CN100494177C - Bi-amido heterocyclic derivative with antitumour activity and its preparation method and use - Google Patents

Abstract

A biamidoheterocyclic derivative with antineoplastic activity and its preparing process are disclosed. It can be used to treat cancers, such as chronic granulocyte leukemia, acute lymphocyte leukemia and melanotic cancer etc.

Description

Has bisamide base heterocyclic derivative of anti-tumor activity and its production and use

Technical field

The present invention relates to antitumor drug and synthetic, relate to a kind of two amido heterocyclic derivatives and preparation method thereof in particular with anti-tumor activity, and the pharmaceutical composition and the application of said composition aspect multiple malignant tumours such as treatment chronic myelocytic leukemia (CML), adult's acute lymphoblastic leukemia (ALL), neuroblastoma, human medullary erythroleukemia and melanoma that contain this analog derivative for the treatment of significant quantity.

Background technology

Cancer is a big class disease of serious threat human health, seeks effective methods of treatment and goes to conquer cancer, and be the research field that people pay close attention to always.Traditional cancer therapy drug is mainly cell toxicity medicament, difference between the kinetics of their dependence tumour cells and Normocellular growth, reparation, death is come killing tumor cell, therefore this class medicine inevitably can influence normal cell, treatment window clinically is very narrow, has also limited the enforcement of multiple medicines combination therapy simultaneously.The cell killing treatment of non-selectivity can't really reach the purpose of curing cancer forever.In recent years, there are many cancer therapy drugs to occur in succession at molecular target, this class medicine with strong points, effect is remarkable, just looks like that to hit target the same, therefore can be called " target agent ".Paul Ehrlich has just proposed the notion of targeted therapy (targetingtherapy) before 100 years, the going deep into along with development of molecular biology and people to the research of cancer mechanism, target agent at specific carcinogenic mechanism has obtained very fast development in recent years, as micromolecular medicine according to imatinib (ImatmibMesilate, STI-571) can the carcinogenic cause of disease of directtissima, selectivity is strong, the clinical trial proving effect is remarkable, and side effect is light, and multiple medicines is united the effect that can strengthen traditional chemotherapeutics when using.Especially to chronic myelocytic leukemia, adult acute lymphoblastic leukemia the treatment aspect, obvious improvement has been arranged, but still having some problems, new clinical report shows that the chronic myelocytic leukemia of some middle and advanced stages has produced resistance to STI-571 class medicine.In addition, the patient must take medicine for a long time, otherwise the state of an illness worsens rapidly.At the CML chronic phase, the leukemia cell is by the easy Be Controlled of cell toxicity medicament (hydroxyurea, Myelosan etc.), in case the final sudden turn of events of disease, the patient is because of out of hand and dead.Though bone marrow transplantation may be cured this disease having preferably curative effect at present, is subjected to all multifactor restrictions such as bone marrow donor difficulty, rejection, age, expense costliness; The application of interferon alpha can make patient's " Philadelphia chromosome " turn out cloudy, but the effect of raising patient chance for survival is still imprecise.Therefore, seeking new methods of treatment, to reach the leukemic target of radical cure imperative.In view of Tyrosylprotein kinase plays critical biological action in CML and part A LL form, design micromolecular inhibitor at fusion protein BCR-ABL, be proved to be a kind of positive therapeutic strategy thereby suppress the BCR-ABL Tyrosylprotein kinase, become the research focus of treatment in recent years.

Summary of the invention

The tyrosine kinase inhibitor that BCR-ABL protein is relevant is divided into natural by its source and synthetic two big classes at present.In natural product, study more have Herbimycin A, Genistein (genistein) etc.Herbimycin A is a benzoquinone class hydrogen-containing compound, interacts competition ATP-binding site, the activity of inhibitory enzyme by its benzoquinones part and near the kinase activity center sulfydryl.It mainly suppresses the autophosphorylation of P210BCR-ABL.Genistein relies on the kinase whose ATP-binding site of competitive inhibition, thereby plays a role.The inhibitor of synthetic all is to design for the guide with these natural active compounds, and synthetic and optimization obtains a series of inhibitor.Catalytic domain according to protein kinase keeps this sign of unique conformation when not activating, seek special kinases inhibitor and be considered to an extremely promising drug development direction.The present invention is just according to this up-to-date result of study, the disactivation conformation of the ABL of utilization and STI-571 cocrystallization, carry out database search as receptor binding site, screening does not produce drug-fast new medicine to CML, explores and seeks the design new drug at the important Disease-causing gene of neoplastic hematologic disorder and the approach of playing a role thereof.

One object of the present invention overcomes present STI-571 class medicine exactly and easily produces resistance and take medicine the dependent shortcoming of generation for a long time, a kind of brand-new bisamide base heterocyclic derivative is provided, is used for the treatment of chronic myelocytic leukemia and adult's acute lymphoblastic leukemia medicine.

Another object of the present invention has been to disclose the new preparation method of a kind of bisamide base heterocyclic derivative.

A further object of the present invention has been to provide two amido heterocyclic derivatives of treatment significant quantity and the pharmaceutical composition that pharmaceutically acceptable carrier, thinner, excipient form.

More pleasantly surprised is, of the present invention pair of amido heterocyclic derivative is in preparation some malignant cell of treatment such as cancers such as neuroblastoma, leukemia and melanoma, have and induce the differentiation cancer cells to change into normal cell or approximate Normocellular function, we can say that the present invention is that antitumor drug research opens up a new way.

The invention provides amide group heterocyclic derivative with anti-tumor activity as shown in the formula I

Its general formula is as follows:

Wherein:

Represent one five Yuans or six Yuans N heterocycles or contain multiple heteroatomic heterocycle or benzheterocycles such as N;

Y is that 0-3 N atom comprises;

(a). randomly contain N, O and/or S as extra heteroatoms, they be in not be connected N atom position adjacent on;

(b). on one or two carbon atom adjacent, connect N, S or O atom with being connected the N atom;

X-represents negatively charged ion, as acetate moiety, trifluoroacetic acid root, tosylate, phosphate radical, halogen, fumaric acid or other organic acid;

R is for containing C ₁-C ₆Straight or branched alkyl, C ₁-C ₄Alkyl or aryloxy, aryl, substituted aryl, R is C preferably ₁-C ₄Alkyl such as methyl, ethyl, propyl group, butyl, preferred ethyl or butyl; C ₁-C ₄Aryloxy is generally benzyloxy, benzene oxyethyl group, benzene propoxy-, is benzyloxy, benzene oxyethyl group preferably, preferred benzene oxyethyl group; Aryl, substituted aryl can be phenyl, chlorobenzene, phenol, anilino etc., are preferably phenyl, phenol or chlorobenzene; X ^-The expression negatively charged ion is as acetate moiety, trifluoroacetic acid root, tosylate, phosphate radical, halogen, fumaric acid or other organic acid; Generally be expressed as chlorion, trifluoroacetic acid root, bromide anion, tosylate, phosphate radical, fumaric acid, be preferably chlorion, trifluoroacetic acid root, bromide anion, phosphate radical, tosylate, fumaric acid are preferably chlorion, bromide anion, tosylate, fumaric acid.

Expression is organized compound with next;

The two amido heterocyclic derivatives with anti-tumor activity described in the claim 1 comprise butyrylamino-α-(3-benzamido pyrazoles)-methyl phenyl ketone fumarate; Adjacent-to oxybenzene formamido group-α-(2-benzene carbon amide yl pyrimidines)-methyl phenyl ketone hydrochloride; 4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone hydrobromate; 4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone fumarate; 4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone benzene methanesulfonic acid salt.

The preparation method of one class bisamide base heterocyclic derivative is characterized in that comprising the steps:

(1). make compound (IV) and compound (VI) with compound (III) reaction respectively at the alkaline condition compound (II) of organic solvent with (V);

(2). compound (IV) and halogen react compound (VII);

(3). compound (VI) and compound (VII) are with the mixed target compound (I) that gets of certain proportion;

Wherein

X ^-, R has the definition with claim 1; X is expressed as halogen.

The present invention prepares the amino substituted acetophenone of starting raw material in the method for target compound (I), amino can adjacent,, contraposition, preferred neighbour or contraposition aminoacetophenone; Amino substituted heterocycle comprises pyrimidine, thiazole, pyrazoles, pyridine, quinoline, benzo pyrimidine, purine, preferred pyrimidine, pyrazoles, pyridine, benzo pyrimidine, more preferably pyrazoles, pyridine, benzo pyrimidine.Make in the reaction of compound IV and compound VI at Compound I I and V and compound III reaction, used organic solvent is generally inert organic solvents such as benzene, chloroform, pyridine, toluene, methylene dichloride, preferred chloroform, pyridine, methylene dichloride; Used alkali is as alkaline carbonate, alkali metal hydrocarbonate, alkali metal hydroxide, ammoniacal liquor, C ₁-C ₄Secondary amine or tertiary amine that alkane replaces, as triethylamine, TERTIARY BUTYL AMINE etc., preferred ammoniacal liquor, yellow soda ash, triethylamine, TERTIARY BUTYL AMINE, more preferably yellow soda ash, triethylamine; For every mole compound (III), the consumption of alkali is usually at the 0.50-10.0 mole, preferred 1.0-5.0 mole, more preferably 1.0-3.0; Compound (III) is the 1:1-5 mole with the mol ratio of compound (II) or compound (V) reaction, preferred 1:1-3 mole.Compound (IV) makes the used halogen of compound (VII) with the halogen reaction and comprises chlorine, liquid bromine, iodine, preferred liquid bromine; Compound (IV) is 1:1-8 with liquid bromine mol ratio, preferred 1:1-3 mole.Compound (VI) is dissolved in inert organic solvents such as benzene, chloroform, pyridine, toluene or the methylene dichloride with the 1:1-5 mole with compound (VII), temperature of reaction is usually at 0-80 ℃ of preferred 20-50 ℃, reaction times is usually at 1-48 hour, and preferred 5-30 hour, more preferably 10-24 hour; Reaction is finished after product and is separated out, and filter and collect, and refining with ethanol or ethyl acetate, obtain high yield, highly purified target compound (I).

At this, in order to show the practicality of target compound (I), provide exemplary embodiments 14 of the present invention below, the pharmacological experimental data of (4-benzoylamino-α-(3-benzamide pyridyl)-methyl phenyl ketone hydrobromate).

Bisamide base heterocyclic derivative of the present invention is in the transplanted tumor model of chronic myelocytic leukemia sensitive cells (K562) and acute myeloid leukaemia sensitive cells (HL60), with the solvent is contrast, preliminary observation the interior curative effect of bisamide base heterocyclic derivative, typical case's representative is as embodiment 12,13,14,15,16 compounds, tested with embodiment 14 especially, the result shows: after the administration in experimental period, embodiment 14 presses 50mg/kg and 42mg/kg abdominal injection, the maximal percentage inhibition of K562 is respectively 87.25% and 65.46%, embodiment 14 does not have other toxic side effects and occurs, this explanation is according to used dosage regimen, the dosage of embodiment 14 also can suitably increase, to obtain better therapeutic.When observing 14 pairs of function of tumor of embodiment, whether also keep a close eye on embodiment 14 can increase the toxicity of antineoplaston, utilize the toxic action of the indirect reflection pharmacological agent of treatment back nude mice body weight change, the result shows that the body weight of not treating control group and high and low dose group mouse is the trend that increases gradually, and the treatment group is compared with the solvent control group does not have significant difference.From above result as can be seen embodiment 14 have efficiently, the antitumor action of low toxicity.Bisamide base heterocyclic derivative of the present invention has and induces the differentiation cancer cells to change into normal cell or approximate Normocellular function in some malignant cell of treatment such as cancers such as neuroblastoma, leukemia and melanoma simultaneously.

One. oxyphorase (Hb) assay

Principle: immature red corpuscle can not synthetic hemoglobin, has only sophisticated red corpuscle that oxyphorase is just arranged.Content of hemoglobin is very few in the human medullary erythroleukemia K562 cell, and Hb content can raise after compound is induced differentiation.

Experimental technique 1: get K562 cell 5 * 105/ml, be inoculated in 6 orifice plates, the embodiment 14 that adds 2 μ g/ml (IC10) or 6 μ g/ml (IC30), contrast adds coordinative solvent, in 37 ℃, after 5%CO2 is hatched 72 hours, phosphoric acid buffer (PBS) is washed cell 2 times, with 100 μ L PBS suspension cell again, adds 40 orifice plates, every hole adds antibody glycophorin antibody (CD235ab) 10 μ L, mixing, blank only add phycoerythrin (PE), and lucifuge is hatched under the room temperature, PBS washes 1 time, and flow cytometer detects the PE fluorescence intensity.The result as shown in Figure 1.

Two. preliminary study in the body

Utilization is set up the transplanted tumor in nude mice model through the chronic myelocytic leukemia sensitive cells (K562) that FISH detects Philadelphia chromatin-positive, in order to assessing compound antitumor action in vivo.

(1) foundation of the one-sided model of transplanted tumor in nude mice

The Balb/cnu/nu nude mice, female, 4-6 week in age week, body weight 16-20g, through 137 caesium 400RAD irradiation, the 3rd day in right fore root dorsal part subcutaneous vaccination K562 sensitive cells, every mouse inoculation cell count is 1 * 107 cell/0.2ml, and the 5th day with the animal random packet, every group of 3 nude mices.

(2) overriding resistance TAT in the body

1. grouping and dosage setting: experiment minute negative control group and treatment group, negative control group gives corresponding solvent, and embodiment 14 establishes two groups of high dosage (50mg/Kg) and low dosages (42mg/Kg) in the treatment group.

2. medication: the random packet same day (being transplanted tumor inoculation back the 3rd day) beginning administration, at interval medication in 3 days once, continuous 5 times, abdominal injection (i.p.).

3. judgement criteria: Model in Nude Mice is used the vernier caliper measurement diameter of tumor, dynamic observes the anti-tumour effect of medicine, and once the calculation formula of gross tumor volume was in per three days in the measurement of diameter of tumor:

V＝1/2×a×b2

A and b are respectively the major diameter and the minor axis of tumour

Each relative tumour volume of measuring than (Relative tumor volume, RTV) calculation formula is:

RTV＝Vt/VO

VO is the volume that GP TH is measured when beginning, the volume of Vt when measuring each time

The anti-tumor activity evaluation index is tumor control rate (IR%), and formula calculates below adopting:

1R％＝(1-TRTV/CRTV)×100％

TRTV is treatment group RTV, and CRTV is control group RTV

4. toxicity assessment: claim mouse heavy at every turn when measuring, calculate relative body weight than (Relative Body Weight is RBW) to assess the toxic reaction of medicine.

RBW＝Wt/WO

Body weight when Wt is test, body weight when WO is on-test

Experimental result:

Embodiment 14 shows the growth-inhibiting experimental result that influences of " Philadelphia chromosome " male K562 tumor cell proliferation, the IC50 value of the embodiment 14 of cell in vitro screening is 24.03 μ M, 14 pairs of BCR-ABL protein of embodiment are expressed and active high embodiment 14 in cell screening has been chosen in active influence, with the influence of Western blot method detection compound to the BCR-ABL protein expression; Detect the influence of 14 pairs of BCR-ABL protein Tyrosylprotein kinases of embodiment phosphorylation activity with the co-immunoprecipitation method.As shown in Figure 2: embodiment 14 is in less than 200 μ M, and BCR-ABL protein expressed does not have influence; And all have significant inhibition active to BCR-ABL protein Tyrosylprotein kinase phosphorylation, along with the increase of compound dosage, the degree of Tyrosylprotein kinase phosphorylation obviously reduces, and presents dose-dependently from figure.

Three. preliminary experiment in the body

With relative tumour volume (RTV) is that the tumor growth curve of index shows after the administration in experimental period (18 days), embodiment 14 high dose group (50mg/kg, ip * 5) in vivo K562 there is the obvious suppression effect, inhibiting rate is 87.25%, has compared significant difference (P＜0.05) with the solvent control group; Low dose group (42mg/kg, ip * 5) is 65.46% to the inhibiting rate of K562 in vivo, has compared significant difference (P＜0.05) with the solvent control group.This is consistent with the experiment in vitro result, has reconfirmed embodiment 14 obvious antineoplastic.As shown in Figure 3

When observing the antitumor drug drug action, also must keep a close eye on the toxicity whether compound can increase antineoplaston, treatment back nude mice body weight change can reflect the toxic action of medicine indirectly, and we adopt relative body weight than the changing conditions of weighing nude mice body weight between different treatment groups.As shown in Figure 4, the result shows that the body weight do not treat control group and high and low dose group mouse is the trend that increases gradually, compare with the solvent control group and do not have significant difference (P〉0.05).The PRELIMINARY RESULTS prompting, embodiment 14 has efficiently, the effect of low toxicity.

The experimental therapy effect of 14 couples of nude mice K562 of Table 1 embodiment transplanted tumor

^*Compare with control group

The influence of 14 couples of lotus people of Table 2 embodiment K562 transplanted tumor nude mice body weight

Description of drawings:

Fig. 1 .FACS measures content of hemoglobin, Fig. 2. the influence of 14 pairs of BCR-ABL protein Tyrosylprotein kinases of embodiment phosphorylation activity, Fig. 3. and the experimental therapy effect of 14 couples of nude mice K562 of embodiment transplanted tumor, Fig. 4. the influence of 14 pairs of K562 transplanted tumors of embodiment nude mice body weight

Embodiment

The present invention is described further below in conjunction with embodiment, but and unrestricted the present invention.Initial substance of the present invention and intermediate can have been bought from market as the aminoacetophenone of adjacent a, position, Benzoyl chloride, 3-aminopyridine etc. or the method for easily instructing by relevant textbook prepares.

Embodiment 1

To benzene carbon amide benzoylformaldoxime (IV)

The 4-aminoacetophenone (16.4g, 120mmol) and Benzoyl chloride (14g 100mmol) is dissolved in the 1000ml methylene dichloride, adds triethylamine (18g, 180mmol), stirring at room 4 hours, reaction solution 1N salt pickling, anhydrous sodium sulfate drying, steam desolventize product 20g, yield 83.68%.m.p.126-128℃。

Embodiment 2

To butyrylamino methyl phenyl ketone (IV)

Method just changes Benzoyl chloride into butyryl chloride with embodiment 1, must measure 17g yield 71%.

Embodiment 3

To ethoxy benzene carbon amide benzoylformaldoxime

Method just changes Benzoyl chloride to ethoxy benzoyl chloride into embodiment 1, must measure 35g yield 73%.

Embodiment 4

Adjacent-to oxybenzene formamido group methyl phenyl ketone (IV)

2-aminoacetophenone (1.64g, 12mmol) with para hydroxybenzene formyl chloride (1.4g, 10mmol) be dissolved in the 100ml chloroform, and the adding triethylamine (1.8g, 18mmol), stirring at room 4 hours, reaction solution is with the pickling of 1N salt, anhydrous sodium sulfate drying, steam desolventize product 1.8g, m.p.138-140 ℃, yield 75.3%.

Embodiment 5

The p-chlorobenzamido methyl phenyl ketone

Method just changes the para hydroxybenzene formyl chloride into parachlorobenzoyl chloride with embodiment 4, must measure 30g yield 68%.

Embodiment 6

3-benzene carbon amide yl pyridines (VI)

The 3-aminopyridine (56.4g, 600mmol) and Benzoyl chloride (70g 500mmol) is dissolved in the 1500ml pyridine, stirring at room was reacted about 1 hour, and reaction solution is used dichloromethane extraction then with the pickling of 1.0N salt, anhydrous magnesium sulfate drying, steam desolventize product 86g, yield 87%.

Embodiment 7

2-benzamido pyrazoles (VI)

Method just changes the 3-aminopyridine into the 3-amino-pyrazol with embodiment 6, must measure 70.2g, yield 78.5%.

Embodiment 8

2-benzamido benzo pyrimidine (VI)

Method just changes the 3-aminopyridine into the amino benzo pyrimidine of 2-with embodiment 6, must measure 90g, yield 84%.

Embodiment 9

To benzamido benzene bromo ethyl ketone (VII)

Will to the benzene carbon amide benzoylformaldoxime (33g 138mmol) is dissolved in the 1000ml chloroform, add bromine liquid (22g, 138mmol), stirring at room 3 hours, the reaction solution washing, anhydrous magnesium sulfate drying, solvent evaporated gets product 41g, yield 93.18%.

Embodiment 10

To butyrylamino bromoacetophenone (VII)

Method just will change into the butyrylamino methyl phenyl ketone the benzene carbon amide benzoylformaldoxime with embodiment 9, must measure 38g, yield 85%

Embodiment 11

Adjacent-to oxybenzene formamido group chloroacetophenone (VII)

With neighbour-to hydroxyl-benzene carbon amide benzoylformaldoxime, (400g 1.67mol) is dissolved in the 1500ml chloroform, feed chlorine (122g, 1.67mol), stirring at room 3 hours, the reaction solution washing, anhydrous magnesium sulfate drying, solvent evaporated gets product 410g, yield 80.18%.

Embodiment 12

To butyrylamino-α-(3-benzamido pyrazoles)-methyl phenyl ketone hydrobromate (I)

With 3-benzamido pyrazoles 150g, 470mmol and to butyrylamino bromoacetophenone (100g, 470mmol) be dissolved in the 2500ml first stupid in, room temperature was placed one day, and the adularescent crystallization is separated out, filter product 100g, the gained crude product is refining with the 1000ml ethyl acetate, obtain the 85g target compound, m.p.247-249 ℃, yield 73.2%.

Embodiment 13

Adjacent-to oxybenzene formamido group-α-(2-benzene carbon amide yl pyrimidines)-methyl phenyl ketone hydrochloride (I)

With 2-benzene carbon amide yl pyrimidines (150g, 470mmol) and adjacent-to oxybenzene formamido group chloroacetophenone (VII) (120g, 470mmol) be dissolved in the 2500ml chloroform, 50-55 ℃ the reaction 24 hours, the adularescent crystallization is separated out, filter product 180g, the gained crude product is refining with 95% ethanol, obtain the 130g target compound, m.p.274-276 ℃, yield 70.5%.

Embodiment 14

4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone hydrobromate (I)

Will be to benzamido benzene bromo ethyl ketone (50g, 157mmol) with 3-benzene carbon amide yl pyridines 31g, (157mmol) be dissolved in the 1000ml benzene, room temperature was placed one day, and the adularescent crystallization is separated out, filter product 80g, the gained crude product is refining with 95% ethanol, obtain the 60g target compound, yield 87.71%, m.p.255-258 ℃.

¹H-NMR (DMSO-d6) δ (dimethyl sulfoxide (DMSO)): 9.25 (it is unimodal, ¹H pyridine 2-H), 8.90 (multiplet, 1H, pyridine 6-H), 9.05 (multiplet, ¹H, pyridine 4-H), 8.51 (multiplet, ¹H, pyridine 5-H) 7.95 (multiplet, 4H, the benzamide ortho position-H), 7.85 (multiplet, 2H, the methyl phenyl ketone ortho position-H), 7.76 (multiplet, 2H, position between methyl phenyl ketone-H), 7.50 (multiplet, 2H, the benzamide contraposition-H), 7.45 (multiplet, 4H, position between benzamide-H), 2.61 (methyl phenyl ketone CH ₂)

C ¹³-NMR δ (dimethyl sulfoxide (DMSO)): 196.5,165.3,142.8,142.6,133.1,131.8,128.6,128.5,127.2,120.2,62.8.

Embodiment 15

4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone fumarate (I)

With embodiment 14 products therefrom 60g, join in 30% the aqueous sodium hydroxide solution (500ml) free, add the fumarate that the 15g fumaric acid obtains embodiment 14 subsequently.

Embodiment 16

With reference to embodiment 15, be raw material with embodiment 14 products therefroms, with the tosic acid reaction, be equipped with the tosilate of embodiment 14 with legal system.

One class is by containing two formed pharmaceutical compositions of amido heterocyclic derivative, and it comprises medicine and pharmaceutically acceptable carrier, thinner or the vehicle of the significant quantity of claim 1-7.

Bisamide base heterocyclic derivative of the present invention can be with the oral or non-oral administration of itself safety, perhaps with the oral or non-oral administration of compound (as tablet, sustained release preparation, capsule, injection, the solution) safety that forms with pharmaceutically acceptable carrier, vehicle and other additive.When oral administration, composition can be mixed with tablet, sugar-coat agent or capsule.For the preparation oral compositions can adopt lactose or starch to do carrier, gelatin, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone etc. are suitable wedding agents or become an agent.Can select starch or Microcrystalline Cellulose for use as disintegrating agent, often with talcum powder, santocedl, stearin, calcium stearate or magnesium etc. are as suitable antiadhesives and lubricant.For example, can prepare tablet by the compacting wet granular.Activeconstituents and carrier and optionally with a disintegration additive composition mixture; the aqueous solution of this mixture and tackiness agent; alcohol or aqueous alcohol solution carry out granulating in suitable device; dried particles adds other disintegrating agent subsequently, and lubricant and antisticking agent are with this mixture compressing tablet.

Bisamide base heterocyclic derivative of the present invention is not soluble in water, after can dissociating heterocyclic derivative, solvability makes pharmaceutically acceptable organic acid for increasing, be toluenesulphonic acids preferably, fumaric acid etc. are to help with the injection form administration, though dosage is according to treatment target, administering mode, symptom and other factor and change, but work as chronic myelocytic leukemia, be generally the about 0.1mg/kg of every dosage-1000mg/kg body weight during the non-oral administration of adult of adult's acute lymphoblastic leukemia, preferred about 0.1mg/kg-800mg/kg body weight, preferred 0.5mg/kg-500mg/kg body weight, at interval medication in 3 days once, administration in continuous 5 days is useful.When parenterai administration, composition of the present invention is made into injection solution, when preparing this type of injection liquid, be dissolved in activeconstituents in the sterile distilled water or in the various medicinal organic solvent, also can add solubility promoter such as sorbityl monododecanoate, monostearate or monoleate or the like, injection liquid also can contain various additives commonly used, sanitas etc.Before can peace bottle, the injection liquid that needs to contain the present composition filters, and sterilizes after the can.

In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.Preparation can adopt the activeconstituents of any one compound among the present invention.

Preparation 1

Every tablet preparation that contains the 10mg activeconstituents is as follows:

Consumption/sheet weight concentration (%)

Embodiment 11 10mg 10.0

Microcrystalline Cellulose 35mg 35.0

Starch 45mg 45.0

Polyvinylpyrrolidone 4mg 4.0

Carboxymethyl starch sodium salt 4.5mg 4.5

Magnesium Stearate 0.5mg 0.5

Talcum powder 1mg 1.0

Amount to 100 100.0

With activeconstituents, starch and Mierocrystalline cellulose sieve, and thorough mixing, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.

Preparation 2

The preparation of injection liquid

Embodiment 12 400mg

Sorbityl monododecanoate 100mg

Citric acid 700mg

Monoleate 90mg

Distilled water 300ml

Making the pH value is 3 mg/ml for 7.0-7.5 filters filter liquor concentration, and by 2 milliliters of packing of every peace bottle, 120 ℃ of high-temperature sterilizations promptly got intramuscular injection in 30 minutes.

Preparation 3

Every capsule contains the capsular of 100mg activeconstituents and is prepared as follows:

Consumption/capsule weight concentration (%)

Embodiment 13 100mg 30.0

Polyoxyethylene dehydration sorb 0.05mg 0.02

The sugar alcohol monoleate

Starch 250mg 69.98

Amount to 350.05mg 100.00

Claims (7)

1, a kind of two amido N Hete rocyclic derivatives with anti-tumor activity, its general formula is as follows:

Wherein:

Represent one 5 yuan or 6 yuan of N-heterocycles; Y is a 0-3 N atom;

R is C ₁-C ₄Alkyl, C ₁-C ₄Aryloxy, aryl or substituted aryl;

Described C ₁-C ₄Alkyl is methyl, ethyl, propyl group or butyl;

Described C ₁-C ₄Aryloxy is benzyloxy, benzene oxyethyl group or benzene propoxy-;

Described aryl, substituted aryl are phenyl, chlorobenzene, phenol or anilino;

Be acetate moiety, Hydrogen bromide root, trifluoroacetic acid root, tosylate, salt acid group or fumaric acid radical.

2, derivative as claimed in claim 1 is characterized in that R is C ₁-C ₄Alkyl, phenyl, phenol or chlorobenzene; X ^-Be Hydrogen bromide root, tosylate, salt acid group or fumaric acid radical.

3, derivative as claimed in claim 1, its chemical name is:

Right-butyrylamino-α-(3-benzamido pyrazoles)-methyl phenyl ketone hydrobromate;

4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone hydrobromate;

4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone fumarate;

Adjacent-to oxybenzene formamido group-α-(2-benzene carbon amide yl pyrimidines)-methyl phenyl ketone hydrochloride;

4-benzamido-α-(3-benzene carbon amide pyridyl)-methyl phenyl ketone tosilate.

4, the preparation method of the described derivative of one of claim 1-3 is characterized in that comprising the steps:

(1) under the alkaline condition of organic solvent, compound (II) and (V) make compound (IV) and compound (VI) with compound (III) reaction respectively;

(2) compound (IV) makes compound (VII) with the halogen reaction;

(3) compound (VI) and compound (VII) are with the mixed target compound (I) that gets of certain proportion;

Wherein X ^-, R has the definition with one of claim 1-3; X among the formula VII is expressed as halogen.

5, a kind of formed pharmaceutical composition of two amido N Hete rocyclic derivatives with anti-tumor activity, it comprises two amido N Hete rocyclic derivatives and pharmaceutically acceptable carrier, thinner or the vehicle of one of the claim 1-3 of significant quantity.

6, each described two amido N Hete rocyclic derivatives application in preparation treatment chronic myelocytic leukemia or adult's acute lymphoblastic leukemia medicine of claim 1-3 with anti-tumor activity.

7, each described two amido N Hete rocyclic derivatives with anti-tumor activity of claim 1-3 are treated acute myeloid leukaemia, neuroblastoma and are induced the differentiation cancer cells in preparation, improve the application in the patient blood hemoglobin content medicine.

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