CN103833655A - Crystal compound and application thereof - Google Patents

Abstract

The invention discloses a compound crystal and medicinal application thereof, particularly a crystal form of the compound, and application of the crystal form in anesthetization applicable to mammals.

Description

A kind of crystalline compounds and uses thereof

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 development, classification and the typical medicaments of medicine, has also introduced the structure activity relationship of local anaesthetics.

Anesthesia be the part of body or body under the impact of medicine or other factors, temporarily lose a kind of state of irritant reaction to external world.The medicine that can cause anesthesia is 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 classes.General anesthetic acts on nervus centralis, can cause that all consciousness of patient, 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.In the dosage range that acts on permission of this two classes medicine, be all reversible, i.e., after the action time of medicine, anesthesia disappears, and neural function recovers completely, and cell is not shown to any structural infringement.

General anesthetic can be divided into inhalation anesthetic (inhalation anesthetics) and intravenous anesthetic (intravenous anesthetics) according to the mode of administration.The desirable requirement to this type of medicine is: 1, rapid-action, after drug withdrawal, remove rapidly; 2, harmless to health, particularly to the heart, kidney, liver; 3, be easy to control dosage and anesthesia level and time; 4, character is more stable.

Inhalation anesthetic is the inactive volatile liquid of a class chemical property (as ether, fluothane) and gas (as Nitrous Oxide), is mainly hydro carbons, halohydrocarbon, ethers and mineral compound etc. by its structure.The picked-up of main dependence alveolar ventilation and eliminating.Inhale people's narcotic and enter blood flow arrival cerebral tissue through alveolar, when in cerebral tissue

When its dividing potential drop reaches certain level, produce generalized anesthetic state clinically.

Therefore, how to develop efficient anesthesia and the medical compounds that has no side effect is the important topic that researcher need to solve all the time.

Applicant of the present invention studies some compound of the prior art, finds that wherein some compound, particularly crystalline compounds have certain restraining effect to mammiferous neural system.

Summary of the invention

The anesthesiophore compound of a kind of tool, shown in its structural formula following (I):

（I）

There is characteristic peak at the following 2 θ angles of described crystal in X ray diffracting spectrum: 12.3,13. 5,14.0,16.1,17.0,18.3,19.1,21.2,22. 7,23.4,25.8,28.3,28.9 and 30.0.

Described compound synthetic can by directly fluoridize method realize.Conventional fluorination reagent has the fluorination reagent such as diethylaminosulfurtrifluoride, pyridine hydrofluoride.In reaction, add bromo-succinimide, N-iodosuccinimide, bromine or iodine etc.

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.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction pattern of formula I compound crystal of the present invention.

Embodiment

Modus ponens I compound crude product solid 400g, in reactor, adds normal hexane 2L stirring and makes suspension, is cooled to 6 ℃, stirs and obtains white suspension liquid; Add 6 ℃, the sodium bicarbonate aqueous solution of 1mol/L, limit edged stirs, and controlling pH value is 7.0, obtains clear solution; In dropping process, use the air in nitrogen replacement reactor; Stirring velocity is 45 revs/min; Solution is warming up to 10 ℃, adds gac, stir 1 hour; Suction filtration, collects filtrate, obtains solution; To add the ratio of gac be solution quality 0.02%; Under 6 ℃ of conditions, in 10L reactor, adding frequency is the sound field that 25KHz, output rating are 50W, drips while stirring the mixing solutions 6L of ethanol and ether, after mixing solutions adds, stops sound field, leaves standstill growing the grain 7 hours; Obtain filtering after crystal, with absolute ethanol washing, vacuum-drying 4 hours, obtains formula I compound crystal; Wherein ethanol: the volume ratio of ether is 1:4; The speed that mixed solvent adds is 80ml/min, and stirring velocity is 150 revs/min.Fusing point: 211 ~ 212 ℃.

Embodiment 2: pharmacology test

sample preparation method:tested medicine: compound or its crystal are ground and are made into desired concn with distilled water.

test method:the effect of having assessed by the expection anesthesia test in mouse in the body of described medicinal extract is (with reference to the people such as D. J. Sanger, Eur. J. Pharmacol., 313,35-42,1996; With the people such as G. Griebel, Psychopharmacology, 146,205-213,1999).Adopt only multiple groups of male CD1 mouse (body weight 22-26 gram when test) of 5-8.Volume according to 10ml/kg is used test compounds, and according to single equimolecular intraperitoneal dosage, described sample is suspended in 0.25% agar that contains a Tween 80.Two dosage of each approach test.Control animal receives independent carrier.Use Smart System (Panlab, S. L., Spain), with the interval of 5 minutes record in every mouse peritoneum after (ip) administration 30 minutes and oral cavity (po) administration after during 60 minutes in the distance of walking, take cm as unit.Compared with control animal, the inhibition percentage ratio of the travel distance of computing animal (being rejected for first 5 minutes).The results are shown in Table 1.

the impact of table 1 formula I compound on mouse anesthesia

Mouse is through peritoneal administration as shown in Table 1, or after orally administering, formula I compound of the present invention has obvious anesthetic action with Compound Phase ratio of the prior art.

Claims (3)

1. the compound that formula (I) represents, or its pharmacy acceptable salt:

（I），

It is characterized in that for crystalline form, this crystal belongs to oblique system, and there is characteristic peak at the following 2 θ angles of described crystal in X ray diffracting spectrum: 12.3,13. 5,14.0,16.1,17.0,18.3,19.1,21.2,22. 7,23.4,25.8,28.3,28.9 and 30.0.

2. compound as claimed in claim 1, is characterized in that described compound can be used for preparing the purposes of narcotic.

3. a pharmaceutical composition, the compound that it contains claim 1, also contains one or more pharmaceutically acceptable auxiliary agents that are selected from W-Gum, maltodextrin, glucose, lactose, sorbyl alcohol, N.F,USP MANNITOL, sodium starch glycolate, polyvinylpyrrolidone, cyclodextrin derivative, derivatived cellulose, talcum powder, Magnesium Stearate, stearic acid, carnauba wax, Vinlub, beeswax in addition.