CN102702126A - Compound for anesthetics - Google Patents
Compound for anesthetics Download PDFInfo
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- CN102702126A CN102702126A CN201210125805XA CN201210125805A CN102702126A CN 102702126 A CN102702126 A CN 102702126A CN 201210125805X A CN201210125805X A CN 201210125805XA CN 201210125805 A CN201210125805 A CN 201210125805A CN 102702126 A CN102702126 A CN 102702126A
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Abstract
The invention provides an organic compound for anesthetics, functioning as sedative/hypnotic and used for anesthetization.
Description
Technical field
That the present invention relates to the medical chemistry field and be used to regulate the excited organic cpds of brain and method.
Background technology
The neuroactive steroids of natural generation is not suitable for as tranquilizer/hypnotic; Because their oral administration biaavailability is not good; Be because their first pass metabolisms (the Hogenkamp. D. J. etc., " medical chemistry journal 40:61-72 (1997)) that cause rapidly by inference.Add 3-replace and produced the neuroactive steroids that does not show strong Orally active in animal body, but they can continue long time so that can't be as useful tranquilizer/hypnotic usually.Tranquilizer/hypnotic should have in human body that < 5 hours elimination transformation period is to avoid residual inferior diurnal effect and accumulating after the administration (Nicholson, A. N. " medicine " /> 31:164-176 (1986)) every night continuously.Yet we have found that 3-methoxymethyl-substituted steroid also has in the Orally active that has kept other 3-substituted neuroactive steroidses makes them can be used as tranquilizerhypnotic and narcotic continuous action time.
Bolger etc. are at USP 5,232, disclose a series of compounds in 917, and wherein said compound has a large amount of groups.These compound records can be used for anticonvulsive drug, tranquilizer/hypnotic and narcotic.
The WO95/21617 of International Publication discloses a series of compounds, and it also has a large amount of groups.These compound records can be used for anticonvulsive drug, tranquilizer/hypnotic and narcotic.
Summary of the invention
The object of the invention is to provide a kind of narcotic organic cpds and compsn thereof of can be used for.
Saidly can be used for narcotic organic cpds, it has following chemical structural formula
Preferably, it is a crystal, and said crystal belongs to rhombic system, and its spacer is P2
1, a=6.30, b=7.90, c=9.10, β=89.5 °, V=452.9
3
Described organic cpds becomes can be used for narcotic compsn with pharmaceutically acceptable preparing carriers;
Pharmaceutical composition of the present invention can be with any mode administration that can reach their predetermined purposes.For example, can pass through parenteral, subcutaneous, intravenously, intramuscular, intraperitoneal, through skin or through the cheek administration.On the other hand, perhaps concurrently, can the by oral route administration.Dosage will depend on recipient's age, healthy state, and body weight, the kind of concurrent treatment, as adopt the character of therapeutic frequency and required effect.
Pharmaceutical composition of the present invention is produced with self known mode, for example utilizes conventional mixing, granulation, system drageeing, dissolving or freezing dry process.So being used for oral pharmaceutical prepn can obtain like this: with active compound, it is micronization advantageously, with group's mixed with excipients.
Grind the gained mixture alternatively and this particulate mixture is processed, alternatively, after having added proper auxiliary agent, process, thereby obtain tablet or drageeing core.Suitable vehicle is particularly: weighting agent is such as carbohydrate; For example lactose or lamb are sugared; Mannitol or Sorbitol Powder, cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or secondary calcium phosphate; And tackiness agent is such as the starch paste, for example uses W-Gum, wheat starch, rice starch, yam starch, gelatin, west yellow work glue, methylcellulose gum, U.S. holy third methylcellulose gum, the number methylcellulose gum is received and/or Vilaterm is suck and coughed up a heatable brick bed and succeed.Like needs, can add disintegrating agent (utter a sound or a word such as above-mentioned starch and CMS, crosslinked polyethylene and to cough up that a heatable brick bed turn over, agar or alginic acid) or its salt, such as the alginic acid hook.Auxiliary agent is flowing regulator and lubricant especially, and for example silicon-dioxide, talcum, Triple Pressed Stearic Acid or its salt are waited or calcium stearate such as Triple Pressed Stearic Acid, and/or polyoxyethylene glycol.The drageeing core has suitable dressing, and if desired, this dressing is can anti-gastric juice.For this purpose, can use concentrated sugar solution, it can contain gum arabic, talcum, Vilaterm alternatively and suck and cough up a heatable brick bed heir, polyoxyethylene glycol and/or titanium oxide, lacquer solution and suitable organic solvent or solvent mixture.
In order to produce the dressing of anti-gastric juice, use the solution of suitable cellulose preparation (such as cellulose acetate O-phthalic vinegar or HPMC O-phthalic vinegar).For example, in order to differentiate or, can in tablet or drageeing core dressing, to add dyestuff or pigment for the characteristic of the cooperative programs of describing active compound doses.
Embodiment
Through embodiment the present invention is described further below.It should be understood that the said preparation method of the embodiment of the invention is only used for explaining the present invention, rather than limitation of the present invention, under design prerequisite of the present invention, preparing method's of the present invention simple modifications is all belonged to the present invention and require the scope protected.
Preparation embodiment 1
Synthesis step:
(1) 2-fluoro-4-bromo-bromotoluene is synthetic
In the reaction flask of being furnished with mechanical stirring and reflux condensing tube, add 75.6g (0.4mol) 2-fluoro-4 toluene bromides and 14.4g Lucidol; After being heated to backflow under stirring; With 71.2g (0.4mol) 2-bromo-2; 5-pyrroledione (NBS) added reaction flask in batches in 20 minutes, reflux 2 hours, reaction yield 65% (GC).Reaction solution adds the yellow soda ash neutralization, concentrates, and (1g: 1mL) backflow dissolving is cooled to-15 ℃ and carries out recrystallization, about 90% (GC) of purity with industry anhydrous ethanol.Its purity＞99% behind the recrystallization repeatedly.
(2) 4-triphen amido formaldehyde is synthetic
Under the nitrogen protection, in the reaction flask of being furnished with mechanical stirring and reflux condensing tube, add 12.3g (0.05mol) triphenylamine, 100mL DMF; Be cooled to 5 ℃ in the ice bath, stir and slowly drip POCl3 18.5g (0.1mol) down, after being added dropwise to complete; Remove ice bath, rise to room temperature after 1 hour.Reflux 12 hours.Reaction solution adds 100mL water, divides with 400mL ETHYLE ACETATE to extract for 4 times again, and organic phase merges, and washing is to neutral, anhydrous magnesium sulfate drying, remove ETHYLE ACETATE after, silica gel chromatography gets white solid, isolated yield 62%.
(3) 1-(4-triphen amido)-2-(2-fluoro-4-bromophenyl) ethene is synthetic
Under the nitrogen protection, in the reaction flask of being furnished with mechanical stirring and reflux condensing tube, add 8.0g (0.03mol) 2-fluoro-4-bromo-bromotoluene, 15g (0.09mol) triethyl-phosphite is heated to backflow under stirring, and reacts 1 hour.After reaction stopped, underpressure distillation went out excessive triethyl-phosphite.After distillation is accomplished, be cooled to room temperature, with cooling reaction temperature to 5 in the ice bath ℃.Keeping temperature of reaction is 5 ℃, in 20 minutes, adds 3.5g (0.03mol) potassium tert.-butoxide in batches, reacts after 1 hour, drips the THF solution 35mL that contains 7.5g (0.03mol) 4-pentanoic benzaldehyde, reacts 2 hours.Reaction solution adds 100mL water and 100mL methylene dichloride, and separatory, water are used the 100mL dichloromethane extraction again; After merging organic phase and water and a small amount of Hydrogen chloride were washed till neutrality, anhydrous magnesium sulfate drying was removed methylene dichloride; Silica gel chromatography gets yellow solid, isolated yield 45%.
(4) 1-(4-triphen amido)-2-(2-fluoro-4-(5 '-oxazolyl) phenyl) ethene is synthetic
Under the nitrogen protection; In the reaction flask of being furnished with mechanical stirring, reflux condensing tube, add 4.4g (0.01mol) 1-(4-triphen amido)-2-(2-fluoro-4-bromophenyl) ethene, 4.5g (0.012mol) 2-(tributyl tinbase) oxazole, 3%mol four (triphenylphosphinyl) palladium; 50mL toluene; Stir, be heated to backflow, reacted 48 hours.Reaction solution is dry under vacuum, adds the dissolving of 100mL methylene dichloride, divides three washings with 6M hydrochloric acid 60mL; Water neutralizes with 10% ammoniacal liquor under the state of cooling; Use the 100mL dichloromethane extraction again, merge organic phase, add 50mL water and extremely neutral with 10% ammonia scrubbing.Collect organic phase, drying is crossed silica gel column chromatography and is purified, and gets yellow solid, isolated yield 43%.
Structure is identified:
Ir spectra (KBr, cm-1): 3034,1274 (C=C-H), 1628 (C=C), 1587,1556,1491,1461 (aromatic ring C=C), 972 (trans dihydros), 899,833,778,751,694 (aromatic ring C-H), 1315 (C-N), 990 (C-F)
Nuclear-magnetism: δ (ppm), 8.744-8.753 (d, 1H, J=4.5Hz), 7.889 (s, 1H), 7.830-7.845 (d, 1H; J=7.5Hz), 7.764 (s, 1H), 7.674-7.691 (d, 1H, J=8.5Hz), 7.519-7.535 (d, 1H; J=8.0Hz), 7.396-7.439 (m, 2H), 7.341 (s, 1H), 7.248-7.280 (m, 4H), 7.174-7.207 (d; 1H, J=16.5Hz), 7.112-7.127 (d, 4H, J=7.5Hz), 7.019-7.069 (m, 4H)
Ultimate analysis: actual measurement C:80.56, N:6.50, H:4.88, F:4.40, O:3.68
Mass spectrum: M/Z 432 (M+)
The above-mentioned reaction gained of above data acknowledgement compound is 1-(4-triphen amido)-2-(2-fluoro-4-(5 '-oxazolyl) phenyl) ethene.Through measuring, the fusing point of this material is 181-182 ℃.
Preparation embodiment 2
The organic cpds of above-mentioned (4) step preparation is placed in the silica tube (quartz ampoule).Under 100 ℃ of temperature, with the compound vacuum hydro-extraction of this preparation.Should manage disengagement, and be placed in the crystal growing furnace.In having the dual stove of barrier film (double furnace), pass through Bridgman (Bridgman) method growing crystal.Finally, obtain colourless strip crystal.This crystal is carried out monocrystalline X-ray diffraction crystallographic analysis, and its crystallographic parameter is as follows: be rhombic system, its spacer is P2
1, a=6.30, b=7.90, c=9.10, β=89.5 °, V=452.9
3
Biological activity embodiment:
Compared in the table 1 embodiment 1 compound and embodiment 2 compounds external usefulness [suppress [
35S]-tertiary butyl two epithios are for the bonded ability of phosphoric acid Portugal (TBPS)], rotating rod TD
50(dosage when the half experimental animal can not stop 1 minute on the rod of rotation) and all experimental animals can both be through the length (acting duration) of time before the rotating rod test.These method full disclosures of external and activity in vivo that are used to measure The compounds of this invention are at USP 5,232, in 917.TBPS measures the external usefulness obtained compound, and the rotating rod evaluation of measuring tranquilizer of compound/hypnotic active.Since the acting duration of compound depends on dosage and will under higher dosage, prolong, so under the lowest dose level that all animals are not all tested through rotating rod, measure acting duration.For acting duration>240 minutes compound, the animal number scale through the rotating rod test in the time of 240 minutes is in parenthesis.Can find out that The compounds of this invention has the biology continuous action time greater than 240 minutes, in addition, only test through rotating rod when The compounds of this invention is presented at 240 minutes that this its acting duration of prompting is obviously longer less than half the animal.This shows The compounds of this invention to provide unique and unexpected pharmacokinetics performance makes them especially can be used as tranquilizer/hypnotic and narcotic.
The life specific activity of table 1 embodiment 1 compound and embodiment 2 compounds
| Compound | TBPS IC 50 (nM) | RR TD50 oral (mg/kg) | Acting duration (minute) |
| Embodiment 1 | 46 | 31 | 240 (3/8 passes through) |
| Embodiment 2 | 44 | 15 | 240 (0/8 passes through) |
Claims (5)
1. one kind is used for narcotic organic cpds, it is characterized in that representing with following chemical structural formula:
2. organic cpds according to claim 1 is characterized in that it is a crystal, and said crystal belongs to rhombic system, and its spacer is P2
1, a=6.30, b=7.90, c=9.10, β=89.5 °, V=452.9
3
3. one kind can be used as the compsn that narcotic uses, and it is characterized in that containing described arbitrary organic cpds of claim 1-2 and pharmaceutically acceptable carrier.
4. compsn according to claim 3 is characterized in that, it is solution, suspension-s, ointment, emulsion, sprays, sticking patch or suppository.
5. the said organic cpds of claim 1-2 is in the purposes that is used to prepare aspect the anesthetic agents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210125805.XA CN102702126B (en) | 2012-04-26 | 2012-04-26 | Compound for anesthetics |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210125805.XA CN102702126B (en) | 2012-04-26 | 2012-04-26 | Compound for anesthetics |
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|---|---|
| CN102702126A true CN102702126A (en) | 2012-10-03 |
| CN102702126B CN102702126B (en) | 2014-08-06 |
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|---|---|---|---|
| CN201210125805.XA Expired - Fee Related CN102702126B (en) | 2012-04-26 | 2012-04-26 | Compound for anesthetics |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232917A (en) * | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
| WO1995021617A1 (en) * | 1994-02-14 | 1995-08-17 | Cocensys, Inc. | Androstanes and pregnanes for allosteric modulation of gaba receptor |
| CN101712707A (en) * | 2008-10-06 | 2010-05-26 | 中国医学科学院药物研究所 | Three crystal-form substances of roxithromycin, preparation method, pharmaceutical composition and application thereof |
| CN101759743A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Methylprednisolone aceponate monohydrate, crystal form and preparation method thereof |
| CN101775652A (en) * | 2010-02-08 | 2010-07-14 | 中国科学院理化技术研究所 | Preparation and application of K3Al2(PO4)3 non-linear optical crystal |
-
2012
- 2012-04-26 CN CN201210125805.XA patent/CN102702126B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5232917A (en) * | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
| WO1995021617A1 (en) * | 1994-02-14 | 1995-08-17 | Cocensys, Inc. | Androstanes and pregnanes for allosteric modulation of gaba receptor |
| CN101712707A (en) * | 2008-10-06 | 2010-05-26 | 中国医学科学院药物研究所 | Three crystal-form substances of roxithromycin, preparation method, pharmaceutical composition and application thereof |
| CN101759743A (en) * | 2008-11-06 | 2010-06-30 | 天津金耀集团有限公司 | Methylprednisolone aceponate monohydrate, crystal form and preparation method thereof |
| CN101775652A (en) * | 2010-02-08 | 2010-07-14 | 中国科学院理化技术研究所 | Preparation and application of K3Al2(PO4)3 non-linear optical crystal |
Non-Patent Citations (2)
| Title |
|---|
| 张海斌，等: "Bridgman法晶体生长的热物性各向同性坩埚的选择", 《人工晶体学报》 * |
| 张海斌，等: "环境条件对Bridgman法晶体生长过程的影响", 《人工晶体学报》 * |
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| CN102702126B (en) | 2014-08-06 |
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