CN85106970A - Be used as the preparation method of the aminoalkoxy benzopyrone of major tranquilizer and tranquillizer - Google Patents
Be used as the preparation method of the aminoalkoxy benzopyrone of major tranquilizer and tranquillizer Download PDFInfo
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Abstract
Herein disclosed is molecular formula as shown in the formula aminoalkoxy benzopyrone (I), (R in the formula
1Be as above group) or and manufacture method, treatment anxiety disorder and psychosis are as schizoid medical components and methods of treatment.
Description
The existing in the literature report of various aminoalkoxy benzopyrones.Molecular formula is:
R wherein
2Be the compound of low alkyl group,, also be described in 810,898 that it has the Ivy extract activity, and the infiltrative ability of the blood capillary that reduces to enlarge at United States Patent (USP) NO.3.
It is found that existing benzopyrone has the characteristic of effectively loosening nerve (neuroleptic), thereby can be used as major tranquilizer and tranquillizer.
What correspondingly, the present invention relates to is that molecular formula is
Compound, wherein n is the integer of 2-5; R is a hydrogen, low alkyl group, trifluoromethyl, or lower alkoxy; R
1Be the following group of molecular formula:
Wherein
Represent singly-bound or two key, Ar is a phenyl or by low alkyl group, rudimentary thio alkoxy, and the phenyl that halogen or trifluoromethyl replace, Het is 2-, 3-, or 4-pyridyl or by low alkyl group, lower alkoxy, or the 2-that replaces of halogen, 3-, or 4-pyridyl; 2-, 4-, or 5-pyrimidyl or, the 2-that lower alkoxy or halogen replace, 4-, or 5-pyrimidyl by low alkyl group; 2-pyrazinyl or by low alkyl group, lower alkoxy, or the 2-pyrazinyl that replaces of halogen; 2-, or 3-thienyl or the 2-that replaced by low alkyl group or halogen, or 3-thienyl; 2-, or 3-furyl or the 2-that replaced by low alkyl group or halogen, or 3, furyl, 2-, or 5-thiazolyl or the 2-that replaced by low alkyl group or halogen, or 5-thiazolyl, or its medicinal acid salt that adds, this does not comprise that wherein subordinate's compound: n is 3, R is a methyl, R
1Be that molecular formula is:
Group, wherein Ar is a phenyl.
The invention still further relates to a kind of medicinal component, it is its medicinal acid salt and pharmaceutical carrier composition of adding of compound (psychotolytic significant quantity or the quelling effect amount) generation of molecular formula I.
The invention still further relates to and plant suffering from the method that psychosis (as schizophrenia) or anxiety disorder person treat, allow the patient take the compound of the molecular formula I of significant quantity exactly, wherein n is the integer of 2-5; R is a hydrogen, low alkyl group, lower alkoxy, or trifluoromethyl; R
1Be the following group of molecular formula:
Wherein
Represent singly-bound or two key, Ar is a phenyl or by low alkyl group, lower alkoxy, rudimentary thio alkoxy, the phenyl that halogen or trifluoromethyl replace; Het is 2-, 3-, or 4-pyridyl or by low alkyl group, the 2-that lower alkoxy or halogen replace, 3-, or 4-pyridyl; 2-, 4-, or 5-pyrimidyl, or by low alkyl group, lower alkoxy, the 2-that lower alkoxy or halogen replace, 4-, or 5-pyrimidyl; 2-pyrazinyl or by low alkyl group, the 3-pyrazinyl that lower alkoxy or halogen replace; 2-, or 3-thienyl, or by the 2-of low alkyl group or halogen replacement, or the 3-thienyl, 2-, or 3-furyl or replaced 2-by low alkyl group or halogen, or the 3-furyl, 2-, or 5-thiazolyl or the 2-that replaced by low alkyl group or halogen, or 5-thiazolyl, the perhaps medicinal acid salt that adds of the compoundmolecularformula of unit dosage form.
Term in the compound of molecular formula I " low alkyl group " means and comprises that carbonatoms is the straight or branched alkyl of 1-6, as: methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, or the like.
Halogen refers to fluorine, chlorine or bromine especially.
The carbonatoms that lower alkoxy is identical with " low alkyl group " definition with rudimentary thio alkoxy is O-alkyl or the S-alkyl of 1-6.
A compound that priority scheme is the molecular formula II of the present invention:
Wherein n, R and R
1As above definition, the perhaps medicinal acid salt that adds of this compound.
Another priority scheme of the present invention is the compound of molecular formula II, and wherein n is the integer of 2-5; R is a hydrogen, R
1As preceding definition, perhaps the medicinal acidity of this compound is added salt.
Another priority scheme of the present invention is the compound of molecular formula II, wherein is 2-5; R is a hydrogen, R
1Be the group of subordinate's molecular formula:
Wherein
Represent singly-bound or two key; Ar is a base or by methyl, methoxyl group, and the phenyl that sulfo-methoxyl group or chlorine replace, Het is 2-, 3-, or 4-pyridyl; 2-, 4-, or 5-pyrimidyl; 2-pyrazinyl, or 2-thiazolyl.
Another priority scheme of the present invention is the compound of molecular formula II, and wherein n is 2-5, but 3-4 preferably; R is a hydrogen, R
1Be the group of subordinate's molecular formula:
Wherein Het is 2-, 3-, or 4-pyridyl; 2-, 4-, or 5-pyrimidyl; 2-pyrazinyl or 2-thiazolyl.
Preferred plan of the present invention is: 7-(3-(4-phenyl-peiperazinyl) propoxy-)-and 2H-1-Ben And pyran-2-one, 7-(3-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl) propoxy-)-2H-1-Ben And pyran-2-one, 7-(3-(4-(2-pyrimidyl)-1-piperazinyl) propoxy-)-2H-1-Ben And pyran-2-one, and 7-(4-phenyl-peiperazinyl) butoxy)-2H-1-Ben And pyran-2-one, or the medicinal acid salt that adds of these compounds.
Except above-mentioned preferential compound, the antipsychotic best method of the present invention makes the patient obey significant quantity, the 7-of unit dosage form (3-(4 phenyl-peiperazinyl)-propoxy-)-4-methyl-2H-1-Ben And pyran-2-one.
Compound of the present invention and organic or inorganic acid-respons form the medicinal acid salt that adds.Be suitable for the sour example hydrochloric acid that salt generates, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, Pingguo acid, FUMARIC ACID TECH GRADE, Succinic Acid, xitix, maleic acid, methylsulfonic acid, or the like.The preparation of salt is to use ordinary method, and the required acid of free alkali and capacity is contacted.The free alkali available bases (as, with the aqueous solution of alkali of dilution) handle salt and regenerate.Be suitable for the sodium hydroxide of the alkali of this purpose, salt of wormwood, ammoniacal liquor, sodium bicarbonate aqueous solution as dilution.Free alkali and their salt separately certain physical in nature (as the solubleness in polar solvent) some is different.But salt or its corresponding free alkali are identical to the effectiveness of invention.
Compound of the present invention can be with non-solubilised state, and solubilised state comprises that hydrated state exists.In general, solubilised state (with medicinal solvent such as water, alcohol etc.) is identical with non-solubilised state to the effectiveness of inventing.
The compound of compound of the present invention and molecular formula I can make as follows.The first step makes molecular formula be
Wherein the hydroxyl of R such as preceding definition-2H-1-chromen-2-one and molecular formula are
Compound reaction, wherein n is the integer of 2-5, X can be a leavings group (as halogen) or sulfonyloxy, as sulfonyloxy methyl oxygen base or tosyloxy with can be different with Y; Second goes on foot, and makes the compound of the molecular formula IV of generation
With a kind of amine reaction in the following molecular formula,
Wherein Ar and Het such as preceding definition, and, if necessary, can make the free alkali of formation change into the medicinal acid salt that adds by currently known methods.
The reaction of the compound of the benzene pyran-2-one of molecular formula III and molecular formula III a, at inert solvent, be preferably in polar solvent such as the ketone (for example, acetone or mibk), at acid scavenging agent such as anhydrous sodium carbonate or preferably in the presence of the Anhydrous potassium carbonate, under the reflux temperature of solvent, carry out.
Then, the intermediate product of molecular formula IV and suitable amine, react in the presence of neutralization reagent such as sodium bicarbonate for example in the dimethyl formamide at polar aprotic solvent.The temperature that is reflected at rising is carried out under 50-150 ℃ according to appointment.
Another method of the compound of preparation molecular formula I is as follows: the first step, press Ind.J.Chem.435(1982) method of Miao Shuing, the preparation molecular formula is
Compound, wherein X and R
1As preceding definition.In second step, the compound chromen-2-one direct and the molecular formula III of molecular formula V is reacted.This reaction preferably also under the temperature that raises such as 50-150 ℃, in solvent such as dimethyl formamide, is carried out in the presence of acid neutralization reagent such as sodium bicarbonate.
Hydroxyl-the coumarin derivatives that is fit to, the compound of molecular formula III, sulfonamide derivatives can make from commercial acquisition or by known method.Can be as 4-replacement-7-hydroxyl-tonka bean camphor by " organic synthesis " Coll Vol3, the method that P282 prepares 4-methyl-7-hydroxyl-tonka bean camphor is done change a little and is made.
Compound of the present invention is a kind of new chemical substance, and it can be used as treatment psychosis such as schizoid medicament.The antipsychotic activity of typical compound of the present invention can be by following " the active and sieve analysis method of mouse " (MAST) (Mouse Activity and Screen Test Procedure) mensuration:
Animal: 9 the heavy 20-30g not male mouse of Suiss-Webster (Buckberg Labs) of fasting are divided into three groups equably corresponding to each medicament to be measured.Also promptly, from three groups of separating that respectively contain three mouse, measure the data of each dose levels respectively.
Medicament: to each medicament, test three kinds of dose levels (10,30, minimum 100mg/kg).Tested preceding 1 hour, and carried out the intraperitoneal administration and handle.All dosage are pressed initial compounds and are calculated, and with the dosage dispensing of 10mg/kg.Compound dissolution or be suspended in 0.2% the methylcellulose gum.Control animal injection methylcellulose gum.
Test: inject two step of beginning in back 1 hour method of testing.The first step is finished the screen cloth examination and (is seen Pharmac Biochem Behav.6,351-353.1977).In brief, this test is, it is online that mouse is placed on independent wire screen, and screen cloth Rotate 180 ° then begins observation period of 60 seconds simultaneously, notes the mouse number that the screen cloth after the upset falls.
And then screen cloth test, second step of carrying out whole analysis.Every group of one group of three mouse put into (" living science ") 22 in the motion photoinstrumentation (actphotometer), 1067-1076,1978), the motion photoinstrumentation has a cylindrical chamber, the center of cylindrical chamber is another right cylinder, and cylindrical chamber has 6 phototube irradiations that are installed on its periphery.6 road beam interferences form single spike, and the activity of the mouse that can move was got off by computer recording every 10 minutes, continue 60 minutes.
Data: the data that screen cloth test obtains are represented with the percentage ratio of the mouse that falls from screen cloth.The ratio of activity data of mouse of moving after take medicine back and the shape agent of taking medicine of gained is represented the percentage ratio to the inhibition of autonomic movement.To depressomotor total percentage ratio based on cumulative data in 1 hour.Two stages analyzing all grade by following: A=60-100%; C=31-59%; N=0-30% promptly obtains full dose levels from following rule:
The dose levels of the sieve analysis of motion
Lines such as inhibition are equal to the failure grade and equal
A-N or C=A
A????-????A????＝????C
C-N or C=C
All other combination=N
The compound that reaches full dose levels A with 100mg/kg or littler dosage inhibition is promptly thought active compound.Use this method, promptly obtain showing 1(listed be the compound that has been issued to full dose levels A at specified dosage):
Table 1
R n R
1Dosage
mg/kg
H 3
3.0
CH
33
1.0
H 3
3.0
H 3
1.0
Thioridazine
*10.0
（Thiorida-
zine）
*Annotate: a kind of antipsychotic drug
The antipsychotic activity of exemplary compounds of the present invention, also available (
3H) haloperidol binding assay (HRBA) is measured.This method is extremely different from Mol.Pharmacol.12,800,1976) on, and between binding capacity and clinical efficacy amount, fabulous compatibility is arranged according to reports.
(
3H) Haloperidol binding assay: to the relative affinity of the compound of Dopamine Receptors, can according to this compound from by replace in the striated barrier film (Rtriatal membranes) that obtains the different mouse of Long-Evans body color (
3H) ability of Haloperidol is determined.Mouse is put to death by disconnected neck; Remove brain, dissect mouse body line (corpus Dtriata).Mouse body line stirs evenly in 40 portions of (Volumes) 50nm Tris damping fluids (PH=7.6), centrifugal compression.The line sheet stirs evenly in 50 portions of same damping fluids again, is used for carrying out combination and measures.Make 10ml50nM Tris-HCl damping fluid (PH=7.6) insulation, damping fluid also contains the initial homogenate of 2mg/ml, 100 μ l test agent or solvents, and 0.6nM (
3H) haloperidol.At 0.1 μ M(+)-the butaclamol(butaclamol, a kind of antipsychotic drug) exist and measure unspecific combination down.Sample is incubated 40 minutes in 25 ℃ of reciprocal water-baths.Under reduced pressure filter fast, stop insulation by glass fibre filter screen (What man GF/B).With 10ml Tris-HCl damping fluid drip washing filtrate three times.The filtrate example is (Beckman Ready-Solu HP) in the luminous Coctail of 10ml, shakes 1 hour.The radioactivity that exists on the filtrate is measured with the liquid spectrophotometer that glitters.Begin just to estimate that compound is at 10nM.When determining IC5os, from non-linear computation machine curve calculation, data should be concentrated 4 times or more times, do three times for every.
The IC50s such as the table 2 of exemplary compounds of the present invention.
HRBA measures
Table 2
R n R
1IC
50
H 3
1.5×10.8
CH
33
5.0×10
-8
H 3
93×10
-8
H 3
1.5×10
-8
Thioridazine 1.9 * 10
-9
Compound of the present invention is new chemical substance, and it also can be used as the medicament for the treatment of anxiety disorder, promptly as tranquillizer (anxiolytic agents).The anxiety activity of exemplary compounds of the present invention, it is the anxiety activity of the compound of molecular formula I of the present invention, the animal model of available anxiety measures, and this method is Psychopharmacologihl:482(1960) the middle Geller-Seifter conflict method of testing of describing.Need particularly point out, this method has a response fast when beginning, then produced test conflict, is instructed when animal and tests after refining more stable performance again.Each animal is as the contrast of himself, and testing method is described below;
Experimenter: body weight 300-350g, the different mouse (Long-Evans system) of sophisticated male body color.
Equipment: testing laboratory's structure is: be equipped with the close beta compartment of a lever on the wall of one side, grizzly bar base plate, automatic feeding device and loud speaker.Testing laboratory is sealed by a soundproof room.Electric shock is sent by a LVE type 1531 current stabilization electric shock devices, and white Gaussian noise is produced by-LVE type 1524 noisemakers, and monotone (tone) is produced by a LVE1664 4.5KC tone generator.All incidents and record carry out all automatically, and program is by suitable electric timer and rly. control.
Step: transfer interval (VI)=2 minute; Test period=4; Electric shock=0.6-0.8ma; Food award=Borden ' s sweetened condensed milk (every portion of milk is joined 2 parts of water dilutions); 70% of cancellation animal ad lib amount makes it be subjected to starve 23 hours; The test duration=hours 12 minutes.
Conflict is produced by following method: make hungry mouse be forced to get used to the lever of leaving behind, reward to obtain food.Along with lever is left behind, a unexpected recompense is arranged, on average to repeat once every 2 minutes transfer interval-VI2 minute.(see Ferster; C.B; With Qkinner B.F.; " program of recompense " Appleton-Century-Crofts, New York, 1957).
Carry out 4 circulations in 3 minutes at certain intervals at duration of test.In these test periods, one monotone shows, each lever is left behind, once food compensation (CRF), and also once shock by electricity as punishment on the pin of pain simultaneously.
In other words, jejunitas mouse is trained to, and the lever of must leaving behind just can obtain food (sweetened condensed milk).Usually, mouse is finished This move with the transfer interval (VI) that is planned, and once lever was left behind in promptly average two minutes, and food is delivered to; Interbody spacer in the cycle of the obtained food of two successive can be regulated continuously, and foundation is that animal is to the reaction of the low but stable speed of the food of acquisition once in a while.
After 12 minutes, the lamp of testing laboratory breath goes out, and only lights two lampets by this program behavior of animal, to indicate in 3 minute test period the obtainable food of lever of leaving behind each time.In test, each lever is left behind, and produces one simultaneously and slight passes through the electric shock (0.8am, 0.25 second) (punishment) that the grizzly bar base plate transmits.Like this, just produced the conflict of a close-escape, also be attended by anxiety simultaneously: response each time, food are easy to obtain, but response each time also has punishment (to see Miller, N, E., " some recent developments of conflict form and medicine ", the united states drug scholar, 16: 12,1961).In this test procedure, we are with four continuously testeds, each 12 minutes one-period, and food compensation VI is effective in this cycle.
In administration testing period not, usually, mouse has the stable speed of response in the VI unit, but in the testing period of band punishment, has only few response.
Give mouse with 55 and 80mg/kg PO, rather than, take 7-(3-(4-(2-pyrimidyl)-1-piperazinyl) propoxy-with the dosage of 27.5mg/kg PO)-the 2H-chromen-2-one, can increase its response in the testing period.This effect is not to be that condition realizes with the response times that reduces in the VI unit.In other words, there is not significant total sedation effect.This compound has three response times that increased band punishment during with 55mg/kg dosage in four mouse being tried, during with 80mg/kg dosage, and four response times that increased band punishment in four mouse being tried.Following is to specified compound, four total degrees that tried mouse in prerun and band punishment response in the testing period:
The prerun overall response number test of compound dosage (mg/kgPO) band punishment
7-〔3-〔4-????27.5????39????44
(2-pyrimidyl)-
The 1-piperazinyl) third 55 78 147
The oxygen base)-2H-benzene
And pyran-2-one 80 23 77
The prerun responder is the responder of the 3 minutes interim accumulative total of build-in test when beginning not administration.
Testing period in the increase (reducing of conflict) of responder show that less calm activity is arranged.This can be represented by the increase of test/prerun ratio.Total responsiveness is to cause weak tolerance of paying effect.The effect of paying is represented in the decline of overall response number.
Can the be multiple oral or non-enteron aisle medicine type preparation of compound of the present invention and taking.For the professional and technical personnel, following medicine type, that is: or with the compound of molecular formula I, or the pharmaceutical salts of the compound of corresponding molecular formula I, or the mixture of these compounds and/or salt, as its active ingredient, be conspicuous.
By the compound medicine component that the present invention describes, used inert pharmaceutical carrier can be solid, also can be liquid.Solid-state patent medicine comprises pulvis, tablet, dispersive granula, wafer, cachet and suppository.Solid-state carrier can be one or more materials, also can be simultaneously as thinner, and deodorant tune, solubilizing agent, lubricant, suspension agent, tackiness agent or tablet dispersion agent; It also can be a sealing material.If pulvis, carrier are to mix accurate dispersed solids with accurate dispersive active compound, if tablet, active compound must mix with a certain proportion of carrier with required bond properties, forms required shape and size.Pulvis and tablet preferably comprise 5 or 10 to about 70% activeconstituents.The solid-state carrier such as the magnesiumcarbonate that are suitable for, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, cocoa cream, or the like.Term " preparation " refers to, and active compound is mixed with the sealing material of making carrier, forms wafer, and active ingredient in the capsule (with or without other carrier) is surrounded by carrier, and this is the content of preparation.Similarly, cachet also is preparation like this.Tablet, pulvis, cachet and wafer can be used with solid dosage forms, are suitable for closing clothes.
Liquid patent medicine comprises solution, suspension and emulsion.For example water or water-propyleneglycoles solution can be made non-enteron aisle injection.Liquid patent medicine also can generate in the polyethylene glycol aqueous solution.Be suitable for the oral aqueous solution, can be by water-soluble, on demand then active ingredient, the tinting material that add to be fit to, deodorant tune, stablizer or viscosifying agent and make, be suitable for oral suspension, can make by accurate dispersive active ingredient is distributed in the water that contains viscous material.These viscous materials as, natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine and other known suspension agents.
Ideal comparatively when medical is that patent medicine is unit dosage form.Like this, patent medicine is divided into the unitary dose of content active ingredient again.Unit dosage form can be wrapped product, whenever includes a certain amount of patent medicine, as package troche, and wafer and phial or ampoule dress pulvis.Unit dosage form also can be wafer, these packaged forms of cachet or tablet itself or proper number.
In unitary dose patent medicine, the quantity of active compound can be according to the drug effect of specific end use and active ingredient, at 1mg to changing between the 100mg or regulating.
When using as antipsychotic agent treatment, the compound that uses in the methods of treatment of the present invention, during beginning by every day every kilogram of about 0.1mg take to the dosage of medicine 10mg, if every day, dosage was extremely about 10mg of every kilogram of about 1.0mg, better effects if.
When using as tranquillizer treatment, the compound that uses in the methods of treatment of the present invention, during beginning by every day about 0.1mg/kg to the dosage of about 20mg/kg, about 1mg/kg is about 3mg/kg extremely, better effects if.
Yet dosage can be according to patient's needs, the severity of the state of an illness, and used compound and changing.To specific situation, determine suitable dosage, belong to those skilled in the art's skill.Usually, during treatment, begin with less dosage, it is littler than the optimum dosage of this compound.Then, dosage progressively increases with less increment, up to the optimum effect under specific condition.For simplicity, TDD is divided into several parts again, as needs, then takes in proportion in one day.
Following non-limiting examples can illustrate that the inventor is used for preparing the preferential method of The compounds of this invention.
Embodiment 1
7-(3-(4-phenyl-peiperazinyl) propoxy-)-2H-1-chromen-2-one 7-(3-halo propoxy-)-the 2H-1-chromen-2-one
With 32g(0.3mol) 7-hydroxyl-2H-1-chromen-2-one, 43g(0.3mol) Anhydrous potassium carbonate and 48g(0.3mol) mixture formed of 1-bromo-3-chloropropane stirring and refluxing 18 hours in 350ml acetone.Filter this mixture, and with the filtrate vaporising under vacuum.Residuum is dissolved in methylene dichloride and wash with water.Organic phase is drying vaporising under vacuum again on anhydrous magnesium sulfate.Remaining thick product is come out by recrystallization in vinyl acetic monomer-sherwood oil.Thereby obtain 32g(68%) solid, promptly fusing point be 92-98 ℃ contain 7-(3-chlorine propoxy-)-and 7-(3-bromine propoxy-)-mixture of 2H-1-chromen-2-one.
7-(3-(4-phenyl-peiperazinyl) propoxy-)-the 2H-1-chromen-2-one
Will be by 6.3g(0.025mol) 7-(3-halo propoxy-)-2H-1-chromen-2-one, 10g(0.12mol) sodium bicarbonate and 4.1g(0.025mol) mixture formed of 1-phenylpiperazine stirs in the 100ml dimethyl formamide and 80 ℃ of heating 16 hours.Filter this mixture, vaporising under vacuum filtrate.Residuum is dissolved in methylene dichloride, water extraction again.Organic phase is dry and vaporising under vacuum on anhydrous magnesium sulfate.Residuum crystallizes out from vinyl acetic monomer, thereby obtains 5.9g(61%) title compound, fusing point is 117-118 ℃.
Embodiment 2
7-(3-(4-(2,3-xylyl)-1-piperazinyl) propoxy-)-the 2H-1-chromen-2-one
By the method identical, but use 4.8g(0.025mol with embodiment) 1-(2, the 3-xylyl) piperazine replacement 1-phenylpiperazine, from vinyl acetic monomer, obtain 3.7g(37%) title compound, fusing point is 89 ℃.Corresponding hydrochlorinate salt can obtain with the vinyl acetic monomer dilution by free alkali being dissolved in the hydrochloric acid that contains 10% Virahol again, and its fusing point is 247-250 ℃.
Embodiment 3
With with the similar method of embodiment 1, make following compounds:
7-(3-(4-phenyl-peiperazinyl)-propoxy-)-and 4-methyl-2H-1-chromen-2-one, fusing point is 127-130 ℃, its hydrochloride, fusing point are 253 ℃;
7-(3-(4-(2,3-xylyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 4-methyl-2H-1-chromen-2-one, fusing point is 253-255 ℃;
7-(3-(4-(2-tolyl) 1-1 piperazinyl) propoxy-)-and the 2H-chromen-2-one, fusing point is 123-125 ℃;
7-(4-(4-phenyl-peiperazinyl)-butoxy)-and the 2H-1-chromen-2-one, fusing point is 145-147 ℃;
7-(3-(4-phenyl-peiperazinyl) propoxy-)-and 4-trifluoromethyl-2H-1-chromen-2-one, dihydrochloride, fusing point are 190 ℃;
7-(3-(4-(3-tolyl-1-piperazinyl) propoxy-)-and 2H-1-chromen-2-one hydrochloride, fusing point is 217-220 ℃;
7-(3-(4-(4-tolyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 140-142 ℃;
7-(3-(4-(3-chloro-phenyl-)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-1-chromen-2-one, fusing point is 228 ℃;
7-(3-(4-(4-chloro-phenyl-)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 129-131 ℃;
7-(3-(4-(2,3-dichlorophenyl)-1-piperazinyl) propoxy-)-and the hydrochlorinate compound of 2H-1-chromen-2-one, fusing point is 215 ℃;
7-(3-(4-(3,4-xylyl)-1-piperazinyl) propoxy-)-and 2H-1-and pyran-2-one, fusing point is 132 ℃, its hydrochloride, fusing point are 220 ℃;
7-(3-(4-(3,4-dichlorophenyl)-1-piperazinyl) propoxy-)-and 2H-1-chromen-2-one-2-ketone, fusing point is 135-136 ℃;
8-(3-(4-phenyl-peiperazinyl) propoxy-)-2H-1-chromen-2-one, fusing point is 95-97 ℃;
7-(3-(4-(2-pyrimidyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 135-137 ℃;
7-(3-(4-(3-chloro-2-pyridyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-1-and pyran-2-one, fusing point is 235-238 ℃;
7-(3-(4-(3-pyridyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromene, fusing point is 122-125 ℃;
7-(3-(4-(6-fluoro-2-pyridyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-1-chromen-2-one, fusing point is 241-243 ℃;
7-(3-(4-(6-bromo-2-pyridyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 95-97 ℃;
7-(3-(4-(5-methyl-2-pyridyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 120-122 ℃;
7-(3-(4-(3-methyl-2-pyridyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-1-chromen-2-one, fusing point is 210-215 ℃;
7-(3-(4-(4-methyl-2-pyridyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 113-115 ℃;
7-(3-(4-(6-methyl-2-pyridyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 105-107 ℃;
7-(3-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl) propoxy-)-2H-1-pyran-2-one, fusing point is 127 ℃;
7-(2-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl) oxyethyl group)-2H-1-chromen-2-one, fusing point is 120-125 ℃;
The hydrochloride of 7-(4-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl) propoxy-)-2H-1-chromen-2-one, fusing point is 195 ℃; With
The hydrochloride of 7-(3-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl) propoxy-)-4-methyl-2H-1-chromen-2-one, fusing point is 219-221 ℃;
The hydrochloride of 7-(3-(4-(2-thiotolene base)-1-piperazinyl)-2H-chromen-2-one, fusing point is 228-232 ℃;
7-(3-(4-(2-methoxyphenyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-chromen-2-one, fusing point is 228-231 ℃;
7-(3-(1,2,3,4,5, the hydrochloride of 6-six hydrogen-4-phenyl-1-pyran-2-one, fusing point is 218-221 ℃;
7-(3-(4-(2-pyrazinyl)-1-piperazinyl) propoxy-)-and the 2H-1-chromen-2-one, fusing point is 176-179 ℃; With
7-(3-(4-(2-thiazolyl)-1-piperazinyl) propoxy-)-and the hydrochloride of 2H-1-chromen-2-one, fusing point is 167-170 ℃.
Embodiment 4
7-(3-(4-phenyl-peiperazinyl) propoxy-)-4-propyl group-2H-1-chromen-2-one
By magazine Ind.J.Chem.435(1982) described method prepares N-(3-chloro propoxy-) N
4-phenylpiperazine.Be about to 87g(0.55mole) 1-bromo-3-chloro-propane splashes into by 81g(0.5mole) in the stirred solution that is made into of the aqueous NaOH of N-phenylpiperazine, 100ml acetone and 75ml 25%.Organic layer is separated, concentrates, uses the vinyl acetic monomer pulp, washing then, dry on sal epsom, be condensed into the oily matter that weighs 85g at last, prove title compound through tlc and analytical reagent composition.
Make 4.6g(0.02mole) 4.4g(0.02mole in above-mentioned oily compound and the 100ml dimethyl formamide) 7-hydroxyl-4-propyl group tonka bean camphor and 4g Carbon Dioxide nak response.Reaction mixture 85-95 ℃ of stirring 16 hours, is filtered this mixture, concentrate again and with sodium bicarbonate washing METHYLENE CHLORIDE solution oily matter is extracted, and drying also concentrates on sal epsom then.With this oily matter place solidify and with recrystallization in the vinyl acetic monomer to obtain 5g 7-(3-(4-phenyl-peiperazinyl) propoxy-)-4-propyl group-2H-1-chromen-2-one, fusing point is 114-116 ℃.
Embodiment 5
7-(3-(3,6-dihydro-4-(2-thienyl)-1(2H)-pyridyl)-propoxy--2H-1-chromen-2-one, the 4-(2-thienyl) tetrahydropyridine
Will be by 1.3g(0.01mole) AlCl
3The nitrogen stress solution that is made into the 40ml ether adds by 1.2g(0.03mole down at 15 ℃) in the suspension that is stirring that is made into of LAN, 100ml ether and 75ml tetrahydrofuran (THF), and then stirred 15 minutes.Add in the suspension that stirs a kind of lentamente by 3g(0.018mole) the 4-(2-thienyl)-solution that pyridine and 30ml tetrahydrofuran (THF) are made into.This mixed solution was at room temperature stirred 5 hours, then by adding 2ml H carefully
2The NaOH of O, 3ml40% and add 2mlH again
2O makes it disassociation.Filter this mixture, and vaporising under vacuum.Residuum is dispersed in the HCl-ether of 1N.Aqueous part is mixed mutually with methylene dichloride, and alkalize, with dichloromethane layer drying (MgSO with dense NaOH
4), vaporising under vacuum promptly obtains the 2g4-(2-thienyl again)-tetrahydropyridine.
Mass spectrum calculates: 165.25
Theoretical value (Found) is: 165
With 2.9g(0.012mole) the 7-(3-chloro propoxy-of preparation in the previous embodiment 1)-2H-1-chromen-2-one sample, 2g(0.012mole) the 4-(2-thienyl) tetrahydropyridine and 5g NaHCO
3In 80ml DMF, under 80-90 ℃ temperature, stirred 7 hours earlier, at room temperature stir a whole night again, filter then and vaporising under vacuum.Use NaHCO
3Residuum in the washing methylene dichloride is used MgSO
4Drying, then vaporising under vacuum.So obtain the dark-coloured buttery 7-(3-(3,6-dihydro-4-(2-thienyl) 1-(2H) of 4.3g-pyridyl) propoxy-)-the 2H-1-chromen-2-one.This oily matter is dissolved in the 20ml 2-propyl alcohol and handles with the hydrogen chloride solution that 3ml(contains the 20%2-propyl alcohol, obtain the independent hydrochlorinate salt of 2.4g, fusing point is 235-7 ℃.
With the following formula analytical calculation): C
21H
21NO
3S.HCl.0.5H
2O
C，60.99;H，5.62;N，3.39
Theoretical value (Found) is: C, 61.06; H, 5.60; N, 3.27
Claims (11)
1, the compound shown in the preparation following formula or the method for its acid salt,
Wherein n is an integer among the 2-5; R is a hydrogen, low alkyl group, trifluoromethyl, or lower alkoxy; R
1It is the group shown in the following formula;
In the formula
Represent a singly-bound or two key, Ar is a phenyl, or the phenyl that is replaced by low alkyl group, lower alkoxy, rudimentary thio alkoxy, fontanel element or trifluoromethyl, Het is 2-, 3-or 4-pyridyl or by plain 2-, 3-or the 4-pyridyl that replaces of low alkyl group, lower alkoxy or fontanel; 2-, 4-or 5-pyrimidyl or 2-, the 4-or the 5-pyrimidyl that are replaced by low alkyl group, lower alkoxy or fontanel element; 2-pyrazinyl or the 2-pyrazinyl that is replaced by low alkyl group, lower alkoxy or fontanel element; 2-or 3-thienyl, or by low alkyl group or plain 2-or the 3-thienyl that replaces of fontanel; 2-or 3-furyl, or by plain 2-or the 3-furyl that replaces of low alkyl group or fontanel, or 2-or 5-thiazolyl or by low alkyl group or plain 2-or the 5-thiazolyl that replaces of fontanel, but except subordinate's compound, promptly n is 3, and R is methyl and R
1Be the group shown in the following formula:
When (Ar is a phenyl in the formula) except the compound of representative,
It is characterized in that, make molecular formula be
(X is-leavings group in the formula)
Compound and molecular formula be
Amine (definition of Ar and Het as mentioned above in the formula) in inert solvent, under the situation that neutralizing agent exists, reaction at high temperature.
2,, it is characterized in that prepared compound has following structure according to the method for claim 1:
According to the method for claim 2, it is characterized in that 3, R is a hydrogen.
4, according to the method for claim 3, it is characterized in that R
1Be one of group shown in the following formula:
In the formula
Expression singly-bound or two key; Ar is phenyl or the phenyl that replaced by methyl, methoxyl group, sulfo-methoxyl group or chlorine; Het is 2-, 3-or 4-pyridyl, by 2-, 3-or the 4-pyridyl of methyl, chlorine or bromine replacement; 2-, 4-or 5-pyrimidyl; 2-pyrazinyl or 2-or 5-thiazolyl.
5, according to the method for claim 4, it is characterized in that R
1Be one of group shown in the following formula:
Het is 2-, 3-or 4-pyridyl in the formula; 2-, 4-or 5-pyrimidyl; 2-pyrazinyl, or 2-or 5-thiazolyl.
6,, it is characterized in that n equals 3 or 4 according to the method for claim 5.
7,, it is characterized in that prepared compound is 7-(3-(4-phenyl-1-according to the method for claim 6
The piperazine base)-propoxy-) but-acid salt of the hyoscine of 2H-1-chromen-2-one or this compound.
8,, it is characterized in that prepared compound is 7-(3-(4-(2-pyrimidyl)-1-according to the method for claim 6
The piperazine base) propoxy-) but-acid salt of the hyoscine of 2H-1-chromen-2-one or this compound.
9,, it is characterized in that prepared compound is 7-(3-(1,2,3,6-tetrahydrochysene-4-phenyl-1-pyridyl)-propoxy-according to the method for claim 6) but-acid salt of the hyoscine of 2H-1-chromen-2-one or this compound.
10,, it is characterized in that prepared compound is 7-(4-(4-phenyl-1-according to the method for claim 6
The piperazine base) butoxy) but-acid salt of the hyoscine of 2H-1-chromen-2-one or this compound.
11,, it is characterized in that prepared compound is 7-(3-(3,6-dihydro-4-(2-thienyl)-1(2H)-pyridyl)-propoxy-according to the method for claim 6)-the 2H-1-chromen-2-one.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/745,971 US4701456A (en) | 1984-09-19 | 1985-06-18 | Aminoalkoxybenzopyranones as antipsychotic and anxiolytic agents |
| US745,971 | 1985-06-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85106970A true CN85106970A (en) | 1987-04-01 |
| CN1007351B CN1007351B (en) | 1990-03-28 |
Family
ID=24999002
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85106970 Expired CN1007351B (en) | 1985-06-18 | 1985-09-17 | Be used as the preparation method of the aminoalkoxy benzopyrone of major tranquilizer and tranquillizer |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1007351B (en) |
| CA (1) | CA1248101A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100393716C (en) * | 2006-05-18 | 2008-06-11 | 中国药科大学 | Coumarin derivatives, and their preparing method and use as alpha, receptor agonist |
| CN102050809A (en) * | 2009-11-03 | 2011-05-11 | 中国医学科学院药物研究所 | Chemokine-like factor 1 (CKLF1)/C chemokine receptor 4 (CCR4) interaction-antagonistic 3-peperazinyl coumarin derivatives |
| CN102206214A (en) * | 2011-04-07 | 2011-10-05 | 华中科技大学 | Benzopyrone derivative and application thereof |
| CN102267966A (en) * | 2011-08-01 | 2011-12-07 | 华中科技大学 | Substituted benzopyrone derivatives and application thereof |
| CN102482263A (en) * | 2009-08-04 | 2012-05-30 | 大日本住友制药株式会社 | Benzyl piperidine compound |
| CN104059046A (en) * | 2013-03-18 | 2014-09-24 | 江苏恩华药业股份有限公司 | Flavonoid derivative and application thereof |
| CN105163727A (en) * | 2013-05-03 | 2015-12-16 | 豪夫迈·罗氏有限公司 | Neurogenesis-stimulating isoquinoline derivatives |
| CN105431150A (en) * | 2013-08-27 | 2016-03-23 | 中国中化股份有限公司 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
-
1985
- 1985-09-17 CN CN 85106970 patent/CN1007351B/en not_active Expired
-
1986
- 1986-02-20 CA CA000502293A patent/CA1248101A/en not_active Expired
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100393716C (en) * | 2006-05-18 | 2008-06-11 | 中国药科大学 | Coumarin derivatives, and their preparing method and use as alpha, receptor agonist |
| CN102482263A (en) * | 2009-08-04 | 2012-05-30 | 大日本住友制药株式会社 | Benzyl piperidine compound |
| CN102050809A (en) * | 2009-11-03 | 2011-05-11 | 中国医学科学院药物研究所 | Chemokine-like factor 1 (CKLF1)/C chemokine receptor 4 (CCR4) interaction-antagonistic 3-peperazinyl coumarin derivatives |
| CN102050809B (en) * | 2009-11-03 | 2014-12-17 | 中国医学科学院药物研究所 | Chemokine-like factor 1 (CKLF1)/C chemokine receptor 4 (CCR4) interaction-antagonistic 3-peperazinyl coumarin derivatives |
| CN102206214B (en) * | 2011-04-07 | 2014-03-12 | 华中科技大学 | Benzopyrone derivative and application thereof |
| CN102206214A (en) * | 2011-04-07 | 2011-10-05 | 华中科技大学 | Benzopyrone derivative and application thereof |
| US9315496B2 (en) | 2011-04-07 | 2016-04-19 | Huazhong University Of Science & Technology | Benzopyrone derivative and use thereof |
| WO2012136147A1 (en) * | 2011-04-07 | 2012-10-11 | 华中科技大学 | Benzopyrone derivative and use thereof |
| WO2013017068A1 (en) * | 2011-08-01 | 2013-02-07 | 华中科技大学 | Substituted benzopyrone derivative and use thereof |
| CN102267966B (en) * | 2011-08-01 | 2013-02-27 | 华中科技大学 | Substituted benzopyrone derivatives and application thereof |
| CN102267966A (en) * | 2011-08-01 | 2011-12-07 | 华中科技大学 | Substituted benzopyrone derivatives and application thereof |
| CN104059046A (en) * | 2013-03-18 | 2014-09-24 | 江苏恩华药业股份有限公司 | Flavonoid derivative and application thereof |
| CN104059046B (en) * | 2013-03-18 | 2017-02-08 | 江苏恩华药业股份有限公司 | flavonoid derivative and application thereof |
| CN105163727A (en) * | 2013-05-03 | 2015-12-16 | 豪夫迈·罗氏有限公司 | Neurogenesis-stimulating isoquinoline derivatives |
| CN105431150A (en) * | 2013-08-27 | 2016-03-23 | 中国中化股份有限公司 | Applications of substituent benzyloxy group containing ether compounds for preparing antitumor drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1007351B (en) | 1990-03-28 |
| CA1248101A (en) | 1989-01-03 |
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