CN101675931B

CN101675931B - New uses of acyl chloride and sulfonyl chloride derivatives in preparing anti-tumor drug

Info

Publication number: CN101675931B
Application number: CN2008101514740A
Authority: CN
Inventors: 刘巍; 刘默; 刘登科; 徐为人; 刘颖; 任晓文; 王玉丽; 张士俊; 汤立达; 王景阳
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2008-09-19
Filing date: 2008-09-19
Publication date: 2011-09-07
Anticipated expiration: 2028-09-19
Also published as: CN101675931A

Abstract

The invention relates to new medical uses of acyl chloride and sulfonyl chloride derivatives having a general formula I structure described in the Chinese patent application (CN 200710060530.5) in aspect of anti-tumor, especially new uses of this type compounds and pharmaceutically acceptable salts or medicinal compositions thereof in preparing anti-tumor drugs. Specifically speaking, the present invention relates to application in treating colorectal carcinoma, leukemia, gastric adenocarcinoma, breast cancer, oral cancer, lung cancer, sarcoma and melanoma. Wherein, the definition of each group is described as the specification.

Description

Acyl chlorides and sulfonyl chloride derivant are in the purposes of preparation antitumor drug

Technical field

The invention belongs to the relevant drug world of tumor, more particularly, relate to a class acyl chlorides and the sulfonic acid chloride isoxazoline derivative new purposes aspect the preparation antitumor drug.

Background technology

Tumor is the malignant disease of serious harm human health, and its mortality rate is only second to cardiovascular disease, occupies second of all kinds of disease death rates.Since nineteen ninety-six the tumor patient newly made a definite diagnosis every year of the whole world is all more than 1,030 ten thousand, and annual global tumor mortality sum reaches 7,000,000 people.WHO calendar year 2001 reports that world's cancer morbidity and mortality rate have risen 22% than the nineteen ninety, also will rise about 50% in 20 years from now on.The cancer that western developed country is more easily sent out is followed successively by breast carcinoma, pulmonary carcinoma, carcinoma of prostate, colon cancer, rectal cancer and ovarian cancer.In recent years, the annual newly-increased tumor patient of China has 160～1,700,000 people, and Estimate of Total Number is about 4,500,000 people.The cancer of harm China residents ' health is followed successively by gastric cancer (21.76%), hepatocarcinoma (17.83%), pulmonary carcinoma (15.19%), the esophageal carcinoma (15.02%), colorectal cancer (4.54%), leukemia (3.53%), cervical cancer (1.64%), nasopharyngeal carcinoma (1.53%) and breast carcinoma (1.49%).Tumor treatment is still based on operation, chemotherapy and radiation at present.The chemotherapy of tumor plays a part very important in the tumor treatment process, and many tumors have obtained the treatment of curative effect preferably, particularly leukemia and malignant lymphoma by single chemotherapy.Can further improve therapeutic effect by chemotherapy as the auxiliary treatment of tumor with postoperative before the clinical trial certificate, art.Traditional chemotherapeutics is based on cytotoxic drug, and the research and development of antitumor drug have in recent years been made significant headway, and the medicine of many different mechanism of action continues to bring out, but still has some problems: as the solid tumor that accounts for tumor 90% still lacks effective medicine; The toxic and side effects of existing antitumor drug is big, selectivity is low and easily develop immunity to drugs etc.Tumor brings human harm and to the increasing the weight of day by day of social pressure, has also proposed stern challenge to medical circle, and it is imperative that exploitation has specific new type antineoplastic medicine.

Chinese patent application (application number: 200710060530.5) described acyl chlorides and sulfonyl chloride derivant, disclose general formula compound, its preparation method, contained their pharmaceutical composition and the purposes of preparation antibacterials, do not related to the new purposes of these materials in the description of this application at the preparation antitumor drug.

Summary of the invention

Acyl chlorides and sulfonyl chloride derivant and the new purposes of pharmaceutically acceptable salt aspect the preparation antitumor drug thereof have been an object of the present invention is to provide with general formula I structure.

Another object of the present invention provides the chemical compound that contains the general formula I structure or its pharmaceutically acceptable salt as effective ingredient, with the Pharmaceutical composition of one or more pharmaceutically acceptable carriers, excipient or diluent in the new purposes aspect the preparation antitumor drug.

Now content of the present invention is specifically described in conjunction with purpose of the present invention.

Compound of Formula I of the present invention has following structural formula:

Wherein:

X is: C=O; O=S=O;

N=0,1,2,3; Wherein:

When X is C=O, n=0,1,2,3; When X is O=S=O, n=0;

R ₁For:

Aryl contains the C of sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical, aryl and the heterocyclic radical (C that contains sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical);

By halogen, hydroxyl, carboxyl, amino, nitro, itrile group, C ₁-C ₆Alkoxyl, C ₁-C ₆Dialkyl amido, C ₃-C ₆Cycloalkyl, C ₃-C ₆Group list or polysubstituted aryl such as heterocyclic radical, aryl, substituted aryl;

By halogen, hydroxyl, carboxyl, amino, nitro, itrile group, C ₁-C ₆Alkoxyl, C ₁-C ₆Dialkyl amido, C ₃-C ₆Cycloalkyl, C ₃-C ₆Group list or the polysubstituted C that contain sulfur, oxygen, nitrogen heteroatom such as heterocyclic radical, aryl, substituted aryl ₃-C ₆Heterocyclic radical;

By halogen, hydroxyl, carboxyl, amino, nitro, itrile group, C ₁-C ₆Alkoxyl, C ₁-C ₆Dialkyl amido, C ₃-C ₆Cycloalkyl, C ₃-C ₆Group list or polysubstituted aryl and the heterocyclic radical (C that contain sulfur, oxygen, nitrogen heteroatom such as heterocyclic radical, aryl, substituted aryl ₃-C ₆Heterocyclic radical).

R ₂: be hydrogen, the single replacement or polysubstituted C ₁-C ₆Alkyl.

R ₃: replace or polysubstituted halogen for single.

R ₄: be C ₁-C ₆Alkyl is replaced or polysubstituted C by the halogen list ₁-C ₆Alkyl.

Preferred following compound of Formula I or its pharmaceutically acceptable salt, wherein:

R ₁For:

Phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furan, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, oxolane, benzofuran;

By fluorine, chlorine, bromine, hydroxyl, carboxyl, amino, nitro, itrile group, C ₁-C ₆Alkoxyl, C ₁-C ₆Dialkyl amido, C ₃-C ₆Cycloalkyl, C ₃-C ₆Group lists such as heterocyclic radical, aryl, substituted aryl or polysubstituted phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furan, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, oxolane, benzofuran.

R ₂: be hydrogen, list or polysubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl.

R ₃: replace or polysubstituted fluorine, chlorine for single.

R ₄: be methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl, perhaps by fluorine, the replacement of chlorine list or polysubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl.

More preferably following compound of Formula I or its pharmaceutically acceptable salt, wherein:

I-1:(±)-N-[[3-[3-fluoro-4-[4-(to the fluorophenethyl acyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-2:(±)-N-[[3-[3-fluoro-4-[4-(a fluorophenethyl acyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-3:(±)-N-[[3-[3-fluoro-4-[4-(adjacent fluorophenethyl acyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-4:(±)-N-[[3-[3-fluoro-4-[4-(chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-5:(±)-N-[[3-[3-fluoro-4-[4-(adjacent chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-6:(±)-N-[[3-[3-fluoro-4-[4-(to chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-7:(±)-N-[[3-[3-fluoro-4-[4-(3,5-dichloro-benzenes acetyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-8:(±)-N-[[3-[3-fluoro-4-[4-(O-methoxy benzoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-9:(±)-N-[[3-[3-fluoro-4-[4-(to the trifluoromethyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-10:(±)-N-[[3-[3-fluoro-4-[4-(a carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-11:(±)-N-[[3-[3-fluoro-4-[4-(2-chloropyridine-3-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-12:(±)-N-[[3-[3-fluoro-4-[4-(2-chloro-4-fluoro-5-carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-13:(±)-N-[[3-[3-fluoro-4-[4-(2,3-Dihydrobenzofuranes-5-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-14:(±)-N-[[3-[3-fluoro-4-[4-(adjacent fluorobenzene sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-15:(±)-N-[[3-[3-fluoro-4-[4-(5-bromothiophene-2-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-16:(±)-N-[[3-[3-fluoro-4-[4-(4-bromo-2,6-dichloro-benzenes sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-17:(±)-N-[[3-[3-fluoro-4-[4-(m-nitro sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-18:(±)-N-[[3-[3-fluoro-4-[4-(metanilyl base)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide.

I-19:(±)-N-[[3-[3-fluoro-4-[4-(2-chloropyridine-3-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide hydrochloride.

I-20:(±)-N-[[3-[3-fluoro-4-[4-(2-chloropyridine-3-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] the acetamide citrate.

I-21:(±)-N-[[3-[3-fluoro-4-[4-(a carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide potassium salt.

Pharmaceutically acceptable salt with general formula I structural compounds of the present invention means: The compounds of this invention and mineral acid, organic acid salify, particularly preferred salt is: hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate or the like.In addition, salt of the present invention can also be the salt that chemical compound and potassium hydroxide, sodium hydroxide form.

The preparation of pharmaceutical compositions of chemical compound of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid-carrier are combined, and make it at random to combine and be prepared into microgranule or microsphere with acceptable adjuvant and excipient on the galenic pharmacy.Peroral dosage form comprises tablet, dispersible tablet, chewable tablet, effervescent tablet, oral cavity disintegration tablet, capsule, granule, slow releasing tablet, slow-release micro-pill, drop pill etc.; Injection type comprises small-volume injection, bulk capacity injection, aseptic powder injection etc.Carrier can be the combination of a kind of material or multiple material, and it can serve as diluent, binding agent, disintegrating agent, lubricant, coating materials, correctives, sweeting agent, solubilizing agent, suspensoid, antiseptic and antibacterial etc.Diluent comprises calcium hydrogen phosphate, lactose, starch, mannitol, glucose, sucrose, dextrin calcium sulfate one or more combination thing; Binding agent comprises one or more combination things such as methylcellulose, hydroxypropyl methylcellulose, carmethose, polyvidone, Polyethylene Glycol (400-6000), gelatin, pectin, ethyl cellulose; Disintegrating agent comprises one or more combination things such as polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, carboxymethylstach sodium, low substituent methyl cellulose, microcrystalline Cellulose, Powderd cellulose; Lubricant or fluidizer comprise the one or more combination thing of stearic acid, magnesium stearate, calcium stearate, Pulvis Talci, silicon dioxide, Polyethylene Glycol, hydrogenated vegetable oil, polyoxyethylene monostearate; Coating materials comprises hydroxypropyl methylcellulose, polyvidone, crylic acid resin gastric solubleness and enteric, slow-release material; Correctives and sweeting agent comprise that A Siba is sweet, stevioside, protein sugar, essence, sucrose, sorbitol one or more combination thing; Solubilizing agent comprises anion or cationic surfactant, citric acid, arginine, trihydroxy methyl bromo-silicane, sodium lauryl sulphate, dodecyl sodium sulfate etc.; Suspensoid comprises methylcellulose, cross-linked carboxymethyl cellulose sodium, hydroxypropyl methylcellulose etc.; Antiseptic and antibacterial comprise propylene glycol, polyoxyethylene sorbitan monoleate, sodium benzoate, nipalgin, ethanol etc.

The application aspect the preparation antitumor drug of chemical compound of the present invention or its compositions.The amount of used chemical compound or concentration are regulated in the scope of a broad, and the weight range of reactive compound of the present invention is the 0.5%-99% of compositions, and preferred range is 0.5%-50%.The amount of pharmaceutical composition or the active ingredient that contains can be according to patient's the state of an illness, specific being applied of situation of diagnosis, these situations comprise: by the condition of therapist, route of administration, age, body weight, to the individual reaction of medicine, the order of severity of symptom etc.

Chemical compound of the present invention or its compositions can be applicable to treat colon cancer, leukemia, adenocarcinoma of stomach, breast carcinoma, oral cancer, pulmonary carcinoma, sarcoma, melanoma.

The specific embodiment:

The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.

Embodiment 1

100 in tablet

I-1 5.0g

Lactose 15.0g

Pregelatinized Starch 2.5g

Microcrystalline Cellulose 3.5g

Carboxymethylstach sodium 0.8g

10% povidone solution QS

Magnesium stearate QS

Pulvis Talci QS

Preparation technology: with active component and adjuvant crushing screening 100 orders in advance, take by weighing principal agent and add adjuvant lactose, pregelatinized Starch carboxymethylstach sodium and microcrystalline Cellulose and fully mix, cross 60 mesh sieves three times, add povidone solution, mix, the system soft material is crossed 20 mesh sieves, the system wet granular, after 50-60 ℃ of drying, add magnesium stearate and Pulvis Talci sieves in advance, join then fully mix in the above-mentioned granule after, measure midbody particle, tabletting.

Embodiment 2

100 of capsules

I-2 99.0g

Silica 1 .0g

Magnesium stearate QS

Preparation technology: active component was pulverized 100 mesh sieves, add adjuvant silicon dioxide, magnesium stearate mix homogeneously, and measured intermediate content, fill is in No. 4 capsules.

Embodiment 3

100 of dispersible tablets

I-3 20.0g

Lactose 20.0g

Microcrystalline Cellulose 5.0g

Polyvinylpolypyrrolidone 2.0g

Aspartame 0.2g

Fructus Citri tangerinae essence 0.2g

2% hypromellose QS

Silicon dioxide QS

Magnesium stearate QS

Preparation technology: active component is added adjuvant lactose, partial cross-linked polyvidone, microcrystalline Cellulose, aspartame and the Fructus Citri tangerinae essence abundant mix homogeneously that sieves, add 2% hypromellose solution, mix, the system soft material is crossed 24 mesh sieves, the system wet granular, after 50-60 ℃ of drying, 20 mesh sieve granulate.To remain after polyvinylpolypyrrolidone, magnesium stearate and Pulvis Talci sieve, join fully mix in the above-mentioned granule after, measure midbody particle, tabletting.

Embodiment 4

100 of oral cavity disintegration tablets

I-5 1.0g

Mannitol 19.0g

Microcrystalline Cellulose 19.0g

Cross-linked carboxymethyl cellulose sodium 1.0g

Magnesium stearate QS

Silicon dioxide QS

Preparation technology: principal agent and adjuvant are crossed 100 mesh sieves respectively, fully mix, adopt the roll squeezer cake of press, 18 mesh sieve granulate are crossed in the agent of reuse granulate, add magnesium stearate lubricant at last, the mix homogeneously tabletting.

Embodiment 5

100 of effervescent tablets

I-7 10.0g

Lactose 16.0g

Tartaric acid 5.0g

Sodium bicarbonate 6.0g

Maltose alcohol 0.5g

Fructus Citri Limoniae essence 0.5g

2% methylcellulose QS

Magnesium stearate QS

Pulvis Talci QS

Preparation technology: active component 5g is added adjuvant lactose 8g, tartaric acid, maltose alcohol, Fructus Citri Limoniae essence sieve, fully mix, add methylated cellulose aqueous solution, mix, the system soft material sieves, system wet granular A; Active component 5g added adjuvant lactose 8g again, fully mix with sodium bicarbonate, add methylated cellulose aqueous solution, mix, the system soft material sieves, system wet granular B.A, B granule be in 50-60 ℃ respectively after the drying, 18 mesh sieve granulate.Then magnesium stearate and Pulvis Talci are joined fully mix in the above-mentioned granule after, measure midbody particle, tabletting.

Embodiment 6

100 of chewable tablet

I-8 20.0g

Mannitol 25.0g

Sorbitol 3.0g

5% polyethylene glycol 6000 (50% ethanol) QS

Stevioside 0.5g

Pericarpium Citri junoris tincture 0.5g

Stearic acid QS

Preparation technology: active component was pulverized 100 mesh sieves, add adjuvant mannitol, sorbitol, stevioside and Pericarpium Citri junoris tincture, and fully mixed, and added 5% polyethylene glycol 6000 solution, mix, the system soft material is crossed 18 mesh sieves, the system wet granular, after 50-60 ℃ of drying, 18 mesh sieve granulate.Magnesium stearate and Pulvis Talci are sieved in advance, join then in the above-mentioned granule fully mix after, measure midbody particle, tabletting.

Embodiment 7

100 bags of granules

I-10 40.0g

Lactose 45.0g

Mannitol 14.0g

The sweet 0.05g of A Siba

Essence 0.05g

2% hypromellose (pure water preparation) QS

Preparation technology: principal agent and adjuvant are crossed 100 mesh sieves respectively, fully mix, take by weighing the recipe quantity adjuvant then and fully mix with principal agent.Add binding agent system soft material again, 14 mesh sieves are granulated, 55 ℃ of dryings, and 12 mesh sieve granulate are measured heavily packing of bag.

Embodiment 8

100 of enteric coatel tablets

Plain tablet recipe,

I-11 5.0g

Calcium hydrogen phosphate 8.0g

Pregelatinized Starch 1.0g

Hyprolose 0.5g

Carboxymethylstach sodium 0.5g

8% polyvidone QS

Magnesium stearate QS

Preparation technology is with embodiment 1.

The coating prescription:

Plain sheet 80.0g

Acrylic resin L100-55 15.0g

Pulvis Talci 3.0g

Titanium dioxide 1.5g

Triethyl citrate QS

95% ethanol adds to 145ml

Art for coating:

A, acrylic resin L100-55, titanium dioxide, Pulvis Talci, the triethyl citrate of recipe quantity be dissolved in 95% the ethanol, fully mixing.

B, the plain sheet of recipe quantity is placed coating pan, start air blast, making the sheet temperature is about 40 ℃, sprays into enteric coating with spray gun, and spray speed is 5ml/ minute, sprayed to enteric coating, and dry 1h, packing gets final product.

Embodiment 9

100 of enteric coated capsulees

I-13 5.0g

Lactose 15.0g

Pregelatinized Starch 4.5g

Hyprolose 2.0g

Carboxymethylstach sodium 1.5g

30% ethanol QS

Magnesium stearate QS

Preparation technology: with active component and lactose, pregelatinized Starch, hyprolose, carboxymethylstach sodium mix homogeneously, add binding agent 30% ethanol system soft material, crossing 20 mesh sieves granulates, 55 ℃ of dryings, 18 mesh sieve granulate, measure granule content, pack into enteric coated capsule or enteric coated back dress conventional capsule can be realized.

Get with example 2.

Embodiment 10

100 bottles of amounts of oral administration solution suspensoid

I-14 20.0g

Mannitol 16.0g

Sorbic acid 2.0g

Orange flavor essence 1.0g

Stevioside 1.0g

Nipalgin QS

Distilled water 1.0L

Preparation technology: get distilled water 0.8L, the sorbic acid, mannitol, orange flavor essence, stevioside, the sample that take by weighing recipe quantity stir and make dissolving, after the adding antiseptic, add water to full dose, and fill is in the 10ml bottle.

Embodiment 11

100 of slow releasing tablet

I-15 5.0g

Stearic acid 22.0g

River wax 12.0g

Hyprolose 1.0g

Magnesium stearate QS

Preparation technology: after the active component that takes by weighing recipe quantity adds stearic acid, river wax, the abundant mix homogeneously of hyprolose, after placing in 80 ℃ of water-baths heated and stirred fusion evenly, took out 20 mesh sieves and granulated, dried to room temperature, after adding the magnesium stearate mixing, press designation card weight sheet with special-shaped dashing.

Embodiment 12

100 of enteric-coated sustained-release tablets

I-16 2.0g

Lactose 15.0g

Ethyl cellulose 13.0g

2% hypromellose QS

Magnesium stearate QS

Pulvis Talci QS

Preparation technology: take by weighing active component and add lactose, ethyl cellulose mix homogeneously, add 2% hypromellose system soft material, cross 24 mesh sieves, 55 ℃ of oven dryings, dried granule 20 order granulate add the magnesium stearate mix homogeneously, and tabletting makes slow releasing tablet.Again according to the enteric coated enteric-coated sustained-release tablet that promptly gets of embodiment 8 prescriptions.

Embodiment 13

Slow releasing capsule

The pastille prescription:

I-17 100.0g

Lactose 20.0g

Microcrystalline Cellulose 50.0g

Starch 40.0g

Polyethylene glycol 6000 15.0g

Silicon dioxide 5.0g

Magnesium stearate 5.0g

50% ethanol QS

Preparation technology: with active component, lactose, microcrystalline Cellulose, starch mix homogeneously; the binding agent that adds the polyethylene glycol 6000 preparation; play female also pill-rolling to required order with comminutor (or coating pan) and count 15-30 order (pill-rolling limit, limit adds lubricant and fluidizer); oven dry is sifted out best 18-25 order as the pastille micropill.

The coating prescription:

Pastille micropill 150.0g

Acrylic resin RS100 20.0g

Acrylic resin RL100 2.0g

Triethyl citrate 3.0g

Pulvis Talci 12.0g

90% ethanol 250ml

Coating: the pastille micropill is placed fluid bed (or coating pan), make the temperature of micropill remain on 35 ℃-40 ℃.Acrylic resin is dissolved in the ethanol, adds triethyl citrate and Pulvis Talci again, stir, with the flow velocity of 5ml/min, the skin that is sprayed at the pastille micropill is made slow-release micro-pill.Measure content, the capsule different according to the different size fill.

Embodiment 14

Injection with small volume specification 1mg/ml

I-18 50.0mg

Sodium dihydrogen phosphate 15.0mg

Citric acid 35.0mg

Sodium chloride 50.0mg

Water for injection 50ml

Preparation technology: get water for injection 50ml, the citric acid, sodium dihydrogen phosphate, the sodium chloride that take by weighing recipe quantity stir and make dissolving, adding the principal agent stirring and dissolving, is 4.0-7.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the activated carbon adsorption of adding 0.1% 20 minutes.Filter reuse 0.22 μ m fine straining earlier with 0.45 μ m filter membrane.Press 1 milliliter of fill of per ampoule, 105 ℃ of high temperature sterilizes promptly got injection in 30 minutes.

Embodiment 15

Lyophilized preparation

I-19 5.0g

Poloxamer 1.0g

Sodium hydroxide 0.2g

Citric acid QS

Mannitol 23.0g

Lactose 20.0g

Water for injection 100ml

Preparation technology: get water for injection 80ml, add principal agent, mannitol, lactose, poloxamer stir make dissolving after, the citric acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100ml.Add the 0.5g active carbon, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal promptly.

Embodiment 16

Small injection

I-20 1.0g

Sodium pyrosulfite 3.0g

Sodium hydroxide 0.5g

Sodium bicarbonate QS

Water for injection 200ml

Preparation technology: get water for injection 100ml, add principal agent, sodium pyrosulfite, sodium bicarbonate stir make dissolving after, adding an amount of sodium hydroxide adjusting PH is 7.0-9.0, add water for injection to 200ml, add the 2g active carbon, stirring and adsorbing 30 minutes, carbon removal, fine straining, with every 2ml embedding, sterilization, promptly.

Embodiment 17

Primary infusion

I-21 25.0g

Tris 15.0g

Low molecular dextran 500.0g

EDTA-2Na 15.0g

Sodium bicarbonate QS

Water for injection 5000ml

Preparation technology: get water for injection 2000ml, add principal agent, Tris, low molecular dextran, EDTA-2Na stir make dissolving after, regulating PH with sodium bicarbonate is 7.0-9.0, add the 10g active carbon, 20-50 ℃ of following stirring and adsorbing 30 minutes, carbon removal, benefit adds water to 5000ml, fine straining, every bottle of 50ml of embedding, sterilization, promptly.

Embodiment 18

(1) material

Cell strain: colon cancer SW-480 cell, leukemia HL-60 cell, adenocarcinoma of stomach SGC-7901 cell, breast carcinoma MCF-7 cell, oral cancer KB cell, pulmonary carcinoma A-549 cell, all available from Shanghai cell research institute of the Chinese Academy of Sciences.

Reagent: MTT, Amresco packing, lot number: 04M0904; The DMEM culture medium, Gibco, lot number: 1290007; Calf serum, Lanzhou people's marine growth, lot number: 20080218; Trypsin, Amresco packing, lot number: 016B0604; Fluorouracil Injection, 0.25g/10ml (propping up), Tianjin gold credit aminoacid company limited, lot number: 0512022.

Instrument: superclean bench, Suzhou Decontamination Equipment Plant; CO ₂Incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert 200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Centrifuge, Kerdro company, model: Heraeus.

(2) method

Cell culture: tumor cell inoculation is containing 10% calf serum, in the DMEM culture fluid of 100IU/ml penicillin G sodium salt and 100ug/ml streptomycin sulfate, puts 37 ℃, 100% relative humidity, contains 5%CO ₂Incubator in, it is standby after 3 times to go down to posterity.

Mtt assay is measured: the cell of the trophophase of taking the logarithm, behind 0.25% trypsinization (suspension cell need not digest), be suspended in the DMEM culture fluid that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration living cells with the glass dropper.(cell concentration is adjusted into 8～10 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ l ⁴Individual/ml), at 37 ℃, 100% relative humidity, contain 5%CO ₂, 95% air incubator cultivate 24h after, every hole adds 10 μ l medicinal liquids (final concentration is made as: 40 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml and five concentration of 2.5 μ g/ml).In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), and each group is all established 6 multiple holes.Continuous culture 24h again, every then hole adds the MTT solution of 10 μ l 5mg/ml, and after continuing to cultivate 4h, the careful suction removed supernatant (suspension cell needs earlier centrifugally, inhales and removes supernatant).Every hole adds 100 μ l DMSO, puts the micro oscillator concussion so that crystallization is dissolved fully, and the single wavelength colorimetric of microplate reader 492nm is measured the OD value.Calculate inhibitory rate of cell growth as evaluation index with following method.

Suppression ratio (%)=[1-(experimental group OD average-blank group OD average)/(matched group OD average-blank group OD average)] * 100%.According to inhibitory rate of cell growth, calculate IC with the rectilinear regression method ₅₀Value.

(3) result

The IC of the tumor cell of table 1. pair In vitro culture ₅₀(μ g/ml)

(4) conclusion

From above-mentioned in vitro tests result as can be seen, acyl chlorides and sulfonyl chloride derivant with general formula I structure all have stronger inhibitory action to these 6 kinds of human cancer cells behind interaction in vitro 24h, wherein I-3, I-5, I-7, I-10, I-15, I-18, I-19 are to the IC of cell more than 3 kinds ₅₀Value is less than 20 μ g/ml.

Embodiment 19

(1) material

Cell strain: sarcoma S180 cell, melanin tumour b16 cell, all available from Shanghai cell research institute of the Chinese Academy of Sciences.

Positive control drug: cyclophosphamide, lot number: 07020121, Hengrui Medicine Co., Ltd., Jiangsu Prov..

Instrument: PB303-N type one thousandth electronic balance, Mettler Toledo Inc. produces.

Animal: kunming mice, C57BL/6 mice, the SPF level, male, body weight 18～22g purchases in Institute of Radiation Medicine, Chinese Academy of Medical Sciences, the quality certification number: SCXK (Tianjin) 2005-0001.

(2) method: get inoculation tumor strain 7 days, the tumor-bearing mice that tumor growth is good, aseptic condition operation, reject peplos and downright bad part, choose intact tumor piece, place in the glass homogenizer, add an amount of normal saline, be made into the oncocyte suspension, cell number is (1～2) * 10 ⁷/ ml is inoculated in mice right fore armpit subcutaneous (0.2ml/ Mus), and all operations is finished in 30min.To inoculate tumor liquid mice next day by the body weight random packet, i.e. lotus tumor matched group, cyclophosphamide group (25mg/kg), I-3 organizes (100mg/kg, 50mg/kg, 25mg/kg).The equal intraperitoneal injection of each administration group, once a day, matched group gives with the volume normal saline.Mice successive administration 10 days behind the last administration 24h, takes off cervical vertebra and puts to death, and peels off tumor, takes by weighing the heavy and the weight of animals of tumor, calculates and respectively organizes heavy meansigma methods of mouse tumor and suppression ratio.

Suppression ratio=[(the average tumor of the average tumor weight-experimental group of matched group is heavy)/average tumor of matched group is heavy] * 100%

(3) result

Table 2. pair S180 tumor-bearing mice tumor heavily reaches the influence (x ± sd) of suppression ratio

Annotate: compare with matched group ^*P＜0.01, ^*P＜0.05.

Table 3. pair B16 tumor-bearing mice tumor heavily reaches the influence (x ± sd) of suppression ratio

Annotate: compare with matched group ^*P＜0.01, ^*P＜0.05.

(4) conclusion

From above-mentioned animal vivo test result as can be seen, I-3 has certain inhibitory action to the tumor growth of S180 and B16 tumor-bearing mice, and is dose-dependence, wherein when 100mg/kg dosage intraperitoneal injection suppression ratio all greater than 40%.

Claims

1. the chemical compound or the purposes of its pharmaceutically acceptable salt aspect the preparation antitumor drug that have general formula I:

General formula I:

Wherein:

X is: C=O; O=S=O;

N=0,1,2,3; Wherein:

When X is C=O, n=0,1,2,3; When X is O=S=O, n=0;

R ₁For:

Phenyl contains the C of sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical, aryl also contains the C of sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical;

By fluorine, chlorine, bromine, carboxyl, amino, nitro, C ₁-C ₆Alkoxyl list or polysubstituted phenyl;

By halogen, carboxyl, amino, nitro, C ₁-C ₆Alkoxyl list or the polysubstituted C that contains sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical;

By halogen, carboxyl, amino, nitro, C ₁-C ₆Alkoxyl list or polysubstituted aryl also contain the C of sulfur, oxygen, nitrogen heteroatom ₃-C ₆Heterocyclic radical;

R ₂: be hydrogen;

R ₃: be halogen;

R ₄: be C ₁-C ₆Alkyl.

2. purposes as claimed in claim 1 is characterized in that compound of Formula I is selected from following chemical compound:

(±)-N-[[3-[3-fluoro-4-[4-(to the fluorophenethyl acyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(a fluorophenethyl acyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(adjacent chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(to chloro acetyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(3,5-dichloro-benzenes acetyl group)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(O-methoxy benzoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(a carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(2-chloro-4-fluoro-5-carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(2,3-Dihydrobenzofuranes-5-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(adjacent fluorobenzene sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(5-bromothiophene-2-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(4-bromo-2,6-dichloro-benzenes sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(m-nitro sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(metanilyl base)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide;

(±)-N-[[3-[3-fluoro-4-[4-(2-chloropyridine-3-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide hydrochloride;

(±)-N-[[3-[3-fluoro-4-[4-(2-chloropyridine-3-sulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] the acetamide citrate;

(±)-N-[[3-[3-fluoro-4-[4-(a carboxyl benzenesulfonyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide potassium salt.

3. purposes as claimed in claim 1 is characterized in that active ingredient is selected from the pharmaceutically acceptable salt of described formula I chemical compound, is and mineral acid, organic acid salify.

4. purposes as claimed in claim 1 is characterized in that active ingredient is selected from the pharmaceutically acceptable salt of described formula I chemical compound, is the salt that forms with potassium hydroxide, sodium hydroxide.

5. purposes as claimed in claim 3; it is characterized in that active ingredient is selected from the pharmaceutically acceptable salt of described formula I chemical compound, comprises hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, phosphate, acetate, propionate, butyrate, lactate, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate.

6. as arbitrary described purposes among the claim 1-5, it is characterized in that a kind of compound of Formula I or its pharmaceutically-acceptable salts and adjuvant form pharmaceutical composition, its content calculates at 0.5%-99% with part by weight.

7. the purposes described in claim 6 is characterized in that a kind of compound of Formula I or its pharmaceutically-acceptable salts and adjuvant form pharmaceutical composition, and its content calculates at 1%-50% with part by weight.

8. as arbitrary described purposes in the claim 6, it is characterized in that preparation of pharmaceutical compositions becomes oral formulations, its form is one of following dosage forms: tablet, capsule, granule, solution.

9. the purposes described in claim 8 is characterized in that preparation of pharmaceutical compositions becomes oral formulations, and its form is one of following dosage forms: dispersible tablet, oral cavity disintegration tablet, enteric coatel tablets, slow releasing tablet, chewable tablet, effervescent tablet, enteric coated capsule, slow releasing capsule.

10. as arbitrary described purposes in the claim 6, it is characterized in that preparation of pharmaceutical compositions becomes injection, its form is one of following dosage forms: little pin, transfusion, aseptic powder injection.

11. as arbitrary described purposes among the claim 1-5, its antitumor comprises colon cancer, leukemia, adenocarcinoma of stomach, breast carcinoma, oral cancer, pulmonary carcinoma, sarcoma, melanoma.