CN1597668A - Biamido heterocyclic derivative with antitumour activity and its preparation method and use - Google Patents

Abstract

The present invention relates to a class of bisamidoheterocyclic derivatives with anti-tumor activity of the general formula (I), its preparation method and application. For the definition of each group in the formula and the detailed description of the preparation method, see the specification. The compound of the general formula (I) shows an obvious effect of inhibiting tumor cells, and has the characteristics of high efficiency and low toxicity, so it is expected to be used to treat various malignant diseases such as chronic myeloid leukemia, adult acute lymphoblastic leukemia, human myeloid erythroleukemia, etc. Tumors, at the same time, the bisamide-based heterocyclic derivatives of the present invention have the ability to induce differentiated cancer cells to turn into normal cells or approximate normal cells in the preparation and treatment of some experimental malignant tumors, such as neuroblastoma, leukemia and melanoma. function of the cells.

Description

Bisamido-heterocyclic derivatives with anti-tumor activity, preparation method and use thereof

technical field

The present invention relates to antitumor drugs and their synthesis, more specifically to a bisamidoheterocyclic derivative with antitumor activity and its preparation method, and a pharmaceutical composition containing such derivatives in a therapeutically effective amount And the application of the composition in treating various malignant tumors such as chronic myelogenous leukemia (CML), adult acute lymphocytic leukemia (ALL), neuroblastoma, human myeloid erythroleukemia and melanoma.

Background technique

Cancer is a large class of diseases that seriously threaten human health. Finding effective treatments to conquer cancer has always been a research area that people pay close attention to. Traditional anticancer drugs are mainly cytotoxic drugs, which rely on the differences in the kinetics of growth, repair, and death between tumor cells and normal cells to kill tumor cells, so these drugs will inevitably affect normal cells. The therapeutic window on the drug is very narrow, which also limits the implementation of multi-drug combination therapy. Non-selective cell killing therapy can never really achieve the purpose of curing cancer. In recent years, many anticancer drugs targeting molecular targets have emerged one after another. These drugs are highly targeted and effective, just like hitting a target, so they can be called "targeted drugs". As early as 100 years ago, Paul Ehrlich proposed the concept of targeting therapy. With the development of molecular biology and the deepening of people's research on the mechanism of cancer, targeted drugs targeting specific carcinogenic mechanisms have gained a lot of attention in recent years. Rapid development, such as the small molecule drug imatinib (ImatmibMesilate, STI-571) can directly attack the cause of cancer, with strong selectivity, clinical trials have proved that the effect is remarkable, and the side effects are mild. When used in combination with multiple drugs, it can strengthen traditional chemotherapy. The effect of the drug. Especially in the treatment of chronic myelogenous leukemia and adult acute lymphoblastic leukemia, significant progress has been made, but there are still some problems. New clinical reports show that some middle and advanced chronic myelogenous leukemias have no effect on STI-571 drugs. drug resistance. In addition, the patient must take the medicine for a long time, otherwise the condition will deteriorate rapidly. In the chronic stage of CML, leukemia cells are easily controlled by cytotoxic drugs (hydroxyurea, marylan, etc.), and once the disease finally changes suddenly, the patient dies due to loss of control. Although bone marrow transplantation has a good curative effect at present and may cure the disease, it is limited by many factors such as the difficulty of bone marrow donors, rejection, age, and high cost; the application of interferon α can make the patient's "Philadelphia chromosome" negative, But the effect of improving a patient's chances of survival is uncertain. Therefore, it is imperative to find new therapeutic methods to achieve the goal of eradicating leukemia. In view of the key biological role of tyrosine kinase in the formation of CML and some ALL, it has been proved to be a positive strategy to design small molecule inhibitors against the fusion protein BCR-ABL to inhibit BCR-ABL tyrosine kinase. The treatment strategy of the disease has become a research hotspot in recent years.

Contents of the invention

At present, the tyrosine kinase inhibitors related to BCR-ABL protein are divided into two categories: natural and synthetic according to their sources. Among natural products, Herbimycin A, Genistein (genistein) and so on have been studied more. Herbimycin A is a kind of benzoquinone hydrogen-containing compound, which interacts with the sulfhydryl group near the active center of the kinase through its benzoquinone part, competes for the ATP binding site, and inhibits the activity of the enzyme. It primarily inhibits autophosphorylation of P210BCR-ABL. Genistein works by competitively inhibiting the ATP binding site of the kinase. Synthetic inhibitors are designed, synthesized and optimized based on these natural active compounds to obtain a series of inhibitors. According to the sign that the catalytic region of protein kinase maintains a unique conformation when it is not activated, it is considered to be a very promising direction for drug development to find specific protein kinase inhibitors. Based on this latest research result, the present invention uses the inactivated conformation of ABL co-crystallized with STI-571 as the receptor binding site to search the database, screen for new therapeutic drugs that do not produce drug resistance to CML, and explore anti-blood Important pathogenic genes of tumors and their pathways of action to find and design new drugs.

An object of the present invention is to overcome the shortcomings of current STI-571 drugs that are prone to drug resistance and long-term drug dependence, and provide a brand-new bisamide-based heterocyclic derivative for the treatment of chronic myeloid leukemia and adult Acute lymphoblastic leukemia drugs.

Another object of the present invention is to disclose a new preparation method of bisamide heterocyclic derivatives.

Another object of the present invention is to provide a pharmaceutical composition formed of a therapeutically effective amount of bisamidoheterocyclic derivatives and pharmaceutically acceptable carriers, diluents, and excipients.

What is even more surprising is that the bisamidoheterocyclic derivatives of the present invention have the ability to induce differentiated cancer cells to turn into normal cells or approximate normal cells in the preparation and treatment of certain malignant cells such as neuroblastoma, leukemia and melanoma. It can be said that the present invention has opened up a new approach for antitumor drug research.

The present invention provides amidoheterocyclic derivatives having antitumor activity as follows:

Its general formula is as follows:

in:

Represents a five-membered or six-membered N heterocycle or a heterocycle or benzoheterocycle containing various heteroatoms such as N;

Y is 0-3 N atoms including;

(a). Optionally contain N, O and/or S as additional heteroatoms at positions not adjacent to the connecting N atom;

(b). N, S or O atoms are attached to one or two carbon atoms adjacent to the N atom;

X- represents anion, such as acetate, trifluoroacetate, tosylate, phosphate, halogen, fumaric acid or other organic acid radicals;

R is C ₁ -C ₆ straight chain or branched alkyl, C ₁ -C ₄ alkyl or aryloxy, aryl, substituted aryl, preferably R is C ₁ -C ₄ alkyl such as Methyl, ethyl, propyl, butyl, preferably ethyl or butyl; C ₁ -C ₄ aryloxy is generally benzyloxy, phenethoxy, phenylpropoxy, preferably benzyl Oxygen, phenethoxy, preferably phenethoxy; aryl, substituted aryl can be phenyl, chlorobenzene, phenol, anilino, etc., preferably phenyl, phenol or chlorobenzene; X ^- represents anion, such as Acetate, trifluoroacetate, tosylate, phosphate, halogen, fumaric acid or other organic acid radicals; generally expressed as chloride, trifluoroacetate, bromide, tosylate, phosphate, fumaric acid, Chloride, trifluoroacetate, bromide, phosphate, tosylate, and fumaric acid are preferred, and chloride, bromide, tosylate, and fumaric acid are more preferred.

表示以下一组化合物；

denotes the following group of compounds;

Bisamidoheterocyclic derivatives with anti-tumor activity described in claim 1, comprising p-butyrylamino-α-(3-benzamidopyrazole)-acetophenone fumarate; o- p-Hydroxybenzoylamino-α-(2-Benzamidopyrimidine)-Acetophenone Hydrochloride; 4-Benzamido-α-(3-Benzamidopyridyl)-Acetophenone Hydrobromide; 4-Benzamido-α-(3-Benzamidopyridyl)-acetophenone fumarate; 4-Benzamido-α-(3-Benzamide pyridyl)-acetophenone benzene mesylate.

The preparation method of a class of bisamido-heterocyclic derivatives is characterized in that it comprises the following steps:

(1). Compounds (II) and (V) react with compound (III) respectively under alkaline conditions in an organic solvent to prepare compound (IV) and compound (VI);

(2). Compound (IV) reacts with halogen to obtain compound (VII);

(3). Compound (VI) and compound (VII) are mixed in a certain proportion to obtain target compound (I);

in

X^-、R具有同权利要求1的定义；X表示为卤素。

X ^- and R have the same definitions as in claim 1; X represents halogen.

The starting material amino-substituted acetophenone in the method for preparing target compound (I) of the present invention, amino group can be in ortho, meta-position, para-position, preferably ortho- or para-position aminoacetophenone; Amino-substituted heterocycle includes pyrimidine, thiazole, Pyrazole, pyridine, quinoline, benzopyrimidine, purine, preferably pyrimidine, pyrazole, pyridine, benzopyrimidine, more preferably pyrazole, pyridine, benzopyrimidine. In the reaction of compound II and V reacting with compound III to obtain compound IV and compound VI, the organic solvent used is generally an inert organic solvent such as benzene, chloroform, pyridine, toluene, dichloromethane, preferably chloroform, pyridine, dichloromethane Chloromethane; used bases, such as alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, ammonia water, C ₁ -C ₄ alkane-substituted secondary or tertiary amines, such as triethylamine, tert-butylamine, etc., Preferred ammoniacal liquor, sodium carbonate, triethylamine, tert-butylamine, more preferably sodium carbonate, triethylamine; For every mole of compound (III), the consumption of base is usually 0.50-10.0 mole, preferably 1.0-5.0 mole, more preferably 1.0-3.0; the molar ratio of compound (III) to compound (II) or compound (V) is 1:1-5 moles, preferably 1:1-3 moles. Compound (IV) reacts with halogen to prepare the halogen used for compound (VII) including chlorine, liquid bromine, iodine, preferably liquid bromine; compound (IV) and liquid bromine molar ratio is 1: 1-8, preferably 1: 1-3 mole . Compound (VI) and compound (VII) are dissolved in an inert organic solvent such as benzene, chloroform, pyridine, toluene or dichloromethane at a ratio of 1:1-5 moles, and the reaction temperature is usually 0-80°C, preferably 20-50°C, The reaction time is usually 1-48 hours, preferably 5-30 hours, more preferably 10-24 hours; after the reaction is completed, the product is precipitated, collected by filtration, and refined with ethanol or ethyl acetate to obtain a high-yield, high-purity target compound (I).

Here, in order to show the practicability of target compound (I), typical embodiment 14 of the present invention is given below, (4-benzamido-α-(3-benzamide pyridyl)-acetophenone hydrobromide Salt) pharmacological experimental data.

The diamidoheterocyclic derivatives of the present invention have been preliminarily observed in the transplanted tumor models of chronic myeloid leukemia sensitive cells (K562) and acute myeloid leukemia sensitive cells (HL60), using solvent as a control. The in vivo curative effect of derivatives, typical representatives such as embodiment 12, 13, 14, 15, 16 compound, especially experiment with embodiment 14, the result shows: in the experimental period after administration, embodiment 14 is according to 50mg/kg and 42mg /kg intraperitoneal injection, the maximum inhibition rate of K562 was 87.25% and 65.46% respectively, and no other toxic and side effects occurred in Example 14, which shows that the dosage of Example 14 can also be appropriately increased to obtain Better curative effect. While observing the effect of Example 14 on tumors, pay close attention to whether Example 14 can increase the toxicity of anti-tumor treatment, and use the body weight change of nude mice after treatment to indirectly reflect the toxic effect of drug treatment. The results showed that the untreated control group and high 1. The body weight of the mice in the low-dose group gradually increased, and there was no significant difference between the treatment group and the solvent control group. From the above results, it can be seen that Example 14 has an antitumor effect with high efficiency and low toxicity. At the same time, the bisamide heterocyclic derivatives of the present invention have the function of inducing differentiated cancer cells to transform into normal cells or approximate normal cells in the treatment of certain malignant cells such as neuroblastoma, leukemia and melanoma.

1. Determination of hemoglobin (Hb) content

Principle: immature red blood cells cannot synthesize hemoglobin, only mature red blood cells have hemoglobin. The content of hemoglobin in human myeloid erythroleukemia K562 cells is very small, and the content of Hb can increase after the compound induces differentiation.

Experimental method 1: Take K562 cells at 5×105/ml, inoculate them into a 6-well plate, add 2 μg/ml (IC10) or 6 μg/ml (IC30) of Example 14, and add the corresponding solvent for the control, at 37 ° C, 5% After CO2 incubation for 72 hours, wash the cells twice with phosphate buffered solution (PBS), resuspend the cells with 100 μL PBS, add 10 μL of the antibody glycophorin antibody (CD235ab) to each well of a 40-well plate, and mix well. Erythroprotein (PE), incubated at room temperature in the dark, washed once with PBS, and detected the fluorescence intensity of PE by flow cytometry. The result is shown in Figure 1.

2. Preliminary study in vivo

The chronic myelogenous leukemia-sensitive cells (K562) that were positive for the Philadelphia chromosome detected by FISH were used to establish a nude mouse xenograft tumor model to evaluate the anti-tumor effect of the compound in vivo.

(1) Establishment of unilateral tumor transplantation model in nude mice

Balb/c nu/nu nude mice, female, aged 4-6 weeks, weighing 16-20g, irradiated with 137 cesium 400RAD, subcutaneously inoculated K562 sensitive cells on the dorsal side of the root of the right forelimb on the third day, and each mouse was inoculated with cells The number was 1×107 cells/0.2ml. On the fifth day, the animals were divided into random groups, with 3 nude mice in each group.

(2) Anti-drug-resistant tumor activity test in vivo

1. grouping and dose setting: the experiment is divided into negative control group and treatment group, negative control group is given corresponding solvent, and embodiment 14 is established high dose (50mg/Kg) and low dose (42mg/Kg) two groups in the treatment group.

②Dosing method: On the day of random grouping (that is, on the 3rd day after transplanted tumor inoculation), the drug was administered once every 3 days, 5 times in a row, intraperitoneal injection (i.p.).

③Evaluation criteria: The nude mouse xenograft tumor model uses a vernier caliper to measure the tumor diameter, and dynamically observes the anti-tumor effect of the drug. The tumor diameter is measured every three days. The calculation formula of the tumor volume is:

V=1/2×a×b2

a and b are the long and short diameters of the tumor, respectively

The relative tumor volume (RTV) calculation formula for each measurement is:

RTV=Vt/V0

V0 is the volume measured at the beginning of group treatment, and Vt is the volume at each measurement

The antitumor activity evaluation index is the tumor inhibition rate (IR%), which is calculated by the following formula:

IR%=(1-TRTV/CRTV)×100%

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

④ Toxicity assessment: Weigh the mice at each measurement, and calculate the Relative Body Weight (RBW) to evaluate the toxicity of the drug.

RBW=Wt/W0

Wt is the body weight at the time of the test, W0 is the body weight at the beginning of the test

Experimental results:

The effect of Example 14 on the proliferation of "Philadelphia chromosome" positive K562 tumor cells The results of growth inhibition experiments show that the IC50 value of Example 14 for in vitro cell screening is 24.03 μM, and the influence of Example 14 on BCR-ABL protein expression and activity is selected Example 14 with high activity in cell screening was detected, and the impact of the compound on BCR-ABL protein expression was detected by Western blot method; the impact of Example 14 on BCR-ABL protein tyrosine kinase phosphorylation activity was detected by immunoprecipitation method . As shown in Figure 2: Example 14 has no effect on BCR-ABL protein expression within less than 200 μM; while it has significant inhibitory activity on BCR-ABL protein tyrosine kinase phosphorylation, with the increase of compound dose, tyrosine The degree of phosphorylation of amino acid kinase was significantly reduced, and it was dose-dependent from the graph.

3. In vivo pre-experiment

The tumor growth curve with the relative tumor volume (RTV) as an index shows that within the experimental period (18 days) after administration, the high-dose group (50mg/kg, ip×5) of Example 14 has a significant inhibitory effect on K562 in vivo, The inhibition rate was 87.25%, which was significantly different from that of the solvent control group (P<0.05); the low dose group (42mg/kg, ip×5) had a 65.46% inhibition rate on K562 in vivo, which was significantly different from that of the solvent control group. There was a significant difference (P<0.05). This is consistent with the results of in vitro experiments, again confirming the obvious anti-tumor effect of Example 14. As shown in Figure 3

While observing the efficacy of anti-tumor drugs, we must also pay close attention to whether the compound can increase the toxicity of anti-tumor therapy. The change in body weight of nude mice after treatment can indirectly reflect the toxic effect of drugs. Changes in body weight of mice. As shown in Figure 4, the results showed that the body weight of mice in the untreated control group and the high and low dose groups gradually increased, and there was no significant difference compared with the solvent control group (P>0.05). Preliminary results suggest that Example 14 has high efficiency and low toxicity.

The experimental therapeutic effect of Table 1 embodiment 14 on nude mouse K562 xenograft tumor

K562 xenograft tumor Average tumor volume RTV

Animal number (mm3) Tumor inhibition rate P value ^*

Group Start Last (Day18) (%) ^*

Control group 3 11.83 202 21.89

High-dose combination group 3 7.17 18.67 2.79 87.25 P＜0.05

Low-dose combination group 3 4.67 34.67 7.56 65.46 P＜0.05

^* compared to control group

Effect of Table 2 Example 14 on body weight of nude mice bearing human K562 transplanted tumor

Average body weight (g) RBW

Group Number of animals Start Last (Day18) P value ^*

Control group 3 15.2 18.3 1.22

High-dose combination group 3 17.3 19.0 1.11 P＞0.05

Low-dose combination group 3 18.2 20.2 1.11 P＞0.05

Description of drawings:

Fig. 1.FACS measures the hemoglobin content, Fig. 2. the effect of embodiment 14 on the phosphorylation activity of BCR-ABL protein tyrosine kinase, Fig. 3. the experimental therapeutic effect of embodiment 14 on nude mouse K562 transplanted tumor, Fig. 4. implement Effect of Example 14 on Body Weight of K562 Transplanted Tumor Nude Mice

Detailed ways

The present invention will be further described below in conjunction with the examples, but the present invention is not limited. The starting materials and intermediates of the present invention, such as ortho- and meta-aminoacetophenones, benzoyl chloride, 3-aminopyridine, etc., can be purchased from the market or easily prepared by methods taught in relevant textbooks.

Example 1

p-Benzamidoacetophenone (IV)

4-Aminoacetophenone (16.4g, 120mmol) and benzoyl chloride (14g, 100mmol) were dissolved in 1000ml of dichloromethane, triethylamine (18g, 180mmol) was added, stirred at room temperature for 4 hours, and the reaction solution was washed with 1N hydrochloric acid , dried over anhydrous sodium sulfate, and distilled off the solvent to obtain 20 g of the product, with a yield of 83.68%. m.p.126-128°C.

Example 2

p-Butyrylaminoacetophenone (IV)

The method is the same as in Example 1 except that benzoyl chloride is replaced by butyryl chloride, and the yield is 71% in 17 g.

Example 3

p-Ethoxybenzamidoacetophenone

The method is the same as in Example 1 except that benzoyl chloride is replaced with p-ethoxybenzoyl chloride, and the yield is 73% in 35 g.

Example 4

O-parabensamidoacetophenone (IV)

2-Aminoacetophenone (1.64g, 12mmol) and p-hydroxybenzoyl chloride (1.4g, 10mmol) were dissolved in 100ml of chloroform, triethylamine (1.8g, 18mmol) was added, stirred at room temperature for 4 hours, and the reaction solution was washed with 1N Washed with hydrochloric acid, dried over anhydrous sodium sulfate, and distilled off the solvent to obtain 1.8 g of product, m.p.138-140°C, yield 75.3%.

Example 5

p-Chlorobenzamidoacetophenone

The method is the same as in Example 4 except that p-hydroxybenzoyl chloride is replaced by p-chlorobenzoyl chloride, and the yield is 68% in 30 g.

Example 6

3-Benzamidopyridine (VI)

3-aminopyridine (56.4g, 600mmol) and benzoyl chloride (70g, 500mmol) were dissolved in 1500ml of pyridine, stirred at room temperature for about 1 hour, the reaction solution was washed with 1.0N hydrochloric acid, and then extracted with dichloromethane, no Dry over magnesium sulfate and distill off the solvent to obtain 86 g of the product, with a yield of 87%.

Example 7

2-Benzamidopyrazole (VI)

The method is the same as in Example 6, except that 3-aminopyridine is replaced by 3-aminopyrazole, and the yield is 70.2 g, and the yield is 78.5%.

Example 8

2-Benzamidobenzopyrimidine (VI)

The method is the same as in Example 6, except that 3-aminopyridine is replaced by 2-aminobenzopyrimidine, the yield is 90 g, and the yield is 84%.

Example 9

p-Benzamidophenylbromoethanone (VII)

Dissolve p-benzamidoacetophenone (33g, 138mmol) in 1000ml of chloroform, add bromine solution (22g, 138mmol), stir at room temperature for 3 hours, wash the reaction solution with water, dry over anhydrous magnesium sulfate, and evaporate to dryness to obtain 41g of the product , yield 93.18%.

Example 10

p-Butyrylaminobromoacetophenone (VII)

The method is the same as in Example 9 except that the p-benzamidoacetophenone is replaced with p-butyrylaminoacetophenone, and the yield is 38g, and the yield is 85%.

Example 11

O-parabensamidochloroacetophenone (VII)

Dissolve o-p-hydroxy-benzamidoacetophenone (400g, 1.67mol) in 1500ml of chloroform, pass through chlorine gas (122g, 1.67mol), stir at room temperature for 3 hours, wash the reaction solution with water, and dry over anhydrous magnesium sulfate , The solvent was evaporated to dryness to obtain 410 g of the product, with a yield of 80.18%.

Example 12

p-Butyrylamino-α-(3-Benzamidopyrazole)-Acetophenone Hydrobromide (I)

150g, 470mmol of 3-benzamidopyrazole and p-butyrylamino bromoacetophenone (100g, 470mmol) were dissolved in 2500ml of toluene, left at room temperature for one day, white crystals were precipitated, and 100g of the product was obtained by filtration, and the resulting The crude product was purified with 1000ml of ethyl acetate to obtain 85g of the target compound, m.p.247-249°C, yield 73.2%.

Example 13

o-P-hydroxybenzoylamino-α-(2-benzamidopyrimidine)-acetophenone hydrochloride (I)

2-benzamidopyrimidine (150g, 470mmol) and o-parabensamidochloroacetophenone (VII) (120g, 470mmol) were dissolved in 2500ml of chloroform, reacted at 50-55°C for 24 hours, and White crystals were precipitated, and 180 g of the product was obtained by filtration. The obtained crude product was purified with 95% ethanol to obtain 130 g of the target compound, m.p.274-276°C, yield 70.5%.

Example 14

4-Benzamido-α-(3-Benzamidopyridinyl)-Acetophenone Hydrobromide (I)

Dissolve p-benzamidophenylbromoethanone (50g, 157mmol) and 31g (157mmol) of 3-benzamidopyridine in 1000ml of benzene, leave it at room temperature for one day, white crystals precipitate, and filter to obtain 80g of the product. The obtained crude product was refined with 95% ethanol to obtain 60 g of the target compound with a yield of 87.71%, m.p.255-258°C.

¹ H-NMR (DMSO-d6) δ (dimethyl sulfoxide): 9.25 (singlet, ¹ H pyridinium 2-H), 8.90 (multiplet, ¹ H, pyridinium 6-H), 9.05 (multiple Peak, ¹ H, pyridinium 4-H), 8.51 (multiplet, ¹ H, pyridinium 5-H), 7.95 (multiplet, 4H, benzamide ortho-H), 7.85 (multiplet, 2H, benzene Ethanone ortho-H), 7.76 (multiplet, 2H, acetophenone meta-H), 7.50 (multiplet, 2H, benzamide para-H), 7.45 (multiplet, 4H, benzamide meta-H), 2.61 (acetophenone CH ₂ )

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

Example 15

4-Benzamido-α-(3-Benzamidopyridinyl)-Acetophenone Fumarate (I)

60 g of the product obtained in Example 14 was added to 30% aqueous sodium hydroxide solution (500 ml) to be free, and then 15 g of fumaric acid was added to obtain the fumarate of Example 14.

Example 16

Referring to Example 15, the product obtained in Example 14 was used as a raw material to react with p-toluenesulfonic acid to prepare the p-toluenesulfonic acid salt of Example 14 in the same way.

A pharmaceutical composition formed from bisamido-containing heterocyclic derivatives, which comprises the effective amount of the drug according to claims 1-7 and a pharmaceutically acceptable carrier, diluent, or excipient.

The bisamido-heterocyclic derivatives of the present invention can be administered orally or non-orally with their own safety, or as compounds formed with pharmaceutically acceptable carriers, excipients and other additives (such as tablets, slow-release Preparations, capsules, injections, solutions) safe oral or parenteral administration. When administered orally, the composition may be formulated as tablets, dragees or capsules. To prepare oral compositions, lactose or starch can be used as carrier, and gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, etc. are suitable binders or granulating agents. Starch or microcrystalline cellulose can be selected as the disintegrant, and talcum powder, colloidal silica gel, glyceryl stearate, calcium or magnesium stearate, etc. are often used as suitable anti-adhesive and lubricants. For example, tablets can be prepared by compressing wet granules. The active ingredient is mixed with a carrier and optionally a disintegrant additive, the mixture is granulated with an aqueous solution of a binder, alcoholic or aqueous-alcoholic solution, and the dried granules are subsequently added to other disintegrants. Debonding agents, lubricants and anti-tacking agents are used to compress this mixture into tablets.

The bisamido-heterocyclic derivatives of the present invention are not easily soluble in water. In order to increase solubility, the heterocyclic derivatives can be dissociated and made into pharmaceutically acceptable organic acids, preferably toluenesulfonic acid and fumaric acid. etc. are advantageous for administration in the form of injections, although the dose varies depending on the subject to be treated, the mode of administration, symptoms and other factors, but when it is administered non-oral to adults with chronic myelogenous leukemia and adult acute lymphoblastic leukemia, it is usually per dose. The dose is about 0.1 mg/kg-1000 mg/kg body weight, preferably about 0.1 mg/kg-800 mg/kg body weight, more preferably 0.5 mg/kg-500 mg/kg body weight, once every 3 days, and it is beneficial to administer it for 5 consecutive days of. When administered parenterally, the composition of the present invention is made into an injection solution. When preparing this type of injection, the active ingredient is dissolved in sterile distilled water or various pharmaceutical organic solvents, and co-solvents such as Sorbitol monolaurate, monostearate or monooleate, etc., the injection can also contain various commonly used additives, preservatives, etc. Before filling the ampoule, the injection solution containing the composition of the present invention needs to be filtered and sterilized after filling.

In order to more fully illustrate the practice of the present invention, the following formulation examples are provided. These examples are merely illustrative, not limiting the scope of the present invention. Formulations may employ the active ingredient of any of the compounds of the present invention.

Preparation 1

Tablets each containing 10 mg of active ingredient are prepared as follows:

Dosage/tablet Weight concentration (%)

Example 11 10mg 10.0

Microcrystalline Cellulose 35mg 35.0

Starch 45mg 45.0

Polyvinylpyrrolidone 4mg 4.0

Sodium carboxymethyl starch 4.5mg 4.5

Magnesium stearate 0.5mg 0.5

Talc powder 1mg 1.0

Total 100 100.0

Sieve the active ingredients, starch and cellulose, and mix them well, mix the polyvinylpyrrolidone solution with the above powder, sieve, make wet granules and dry at 50-60°C, add carboxymethyl starch sodium salt, stearin Magnesium acid and talc powder are pre-screened, and then added to the above-mentioned granules for tableting.

Preparation 2

Preparation of Injection

Example 12 400mg

Sorbitan Monolaurate 100mg

Citric acid 700mg

Monooleate 90mg

Distilled water 300ml

Make the pH value 7.0-7.5 and filter the filtrate concentration to be 3 mg/ml, pack in 2 ml per ampoule, and sterilize at 120°C for 30 minutes to obtain the intramuscular injection.

Preparation 3

Capsules containing 100 mg of active ingredient per capsule are prepared as follows:

Concentration by weight (%) Dosage/capsule

Example 13 100mg 30.0

Polyoxyethylene sorrel 0.05mg 0.02

Sugar Alcohol Monooleate

Starch 250mg 69.98

Total 350.05mg 100.00

Claims (10)

1. A bisamidoheterocyclic derivative with antitumor activity, its general formula is as follows:

in:

Represents a five-membered or six-membered N heterocycle or a heterocycle or benzoheterocycle containing various heteroatoms such as N; Y is 0-3 N atoms including: (a). Optionally contain N, O and/or S as additional heteroatoms at positions not adjacent to the connecting N atom; (b). N, S or O atoms are attached to one or two carbon atoms adjacent to the N atom; X ^- represents anion, such as acetate, trifluoroacetate, tosylate, phosphate, halogen, fumaric acid or other organic acid radicals; R is a C ₁ -C ₆ straight chain or branched alkyl, C ₁ -C ₄ alkyl or aryloxy, aryl, substituted aryl. 2. The derivative according to claim 1 is characterized in that R is C ₁ -C ₄ alkyl, C ₁ -C ₄ aryloxy, phenyl, phenol, chlorobenzene; X ^- represents chloride ion, bromide ion , tosylate, phosphate, fumaric acid. 3. The derivative according to claim 1, characterized in that said denotes the following group of compounds; 4. The derivative according to claim 1, the chemical name is p-butyrylamino-α-(3-benzamidopyrazole)-acetophenone fumarate. 5. The derivative according to claim 1, the chemical name is o-parabensamido-α-(2-benzamidopyrimidine)-acetophenone hydrochloride. 6. The derivative according to claim 1, the chemical name is 4-benzamido-α-(3-benzamidopyridyl)-acetophenone hydrobromide. 7. The method for preparing a class of bisamidoheterocyclic derivatives as claimed in claim 1, characterized in that it comprises the following steps: (1). Compounds (II) and (V) react with compound (III) respectively under alkaline conditions in an organic solvent to prepare compound (IV) and compound (VI);

(2). Compound (IV) reacts with halogen to obtain compound (VII); (3). Compound (VI) and compound (VII) are mixed in a certain proportion to obtain target compound (I);

in , X ⁻ , R have the same definitions as in claim 1; X represents halogen. 8. A pharmaceutical composition containing bisamidoheterocyclic derivatives, which comprises an effective amount of the drug according to claims 1-7 and a pharmaceutically acceptable carrier, diluent, or excipient. 9. Application of a class of bisamide heterocyclic derivatives in the preparation of drugs for treating chronic myelogenous leukemia and adult acute lymphocytic leukemia. 10. The application of a class of bisamidoheterocyclic derivatives in the preparation and treatment of acute myelogenous leukemia, neuroblastoma and inducing differentiation of cancer cells, and increasing the hemoglobin content of patients.

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