CN109251198B - A kind of drug and its preparation method and application for anesthesia - Google Patents
A kind of drug and its preparation method and application for anesthesia Download PDFInfo
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- CN109251198B CN109251198B CN201811119887.0A CN201811119887A CN109251198B CN 109251198 B CN109251198 B CN 109251198B CN 201811119887 A CN201811119887 A CN 201811119887A CN 109251198 B CN109251198 B CN 109251198B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
Abstract
The present invention relates to a kind of phthalazone-Quinazol derivative or its stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrugs.Test result shows the compounds of this invention to effective duration >=4 hour of the local anaesthesia of guinea pig skin, to feeling residence time >=6 hour of rat, therefore with excellent anesthesia and feels blockage effect.Therefore the compounds of this invention is be especially suitable for arcotic especially local anesthetic.
Description
Technical field
The present invention relates to pharmaceutical technology fields, specifically, especially using the present invention relates to a kind of drug for anesthesia
In the drug of part fiber crops acid, the invention further relates to the preparation method of the drug and purposes.
Background technique
Arcotic is essential drug in medical surgery, is generally divided into general anesthetic and local anesthetic.Whole body
Arcotic deeply inhibits cerebral cortex, makes one mind disappearance, the general anesthetic that tradition uses is by ether and fluorochemical.Office
Portion's arcotic refers to those, and energy temporarily, completely, reversibly conduct by block nerves within the scope of the restriction of human body, i.e., does not disappear in consciousness
So that certain a part of human body is lost sensibility under the situation of mistake, in order to surgical operation carry out drug, mechanism of action first is that
After in conjunction with certain privileged sites on the sodium-ion channel on neu, by the sodium ion of sodium-ion channel reduce from
And change neural membrane potentials, cause the conduction of nerve impulse to be blocked, finally realizes anaesthetic effect.
Currently used local anesthetic is mainly cacaine class, such as procaine, totokaine, lidocaine, Bupivacaine
Or Ropivacaine.Electrically charged cacaine class is also widely studied, and QX-314 is lidocaine hydrochloride, can after entering cell membrane
To generate long-acting local anaesthesia effect.It in addition, there will be more literature research and report novel local anaesthetic, such as
US4302465, WO9512576A, CN101050200A, CN103601650A etc..
In order to meet clinical demand, it is still desirable to provide more can quick acting, low toxicity, long-acting anaesthetic, it is special
It is not local anesthetic.
Summary of the invention
For this purpose, the present invention provides a kind of novel narcotics, especially local anesthetic.
It is an object of the present invention to provide a kind of phthalazone-Quinazol derivative and its officinal salts.
It is another object of the present invention to provide a kind of pharmaceutical compositions, contain at least one phthalazone-quinoline
Oxazoline ketone derivatives are as main active.
It is yet a further object of the present invention to provide the phthalazone-Quinazol derivatives in terms of preparing arcotic
Purposes.The preferred local anesthetic of arcotic.
In order to realize above-mentioned purpose of the invention, the present invention provides a kind of formula (I) compound represented or its solid are different
Structure body, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
Wherein:
R1、R2、R3、R4Respectively stand alone as H, D, F, Cl, Br, I, CN, alkyl, halogenated alkyl, alkoxy, alkenyl or alkynyl；
R5For H, alkyl, halogenated alkyl or aryl alkyl；
R6、R7、R8、R9Respectively stand alone as H, D, F, Cl, Br, I, OH, NO2, alkoxy, naphthenic base, aryl, aryl alkyl ,-
CO2Ra、-NRbRcOr-CONRbRc, wherein Ra、Rb、RcFrom standing alone as hydrogen or alkyl.
In one embodiment of the invention, the alkyl and halogenated alkyl, alkoxy, the alkyl in aryl alkyl
Preferably C1-6 alkyl, further preferably C1-4 alkyl.
In one embodiment of the invention, the alkenyl is preferably C2-6 alkenyl.
In one embodiment of the invention, the alkynyl is preferably C2-6 alkynyl.
In one embodiment of the invention, the naphthenic base is preferably C3-8 naphthenic base.
In one embodiment of the invention, the aryl in the aryl and aryl alkyl is preferably C6-10 aryl.
On the other hand, the present invention relates to one kind comprising at least one formula (I) compound represented or its stereoisomer, mutually
The drug of tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug as active constituent
Composition.Described pharmaceutical composition also may include pharmaceutically acceptable excipient, carrier, adjuvant, solvent or their combination.
Another aspect, the present invention relates to formula (I) compound represented or its stereoisomer, tautomer, nitrogen oxidations
The purposes of object, solvate, metabolite, pharmaceutically acceptable salt or prodrug in terms of preparing arcotic.The arcotic
It is preferred that local anesthetic.
Beneficial effect
Test result shows the compounds of this invention to effective duration >=4 hour of the local anaesthesia of guinea pig skin, to big
Feeling residence time >=6 hour of mouse, therefore with excellent anesthesia and feel blockage effect.
Specific embodiment
The embodiment of the present invention is described below in detail.The embodiments described below is exemplary, and is only used for explaining this hair
It is bright, and be not considered as limiting the invention.
Definition and general terms
Term " patient " used in the present invention refers to people or other animals.According to some embodiments of the present invention, " suffer from
Person " refers to people.
Term " stereoisomer " used in the present invention refers to identical chemical constitution, but atom or group are in space
The different compound of upper arrangement mode.Stereoisomer includes enantiomter, diastereoisomer, conformer, geometry
Isomers (cis/trans) isomers, atropisomer, etc..
Term " enantiomter " used in the present invention refers to that two of a compound cannot be overlapped but mutually be mirrored into
The isomers of relationship.
Term " diastereoisomer " used in the present invention refer to there are two or multiple chiral centers and its molecule not
The stereoisomer of mirror image each other.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral property and anti-
Ying Xing.Non-enantiomer mixture can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis and be separated.
Term " chirality " used in the present invention be with its mirror image cannot be overlapped property molecule；And " achirality " is
Refer to its mirror image can be overlapped molecule.
Term " racemate " used in the present invention or " racemic mixture " are hypodactylia optically active two right
Reflect the equimolar mixture of isomers.
Any asymmetric atom (for example, carbon etc.) of disclosed compound of present invention can be enriched with racemic or enantiomer
Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists
(R)-or (S)-configuration in terms of have at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake
Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer
It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they
Mixture, such as the form of racemic modification and non-corresponding isomer mixture (this depends on the quantity of asymmetric carbon atom) deposits
?.Chiral synthon or chiral reagent preparation can be used in optically active (R)-or (S)-isomers, or is torn open using routine techniques
Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing disubstituted cycloalkanes in compound
The substituent group of base, naphthenic base may have cis or trans configuration.
The mixture of resulting any stereoisomer can be separated into according to the difference in component physicochemical properties
Pure or substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization
Method.
The racemic modification of any gained final product or intermediate can be passed through into those skilled in the art by known method
Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production
Object can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.
Term " tautomer " used in the present invention or " tautomeric form " refer to that with different energy can lead to
Cross the constitutional isomer that low energy barrier converts mutually.If tautomerism be it is possible, the chemistry that can achieve tautomer is flat
Weighing apparatus.For example, proton tautomer includes the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and imines-
Enamine isomerizations.Valence tautomerism body includes the mutual inversion of phases carried out by the recombination of some bonding electrons.Unless in addition
It points out, all tautomeric forms of the compounds of this invention are within the scope of the present invention.
Term " optional " used in the present invention or " optionally " refer to the event then described or situation can with but it is different
It makes now, and the description includes the case where the case where wherein event or situation occur and wherein it does not occur.For example,
" optional key " refers to that the key may exist or can be not present.
Term "comprising" used in the present invention is open language, that is, includes content specified by the present invention, but not
Exclude otherwise content.
One or more degrees of unsaturation are contained in term " unsaturation " used in the present invention or " unsaturated " expression part.
As described in the present invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as
General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art
" substituted " the one or more hydrogen atoms indicated in given structure of language are replaced specific substituent group.Unless other aspect tables
Bright, an optional substituent group can be replaced at various substitutable position of that group.When in given structural formula not
Only a position can be replaced one or more substituent groups selected from specific group, then substituent group can identical or differently
Replace at various locations.
In addition, it is necessary to explanation, unless otherwise explicitly point out, in the present invention used by describing mode
" ... respectively stand alone as " shall be understood in a broad sense, expressed specific between the same symbol either refer among the different groups
It does not influence mutually, can also be indicated in the same group between option, between the same symbol between expressed specific option
It does not influence mutually.
Herein, the substituent group of disclosed compound of present invention is disclosed according to radical species or range.It particularly points out, this hair
Each independent sub-combinations thereof of bright each member including these radical species and range.For example, term " C1-5 alkyl "
Refer in particular to the methyl being individually disclosed, ethyl, C3 alkyl, C4 alkyl and C5 alkyl.
Term " alkyl " used in the present invention indicates to contain 1 to 20 carbon atom, the linear chain or branched chain monovalent hydrocarbon of saturation
Base group, wherein replaced the substituent group that the alkyl group can be described optionally by one or more present invention.Unless another
Outer detailed description, alkyl group contain 1-20 carbon atom.According to one embodiment of present invention, alkyl group contains 1-12
Carbon atom；According to another embodiment of the invention, alkyl group contains 1-6 carbon atom；An implementation according to the present invention
Example, alkyl group contain 1-4 carbon atom；According to another embodiment of the invention, alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, uncle
Butyl, amyl, hexyl, heptyl, octyl, etc..
Term " halogen " used in the present invention refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " alkoxy " used in the present invention indicates that alkyl is connected by oxygen atom with molecule rest part, wherein alkane
Base has meaning as described in the present invention.
Term " ring " used in the present invention includes carbocyclic ring, heterocycle, aromatic ring, hetero-aromatic ring, etc., wherein the carbocyclic ring, miscellaneous
Ring, aromatic ring, heteroaromatic group have meaning as described in the present invention.
Term " naphthenic base " used in the present invention indicates containing 3-12 carbon atom, monovalent or multivalence saturation list
Ring, bicyclic or three-ring system.Bicyclic or three-ring system may include condensed ring, bridged ring and loop coil.An implementation according to the present invention
Example, naphthenic base include 3-10 carbon atom；According to one embodiment of present invention, naphthenic base includes 3-8 carbon atom；According to this
One embodiment of invention, naphthenic base include 3-6 carbon atom.The example of group of naphthene base include, but are not limited to cyclopropyl,
Cyclobutyl, cyclopenta, cyclohexyl, etc..The group of naphthene base is optionally by one or more substitutions described in the invention
Replaced base.
Term " aryl " used in the present invention indicates containing 6-14 annular atom or 6-12 annular atom or 6-10
The monocycle of annular atom, bicyclic and tricyclic carbocyclic ring system, wherein at least one ring is aromatic.Aryl group in general, but
Unnecessarily it is connect by the armaticity ring of aryl group with parent molecule.The example of aryl group may include phenyl, naphthalene
And anthracene.The aryl group is optionally replaced one or more substituent groups described in the invention.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo.
Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.
Term " metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism in vivo
Obtained product.The metabolite of one compound can be identified by technology well-known in the art, active
It can experimentally be characterized by adopting as described in the present invention.Such product can be through administrationization
Object is closed through peroxidating, is restored, hydrolysis, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtains.Phase
Ying Di, the present invention include the metabolite of compound, including when the compound of the present invention and mammal are come into full contact with one section
Between generated metabolite.
Term " pharmaceutically acceptable salt " used in the present invention refers to the organic salt of the compound of the present invention and inorganic
Salt.Pharmaceutically acceptable salt is known to us in fields.The salt that pharmaceutically acceptable nontoxic acid is formed
It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate,
Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid
Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable
Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid
Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid
Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid
Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate,
Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake
Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate,
Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4 alkyl)4
Salt.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate
, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulphation
Object, phosphoric acid compound, nitric acid compound, C1-8 sulphonic acid compound and aromatic sulphonic acid compound.
Term " solvate " used in the present invention refers to one or more solvent molecules and the compound of the present invention institute
The associated matter of formation.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide,
Ethyl acetate, acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.When the solvent
When for water, term " hydrate " can be used.According to one embodiment of present invention, the compounds of this invention molecule can be with
One hydrone combines, and can also combine with more than one hydrone, such as dihydrate, can also be less than one
Hydrone combine, such as semihydrate.
Any structural formula that the present invention provides, which is also intended to, indicates these compounds not by the form of isotope enrichment and same
The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, in addition to one or more
A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention
Isotope including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl and125I。
Compound
According to an aspect of the present invention, the present invention provides a kind of formula (I) compound represented or its stereoisomer, mutually
Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug:
Wherein:
R1、R2、R3、R4Respectively stand alone as H, D, F, Cl, Br, I, CN, alkyl, halogenated alkyl, alkoxy, alkenyl or alkynyl；
R5For H, alkyl, halogenated alkyl or aryl alkyl；
R6、R7、R8、R9Respectively stand alone as H, D, F, Cl, Br, I, OH, NO2, alkoxy, naphthenic base, aryl, aryl alkyl ,-
CO2Ra、-NRbRcOr-CONRbRc, wherein Ra、Rb、RcFrom standing alone as hydrogen or alkyl.
In one embodiment of the invention, the alkyl and halogenated alkyl, alkoxy, the alkyl in aryl alkyl
Preferably C1-6 alkyl, further preferably C1-4 alkyl.
In one embodiment of the invention, the alkenyl is preferably C2-6 alkenyl.
In one embodiment of the invention, the alkynyl is preferably C2-6 alkynyl.
In one embodiment of the invention, the naphthenic base is preferably C3-8 naphthenic base.
In one embodiment of the invention, the aryl in the aryl and aryl alkyl is preferably C6-10 aryl.
In one embodiment of the invention, the R1、R2、R3、R4Respectively stand alone as H.
In one embodiment of the invention, the R5For H, methyl, propyl or chloromethyl.
In one embodiment of the invention, the R6、R7、R8、R9Respectively stand alone as H, methoxyl group, trifluoromethyl, benzyl
Base, NO2, Cl or OH.
In one embodiment of the invention, the compound is selected from:
Pharmaceutical composition
According to another aspect of the present invention, the present invention also provides a kind of pharmaceutical compositions, and it includes at least one formula (I)
It is compound represented or its stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable
Salt or prodrug as active constituent.
An embodiment according to the present invention, pharmaceutical composition of the invention further include pharmaceutically acceptable tax
Shape agent, carrier, adjuvant, solvent or their combination.
An embodiment according to the present invention, the compounds of this invention of effective dose can with such as inert diluent or certain
Carrier takes orally together.An embodiment more according to the present invention, the compound of the present invention can be wrapped in gelatine capsule or
It is tabletted.For the purpose of oral medication, the compounds of this invention can be used together with excipient and with tablet, pastille, capsule, mixed
The forms such as suspension, syrup use.An embodiment according to the present invention, above-mentioned preparation should contain at least sheet of 0.5wt%
The reactive compound of invention, but can be changed according to specific dosage form, wherein it is convenient for accounting for the 4% to about 70% of Unit Weight.
The amount of reactive compound should reach dosage appropriate in such pharmaceutical compositions.Currently preferred pharmaceutical composition and system
The oral dosage of agent contains 1.0-300 milligrams of reactive compound of the present invention.
An embodiment according to the present invention, the dosage of the compounds of this invention depend on the type of disease or illness and tight
Principal characteristic additionally depends on the feature of patient, such as general health, age, gender, weight and drug tolerance.Those skilled in the art
Member can determine dosage appropriate according to these or other factors.The effective dose of conventionally used medicine for central nervous system
It is known to technical staff.Every total daily dose is usually between about 0.05mg to 2000mg.
An embodiment according to the present invention, the present invention relates to pharmaceutical composition, per unit dose can be provided about
0.01 arrives the active constituent of 1000mg.Composition can be applied by any approach appropriate, such as capsules per os, with injection
The form parenteral administration of liquid, the local application in the form of paste or lotion, the rectal administration in the form of suppository, with the biography of patch
The form transdermal administration of delivery system.
An embodiment according to the present invention, compound provided by the invention can with solid appropriate or liquid-carrier or
Diluent combines to form capsule, tablet, pill, powder, syrup, solution etc..Tablet, pill, capsule etc. include about 0.01
To active constituent and adhesive such as gelatin, cornstarch, the gum arabic of about 99 weight percent；Excipient such as phosphoric acid
Hydrogen calcium；Disintegrating agent such as cornstarch, potato starch or alginic acid；Lubricant such as magnesium stearate；With Sweetening agents such as sucrose,
Lactose.It also may include liquid-carrier, such as grease in addition to the raw material of the above-mentioned type when dosage form is capsule.
An embodiment according to the present invention, when be used for parenteral administration when, can by compound provided by the invention with
Sterile water or organic media combine the solution or suspension to form injectable.
Purposes
Some embodiments according to the present invention, the present invention relates to formula (I) compound represented or its stereoisomer, mutually
Tautomeric, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug are in terms of preparing arcotic
Purposes.The preferred local anesthetic of arcotic.
Preparation method
The present invention also provides a kind of preparation method of formula (I) compound represented, which is comprised the steps of:
Step 1. reacts formula (II) compound represented to make in the presence of hydrochloric acid with formula (III) compound represented
Standby formula (IV) compound represented
Step 2. makes formula (IV) compound represented and formula (V) compound represented in CuI, 8-hydroxyquinoline, potassium carbonate
In the presence of reaction to prepare formula (I) compound represented
Wherein, R1-R9As defined herein.
Embodiment
Prepare embodiment
Embodiment 1:6- methoxyl group -2- (4- oxo -3,4- dihydro phthalazines -1- base amino) quinazoline -4 (3H) -one (chemical combination
Object 1)
Phthalic anhydride 12mmol is dissolved in 80ml methanol by step 1., and 2ml hydrazine hydrate is added, then in stirring shape
Under state, it is slowly added to 10ml concentrated hydrochloric acid into solution, gained reaction system is heated to reflux, reacts 8 hours.After completion of the reaction,
Reaction mixture, which is carried out ice-water bath cooling, makes that solid, filtering is precipitated, and filter cake is washed twice with water, then with saturation NaHCO3It is molten
Liquid 50ml dissolves, and is transferred to pH value to 2-3 with concentrated hydrochloric acid after elimination insoluble matter, filters the solid of precipitation, obtain 1.83g product 4- hydroxyl
Base phthalazines -1 (2H) -one, yield 94.1%.ESI-MS:163.04 [M+H]+
Step 2. is by -4 (3H) -one 5mmol of product 5mmol, 2- amido -6- methoxyquinazoline hydrochloride, the cuprous iodide of step 1
0.3g, 8-hydroxyquinoline 0.15g, potassium carbonate 0.5g and n,N-Dimethylformamide 25ml mixing, stirring rises under nitrogen protection
Temperature is reacted 4 hours to flowing back.Evaporating solvent under reduced pressure after completion of the reaction is added water 20ml, (50ml is then extracted with ethyl acetate
× 3), merge organic phase, washed with saturation NaCl solution, anhydrous Na2SO4It is dry, with petrol ether/ethyl acetate (v:v=20:1
Silica gel column chromatography is carried out to 10:1), obtains the target compound of 1.32g white solid, yield 79.3%.
Elemental analysis: theoretical value C, 60.89；H,3.91；N,20.89；O,14.31；Measured value C, 60.45；H,4.12；N,
20.79；O,14.64
ESI-MS:336.10 [M+H]+
1H NMR(400MHz,CDCl3)δ10.28(s,1H),8.25(d,1H),8.10(d,1H),7.78(t,1H),7.69
(t,1H),7.42-7.53(m,3H),7.08(s,1H),3.81(t,3H),2.02(s,1H)。
Embodiment 2:2- (3- methyl -4- oxo -3,4- dihydro phthalazines -1- base amino) -6- trifluoromethyl quinazoline -4
(3H) -one (compound 2)
According to the method for embodiment 1, hydrazine hydrate, -4 (3H) -one of 2- amido -6- trifluoromethyl quinazoline are replaced with methyl hydrazine
Instead of -4 (3H) -one of 2- amido -6- methoxyquinazoline hydrochloride, the target compound of gray solid, two step total recoverys 67.2% are obtained.
Elemental analysis: theoretical value C, 55.82；H,3.12；F,14.72；N,18.08；O,8.26；Measured value C, 55.52；H,
3.44；F,14.43；N,18.38；O,8.23
ESI-MS:388.09 [M+H]+
1H NMR(400MHz,CDCl3)δ10.24(s,1H),8.26(d,1H),8.13(d,1H),8.01(s,1H),7.89
(d,1H),7.79(t,1H),7.67(t,1H),7.42(d,1H),2.78(s,3H),2.01(s,1H)。
According to method similar to Example 1, following compound is synthesized:
Test examples
Testing example 1: to the infiltration anesthesia effect of guinea pig skin
The compounds of this invention measures the infiltration anesthesia of guinea pig skin by the intradermal papule method of cavy.
Cavy 40 of weight 300-400g are taken, are randomly divided into 8 groups, every group 5, before its net back is shaved on the day before experiment
Afterwards at each one diameter be 4-5cm size dermatotome.Embodiment compound 1-7 is dissolved in physiological saline, concentration 5mg/ml respectively；?
With 0.25 milliliter of 27G syringe needle intracutaneous injection in the dermatotome that cavy is got ready, papule is formed.At regular intervals with pin with appropriateness
Dynamics stimulates skin at papule, and test randomly chooses 6 points of stimulations in papule center and periphery every time, between the stimulation between every bit
Every 3-6 seconds, the nociceptive reflex (shouting, tremble) of test cavy is observed and recorded；There is nociceptive reflex to be denoted as 1, without pain reflection
It is denoted as 0, until all stimulation point full recovery pain reactions.For every group 8 cavys, the stimulation number of without pain reflection is calculated
Zhan always stimulates the percentage of number, is denoted as inhibiting rate, is determined as that local anaesthesia is effective more than 50%.It measures and the results are shown in Table 1.
Table 1: infiltration anesthesia effect of the compound to guinea pig skin
| Test object | Local anaesthesia effective duration/h |
| Compound 1 | 4 |
| Compound 2 | 5 |
| Compound 3 | 5 |
| Compound 4 | 6 |
| Compound 5 | 4 |
| Compound 6 | 5 |
| Compound 7 | 4 |
By the intradermal papule method of cavy be measured the result shows that, local anaesthesia of the compounds of this invention to guinea pig skin
Effective duration >=4 hour, have excellent anaesthetic effect.
Test examples 2: the feeling of rat nervus coccygeus is blocked
The compounds of this invention measures the feeling retardance of rat nervus coccygeus by the hot tail-flick method of rat.
200-250g male SD rat 40 are taken, 8 groups is randomly divided into, every group 5, is cleaned before experiment with 75% ethyl alcohol gauze
Rat-tail, prepared Chinese ink are applied to the mark at lower the 1/3 of tail portion as light stimulus.Rat is fixed on fixator, with YLS-12A rat-tail illumination
Rat is resistance to is illuminated by the light hot pain time for pain threshold detector test (latent time starts to expose to the time for removing tail).To protect mouse
Tail sets the maximum illumination time as 10 seconds from burn.Each animal basic latent time is first tested, temperature is adjusted, keeps basis latent
Lying prostrate the time is 3-4 seconds.Embodiment compound 1-7 is dissolved in physiological saline, concentration 5mg/ml, by rat-tail bilateral nervus coccygeus respectively
0.1 milliliter is injected respectively.Tail portion is tested after injection at regular intervals to the reaction latent time of thermostimulation.The sense of rat tails
Feel that function retardance determines by comparing reaction latent time increase degree of the administration front and back rat to thermostimulation, based on following equation
Calculate maximum possible effect percentage:
MPE%=100 × (test latent time-basic latent time)/(m- basis irradiation time when maximum illumination).
It is judged to feeling blocking more than 50%.Repeatedly when follow-on test, pain position will be surveyed and slightly moved.Measuring the results are shown in Table
2。
Table 2: feeling retarding effect of the compound to rat nervus coccygeus
| Test object | Feel retardance duration/h |
| Compound 1 | 7 |
| Compound 2 | 8 |
| Compound 3 | 8 |
| Compound 4 | 9 |
| Compound 5 | 6 |
| Compound 6 | 7 |
| Compound 7 | 6 |
By the hot tail-flick method of rat be measured the result shows that, the compounds of this invention to the feeling residence time of rat >=
6 hours, there is excellent feeling blockage effect.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.
Claims (9)
1. a kind of formula (I) compound represented or its stereoisomer, tautomer or pharmaceutically acceptable salt:
Wherein:
R1、R2、R3、R4Respectively stand alone as H, D, F, Cl, Br, I, CN, C1-6 alkyl or halogenated C1-6 alkyl；
R5For H, C1-6 alkyl or halogenated C1-6 alkyl；
R6、R7、R8、R9Respectively stand alone as H, D, F, Cl, Br, I, OH, NO2, C1-6 alkoxy, C6-10 aryl C1-6 alkyl or three
Methyl fluoride.
2. compound according to claim 1, which is characterized in that the R1、R2、R3、R4Respectively stand alone as H.
3. compound according to claim 1, which is characterized in that the R5For H, methyl, propyl or chloromethyl.
4. compound according to claim 1, which is characterized in that the R6、R7、R8、R9Respectively stand alone as H, methoxyl group, three
Methyl fluoride, benzyl, NO2, Cl or OH.
5. compound according to claim 1, is selected from:
6. a kind of pharmaceutical composition, it includes chemical combination shown at least one formula (I) according to claim 1-5
Object or its stereoisomer, tautomer or pharmaceutically acceptable salt are as active constituent.
7. formula (I) compound represented according to claim 1-5 or its stereoisomer, tautomer or
Purposes of the pharmaceutically acceptable salt in terms of preparing arcotic.
8. purposes according to claim 7, which is characterized in that the arcotic is local anesthetic.
9. a kind of method for preparing formula according to claim 1 (I) compound represented, it includes following steps:
Step 1. reacts formula (II) compound represented with preparation formula in the presence of hydrochloric acid with formula (III) compound represented
(IV) compound represented
Step 2. deposits formula (IV) compound represented and formula (V) compound represented in CuI, 8-hydroxyquinoline, potassium carbonate
In lower reaction to prepare formula (I) compound represented
Wherein, R1-R9As defined in claim 1.
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