CN103664822B - Compound used as anesthetic - Google Patents
Compound used as anesthetic Download PDFInfo
- Publication number
- CN103664822B CN103664822B CN201210345746.7A CN201210345746A CN103664822B CN 103664822 B CN103664822 B CN 103664822B CN 201210345746 A CN201210345746 A CN 201210345746A CN 103664822 B CN103664822 B CN 103664822B
- Authority
- CN
- China
- Prior art keywords
- anesthetic
- milliliters
- compound
- reaction
- grams
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
Abstract
The invention provides a compound as shown in formula I in the specification, and a crystal of the compound. The compound can be used for preparing anesthetic.
Description
Technical field
The present invention relates to one and can be used as narcotic compound and preparation method thereof.
Background technology
Narcotic refer to can make whole body or body local temporarily, reversibility loses consciousness and the medicine of the pain sensation.General anesthetic and local anesthetic can be divided into according to its sphere of action, general anesthetic and local anesthetic different with administering mode according to its action character, inhalation anesthetic and intravenous anesthetic can be divided into again;
Have the powder for anethesia of LI Shi-Zhen can toponarcosis the earliest, curative effect be very good.
Narcotic divides general anesthetic and local anesthetic two kinds.General anesthetic from the superficial to the deep suppresses pallium, and people's mind is disappeared.The membrane potential of toponarcosis to nerve plays stabilization or reduces film to the permeability of sodium ion, the conduction of block nerves impulsion, starting anaesthetic effect.
General anesthetic is used for the patient that major surgery maybe can not use local anesthetic.The general anesthetic used the earliest is laughing gas, its stable performance, is applicable to any mode and anaesthetizes, but has the shortcomings such as easy anoxic, anesthesia person are stable not.Used ether afterwards instead and make general anesthetic, it has anesthesia stable, well of flaccid muscles, is convenient to the advantages such as operation.But it is inflammable, put and can produce superoxide for a long time.Should absolute inflammable and on inspection without superoxide when using ether.
Local anesthetic is applicable to the narcotic of small-sized operation or local operation.When using local anesthetic, some vasoconstrictors need be added, as suprarenin.The most frequently used local anesthetic is ethocaine, and be the solution of 0.5 ~ 1% for local anaesthesia, each consumption can not more than 1g, and the solution of 0.1% is commonly used in intravenous injection.Other are as tetracaine hydrochloride, lidocaine hydrochloride, can be used as local anesthetic.Their function is similar with PROCAINE HCL, PHARMA GRADE, and price is all high than ethocaine, and normal PROCAINE HCL, PHARMA GRADE allergy sufferers of giving uses.
Current narcotic is fluorochemicals mostly, the chloro-2-monobromethane of the fluoro-2-of 1,1,1-tri-as by name in chemistry.Also known as Halothane.For colourless, runny heavy liquid, stable in properties, but meet light, heat and wet air can slowly decompose, generate haloid acid (Hydrogen bromide, hydrofluoric acid, hydrochloric acid etc.), usually adding thymol makees stablizer, and this product is insoluble to sulfuric acid, after adding equal-volume sulfuric acid, because proportion is greater than sulfuric acid, then this product is sunken to bottom, is formed two-layer.
Its anesthetic action is stronger than ether, and to mucous membrane nonirritant, the anesthesia induction time is short, not easily causes excess secretion, cough, laryngospasm etc.For general anesthesia and anesthesia induction.After sucking, major part is discharged from lung, and about 20%.
In liver, be converted into the meta-bolitess such as nonvolatile trifluoroethanol, trifluoro acetaldehyde, trifluoroacetic acid, bromide and muriate before discharging, after these products can accumulate at least 2 weeks in liver, residue still finds in urine.Fluothane tool hepatotoxicity, makes range of application be restricted.Intravenous anesthetic is non-volatile general anesthetic, and this type of medicine is rapid through intravenously administrable effect, by stages not obvious, discharges comparatively slow, is alonely only applicable to time short, less demanding minor operation of easing pain.Be usually used in induction and the General anesthesia of inhaling people's anesthesia clinically.Intravenous anesthetic is some water miscible compounds normally, and major part is salt.The barbiturate for super part-time application of early application is as Thiopental Sodium (thiopental sodium, 2-7), hexene Veronal sodium (hexobarbital sodium, 2-8).Sulfo-barbiturates, due to fat-soluble comparatively large, very easily reach cerebral tissue by hemato encephalic barrier, produces anesthetic action very soon, absorb distribution rapidly, therefore the anesthetic action time is short, generally only can maintain several minutes.Be mainly used in induced anesthesia, basal narcosis and combined anesthesia clinically.
Because compound of the prior art has different determinations, therefore need exploitation efficient and the compound had no side effect.
Summary of the invention
An object of the present invention is just to provide one and can be used as narcotic formula I.
Another object of the present invention is to provide the crystalline form of above-claimed cpd.Described crystal belongs to oblique system, and its spacer is P21, a=9.10, b=8.50, c=7.25, β=91.2 °, V=560.8
3.
Above-claimed cpd is by following reaction preparation:
。
Embodiment
Below by embodiment, the invention will be further described.It should be understood that preparation method described in the embodiment of the present invention is only used for the present invention is described, instead of limitation of the present invention, under concept thereof of the present invention, all the scope of protection of present invention is belonged to the simple modifications of preparation method of the present invention.The all raw materials used in embodiment are and are purchased.
Embodiment 1: the preparation of formula VI compound
In the there-necked flask of 250 milliliters, be weighed into o-chloronitrobenzene (VIII) (10 grams, 63.4 mmol) and 2-Thiosalicylic acid (VII) (9.7 grams, 62.9 mmol), add 110 milliliters of dehydrated alcohols, stir, add (7.8 grams, potassium hydroxide again, 138.8 mmol), reflux, solids dissolves gradually.After reaction terminates (about taking 8 hours), by reaction solution cool to room temperature, separate out a large amount of yellow solid.Filter, collect filter cake.After concentrating filter liquor, add ethyl acetate 50 milliliters, have again yellow solid to separate out, refilter.Merge filter cake, with 100 milliliters of ethyl acetate washing leaching cakes.Gained filter cake is proceeded in the beaker of 500 milliliters, add 200 ml waters, stir, regulate pH value to be 3-4 with 6N hydrochloric acid, separate out yellow solid.Filter, filter cake is through washing twice (2 × 100 milliliters), dry, obtains yellow thioether (13.3 grams, yield 76.6%).
1H NMR (400 MHz, DMSO-d
6): δ 7.22 (dd, 1H,
J 1 = 8 Hz,
J 2 = 1.2 Hz ); 7.31 (dd, 1H,
J 1 = 7.8 Hz,
J 2 = 1.2 Hz); 7.48-7.58 (m, 3H); 7.62-7.66 (m, 1H); 7.92 (dd, 1H,
J 1 = 7.52 Hz,
J 2 = 1.6 Hz ); 8.17 (dd, 1H,
J 1 = 8.2 Hz,
J 2 = 1.36 Hz ); 13.3 (s, 1H)。
Embodiment 2: the preparation of formula III compound:
In the there-necked flask of 250 milliliters, be weighed into formula (VI) compound (10 grams, 36.3 mmol), add 120 milliliters of toluene, stir, slowly drip thionyl chloride (12 milliliters, 164.4 mmol), after adding, back flow reaction 12 hours (TLC monitors reaction).After reaction terminates, cool to room temperature, decompression evaporates toluene and excessive thionyl chloride.Add 200 milliliters of toluene in addition, obtain the toluene solution of acyl chlorides (V).The toluene solution of gained acyl chlorides (V) is proceeded in another there-necked flask of 500 milliliters, stir, under ice-water bath cooling, drip triethylamine (8 milliliters, 57.4 mmol), after adding, [2-(2-hydroxyl-oxethyl) piperazine (IV) (36.3 grams, 36.3 mmol), after adding to drip the 1-be dissolved in 50 milliliters of toluene again, insulation reaction is after 30 minutes, and stirring at room temperature is reacted 8 hours (TLC monitors reaction).After reaction terminates, add 150 milliliters of saturated sodium-chloride water solutions, separate organic phase, after organic phase washs 1 time with 150 milliliters of saturated sodium-chloride water solutions again, anhydrous magnesium sulfate drying, filter, vacuum spins off solvent, column chromatography (silica gel H: 200-300 order; N-hexane/ethyl acetate=1:1 → ethyl acetate/ethanol=10:1) obtain nitro-compound (III) (7.9 grams, yellow colloidal liquid, two step yields: 50.4%).
1H NMR (400 MHz, CDCl
3): δ 2.51 (
t, 3H,
J 1 = 5.12 Hz); 2.63 (
t, 3H,
J 1 = 5.32 Hz); 3.27 (s, 2H); 3.58-3.71 (m, 7H), 3.94 (s, 1H); 6.94 (d, 1H.
J 1 = 1.08 Hz); 6.96-7.58 (m, 6H); 8.4 (d, 1H,
J 1 = 1.12 Hz)。
Embodiment 3: the preparation of formula II compound:
By nitro-compound (III) (7.9 grams, 18.3 mmol) join in the single port flask of 500 milliliters, add (6 grams, 10% palladium carbon, moisture 50%), after nitrogen replacement, pass into hydrogen (1 normal atmosphere), stirring at room temperature is reacted 12 hours (TLC monitors reaction).Reaction terminate after, filter, filtrate concentrate, obtain amine compound (II) (7.05 grams, yellow colloidal liquid, yield: 95.6%).
1H NMR (400 MHz, DMSO-d
6): δ 2.55 (s, 2H); 2.64-2.68 (m, 4H); 3.35-3.36 (m, 2H); 3.58-3.71 (m, 6H); 3.79-3.95 (m, 3H), 4.15-4.45 (wIde, 2H); 6.68-6.74 (m, 2H); 6.94-6.97 (m, 1H); 7.15-7.22 (m, 4H); 7.42 (d, 1H,
J 1 = 1.12 Hz)。
Embodiment 4: the preparation of formula I
By amine compound (II) (3.5 grams; 8.7 mmol) join in the there-necked flask of 250 milliliters of band water traps; add titanium isopropylate (20 milliliters again; 67.5 mmol); stir; under nitrogen protection, heating (170 DEG C-180 DEG C), reacts 8 hours.In reaction process, the Virahol of generation is by water trap separating reaction system.After reaction terminates, be cooled to 60 DEG C, add 80 milliliters of dilution with toluene reaction solutions, meanwhile, add 30 milliliters of aqueous sodium hydroxide solutions (containing 10 grams, sodium hydroxide, 250 mmol), heating (80 DEG C-100 DEG C), stirring reaction 1 hour.Cool to room temperature, filters, and filter cake is with 100 milliliters of toluene wash (2 × 50 milliliters), and merging filtrate, separates organic phase, anhydrous magnesium sulfate drying, filtration, and vacuum spins off solvent, column chromatography (silica gel H: 200-300 order; N-hexane/ethyl acetate=1:1 → ethyl acetate/ethanol=10:1) obtain white crystalline solid powder (I) (1.9 grams, yield: 57%).
1H NMR (400 MHz, DMSO-d
6): δ 2.50-2.61 (m, 6H); 3.40-3.57 (m, 10H); 6.62 (s, 1H); 6.89 (d
t, 1H,
J 1 = 7.52 Hz,
J 2 = 1.24 Hz ); 7.01 (dd, 1H,
J 1 = 7.96 Hz,
J 2 = 1.2 Hz); 7.20 (d
t, 1H,
J 1 = 7.96 Hz,
J 2 = 1.48 Hz); 7.36-7.54 (m, 5H); 8.4-8.6 (wide, 1H)。
Embodiment 5: the preparation of crystalline compounds
Accurately take by the molar ratio analytical balance of above-claimed cpd, load weighted reagent is put into the abundant grinding of agate mortar in stink cupboard and make it mix, then sample is loaded in platinum crucible.For making late phase reaction carry out smoothly, put into box-type furnace in 90 DEG C of pre-burnings, grinding.Finally constant temperature 5h at 70 DEG C, through progressively cooling to room temperature stage by stage.Finally, colourless bulk crystals is obtained in crucible bottom.Carry out monocrystalline X-its crystalline structure of ray diffraction crystallographic analysis to this crystal, its crystallographic parameter is described above.
Embodiment 6: the test of pesticide effectiveness:
Compare the external usefulness [suppressing the ability of combination of [35S]-tertiary butyl two cyclic phosphorothioic acid Portugal (TBPS)] of formula I and crystal in table 1, rotating rod TD50(half experimental animal can not stop dosage when 1 minute on the rod rotated) and all experimental animals can pass through the length (acting duration) of time before rotarod test.For measuring these method full disclosures of the in vitro and in vivo activity of the compounds of this invention at United States Patent (USP) 5,232, in 917.TBPS measures and obtains the external usefulness of compound, and the rotating rod evaluation of measuring tranquilizer of compound/hypnotic is active.Since the acting duration of compound depends on dosage and extends under higher dosage, so measure acting duration under all animals are not all by the lowest dose level of rotarod test.For the compound of acting duration >240 minute, 240 minutes time, pass through the animal number scale of rotarod test in parenthesis.Can find out, the compounds of this invention has the biology continuous action time being greater than 240 minutes, in addition, when the compounds of this invention is presented at 240 minutes only less than the animal of half by rotarod test, this points out its acting duration obviously longer.This shows that the compounds of this invention provides unique and unexpected pharmacokinetics performance, make them especially can be used as tranquilizer/hypnotic and narcotic.
The biological activity of table 1 formula I and crystal thereof compares
| Compound | TBPS IC 50 (nM) | RR TD50 oral (mg/kg) | Acting duration (minute) |
| Formula I | 47 | 30 | > 240 (3/8 passes through) |
| Formula I crystal | 42 | 15 | > 240 (0/8 passes through) |
Claims (3)
1. a crystalline compounds, is characterized in that, described compound represents with formula I:
I；
This crystal belongs to oblique system, and its spacer is P21, a=9.10, b=8.50, c=7.25, β=91.2 °, V=560.8
3.
2. the crystalline compounds of claim 1 is preparing the purposes in narcotic.
3. a pharmaceutical composition, is characterized in that, comprises crystalline compounds according to claim 1, in addition also containing pharmaceutically acceptable auxiliary agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210345746.7A CN103664822B (en) | 2012-09-18 | 2012-09-18 | Compound used as anesthetic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210345746.7A CN103664822B (en) | 2012-09-18 | 2012-09-18 | Compound used as anesthetic |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664822A CN103664822A (en) | 2014-03-26 |
| CN103664822B true CN103664822B (en) | 2015-07-15 |
Family
ID=50303698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210345746.7A Expired - Fee Related CN103664822B (en) | 2012-09-18 | 2012-09-18 | Compound used as anesthetic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664822B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304517B (en) * | 2013-07-08 | 2015-07-08 | 天地科技股份有限公司 | Novel derusting material |
| CN104803947A (en) * | 2015-03-12 | 2015-07-29 | 常州康丽制药有限公司 | Preparation method of 11-(1-piperazinyl) dibenzo[b, f][1,4] thiazepine fumarate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006027789A1 (en) * | 2004-09-08 | 2006-03-16 | Jubilant Organosys Limited | PROCESS FOR PRODUCING 11-[4-[2-(2-HYDROXYETHOXY)ETHYL]-1-PIPERAZINYL]DIBENZO[b,f][1,4]THIAZEPINE AND A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF |
| ES2234447B1 (en) * | 2005-03-07 | 2006-03-01 | Union Quimico-Farmaceutica S.A. | PROCEDURE FOR OBTAINING A DERIVATIVE OF 11- (4-SUBSTITUTED-1-PIPERAZINIL) DIBENZO (B, F) (1,4) THIAZEPINE. |
-
2012
- 2012-09-18 CN CN201210345746.7A patent/CN103664822B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| Edward J. Warawa et al..Behavioral Approach to Nondyskinetic Dopamine Antagonists:Identification of Seroquel.《J. Med. Chem.》.2001,第44卷(第3期),372-389. * |
| Measurement of quetiapine and four quetiapine metabolites in human plasma by LC-MS/MS;Danielle S. Fisher et al.;《Biomedical Chromatography》;20120112;第26卷;1125-1132 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664822A (en) | 2014-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10233207B2 (en) | Crystalline form of nicotinamide riboside | |
| TW200817343A (en) | Method of enhancing mucosal hydration and mucosal clearance by treatment with sodium channel blockers and osmolytes | |
| CH650925A5 (en) | CAPSULES CONTAINING THE ACTIVE INGREDIENT OF AN ALLERGEN AND PROCEDURE FOR THEIR PREPARATION. | |
| CN108727248A (en) | A kind of diquaternary ammonium compound and its preparation method and application | |
| CN103739553B (en) | N-substituted imidazolecarboxylic acid ester chiral compound containing ether side chain, preparation method and application thereof | |
| EP1935892A1 (en) | Glycyrrhetinic acid-30-amide derivatives and the uses thereof | |
| CN102863364B (en) | S-(carboxymethyl)-cysteine pharmaceutical compound and preparation method and usage thereof | |
| JP2017523175A (en) | Dimethylanilines long-chain compounds and their preparation, self-assembled structures and uses | |
| WO2009021404A1 (en) | (1s, 2s, 3s, 4r)-3-[(1s)-1-acetylamino-2-ethyl-butyl]-4-guanidino-2- hydroxyl-cyclopentyl-1-carboxylic acid hydrates and pharmaceutical uses thereof | |
| CN103664822B (en) | Compound used as anesthetic | |
| KR101925133B1 (en) | Phillygenin ibuprofen ester, preparation method therefor, and applications thereof | |
| JPH05238996A (en) | N-alkyl-3-phenyl-3-(2-halo-substituted phenoxy) propylamine | |
| CN105431432A (en) | Quinine compounds, and optical isomers, preparation method and medical use thereof | |
| CN102702001B (en) | Stable amorphous ambroxol hydrochloride compound | |
| CN103781771A (en) | Benzothiazolone compound | |
| CN102939281A (en) | Process for the preparation of glycopyrronium chloride | |
| EP0171645B1 (en) | 2h-1-benzopyran-2-on derivatives, process for their preparation and medicines containing these compounds | |
| JPH03503162A (en) | Improving toxicological properties in chemotherapy | |
| CN109776647B (en) | Pyxinol esterified derivative with anti-inflammatory activity and preparation method and application thereof | |
| JPS6117574A (en) | Calcium-antagonistic 1-(bis-(4-fluorophenyl)-methyl)-4- (3-phenyl-2-propenyl)-hexahydro-1h-1,4-diazepine, manufacture and medicinal composition | |
| ES2386550T3 (en) | Pyridazinylamine derivatives, their use in the preparation of picornavirus inhibitors | |
| EP2826479B1 (en) | Ameliorating agent for chronic obstructive pulmonary disease | |
| CN115461052B (en) | Pharmaceutical use of complexes of ARB metabolites with NEP inhibitors for the prevention and/or treatment of kidney disease | |
| JPH06239736A (en) | Keratin layer-repairing promoter | |
| BRPI0615064A2 (en) | combination of compounds that can be used to treat respiratory diseases, especially chronic obstructive pulmonary disease (dpoc) and asthma |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150715 Termination date: 20180918 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |