CN86107756A

CN86107756A - A kind of method for preparing medicinal compositions

Info

Publication number: CN86107756A
Application number: CN 86107756
Authority: CN
Inventors: 约瑟夫·克诺尔; 埃迪特·伯伦伊·德·尼·波德曼; 卡塔林·杜达·尼·希蒙依; 伯塔·克诺尔; 苏萨·福特斯; 朱利亚·蒂马尔; 加布里拉·希拉; 依迪科·尼克亚; 鲁萨·彼托茨; 阿蒂拉·曼迪
Original assignee: Egis Pharmaceuticals PLC
Current assignee: Egis Pharmaceuticals PLC
Priority date: 1986-11-12
Filing date: 1986-11-12
Publication date: 1987-09-23

Abstract

Have been found that 2-methyl-thiazole also [4, the 5-C]-quinoline and the hydrate of acceptable acid salt and they pharmaceutically thereof, have the valuable nervus centralis restraining effect that is different from benzodiazepine  class.The invention relates to 2-methyl-thiazole [4,5-C] quinoline (formula I) also, or its acceptable acid salt pharmaceutically, or their hydrate is the preparation method of the medicinal compositions of effective constituent.

Description

A kind of method for preparing medicinal compositions

The invention relates to the preparation method of medicinal compositions.The present invention especially is related to the preparation method with the inhibiting medicinal compositions of nervus centralis.

On the one hand, the invention provides 2-methyl-thiazole also [4 by the treatment significant quantity, 5-C] quinoline (formula I), or its pharmaceutically acceptable acid salt, or base or its acid salt hydrate, mix the medicinal compositions of being formed with the suitable inert solid or the pharmaceutical carrier of liquid.

On the other hand, the present invention also provides the method for preparing this medicinal compositions, this method comprises makes 2-methyl-thiazole also [4,5-C] quinoline (formula I), or its pharmaceutically acceptable acid salt, or base or its acid salt hydrate, mix with the nontoxic inert solid or the suitable pharmaceutical carrier of liquid.

Again on the one hand, the present invention also provides also [4,5-C] quinoline (formula I) of application 2-methyl-thiazole, or its pharmaceutically acceptable acid salt, or base or its acid salt hydrate prepare the method for medicinal compositions.

2-methyl-thiazole also [4,5-C] quinoline and hydrochloride thereof by Bachman etc. at J.Am, chem.Soc 69,365～371(1947) goes up report.Bachman etc. have made 3-amino-4-sulfydryl-quinoline and acetic anhydride prepared in reaction this compound, and by with hydrochloric acid reaction, with resulting 2-methyl-thiazole also [4,5-C] quinoline be transformed into hydrochloride.But above-mentioned document is not mentioned the also biological action of [4,5-C] quinoline and hydrochloride thereof of 2-methyl-thiazole fully.It only reports that this compound is fully invalid for malaria.

The present invention is based on that following understanding studies, and promptly also [4,5-C] quinoline (formula I) and its pharmaceutically acceptable acid salt have valuable, crucial and special effect to 2-methyl-thiazole.Formula I compound and pharmaceutically the acceptable acid salt have the nervus centralis restraining effect that is different from known depressor of nerve centre.Opposite with major tranquilizer, formula I compound does not suppress nonspecific activation process, even therefore take heavy dose, it also can make animal test in following period of time escape unconditioned reflex, even and common tranquilizer also can cause the inhibition of above-mentioned non-conditioned behavior in minimum doses.

Formula I compound and benzodiazepine The key distinction that acts between the class is that formula I compound is without any spasmolysis, and formula I compound compares benzodiazepine

Class has stronger central inhibitory action.And, formula I compound not with benzodiazepine

Receptors bind.

The esilate of formula I compound demonstrates good especially pharmacological action.This compound is new, and prior art was never reported.

In addition, the present invention also provides also [4,5-C] quinoline esilate (2-methyl-thiazolo-[4,5-C] quenoline-ethanesulfonate) of new compound-2-methyl-thiazole

2-methyl-thiazole is [4,5-C] quinoline the and pharmaceutically pharmacological action of acceptable acid salt is bright with following test card also.

1. acute toxicity

On CFY big white mouse (100～160 gram), carry out acute toxicity test.Every group with 10 big white mouse.Oral (by 10 milliliters/kilogram) and subcutaneous (by 5 milliliters/kilogram) gives and compound.Under case of oral administration, made animal before the test hungry 16 hours.Female, the hero half and half of each dosage treated animal.Write down 48 hours number of animals with interior death.Calculate the LD50 value according to Litchfield and Wilcoxon graphics.

2-methyl-thiazole is [4,5-C] quinoline hydrochloride also

LD ₅₀=160 milligrams/kilogram (intravenous injection)

900 milligrams/kilogram (oral)

750 milligrams/kilogram (subcutaneous injection)

2-methyl-thiazole is [4,5-C] quinoline-esilate also

LD ₅₀=950 milligrams/kilogram (oral)

810 milligrams/kilogram (subcutaneous injection)

2. hot-plate test

Use Porszasz and Herr(1950) improved Woolfe and Mcdonald(1944) method.10 big white mouse of each dosage group.The temperature of hot plate is 56 ℃.Give before the test-compound and after giving test-compound 1 hour, the latent period of mensuration pain reaction.If the time ratio control value of reaction prolongs 2.5 times, this compound is considered to 100% effective so.2-methyl-thiazole is [4,5-C] quinoline-hydrochloride also

ED50=30 milligram/kilogram (intravenous injection)

21 milligrams/kilogram (subcutaneous injection)

120 milligrams/kilogram (oral)

2-methyl-thiazole is [4,5-C] quinoline-esilate also

ED50=22 milligram/kilogram (subcutaneous injection)

80 milligrams/kilogram (oral)

3. pain test

Test according to the method that early stage (Knoll 1967) are described in detail.The main points of this method are vein or 10 milligrams of/kilogram morphines of subcutaneous injection, and the big white mouse pain sensation is lacked fully, so that carry out stomach wall part resection operation under the condition that does not have pain or unable struggle, and require should not occur performing the operation back depletion.The standard evaluation pain sensation according to the rules.To the animal of administration not, the regulation pain reaction is 100 minutes, and zero represents that the pain sensation lacks fully, and ED100 is the dosage that medicine is blocked the animal pain sensation fully, ED ₅₀Be that pain reaction keeps the score be 50 drug dose.In this test, it is effective having only narcotic analgesics.Test-compound is to the not effect of the pain sensation of big white mouse operation.

4. writhing test

This law is by Van der Wende(1956) introduce, be applicable to big white mouse originally, later on respectively through (1961) and Koster and Ander Son(1959 such as Witkin) improve, be applicable to small white mouse.10 animals of each dosage group, and administration after 20 minutes by the acetic acid solution of 60 milligrams of/kilogram abdominal injections 0.6%.Because peritonaeum is subjected to chemical stimulation, characteristic writhing response appears in 90% control animals.With 10 animals that test-compound was handled, behind abdominal injection acetate, observed 20 minutes.The analgesic effect of each dosage is represented with per-cent:

Analgesic effect (%)=100 (number of animals of writhing response appears in treatment group)/(number of animals of writhing response appears in control group) * 100

According to giving first controlled trial and relevant bibliographical information, denominator should get 90%.

If the result compares with the hot-plate test gained, a little less than the effect of writhing test.Therefore we think that hot-plate test is a kind of nonselective analgesic test (it not only comprises analgesic effect, and comprises nonspecific central action), therefore can cause the prolongation in measured reaction times.

2-methyl-thiazole is [4,5-C] quinoline-hydrochloride also

ED50=120 milligram/kilogram (subcutaneous injection)

2-methyl-thiazole is [4,5-C] quinoline-esilate also

ED50=48 milligram/kilogram (subcutaneous injection)

145 milligrams/kilogram (oral)

5. anesthesia booster action

With body weight is 150～200 grams/CFY male white rat only, 10 every group.Measure the length of one's sleep of animal.Brevinarcon (Inactin) injects the tail vein by 35 milligrams/kilogram.The record animal loses and recovers the time of righting reflex.Control group length of one's sleep is 425.59 ± 34.2 seconds (n=120).

Two test-compounds have prolonged the anesthesia duration of barbiturate(s) significantly.

2-methyl-thiazole is [4,5-C] quinoline-hydrochloride also

ED50=100 milligram/kilogram (subcutaneous injection)

400 milligrams/kilogram (oral)

2-methyl-thiazole is [4,5-C] quinoline-esilate also

ED50=50 milligram/kilogram (subcutaneous injection)

170 milligrams/kilogram (oral)

6. improved skip test

This test is to be used to screen mentalistic medicine.Testing apparatus comprises the glass garden tube of 45 ℃ the equal opening of metal sheet and top and bottom.Animal is placed in the glass garden tube on the metal sheet, and allows to jump.From putting into the time that occurs between the jump is latent period.(jump) the required time of will escaping is used as the irritable index of central nervous system (CNS), and with 0～10 expression.Evidence, two kinds of salt of test-compound are invalid for improved skip test.

7. shaker test

This test can be used for studying the ability at for some time big white mouse learning and memory.

During trained reflex forms, train big white mouse to jump onto the top of glass garden tube with the method for charged base plate electric shock (110 volts) toe, cooperate flight reaction (unconditioned reflex is represented with UR) with bell ring as conditioned stimulus.The standard of association is to draw the reflection (representing with CR) of having ready conditions for 10 times during under the situation about not strengthening 10 seconds.The memory positive is still can reflect (CR) by conservation condition in back 24 hours in test.In above-mentioned test, be divided into four types according to the ability of animal learning, lack learning capacity: unconditioned reflex (UR) in 20 long run tests, do not occur; A little less than the learning capacity: UR appears, but not display condition reflection (CR); Learning capacity is medium: CR occurs along with some other cooperations; Learning capacity is strong: CR occurs 10 times immediately after cooperating.

In this test, two compounds all have the effect that rejection condition reflects to form.In the time of 25 milligrams/kilogram, they are the formation of rejection condition reflection fully, and in the time of 10 milligrams/kilogram, their restraining effect is still very strong.

Low dose of haloperidol (0.025 milligram/kilogram) is to the very strong restraining effect that is formed with of trained reflex, and zeisin is in the formation not effect of same dose to CR.

8. back and forth case (Shuttle-box) test

Analyze the conditionality of the dual mode that obtains in the reciprocal case test in continuous 5 days and avoided reflection (CAR).This device is that (Research Institute for Electrical Industry Hungary) makes in Hungary electrical industry institute.It has six chests, and each cabinet interior is had the dividing plate of wicket to separate by a centre.During conditioned stimulus (flash of light/light), animal training passes dividing plate, if animal is not cooked like this, shock by electricity with regard to using so (1.3 milliamperes, US) toes.Carry out 100 tests every day.Each test comprises 15 seconds gap phases of test, then carries out the conditioned stimulus (CS) in 15 seconds.The US that the CS in last 5 seconds began for 1 second carries out simultaneously.Between each learning period, the number of reaction (IR) can be counted automatically between conditionality avoidance reflection (CAR) and signal, and is estimated by multivariate analysis of variance (ANOVA).In reciprocal case test, two compounds all have very strong restraining effect to the acquisition of trained reflex when 10 milligrams/kilogram and 25 milligrams/kilogram, compare with control group, and the numerical value of positive reaction (F) is significantly less than the 1st day test bit.

In the time of 25 milligrams/kilogram, (numerical value f) is higher, and when handling animal with 5 milligrams/kilogram dosage every day, (numerical value f) is still higher for negative reaction for negative reaction.

The numerical value of reaction (IR) is lower slightly between signal.Handle with the zeisin of 10 and 5 milligrams of/kilogram dosage, can keep the trained reflex that obtains, and not change IR, but when 10 milligrams of/kilogram dosage, zeisin has increased negative reaction (numerical value f).

9. the mensuration of mobility in the reciprocal case

Back and forth case apparatus also is used for the mobility of zoologizeing.In mobility test, turn off all stimulations, and allow animal from a Room of reciprocal case freely to another chamber.Write down the number of times that 30 minutes viewing duration animals spontaneously pass door, it is average, with the significance of two mean numbers of t test check.

In this test, the effect of compd A and B is similar, all has the effect that reduces mobility slightly.

The table I

2-methyl-thiazole also [4,5-C] quinoline-hydrochlorides (compd A) and 2-methyl-thiazole also [4,5-C] quinoline-esilates (compd B) animal is obtained the influence of trained reflex in reciprocal case.(subcutaneous administration)

Reference compound: zeisin

Dosage

Test-compound: milligram/kilogram 12345 days

Salt solution-25.3 44.8 54.4 52.9 55.6

Compd A 25 7.0 ^x6.6 ^x2.6 ^x1.6 ^x3.1 ^x

10 12.0 14.7 ^x7.2 ^x5.5 ^x7.3 ^x

5 17.8 29.6 24.3 ^x23.0 ^x29.4 ^x

Compd B 25 8.7 ^x4.2 ^x8.9 ^x4.0 ^x2.5 ^x

10 7.5 ^x20.2 ^x20.2 ^x17.8 ^x14.5 ^x

Zeisin 25 ^x9.7 12.2 17.9 20.0 21.4

10 19.9 37.9 33.7 35.6 41.2

5 23.1 38.7 35.6 41.1 50.8

-f

Salt solution-10.3 7.1 6.1 10.3 8.0

Compd A 25 83.6 ^x85.1 ^x94.3 ^x93.8 ^x95.0 ^x

10 70.4 ^x55.3 ^x58.2 ^x66.8 ^x68.2 ^x

5 14.4 23.0 ^x24.6 ^x25.4 27.5

Compd B 25 54.9 ^x67.4 ^x74.1 ^x80.1 ^x85.0 ^x

10 76.0 ^x40.8 ^x29.3 ^x29.9 ^x37.5 ^x

Zeisin 10 32.7 ^x22.8 ^x31.8 ^x36.5 ^x40.8 ^x

25 ^x74.0 67.5 67.0 65.6 59.8

5 11.8 9.1 10.2 14.9 13.0

IR

Salt solution-12.2 15.8 10.3 9.1 6.4

Compd A 25 10.7 5.7 4.4 ^x3.8 ^x4.2

10 8.9 7.3 2.7 ^x2.1 ^x2.1

5 9.5 8.9 3.2 ^x2.9 ^x2.3

Compd B 25 12.4 5.0 ^x9.2 4.9 ^x3.3

10 11.4 9.1 7.6 4.5 ^x3.3

10 10.8 14.7 8.1 6.3 6.1

Zeisin 5 108 14.0 8.9 6.7 4.2

Two mean numbers calculate its significance through the t test.

10. to the influence of basal metabolism

Press Issekutz and Issekutz(1952) method, measure down the big white mouse oxygen consumption at constant temperature (30 ℃).In order to suppress to increase the possibility of oxygen metabolism because of the animal spontaneous activity, give animal abdominal injection urethane, dosage is 0.6 gram/kilogram, low like this concentration can not influence metabolism.

The oxygen consumption of animal is calculated by the body surface area of animal with milliliter/hour expression, therefore, and finally with milliliter/hour/decimeter ²Expression.After the injection urethane, measure 30 minutes basic oxygen consumption.Inject test-compound subsequently, the immediate record oxygen consumption.Difference between maximum oxygen consumption and the basic value is represented with per-cent.

Calculate the oxygen consumption of animal by following equation:

Oxygen consumption=V (P)/760 273/ (273+t) 1/ (T), wherein

V=2000 centimetre ³

(mmhg) falls in P=pressure

T=temperature (30 ℃)

The T=minute (hour)

Oxygen consumption is pressed body surface area and is calculated, and with ml/min rice ²/ hour expression.Calculate body surface area according to " Diack " formula:

S=7.47 ³W ², wherein

S be body surface area (centimetre ²)

W is body weight (gram)

2-methyl-thiazole also [4,5-C] quinoline-hydrochloride can improve metabolic rate slightly, and 2-methyl-thiazole also [4,5-C] quinoline-esilate to increase the effect of metabolic rate strong and lasting.The reference compound haloperidol reduces oxygen consumption slightly, and amphetamine has increased oxygen consumption, and has dose-dependence.

11., measure Dopamine HCL turnover rate (TR by 30 milligrams of/kilogram subcutaneous injection 2-methyl-thiazoles also after [4,5-C] quinoline-esilate 1 hour _DA), norepinephrine turnover rate (TR _NA) and the turnover rate (TR of serotonin _5HT).

Thrombotonin activating cells body is positioned at brain stem, and serotonin (5HT) content raises significantly, but its turnover rate is constant, and this shows that serotonergic neurotransmission effect is still identical with control group.But in containing the whole diencephalon (teldiencephalon) of serotonergic nerve ending, the 5HT level does not change, but TR _5HTReduced, this is because the result that part rate constant (Kb) reduces.The reduction of part rate constant may reflect the reduction of 5HT utilization ratio.

The table II

The variation of 5HT level and turnover rate in the brain tissue of rat tissue

5HT TR _5HTKb

Nanogram(ng)/gram nanogram(ng)/gram

/ hour hour ^-1Brain

Control group 395.8 ± 26.5 207.9 0.81 whole diencephalons

（Teldiencephalon

2-methyl-thiazole

And 457.9 ± 24.2 53.9 0.26

[4,5-C] quinoline

Quinoline-esilate

Control group 544.0 ± 71.6 255.9 0.58 brain stems

2-methyl-thiazole

And [4,5-C] 792.5 ± 36.9 ^*237.2 0.50

Quinoline-esilate

＊ P＜0.05

12. DOPAMINE CONTENT IN RABBIT rising in the striatum after the administration, and the part rate constant reduces.Because the variation of these two numerical value is mutually adjusted, so TR _DAStill remain unchanged.

The table III

The variation of DA level and turnover rate in the big white mouse striatum

DA TR _DAKb

Nanogram(ng)/gram nanogram(ng)/gram

/ hour hour ^-1

Control group 6.70 ± 0.45 1.5 0.23

2-methyl-thiazole

And [4,5-C] 9.14 ± 0.49* 1.4 0.15

The quinoline esilate

＊ P＜0.05

Inject after 30 and 60 minutes the P in the brain tissue of rat cortex ₂The high affinity of component picked-up NA and 5HT does not change.

13. use rough cortex membrane tissue research benzodiazepine

(BZD) receptors bind.In 0 ℃, in Tutofusin tris-citrate buffer, at PH6.8, with 2 micromoles ³H-is stable hatched 1 hour with above-mentioned film.In the presence of 10 micromoles are stable, measure the specificity combination.In substitution investigation, with zeisin medicine in contrast.Under the relevant concentration, zeisin has been replaced on the acceptor ³H-is stable, and test-compound (formula I) is even can not change under high density ³The stabile specificity combination of H-.

2-methyl-thiazole is [4,5-C] quinoline (formula I) and acceptable acid salt pharmaceutically thereof also, can press the method preparation:

A) make 3-amino-4-sulfydryl-quinoline (formula II) or its acid salt

With acetate (formula III) reaction, or with the response derivative reaction of acetate;

CH ₃-COOH （Ⅲ）

Or

B) in the presence of air, make the reaction of 3-amino-quinoline (formula II) or its acid salt and acetaldehyde (formula V);

CH ₃-CHO （Ⅴ）

Or c) make 3-acetylaminohydroxyphenylarsonic acid 4-sulfydryl-quinoline (formula IV) cyclization,

And if desired, with 2-methyl-thiazole also [4,5-C] quinoline (formula I) be transformed into its pharmaceutically acceptable acid salt, or formula I compound or its acid salt are transformed into hydrate, or from its salt, discharge formula I compound.

According to method a), can be with the response derivative reaction of 3-amino-4-mercaptoquinoline (formula II) or its acid salt and acetate or acetate.Response derivative as acetate is preferably acetic anhydride, triethly orthoacetate, acetyl halide or acetate esters.It is the most favourable to use ortho-acetic acid trialkyl ester.Can use excessive acetic acidreaction derivative (as acetic anhydride or triethly orthoacetate), this moment, it also can be used as reaction medium.Also the formula II compound of available equimolar amount and acetate or acetic acidreaction derivative are prepared, and react having in the presence of the inert solvent.As reaction medium, arene (as benzene, toluene or dimethylbenzene) preferably.Can finish reaction at 20～160 ℃, be preferably in the reaction mixture boiling temperature and react.

According to the concrete grammar of especially preferentially selecting for use a), 3-amino-4-sulfydryl-quinoline (formula II) and excessive ortho-acetic acid trialkyl ester are reacted in 100 °～160 ℃, be preferably under the temperature of low 5～10 ℃ of this ortho-acetic acid trialkyl ester boiling point and react, and constantly remove the alkanol that forms the dereaction from reaction mixture.Preferably use triethly orthoacetate.After reaction is finished, reaction mixture is chilled to room temperature.

By known method (as extraction, cooling, evaporation or filter), can be with formula I compound form with free alkali from reaction mixture, or come out with its isolated in form of acid salt.

According to method b), in the presence of air, make 3-amino-4-sulfydryl-quinoline (formula II) or its acid salt (being preferably hydrochloride) and acetaldehyde (formula V) reaction.Be preferably under the inert organic solvents existence and finish reaction.As reaction medium, it is favourable using alkanol (as methyl alcohol, ethanol or Virahol).Reaction can be carried out under 20～160 ℃, is preferably under the boiling temperature of reaction mixture to carry out.Can use the acetaldehyde of equimolar amount, perhaps make acetaldehyde excessive a little (excessive 5～20%).

Can pass through currently known methods (as cooling, dilute with water, filtration), from reaction mixture, isolate formula I compound.

According to method c), make 3-acetylaminohydroxyphenylarsonic acid 4-sulfydryl-quinoline (formula IV) carry out cyclization.Be preferably in and encircle closure in the inert media.As reaction medium, preferably use arene (as benzene, toluene or dimethylbenzene) or halogenated hydrocarbon (as chlorobenzene).Reaction can be carried out at elevated temperatures, is preferably under 100～180 ℃ and carries out.

In the presence of dewatering agent, react, can strengthen the cyclization effect.Verified, Tripyrophosphoric acid is particularly useful for this purpose.Under the situation that organic solvent-free exists, use excessive Tripyrophosphoric acid as reaction medium, under heating, react especially favourable.

By known method (as dilute with water, alkalization, use organic solvent extraction), formula I compound can be separated in the reaction mixture.

By reacting with corresponding acid, formula I compound can be transformed into pharmaceutically acceptable acid salt.The formation of salt can be undertaken by known method itself.By known method itself, formula I base is discharged from acid salt.

Starting raw material formula II and formula IV are known, can prepare by the method that prior art [J.Am.chem.Soc69,365～371(1947)] are narrated.

Other starting raw material (acetate and response derivative thereof, acetaldehyde) all is production-scale commerical prods.

Medicinal compositions of the present invention is also [4,5-C]-quinoline (formula I) or its a pharmaceutically acceptable acid salt of 2-methyl-thiazole, or the hydrate of formula I base or its acid salt, with the suitable inert solid or the mixture of liquid, medicinal carrier.This medicinal compositions is applicable to oral (as tablet, coated pill, dragee, glutoid wafer or Gelseal, solution, emulsion or suspensoid), parenteral administration (as injection solution) or rectal administration (as suppository).

Medicinal compositions of the present invention can be by the known method of pharmaceutical industry, make 2-methyl-thiazole also [4,5-C] quinoline (formula I) or its acceptable acid salt pharmaceutically, or their hydrate, mix mutually with suitable inert solid or liquid, medicinal carrier and make, and composition is mixed with certain formulation.

The carrier that can be used as tablet, coated pill, dragee and hard gelatin capsule has lactose, corn, starch, talcum, magnesiumcarbonate, Magnesium Stearate, lime carbonate, stearic acid or its salt etc.The carrier that can be used as soft gelatin capsule is by vegetables oil, fat, wax or the suitable polyvalent alcohol of forming.When obtain solution agent or syrup, used water, polyvalent alcohol, polyoxyethylene glycol, sucrose or glucose are as carrier.The carrier of injection solution can comprise water, alcohols, polyvalent alcohol, glycerine or vegetables oil.The carrier of suppository can comprise the polyvalent alcohol of oils, wax, fat, theobroma oil or suitable composition.

Medicinal compositions of the present invention also comprises the common auxiliary that is generally used for pharmaceutical industry.The also additive that can have wide range of applications is as wetting agent, dispersion agent, sanitas, emulsifying agent, solubilizing agent, tinting material, sweeting agent, fragrance matter be used to improve the salt of osmotic pressure.

Take every day 2-methyl-thiazole also the dosage of [4,5-C]-quinoline can in very wide scope, change.Can notice that the oral dosage of formula I compound can be 20 milligrams/kilogram～100 milligrams/kilogram, but not the dosage of footpath enterally administering is 5 milligrams/kilogram～250 milligrams/kilogram.We wish to notice that above-mentioned scope only is about, and the dosage of practical application always changes according to different factor (as the degree that is in a bad way, year zero-sum patient's situation etc.), and is determined by the doctor.The dosage of practical application also can be below or above above-mentioned scope.

Be described in further detail the present invention with following example, but described example does not limit the scope of protection of present invention.

Example 1

The mixture of 17.62 gram (0.1 mole) 3-amino-4-sulfydryl-quinoline and 70 milliliters of acetic anhydrides slowly is heated to boiling temperature, is heated to boiling 3/2 hour then.Reaction mixture also splashes into 600 milliliter of 1% hydrochloric acid under high degree of agitation, makes uniform solution be alkalescence with sodium hydroxide solution, and the base of separating out extracts three times with benzene, and each 100 milliliters, the benzene extraction liquid of merging is clarifying.Drying in vacuum-evaporation, obtains also [4,5-C] quinoline of 2-methyl-thiazole, is 99～100 ℃ with fusing point behind the mixed solution recrystallization of first alcohol and water.

Example 2

With 17.62 gram (0.1 mole) 3-amino-4-sulfydryl-quinoline, the mixtures of 180 milliliters of acetate and 1.5 gram Sodium Pyrosulfites refluxed 4 hours, reaction mixture is pressed the method for example 1 narration and is handled, and the 2-methyl-thiazole also fusing point of [4,5-C]-quinoline is 99～100 ℃.

Example 3

10.9 mixtures that restrain (0.05 mole) 3-acetylaminohydroxyphenylarsonic acid 4-sulfydryl-quinoline and 100 gram Tripyrophosphoric acid in 140～160 ℃ of heating 2 hours, are cooled to 90 ℃ then, and are further adding 600 ml waters under the stirring of cooling and constant.When reaction mixture is cooled to 20 ℃, add the alkalization of 40% sodium hydroxide solution, the precipitation mixture of separating out extracts three times with benzene, each 200 milliliters.From extraction liquid, boil off benzene, obtain also [4,5-C] quinoline of 2-methyl-thiazole, in 99～100 ℃ of fusions.

Example 4

21.27 gram (0.1 mole) 3-amino-4-sulfydryl-quinoline hydrochlorides are mixed with 200 milliliters of triethly orthoacetates, reaction mixture is heated to 120～140 ℃ at leisure, and the ethanol that generates constantly steams, and under this temperature reaction mixture is heated 30 minutes.Cooling adds hydrochloric ethanol and 100 milliliters of ethyl acetate, successively so that make crystallization complete.2-methyl-the thiazole that obtains also [4,5-C]-quinoline hydrochloride in 249～251 ℃ of fusions (disclosed fusing point is 240～245 ℃ in the prior art, decompose)

Example 5

20.0 gram (0.1 mole) 2-methyl-thiazole also [4,5-C]-quinoline is dissolved in 150 milliliters of benzene, under cooling, 11 gram (0.1 mole) ethyl sulfonic acids are splashed into then, reaction mixture carries out the stirring of short period of time, the crystallization that filtration is separated out, washing and dry obtains 2-methyl-thiazole also [4,5-C] quinoline esilate hydrate, fusing point is 144～146 ℃.

Ultimate analysis:

Calculated value: C%=47.54; N%=8.53; S%=19.52;

Measured value: C%=47.83; N%=8.42; S%=19.41;

Example 6

Preparation contains the tablet of following composition:

Become component, milligram/sheet

2-methyl-thiazole is [4,5-C] quinoline also

Esilate 25.0

W-Gum 97.0

Polyvinylpyrrolidone 175.0

Magnesium Stearate 3.0

Gross weight 300.0

The mixture of effective constituent and W-Gum is moistening with 10～15% polyvinylpyrrolidonesolution solution, makes particle and dry, and particle mixes with Magnesium Stearate through dry fully again, is pressed into tablet.

Example 7

Use the capsule that the known method preparation of pharmaceutical industry itself contains following composition:

Become component, milligram/capsule

2-methyl-thiazole is [4,5-C] quinoline also

Hydrochloride 20.0

Lactose 60.0

W-Gum 17.0

Talcum 2.0

Magnesium Stearate 1.0

Gross weight 100.0

Claims

1, the method for preparation medicinal compositions, this method comprises makes 2-methyl-thiazole also [4,5-C] quinoline (formula I) or its acceptable acid salt pharmaceutically, or the hydrate of base or its acid salt mixes mutually with the nontoxic inert solid or the suitable pharmaceutical carrier of liquid.

2, has the method for the inhibiting medicinal compositions of nervus centralis according to the described preparation of claim 1, this method comprises makes 2-methyl-thiazole also [4,5-C] quinoline (formula I) or its acceptable acid salt pharmaceutically, or the hydrate of base or its acid salt, mix mutually with the nontoxic inert solid or the suitable pharmaceutical carrier of liquid.

3, use 2-methyl-thiazole also [4,5-C] quinoline (formula I) or its pharmaceutically-acceptable acid addition, or the method for the hydrate of base or its acid salt preparation medicinal compositions.

4, with 2-methyl-thiazole [4,5-C] quinoline (formula I) or its acceptable acid salt pharmaceutically also, or the preparation of the hydrate of base or its acid salt has the method for the inhibiting medicinal compositions of nervus centralis.

5, preparation 2-methyl-thiazole method of [4,5-C] quinoline esilate and hydrate thereof also, this method comprise makes the 2-methylthiazol also [4,5-C] quinoline react with ethyl sulfonic acid, if desired, the salt of gained can be transformed into its hydrate.