CN103664608B - Crystal compound and application thereof - Google Patents
Crystal compound and application thereof Download PDFInfo
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- CN103664608B CN103664608B CN201210344702.2A CN201210344702A CN103664608B CN 103664608 B CN103664608 B CN 103664608B CN 201210344702 A CN201210344702 A CN 201210344702A CN 103664608 B CN103664608 B CN 103664608B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 24
- 239000013078 crystal Substances 0.000 title claims description 8
- 230000003533 narcotic effect Effects 0.000 claims description 6
- 125000006850 spacer group Chemical group 0.000 claims description 2
- 206010002091 Anaesthesia Diseases 0.000 abstract description 12
- 230000037005 anaesthesia Effects 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 5
- 241000124008 Mammalia Species 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 10
- 230000003444 anaesthetic effect Effects 0.000 description 10
- 239000003193 general anesthetic agent Substances 0.000 description 10
- 239000003983 inhalation anesthetic agent Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960003132 halothane Drugs 0.000 description 5
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003589 local anesthetic agent Substances 0.000 description 5
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 229960000305 enflurane Drugs 0.000 description 4
- JPGQOUSTVILISH-UHFFFAOYSA-N enflurane Chemical compound FC(F)OC(F)(F)C(F)Cl JPGQOUSTVILISH-UHFFFAOYSA-N 0.000 description 4
- 239000001272 nitrous oxide Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- -1 2-1) Chemical compound 0.000 description 3
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229960002725 isoflurane Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 2
- 229920001774 Perfluoroether Polymers 0.000 description 2
- 235000011941 Tilia x europaea Nutrition 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229960003537 desflurane Drugs 0.000 description 2
- DPYMFVXJLLWWEU-UHFFFAOYSA-N desflurane Chemical compound FC(F)OC(F)C(F)(F)F DPYMFVXJLLWWEU-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940005494 general anesthetics Drugs 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000004571 lime Substances 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 2
- 229960002455 methoxyflurane Drugs 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- UJMWVICAENGCRF-UHFFFAOYSA-N oxygen difluoride Chemical class FOF UJMWVICAENGCRF-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229960002078 sevoflurane Drugs 0.000 description 2
- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YZFXEWDDJBQJKF-UHFFFAOYSA-N CC(C)OC(C(C)(C)Oc1ccc(C(c(cc2)ccc2Cl)(F)F)cc1)=O Chemical compound CC(C)OC(C(C)(C)Oc1ccc(C(c(cc2)ccc2Cl)(F)F)cc1)=O YZFXEWDDJBQJKF-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012926 crystallographic analysis Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000002869 intravenous anesthetic agent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000001670 myorelaxant effect Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000013842 nitrous oxide Nutrition 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method and a medical application of a compound. More particularly, the invention relates to crystalline forms of the compounds, which are useful for anesthesia in mammals.
Description
Technical field
The present invention relates to a kind of compound, and the crystalline form of described compound.The invention still further relates to preparation method and the purposes of described compound.
Background technology
Narcotic divides general anesthetic and the large class of local anesthetic two.General anesthetic is divided into inhalation anesthesia medicine and intravenous anesthetic according to administering mode.Local anesthetic is divided into benzoates according to chemical structure, amides and other class.This chapter introduces structure, title, the physico-chemical property of the development of medicine, classification and typical medicaments, also describes the structure activity relationship of local anaesthetics.
Anesthesia be body or body a part medicine or other factors impact under, temporarily lose a kind of state of irritant reaction to external world.The medicine of anesthesia can be caused to be called " narcotic ".Narcotic is divided into general anesthetic (general anesthetics) and the large class of local anesthetic (local anesthetics) two.General anesthetic is divided into again inhalation anesthetic and intravenous anesthetic two class.General anesthetic acts on nervus centralis, and the consciousness that patient can be caused all, sensation and reflex activity disappear, and make it be subject to reversible inhibition; Local anesthetic acts on nerve ending or nerve trunk, and the conduction of reversible blocking-up sensory nerve impulsion, makes patient lose pain, is applicable to local minor operation.Be all reversible in the dosage range acting on permission of this two classes medicine, i.e., after the action time of medicine, anesthesia disappears, and neural function recovers completely, does not show any structural infringement to cell.
General anesthetic can be divided into inhalation anesthetic (inhalation anesthetics) and intravenous anesthetic (intravenous anesthetics) according to the mode of administration.Desirable to the requirement of this type of medicine is: 1, rapid-action, removes rapidly after drug withdrawal; 2, harmless to health, particularly to the heart, kidney, liver; 3, control dose and anesthesia level and time is easy to; 4, Nature comparison is stablized.
Inhalation anesthetic is the inactive volatile liquid of a class chemical property (as ether, fluothane) and gas (as Nitrous Oxide), by mainly hydro carbons, halohydrocarbon, ethers and mineral compound etc. its structure.Main dependence alveolar ventilation picked-up and eliminating.Inhale people's narcotic and enter blood flow arrival cerebral tissue, when in cerebral tissue through alveolar
When its dividing potential drop reaches certain level, namely produce generalized anesthetic state clinically.
Inhale people's narcotic and can have various chemical structural type, but its physico-chemical property is similar: be as chemical property torpescence, volatile, greatly fat-soluble, water-soluble little.The intensity of these character and its anesthetic action has close ties.
Be applied to operating suction general anesthetic the earliest and have ether (Ether), Nitrous Oxide (laughing gas nitrous oxide) and chloroform (chloroform).Ether is clear with its anesthetic stage, be easy to control and have good analgesia and myorelaxant effects, and its shortcoming is inflammableness and explosion hazard, so be rarely used in now clinical; Nitrous Oxide has good analgesic activity, and its anesthetic action is more weak, but due to toxicity low, thus still for clinical; Chloroform is then large because of toxicity, and now eliminating need not.Because this three has different shortcomings, therefore start to find his better general anesthetic.
After research finds to introduce fluorine atom in hydrocarbon or ethers structure, can inflammableness be reduced, increase anesthetic action, find hydrofluoric ether or fluoro ethers inhalation anesthetic on this basis 20th century.Wherein fluothane (Halothane, 2-1), enflurane (Enflurane, 2-2) are the imbedibility GENERAL ANESTHETICS commonly used clinically.
Methoxyflurane (Methoxyflurane, 2-3) is colourless clear liquid, has fruity odours, does not at room temperature fire not quick-fried, all more stable when aerobic, air, light, moisture, alkali, lime exist.General anesthesia usefulness is the strongest, and analgesic effect is good.
The isomer that isoflurane (Isoflurane, 2-4) is enflurane.Transparent, colourless liquid, somewhat pungency ether sample is smelly.Property is stablized, and does not decompose in lime.There is good anesthetic action, induced anesthesia and revive all very fast.
Sevoflurane (Sevoflurane, 2-5) is volatile liquid, boiling point 58.5 DEG C.Heat, strong acid are stablized, do not burn, do not explode.Induction time is short than enflurane, fluothane person, and recovery time three is without big-difference.The respiration inhibition effect of this product is little compared with fluothane; Less than isoflurane on the impact of cardiovascular systems.
Blood/gas the partition ratio of desflurane (Desflurane, 2-6) is all lower than other fluorine-containing inhalation anesthetics, therefore the induction of anesthesia and revive all fast, be easy to regulate depth of anesthesia.
This type of medicine has now become clinically conventional Inhalation Anesthetic, instead of the larger chloroform of the toxicity that uses in one's early years and inflammable and explosive ether.Though the toxicity of hydrofluoric ether or fluoro ethers medicine is little more than chloroform, still have certain hepatotoxicity.More preferably new drug to be studied so still need.
Therefore, efficient anesthesia how is developed and the medical compounds had no side effect is researcher all the time needs an important topic solving.
Summary of the invention
The anesthesiophore compound of a kind of tool, shown in its structural formula following (I):
（I）
The synthesis of described compound can by directly fluoridize method realize.Conventional fluorination reagent has the fluorination reagent such as diethylaminosulfurtrifluoride, pyridine hydrofluoride.Bromo-succinimide is added, N-iodosuccinimide, bromine or iodine etc. in reaction.
In addition, present invention also offers a kind of crystalline form of above-claimed cpd, this crystal of described crystal belongs to oblique system, and its spacer is P21, a=7.10, b=8.70, c=9.05, β=92.1 °, V=559.0
3.
Another aspect of the present invention also relates to pharmaceutical composition, comprising formula (I) compound or their pharmacy acceptable salts of effective dose.
The compounds of this invention can be anaesthetized Mammals effectively.
Embodiment
Embodiment 1: the preparation of formula (II) compound
(III) (II)
15.5 grams of formulas (II) compound (being purchased) are dissolved in 20 milliliters of ether in ice-water bath, then keep constant temperature, the diethylaminosulfurtrifluoride of 10 milliliters solution within the halfhour time is slowly instilled.After being added dropwise to complete, continue stirring 2 hours, TLC monitors reaction, until reaction terminates.Salt solution cancellation is reacted, and is extracted with ethyl acetate.Organic phase uses saturated sodium bicarbonate, water and saturated common salt water washing successively, dry, and concentrated, thick product obtains 13.5 grams of colourless transparent liquids through column chromatography (sherwood oil: ethyl acetate/50:1).
1H NMR(400MHz, CDCl
3) δ1.05(t, J=7.6HZ,6H), 1.20(d,
J=6.4Hz,6H), 1.59(s,6H), 2.26-2.32(m,4H), 5.06-5.09(m, 1H), 6.74(d,J=8.8Hz,2H), 7.24(d,J=8.8Hz,2H), 7.36(d,J=8.8HZ,2H), 7.46(d, J=8.8Hz,2H).
The preparation of formula (I) compound
(II) (I)
Compound obtained above is dissolved in 30 milliliters of chloroforms, under nitrogen protection in ice-water bath, slowly drips 8 grams of two (2-methoxy ethyl) amine sulfur trifluorides, then add the bromo-succinimide of 11.0 grams.Keep ice-water bath constant temperature, continue stirring 30 minutes at this temperature, reaction solution is poured in 100 milliliters of ice saturated sodium bicarbonate solutions, and extracts three times by 30 milliliters of ethyl acetate.Organic phase is concentrated, washing, dry and obtain 9.3 grams of oily matter products through column chromatography (sherwood oil: ethyl acetate/50:1).
1H NMR(400MHz, CDCl
3) δ1.20(d,
J=5.6Hz, 6H), 1.64(s,6H), 5.07(m, 1H) 6.83(d,J=7.6Hz,2H), 7.31-7.43 (m,6H);
13C NMR(100MHz, CDCl
3) ppm 173.3, 157.0, 136.0, 130.3, 128.6, 127.2, 118.0, 79.2, 69.2, 25.3, 21.5; m/z 405(M+Na
+), 383 (M+H
+).
Embodiment 2: the preparation of crystalline compounds
Accurately take by above-claimed cpd analytical balance, 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 80 DEG C of pre-burnings, grinding.Last constant temperature 20h at such a temperature, through progressively cooling to room temperature stage by stage.Finally, colorless plate crystal 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 3: pharmacology test
sample preparation method:test medicine: compound or the grinding of its crystal distilled water are made into desired concn.
test method:effect in the body that be have evaluated described medicinal extract by the expection anesthesia test in mouse (with reference to people such as D. J. Sanger, Eur. J. Pharmacol., 313,35-42,1996; With people such as G. Griebel, Psychopharmacology, 146,205-213,1999).Adopt multiple groups of 5-8 only male CD1 mouse (during test body weight 22-26 gram).Use test compounds according to the volume of 10ml/kg, according to single equimolecular intraperitoneal doses, described sample is suspended in 0.25% agar containing a Tween 80.Each approach tests two dosage.Control animal receives independent carrier.Use Smart System (Panlab, S. L., Spain), to record in every mouse peritoneum after (ip) administration 30 minutes with the interval of 5 minutes and the distance of walking in 60 minutes periods after oral cavity (po) administration, in units of cm.Compared with control animal, the suppression percentage ratio (being rejected for first 5 minutes) of the travel distance of computing animal.The results are shown in Table 1.
table 1 herbal medicine medicinal extract is on the impact of mouse anesthesia
Mouse is through peritoneal administration as shown in Table 1, or after orally administering, compound of the present invention and crystal thereof have obvious anesthetic action with Compound Phase ratio of the prior art.
Claims (2)
1. the compound that formula (I) represents is preparing the purposes in narcotic,
（I）。
2. purposes as claimed in claim 1, is characterized in that, described compound is crystalline form, and this crystal belongs to oblique system, and its spacer is P21, a=7.10, b=8.70, c=9.05, β=92.1 °, V=559.0
3.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210344702.2A CN103664608B (en) | 2012-09-18 | 2012-09-18 | Crystal compound and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210344702.2A CN103664608B (en) | 2012-09-18 | 2012-09-18 | Crystal compound and application thereof |
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| Publication Number | Publication Date |
|---|---|
| CN103664608A CN103664608A (en) | 2014-03-26 |
| CN103664608B true CN103664608B (en) | 2015-04-08 |
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|---|---|---|---|
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002039983A2 (en) * | 2000-11-17 | 2002-05-23 | Lipocine, Inc. | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
| CN103373921A (en) * | 2012-04-26 | 2013-10-30 | 浙江海正药业股份有限公司 | 4-((substituted phenyl) difluoromethyl) phenoxy carboxylic acid derivatives as well as preparation method and medical application for same |
-
2012
- 2012-09-18 CN CN201210344702.2A patent/CN103664608B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002039983A2 (en) * | 2000-11-17 | 2002-05-23 | Lipocine, Inc. | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
| CN103373921A (en) * | 2012-04-26 | 2013-10-30 | 浙江海正药业股份有限公司 | 4-((substituted phenyl) difluoromethyl) phenoxy carboxylic acid derivatives as well as preparation method and medical application for same |
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| Publication number | Publication date |
|---|---|
| CN103664608A (en) | 2014-03-26 |
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