WO2013167991A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of metabolic disorders |
| WO2013167993A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of neurological degenerative disorders |
| WO2013168025A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for treatment of blood clotting disorders |
| SG11201407318UA (en) | 2012-05-10 | 2014-12-30 | Cellix Bio Private Ltd | Compositions and methods for the treatment of metabolic syndrome |
| US9573927B2 (en) | 2012-05-10 | 2017-02-21 | Cellix Bio Private Limited | Compositions and methods for the treatment of severe pain |
| WO2013168001A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of moderate to severe pain |
| US9242939B2 (en) | 2012-05-10 | 2016-01-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of respiratory disorders |
| WO2013167997A2 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of metabolic syndrome |
| US9499527B2 (en) | 2012-05-10 | 2016-11-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of familial amyloid polyneuropathy |
| US9273061B2 (en) | 2012-05-10 | 2016-03-01 | Cellix Bio Private Limited | Compositions and methods for the treatment of chronic pain |
| US9339484B2 (en) | 2012-05-10 | 2016-05-17 | Cellix Bio Private Limited | Compositions and methods for the treatment of restless leg syndrome and fibromyalgia |
| WO2013167999A2 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of neurologic diseases |
| US9346742B2 (en) | 2012-05-10 | 2016-05-24 | Cellix Bio Private Limited | Compositions and methods for the treatment of fibromyalgia pain |
| WO2013168002A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of neurological conditions |
| WO2013168033A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for treatment of neurologic diseases |
| WO2013168015A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of asthma and allergy |
| CA2873098A1 (en) | 2012-05-23 | 2013-11-28 | Cellixbio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
| CA2873096A1 (en) | 2012-05-23 | 2013-11-28 | Cellixbio Private Limited | Compositions and methods for the treatment of inflammatory bowel disease |
| US9227974B2 (en) | 2012-05-23 | 2016-01-05 | Cellex Bio Private Limited | Compositions and methods for the treatment of respiratory disorders |
| US9434729B2 (en) | 2012-05-23 | 2016-09-06 | Cellix Bio Private Limited | Compositions and methods for the treatment of periodontitis and rheumatoid arthritis |
| AU2013264820A1 (en) | 2012-05-23 | 2014-11-27 | Cellixbio Private Limited | Compositions and methods for treatment of mucositis |
| US9492409B2 (en) | 2012-05-23 | 2016-11-15 | Cellix Bio Private Limited | Compositions and methods for the treatment of local pain |
| US9108942B1 (en) | 2014-11-05 | 2015-08-18 | Mahesh Kandula | Compositions and methods for the treatment of moderate to severe pain |
| WO2014020480A2 (en) | 2012-08-03 | 2014-02-06 | Mahesh Kandula | Compositions and methods for the treatment migraine and neurologic diseases |
| US9624168B2 (en) | 2012-09-06 | 2017-04-18 | Cellix Bio Private Limited | Compositions and methods for the treatment inflammation and lipid disorders |
| WO2014037834A2 (en) | 2012-09-08 | 2014-03-13 | Mahesh Kandula | Compositions and methods for the treatment of inflammation and lipid disorders |
| US9333187B1 (en) | 2013-05-15 | 2016-05-10 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammatory bowel disease |
| CA2914461A1 (en) | 2013-06-04 | 2014-12-11 | Cellixbio Private Limited | Compositions and methods for the treatment of diabetes and pre-diabetes |
| WO2016110865A1 (en) | 2015-01-06 | 2016-07-14 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammation and pain |
| US9096537B1 (en) | 2014-12-31 | 2015-08-04 | Mahesh Kandula | Compositions and methods for the treatment of mucositis |
| EP3240779B1 (en) | 2014-09-26 | 2020-10-28 | Cellixbio Private Limited | Compositions and methods for the treatment of epilepsy and neurological disorders |
| JP6698643B2 (en) | 2014-09-29 | 2020-05-27 | セリックス バイオ プライヴェート リミテッドＣｅｌｌｉｘ Ｂｉｏ Ｐｒｉｖａｔｅ Ｌｉｍｉｔｅｄ | Compositions and methods for the treatment of multiple sclerosis |
| CA2965449C (en) | 2014-10-27 | 2020-11-10 | Cellix Bio Private Limited | Three component salts of fumaric acid monomethyl ester with piperazine or ethylene diamine for the treatment of multiple sclerosis |
| US9321716B1 (en) | 2014-11-05 | 2016-04-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of metabolic syndrome |
| US9173877B1 (en) | 2014-11-05 | 2015-11-03 | Cellix Bio Private Limited | Compositions and methods for the treatment of local pain |
| US9150557B1 (en) | 2014-11-05 | 2015-10-06 | Cellix Bio Private Limited | Compositions and methods for the treatment of hyperglycemia |
| US10208014B2 (en) | 2014-11-05 | 2019-02-19 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological disorders |
| US9284287B1 (en) | 2014-11-05 | 2016-03-15 | Cellix Bio Private Limited | Compositions and methods for the suppression of carbonic anhydrase activity |
| US9290486B1 (en) | 2014-11-05 | 2016-03-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of epilepsy |
| US9175008B1 (en) | 2014-11-05 | 2015-11-03 | Cellix Bio Private Limited | Prodrugs of anti-platelet agents |
| US9932294B2 (en) | 2014-12-01 | 2018-04-03 | Cellix Bio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
| US9206111B1 (en) | 2014-12-17 | 2015-12-08 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological diseases |
| CN105693517B (en) * | 2016-02-26 | 2018-12-07 | 西安交通大学 | 3,4- dihydroxyphenyl ethanol fibrate carboxylate compounds and its preparation method and application |
| CN109761826B (en) * | 2019-01-17 | 2022-02-25 | 烟台大学 | O-desmethylvenlafaxine phenyl ether compound and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5530013A (en) * | 1994-02-14 | 1996-06-25 | American Home Products Corporation | Venlafaxine in the inducement of cognition enhancement |
| WO2003042162A1 (en) * | 2001-11-17 | 2003-05-22 | Neurosearch A/S | Prodrugs of antidepressants and their use for treating depressions |
-
2004
- 2004-06-09 CN CNB2004100462825A patent/CN100455560C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5530013A (en) * | 1994-02-14 | 1996-06-25 | American Home Products Corporation | Venlafaxine in the inducement of cognition enhancement |
| WO2003042162A1 (en) * | 2001-11-17 | 2003-05-22 | Neurosearch A/S | Prodrugs of antidepressants and their use for treating depressions |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012041013A1 (en) * | 2010-10-01 | 2012-04-05 | Shan Dong Luye Pharmaceutical Co., Ltd. | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods for preparing the same and use of the same |
| CN103025705A (en) * | 2010-10-01 | 2013-04-03 | 山东绿叶制药有限公司 | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods for preparing the same and use of the same |
| CN103025705B (en) * | 2010-10-01 | 2014-01-22 | 山东绿叶制药有限公司 | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods for preparing the same and use of the same |
| US8741952B2 (en) | 2010-10-01 | 2014-06-03 | Shangong Luye Pharmaceutical Co., Ltd. | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methyl-benzoate hydrochloride, methods for preparing the same and use of the same |
| US9199912B2 (en) | 2010-10-01 | 2015-12-01 | Shandong Luye Pharmaceutical Co., Ltd. | Polymorphs of 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, methods of preparing the same and use of the same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1706813A (en) | 2005-12-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100455560C (en) | Medicine precursor containing long chain fatty acyl group substituted venlafaxine and its prepn and use | |
| TWI830262B (en) | Use of clemizole compounds for prevention and treatment of liver cancer | |
| TWI324066B (en) | A pharmaceutical composition for inhibiting cell migration induced by an angiogenic factor | |
| CN1929829B (en) | (S)-2-N-propylamino-5-hydroxytetralin as a D3-agonist | |
| KR20140101399A (en) | Fluorinated estrogen receptor modulators and uses thereof | |
| KR20160021277A (en) | Estrogen receptor modulator and uses thereof | |
| CN108395452A (en) | The prodrug of pyridine keto-amide as sodium channel modulators | |
| CN110372671A (en) | Autotaxin inhibitors compound | |
| CN106946795A (en) | Substituted dicarbamylamine and diaminourea formonitrile HCN pyrimidine, its composition, and the method treated with it | |
| CN102341391A (en) | Cromolyn derivatives and related methods of imaging and treatment | |
| KR20160054523A (en) | Halogenated compounds for cancer imaging and treatment and methods for their use | |
| CN109790116A (en) | TRPV4 antagonist | |
| CA3168491A1 (en) | Cannabinoid derivatives | |
| CN109400645A (en) | A kind of phosphoric acid derivatives and preparation method and purposes | |
| CN109476628A (en) | Sulfonyl cyclic alkyl amides compound as TRPA1 regulator | |
| JP2013521289A (en) | Fluorouracil derivatives | |
| CN111253412B (en) | Alpha-mangostin derivative and application thereof | |
| CN105294554A (en) | Phenylpiperazine derivative, use method and uses thereof | |
| RU2257387C2 (en) | Taxane pentacyclic compound and antitumor agents based on thereof | |
| CN110023310A (en) | For adjusting the biaryl composition and method of kinase cascade | |
| CA2887420C (en) | Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases | |
| CN106279071A (en) | Phenylpiperazine derivatives and using method thereof and purposes | |
| WO2016061488A1 (en) | Amine reuptake inhibitors | |
| JP2022515156A (en) | Deuterated forms and derivatives of volinanserin | |
| CN108863986A (en) | The Phenylpiperazine derivatives and application thereof that difluoromethyl replaces |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |