CN102838567B - Benzenesulfonyl piperazine compounds or benzoyl piperazine compounds, preparation methods and uses thereof - Google Patents

Abstract

The present invention relates to benzenesulfonyl piperazine compounds represented by a formula I or benzoyl piperazine compounds represented by a formula II, or pharmaceutically acceptable salts, solvates, stereoisomers or precursor drugs thereof, wherein various symbols are described in an instruction. The present invention further relates to preparation methods for the compounds, uses of the compounds in preparation of drugs for treatment and/or prevention of tumors and/or cancers, methods for treatment and/or prevention of tumors and/or cancers by using the compounds, and drug compositions containing the compounds having an effective treatment and/or prevention amount. The compounds of the present invention have characteristics of effective anticancer activity and low toxicity.

Description

A kind of benzene sulfonyl or benzoyl piperazine compounds and its production and use

Technical field

The present invention relates to a class benzene sulfonyl or benzoyl piperazine compounds; the invention still further relates to the method preparing described compound; described compound for the preparation of the purposes treated and/or prevented in the medicine of tumour and/or cancer, and comprises the pharmaceutical composition of described compound.

Background technology

Tumour, as the global disease of one, has become and has threatened people's health and survive, cause the important disease of human death to be planted.Treatment terminal cancer, mainly adopts amic therapy method at present clinically.But current used chemotherapeutics does not all have selectivity to cancer cells substantially, kills a large amount of normal cells while killing cancer cells yet, brings great damage to cancer patients's body and mind.

Molecular targeted therapy is a new way of selective therapy tumour, and molecular targeted agents is that the personalized treatment of cancer patients provides feasibility.People have found the protein procaspase-3 that a class is important in cell in recent years, and procaspase-3 activates as caspase-3 can cause cellular metabolism dead.Bibliographical information is (as Clin Cancer Research 2004,6807; PNAS 2001,6132) procaspase-3 concentration is than hundred times high in corresponding normal cell in multiple cancer cells, and illustrate that procaspase-3 can not be caspase-3 by activation in tumour cell, cancer cells not energy metabolism is dead, and is converted into tumour.Modern molecular pharmacology illustrates the mechanism of action of procaspase-3 in tumor development process, and the compound proposing to activate procaspase-3 can lure cancer cell death into as targeted molecular.

At present, all there is the research making the death of cancer cell start-up routine about caspase-3 both at home and abroad, but be scarcely out of swaddling-clothes, also there is no medicine listing truly.2006, the researchists such as Illinois, US university Paul professor J.Hergenrother screened and synthesize micromolecular compound PAC-1, and this molecule directly can activate Procaspase-3 and change caspase-3 into, thus starts apoptosis in cell.Can be killed in 23 hours after research shows cell acquisition PAC-1, this molecule is to the cancer cells of same person hundreds of times larger than the effect of non-cancerous tumor cell.

But after the researchists such as Paul professor J.Hergenrother report high dosage administration subsequently, PAC-1 has significant neurotoxic symptoms (main manifestations is for jumping, trembling and astasia etc.) to mouse.Mainly because PAC-1 can penetrate hemato encephalic barrier and produce sequestering action with the zine ion on nmda receptor and produce this type of symptom.Therefore design and synthesis PAC-1 derivative thus reduce neurotoxicity there is very strong application prospect.

Summary of the invention

The object of first aspect present invention is to provide a class benzene sulfonyl or benzoyl piperazine compounds.The object of a second aspect of the present invention is to provide the preparation method of described benzene sulfonyl or benzoyl piperazine compounds.The object of third aspect present invention is to provide described benzene sulfonyl or the purposes of benzoyl piperazine compounds in pharmacy.In addition, fourth aspect present invention providing package contains the pharmaceutical composition of benzene sulfonyl of the present invention or benzoyl piperazine compounds.

Put it briefly, first aspect present invention provides the compound of formula I or formula II:

Wherein,

A, B, C, D and E are carbon atom or nitrogen-atoms independently of one another; And

R, R1, R2, R3, R4 and R5 are selected from hydrogen atom, hydroxyl, halogen, C2-C6 alkenyl, C1-C6 alkyl, C1-C6 alkoxyl group, nitro, cyano group independently of one another, sulfoamido, amidino groups, carboxyl, amino, alkylamino radical, di alkylamino group, heterocycle amido, di alkylamino group straight chained alkyl, heterocycle amido straight chained alkyl

Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.

The compound of any one according to a first aspect of the present invention, wherein:

A, B, C, D and E are carbon atom independently of one another; And

R, R1, R2, R3, R4 and R5 are selected from hydrogen atom, hydroxyl, halogen, C2-C6 alkenyl, C1-C6 alkyl, C1-C6 alkoxyl group, nitro, cyano group independently of one another, sulfoamido, amidino groups, carboxyl, amino, alkylamino radical, di alkylamino group, heterocycle amido, di alkylamino group straight chained alkyl, heterocycle amido straight chained alkyl

Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.

Arbitrary described compound according to a first aspect of the present invention, it is following compound:

2-(4-(4-(4-methylpiperazine-1-yl) benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(4-morpholine base benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(p-toluenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(to chlorobenzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(4-((4-methylpiperazine-1-yl) methyl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine; With

2-(4-(4-(4-methylpiperazine-1-yl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine,

Or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.

Second aspect present invention provides the method preparing compound and pharmacologically acceptable salts thereof described in first aspect present invention formula I, and it comprises the following steps:

(1), under alkaline condition, make in organic solvent react with piperazine, generate with following formula Ib compound:

(2) in the basic conditions, Ib compound and ethyl chloroacetate are reacted, generate with following formula Ic compound:

(3) in organic solvent, hydrazine hydrate and formula Ic compound are reacted, generate with following formula Id compound:

(4) formula Id compound and formula in organic solvent, is made reaction, generates with compounds of Formula I:

(5) make formula I and acid-respons, obtain the corresponding salt of formula I,

Wherein each symbol is as described in any one of first aspect present invention.

Method according to a second aspect of the present invention described in any one, wherein said step (1) is carried out in a solvent, described solvent can be organic solvent, this organic solvent includes, but are not limited to methylene dichloride, toluene, benzene, tetrahydrofuran (THF) or its any two or more mixture.

Method according to a second aspect of the present invention described in any one, wherein said step (1) and (2) alkali used include, but not limited to triethylamine, salt of wormwood.

Method according to a second aspect of the present invention described in any one, wherein said step (3) and (4) are carried out in a solvent, two steps solvent used can be organic solvent independently of one another, this organic solvent each can include but not limited to methyl alcohol, ethanol independently, and preferred organic solvent is ethanol.

Second aspect present invention provides the method preparing compound and pharmacologically acceptable salts thereof described in first aspect present invention formula II, and it comprises the following steps:

(1), under alkaline condition, make in organic solvent with 2-(piperazine-1-base) acetic acid ethyl reaction, generate with following formula IIb compound:

(2) in organic solvent, hydrazine hydrate and formula IIb compound are reacted, generate with following formula IIc compound:

(3) formula IIc compound and formula in organic solvent, is made reaction, generates with Formula Il compound:

(4) make formula II compound and acid-respons, obtain the corresponding salt of formula II compound,

Wherein each symbol is as described in any one of first aspect present invention.

Method according to a second aspect of the present invention described in any one, wherein said step (1) is carried out in a solvent, described solvent can be organic solvent, this organic solvent includes, but are not limited to methylene dichloride, toluene, benzene, tetrahydrofuran (THF) or its any two or more mixture.

Method according to a second aspect of the present invention described in any one, wherein said step (1) alkali used includes, but not limited to triethylamine, salt of wormwood.

Method according to a second aspect of the present invention described in any one, wherein said step (2) and (3) are carried out in a solvent, two steps solvent used can be organic solvent independently of one another, this organic solvent each can include but not limited to methyl alcohol, ethanol independently, and preferred organic solvent is ethanol.

In an embodiment of method described in second aspect present invention, the synthetic route of described formula I is as follows:

In an embodiment of method described in second aspect present invention, the synthetic route of described formula II compound is as follows:

Method according to a second aspect of the present invention described in any one, wherein said each raw material or intermediate are commercially available, or those skilled in the art can obtain according to existing knowledge synthesis.

Third aspect present invention provides compound described in any one of first aspect present invention for the preparation of the purposes treated and/or prevented in the medicine of tumour and/or cancer.

Purposes according to a third aspect of the invention we, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:

Malignant tumour, includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney liver cancer, lung cancer (comprising minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);

Lymphoid hematopoetic tumor, includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myelomatosis and Brukett`sShi lymphatic cancer;

The hematopoetic tumor of marrow system, includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;

The tumour of the interstitial origin cause of formation, includes but not limited to fibrosarcoma and rhabdosarcoma;

The tumour of maincenter and peripheral nervous system, comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And

Other tumours, include but not limited to melanoma, spermocytoma, teratoma, osteosarcoma, exophytic look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.

Fourth aspect present invention is provided in the method treating and/or preventing tumour and/or cancer in experimenter in need, and described method comprises described experimenter's administering therapeutic and/or prevents compound described in any one of first aspect present invention of significant quantity.

Method according to a forth aspect of the invention, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:

Malignant tumour, includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney liver cancer, lung cancer (comprising minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);

Lymphoid hematopoetic tumor, includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myelomatosis and Brukett`sShi lymphatic cancer;

The hematopoetic tumor of marrow system, includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;

The tumour of the interstitial origin cause of formation, includes but not limited to fibrosarcoma and rhabdosarcoma;

The tumour of maincenter and peripheral nervous system, comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And

Other tumours, include but not limited to melanoma, spermocytoma, teratoma, osteosarcoma, exophytic look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.

Fifth aspect present invention provides a kind of pharmaceutical composition, it comprise treat and/or prevent significant quantity any one of first aspect present invention described in compound and the acceptable thinner of optional pharmacy, carrier, vehicle, auxiliary material or vehicle.

Pharmaceutical composition according to a fifth aspect of the invention, it can be used for treating and/or preventing tumour and/or cancer.Pharmaceutical composition according to a fifth aspect of the invention, wherein said tumour and/or cancer can be medically known any tumour and/or cancer.Preferably, described tumour and/or cancer include but not limited to:

Malignant tumour, includes but not limited to bladder cancer, mammary cancer, colorectal carcinoma, kidney liver cancer, lung cancer (comprising minicell lung, non-small cell carcinoma), head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma (comprising squamous cell carcinoma);

Lymphoid hematopoetic tumor, includes but not limited to leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myelomatosis and Brukett`sShi lymphatic cancer;

The hematopoetic tumor of marrow system, includes but not limited to acute and chronic granulocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia;

The tumour of the interstitial origin cause of formation, includes but not limited to fibrosarcoma and rhabdosarcoma;

The tumour of maincenter and peripheral nervous system, comprises astrocytoma, becomes neurofibroma, neurospongioma and schwannoma; And

Other tumours, include but not limited to melanoma, spermocytoma, teratoma, osteosarcoma, exophytic look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.

Be further described with feature to various aspects of the present invention below.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

Term used herein " alkyl " refers to comprise and specifies number the straight chain of carbon atom and the saturated hydrocarbyl of side chain, is such as methyl, ethyl usually, and linear propyl, butyl, amyl group, hexyl etc.Term " alkyl " also comprises cycloalkyl, i.e. ring-type C3-C6 alkyl, as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferably, term used herein " alkyl " refers to comprise and specifies number the straight chain of carbon atom and the chain-like alkyl of side chain.When not specifying number, refer to comprise 1-6 carbon atom.

Term used herein " thiazolinyl " refers to comprise and specifies number the straight chain of carbon atom and the alkylene of side chain, usually is such as vinyl, allyl group, propenyl, and straight chain and side chain comprise one or more double bond and double bond is positioned at the butenyl, pentenyl, hexenyl etc. of any feasible location.When not specifying number, refer to comprise 1-6 carbon atom.

Term used herein " alkoxyl group " is independent or combining middle finger alkyl ether groups, wherein term " alkyl " the same definition.The example of suitable alkoxy base includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy etc.

Term used herein " alkylamino radical " refers to the amido including monosubstituted alkyl, wherein term " alkyl " the same definition.Usually such as methylamino, ethylamino-, sec.-propyl amido etc.

Term used herein " di alkylamino group " refers to the amido including two substituted alkyls, wherein term " alkyl " the same definition.Usually such as dimethylin, diethylin, diisopropyl amido etc.

Term used herein " heterocycle amido " refers to have structure shown in following formula:

Wherein: X is C, O, NH or alkyl replacement N, n is 0-3; Usually such as piperidin-1-yl, piperazine-1-base, homopiperazine-1-base, morpholine-1-base or its corresponding alkyl replace N compound such as 4-methylpiperazine-1-yl, 4-methylhomopiperazin-1-base etc.Wherein term " alkyl " the same definition.

Term used herein " di alkylamino group straight chained alkyl " refers to have structure shown in following formula:

Wherein: X ₁and X ₂for alkyl, m is 1-6; Usually such as dimethylamino methyl, diethylin ethyl etc.Wherein term " alkyl " the same definition.

Term used herein " heterocycle amido straight chained alkyl " refers to have structure shown in following formula:

Wherein: X is that to replace N, n be 0-3, m is 1-6 for C, O, NH or alkyl; Usually such as (piperidin-1-yl) methyl, (piperazine-1-base) methyl, (homopiperazine-1-base) ethyl, (morpholine-1-base) ethyl or its corresponding alkyl replace N compound such as (4-methylpiperazine-1-yl) methyl, (4-methylhomopiperazin-1-base) ethyl etc.Wherein term " alkyl " the same definition.

Term used herein " halogen " is defined as in this article and comprises fluorine, chlorine, bromine or iodine, can also comprise their isotropic substance.

The various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also instruction preparation the inventive method according to the present invention can fail other formula I of containing and formula II compound.

Formula I and formula II compound can exist by stereoisomer form.The present invention includes all possible steric isomer, namely along or the mixture of anti-single stereoisomers or the two any required ratio.Contemplated by the invention purified form and the mixed form of all this isomer (such as enantiomer and diastereomer), comprise racemic mixture.Enol forms is also included within the scope of the invention.

Formula I and formula II compound both can itself also can the form of its pharmacologically acceptable salts or solvate use.The pharmacologically acceptable salts of formula I and formula II compound comprises the conventional salt formed with pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases.The example of suitable acid salt comprises with hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt that acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, tannic acid etc. formed.Pharmaceutical salts comprises its inorganic or organic acid salt, comprising but be not limited to: hydriodate, hydrosulfate, hydrophosphate, butyrates, oxalate, pivalate, adipate, alginate, picrate, aspartate, gluconate, esilate, tosilate, embonate, pyruvate salt, glycollate, trifluoroacetate, para-aminosalicylic acid salt, embonate, pyruvate salt, glycollate, trifluoroacetate, para-aminosalicylic acid salt, pamoate and ascorbate salt etc.The example of suitable base addition salt comprises the salt formed with sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N`-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, N-METHYL-ALPHA-L-GLUCOSAMINE and PROCAINE HCL, PHARMA GRADE etc.When relating to the compounds of this invention herein, comprise formula I and formula II compound and pharmacologically acceptable salts thereof or solvate.The compounds of this invention free alkali form and their respective salt forms upper slightly different in some physical properties (solubleness as in polar solvent), but for the object of the invention, each acid salt and they free alkali form is suitable separately.See such as S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977), it is incorporated to herein by reference.

Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount, those skilled in the art similarly can understand according to this explanation the implication that " pharmaceutical composition " has, and " composition " and " pharmaceutical composition " can exchange use in some cases.According to the difference of administering mode, in the present composition, can weight ratio 0.1% be contained, or the active ingredient of more suitably weight ratio 10-60%.But when comprising unitary dose in component, each unit preferably comprises 1-500 milligram activeconstituents.

Compound of the present invention can use with the form derived from mineral acid or organic acid pharmacologically acceptable salts.Word " pharmacologically acceptable salts " refers within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977), has wherein been described in detail pharmacologically acceptable salts.Described salt by the free alkali functionality of the compounds of this invention and suitable organic acid reaction, in the final abstraction and purification process of the compounds of this invention, original position preparation or prepare separately.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, Basic nitrogen-containing groups can be quaternized with following material; Elementary alkyl halide is as the muriate of methyl, ethyl, propyl group and butyl, bromide and iodide; Dialkyl sulfate is as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long chain halide is as the muriate of decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halide as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to be formed the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid is as oxalic acid, toxilic acid, succsinic acid and citric acid.

Base addition salt by make the compounds of this invention containing carboxylic moiety and suitable alkali reaction, in the final abstraction and purification process situ preparation of the compounds of this invention, the oxyhydroxide of the acceptable metallic cation of described alkali such as pharmacy, carbonate and supercarbonate, or ammonia or organic primary amine, secondary amine or tertiary amine.

Pharmacologically acceptable salts includes but not limited to that positively charged ion based on basic metal or alkaline-earth metal is as lithium, sodium, potassium, calcium, magnesium and aluminium salt etc., and nontoxic quaternary amine and amine positively charged ion, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other the representative organic amines that can be used for being formed base addition salt comprise quadrol, thanomin, diethanolamine, piperidines, piperazine etc.

Formula I and formula II compound or its pharmacologically acceptable salts can also form solvate, such as hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that can discharge described activeconstituents in vivo after metabotic change.Selecting and preparing suitable front derivative is technology as well known to those skilled in the art.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.

The dosage form giving the compounds of this invention for local comprises powder, sprays, ointment and inhalation.Aseptically by active compound and pharmaceutically acceptable carrier and any sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, Eye ointments, powder and solution are also considered within the scope of the present invention.

When for above-mentioned treatment or other treatment, a kind of the compounds of this invention for the treatment of significant quantity can be applied in a pure form, or with pharmacologically acceptable salts, ester or prodrug forms (when there are these forms) application.Or described compound can with the pharmaceutical composition administration containing this object compound and the acceptable vehicle of one or more pharmacy.The compounds of this invention of word " treatment significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any therapeutic treatment.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until required effect.In general, the compounds of this invention is used for the dosage of Mammals particularly people can between 0.0001 ~ 1000mg/kg body weight/day, such as between 0.001 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.

Contriver finds, formula I and the formula II compound of novelty provided by the invention have effective antitumour and/or antitumour activity.On this basis, the invention provides a kind of method treating and/or preventing tumour and/or cancer in experimenter in need, described method comprises to the method treating and/or preventing tumour and/or cancer in described experimenter, and described method comprises to the I described in any one of first aspect present invention of described experimenter's administering therapeutic significant quantity and formula II compound or its pharmacologically acceptable salts, solvate, steric isomer or prodrug.Term " experimenter refers to the animal suffering from and maybe will suffer from and maybe may suffer from tumour of the present invention and/or cancer, preference as vertebrates, more preferably such as Mammals, more more preferably particularly such as people.Term " treatment significant quantity " is a kind of dosage, can produce the physiologic response of expectation after it is applied to this experimenter, particularly produces the physiologic response for tumour of the present invention and/or related to cancer.

The present invention goes back the pharmaceutical composition of providing package containing the compounds of this invention optionally formulated together with the acceptable thinner of one or more non-toxic pharmaceutical, carrier, vehicle, auxiliary material or vehicle.Described pharmaceutical composition can to become with solid or liquid form is for oral administration, for parental injection or for rectal administration by particular formulation especially.

Pharmaceutical composition of the present invention by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, locally (as by powder, ointment or drops), mouth cheek give the mankind and other Mammalss, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.

In yet another aspect, the invention provides and comprise the pharmaceutical composition that present component and physiology can tolerate thinner.One or more above-claimed cpds are comprised in invention, it can tolerate with one or more nontoxic physiology or be mixed with composition together with acceptable thinner, carrier, auxiliary material or vehicle (they being referred to as thinner herein), for transmitting in parental injection, nose, with solid or liquid form oral administration, rectum or topical etc.

The composition being suitable for parental injection can comprise physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion agent, suspensoid or emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester as ethyl oleate and their suitable mixture.

These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agent and anti-mycotic agent, as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., the effect preventing microorganism can be determined.Also comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Such as, by using the material that can postpone to absorb, aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.

Also suspension agent can be contained in addition to the active compound, the mixture etc. of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, Microcrystalline Cellulose, partially aluminium hydroxide, wilkinite, agar and Huang work glue or these materials in suspensoid.

In some cases, be the action time of prolong drug, expect absorption that is subcutaneous or intramuscular injection medicine of slowing down.This realizes by using the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.

Injectable depot formulations is by preparing at the microcapsule matrix of biodegradable polymer as formed medicine in polylactide-polyglycolide (polylatide-polyglycolide).According to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopted, drug releasing rate can be controlled.The example of other biological degradable polymer also comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can be prepared in the liposome compatible with bodily tissue or micro emulsion by pharmaceutical pack being embedded in.

Injectable agent can such as by filtering with bacteriological filtration bacterial filter or carrying out sterilizing by the disinfectant mixing aseptic solid composite form, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.

Capsule, tablet, pill, powder and granule is comprised for the solid dosage that can take administration.In this type of solid dosage, active compound can with the acceptable vehicle of the pharmacy of at least one inertia or carrier as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material mix: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silica gel; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) heat preserving agent is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agents is as paraffin; F) accelerator is absorbed as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, described formulation also can comprise buffer reagent.

The solids composition of similar type uses excipients as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.

Tablet, dragee (dragees), capsule, pill with bag and can be prepared with the solid dosage of granule together with shell material other clothing materials as known in enteric coating material and pharmaceutical preparation.These solid dosages optionally can contain opalizer, and its composition can make its just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into microencapsulated form with one or more above-mentioned vehicle.

Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form is except the inert diluent also can commonly used containing this area containing active ingredient beyond the region of objective existence, such as water or other solution, the fat of solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, EtOAc, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcochol), polyoxyethylene glycol and glue sorbyl alcohol and acid esters and their mixture.Oral compositions also can comprise auxiliary material except comprising inert diluent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent.

Composition for rectum or vagina administration is preferably suppository.Suppository is prepared by being mixed with suitable non-irritating excipient or carrier such as theobroma oil, polyoxyethylene glycol or suppository wax by the compounds of this invention, they are at room temperature solid, but be then liquid under body temperature, therefore can rectal cavity or intravaginal fusing and discharge active compound.

The compounds of this invention also can liposomal form administration.Well known in the art, liposome obtains with phosphatide or other lipid materials usually.Liposome formed by the single or multiple lift water liquid crystal be scattered in water-bearing media.Any nontoxic, physiology that can form liposome can to accept and metabolizable lipid all can use.The present composition of liposomal form, except containing except the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is phosphatide that is natural and that synthesize and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method forming liposome is well known in the art.See such as Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.

Term used herein " the acceptable front salt of pharmacy " represents the prodrug of the compounds of this invention, it is suitable for the mankind and zootic contact tissue and does not occur excessive toxicity, stimulation, anaphylaxis etc. within the scope of reliable medical judgment, match with rational effect/Hazard ratio and to its intended purpose effectively, also represent the zwitterionic form of the compounds of this invention in the conceived case.Prodrug of the present invention can such as by being hydrolyzed and being rapidly converted into above-mentioned parent compound in vivo in blood.Discuss fully and be provided in T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, V.14of the A.C.S.Symposium Series and Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), it is incorporated to herein by reference.

I of the present invention and formula II compound, also comprise the pharmaceutical composition formed by them certainly, is useful in antitumor and/or cancer.

The present inventor has carried out the research of antitumor/antitumour activity test to formula I provided by the invention and formula II compound, result shows, formula I of the present invention and formula II compound optionally can kill cancer cells, there is very strong antitumour activity, and can the growth of Tumor suppression, there is the feature that neurotoxicity is low simultaneously.Compared with other cancer therapy drug, demonstrate the advantages such as there is efficient and hypotoxicity simultaneously.

Accompanying drawing explanation

Fig. 1 is that the embodiment of the present invention 1 compound is on the impact of NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, embodiment 1 (80 μMs), embodiment 1 (60 μMs), embodiment 1 (40 μMs), embodiment 1 (20 μMs), embodiment 1 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 1 compound has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 2 is that the embodiment of the present invention 2 compound is on the impact of NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, embodiment 2 (80 μMs), embodiment 2 (60 μMs), embodiment 2 (40 μMs), embodiment 2 (20 μMs), embodiment 2 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 2 compound has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 3 is that the embodiment of the present invention 3 compound is on the impact of NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, embodiment 3 (80 μMs), embodiment 3 (60 μMs), embodiment 3 (40 μMs), embodiment 3 (20 μMs), embodiment 3 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 3 compound has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 4 is that the embodiment of the present invention 4 compound is on the impact of NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, embodiment 4 (80 μMs), embodiment 4 (60 μMs), embodiment 4 (40 μMs), embodiment 4 (20 μMs), embodiment 4 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 4 compound has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 5 is that the embodiment of the present invention 5 compound is on the impact of NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, embodiment 5 (80 μMs), embodiment 5 (60 μMs), embodiment 5 (40 μMs), embodiment 5 (20 μMs), embodiment 5 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 5 compound has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 6 is PAC-1 (according to the preparation of the patent WO2008134474A2 method) impact on NCI-H460 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 60 μMs, 40 μMs, 20 μMs are positive control, PAC-1 (80 μMs), PAC-1 (60 μMs), PAC-1 (40 μMs), PAC-1 (20 μMs), PAC-1 (10 μMs).Ordinate is cell survival rate (%).

Experimental result shows, PAC-1 has obvious restraining effect to NCI-H460 Growth of Cells.

Fig. 7 is that the embodiment of the present invention 1 compound is on the impact of HCT-116 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 30 μMs, 20 μMs, 10 μMs are positive control, embodiment 1 (80 μMs), embodiment 1 (60 μMs), embodiment 1 (40 μMs), embodiment 1 (20 μMs), embodiment 1 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 1 compound has obvious restraining effect to HCT-116 Growth of Cells.

Fig. 8 is that the embodiment of the present invention 6 compound is on the impact of HCT-116 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 30 μMs, 20 μMs, 10 μMs are positive control, embodiment 6 (80 μMs), embodiment 6 (60 μMs), embodiment 6 (40 μMs), embodiment 6 (20 μMs), embodiment 6 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, embodiment 6 compound has obvious restraining effect to HCT-116 Growth of Cells.

Fig. 9 is PAC-1 (according to the preparation of the patent WO2008134474A2 method) impact on HCT-116 cell survival rate.In figure, X-coordinate is the treatment time, 24h, 48h, 72h tri-time points respectively, each time point has ten cylindricalitys, from left to right represents respectively: blank, DMSO contrast, the cis-platinum of 30 μMs, 20 μMs, 10 μMs are positive control, PAC-1 (80 μMs), PAC-1 (60 μMs), PAC-1 (40 μMs), PAC-1 (20 μMs), PAC-1 (10 μMs).Ordinate is cell survival rate (%).Experimental result shows, PAC-1 has obvious restraining effect to HCT-116 Growth of Cells.

Embodiment

Further illustrate the present invention below by specific embodiment and/or test example, but should be understood to, these embodiments and/or test example are only used for the use specifically described more in detail, and should not be construed as and limit the present invention in any form.

The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art.

The preparation of embodiment 1,2-(4-(4-(4-methylpiperazine-1-yl) benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room-temperature water bath, in reaction flask, add piperazine (25.8g, 0.3mol) and DCM (50ml), stir and solid is dissolved gradually, form suspension.Then p-bromobenzenesulfonyl chloride (25.5g is slowly dripped, DCM (50ml) 0.1mol), 30min is stirred again after dropwising, TLC monitoring reaction terminates, then tap water (50ml) washing is added once, separate DCM layer, water layer DCM (50ml) extraction, separates, merge DCM layer, revolve and boil off except DCM, separate out solid, solids with methanol (30ml) is substantially clearly molten, slowly drip tap water (100ml) afterwards, have a large amount of solid to separate out, filter, filter cake water rinses.Infrared drying, obtains white solid thing 24g; Productive rate: 80%.Mass spectrum: 306 (M+1).

Step 2. adds compound 1 (22.5g in reaction flask, 73.7mmol), N-Methyl pyrrolidone (110ml) and N methyl piperazine (22.5g, 225mol), stirring at room temperature makes solid all dissolve, then reaction flask is put into oil bath, balloon seals, and is warmed up to 170 DEG C of isothermal reactions until raw material disappears.React and react end in 15 hours later, be cooled to room temperature, then pour in the beaker of 1L, add DCM (100ml), stir, and then add tap water (500ml), extraction, separate DCM layer, water layer DCM (2*100ml) extracts secondary, separate DCM layer, merge, wash four times with tap water (4*500ml), separate DCM layer, anhydrous magnesium sulfate drying (5g), filter, a small amount of DCM washing of filter cake, merges DCM, concentrated by rotary evaporation obtains faint yellow solid 17g, productive rate: 71.2%.Mass spectrum: 325 (M+1).

Step 3. adds compound 2 (17.6g, 54mmol), DCM (50ml), triethylamine (6.54g, 64.8mmol) and ethyl chloroacetate (7.27g, 59.4mmol) in reaction flask.Stir, be then warmed up to 40 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, occur a small amount of floss in reaction solution, silicon bath soil filters, filter cake DCM washs, merge DCM, wash three times, then separate DCM, anhydrous magnesium sulfate drying, filter, filtrate concentrates, and obtains pale brown oil thing 19g; Productive rate: 85.5%.Mass spectrum: 411 (M+1).

Step 4. adds compound 3 (19g, 46mmol), methyl alcohol (20mmol) and 80% hydrazine hydrate (8.63g, 138mmol) in reaction flask.Stir, then 60 DEG C of back flow reaction 8 hours are warmed up to, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, DCM (50ml) is added in raffinate, tap water (80ml) washing once, separate DCM layer, water layer uses DCM (2*50ml) to wash secondary again, separate DCM layer, merge, anhydrous MgSO4 is dry, filter, the a small amount of DCM washing of filter cake, concentrate and obtain white solid brown oil and the raffinate 15g deposited, oily matter silica column purification (eluent DCM: MeOH=10: 1 to DCM: MeOH=5: 1) obtains white solid 6.8g, yield: 37%.Mass spectrum: 397 (M+1).

Step 5. adds compound 4 (6.8g, 17.1mmol), ethyl acetate (15ml) and 2-hydroxyl-3-allyl benzene formaldehyde (2.78g, 17.1mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete, after reaction terminates, drips normal hexane until muddiness, cooling crystallization.Filter, drain, EtOH/n-Hexane recrystallization used again by filter cake.Obtain white solid 2-(4-(4-(4-methylpiperazine-1-yl) benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 6g, yield: 65%.Hydrogen spectrum (400MHz, DMSO): 11.92 (s, 1H); 11.45 (s, 1H); 8.46 (s, 1H); 7.51 (m, 2H); (7.0-7.25 m, 6H); (6.86 m, 1H); (5.99 m, 1H); (5.02 m, 2H); (3.33 m, 8H); (3.15 s, 2H); (2.91 s, 4H); (2.1-2.4 m, 7H).Mass spectrum: 541 (M+1), 563 (M+23).

The preparation of embodiment 2,2-(4-(4-morpholine base benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Step 1. adds (3.05g in reaction flask, 10mmol) compound 1 (preparation method is shown in embodiment 1), N-Methyl pyrrolidone (10ml) and morpholine (2.61g, 30mol), stirring at room temperature makes solid all dissolve, then reaction flask is put into oil bath, balloon seals, and is warmed up to 170 DEG C of isothermal reactions until raw material disappears.React and react end in 15 hours later, be cooled to room temperature, then pour in the beaker of 50ml, add DCM (10ml), stir, and then add tap water (100ml), extraction, separates DCM layer, washs four times with tap water (4*20ml), separate DCM layer, anhydrous magnesium sulfate drying (2g), filter, the a small amount of DCM washing of filter cake, merge DCM, concentrated by rotary evaporation obtains faint yellow solid 2.32g, productive rate: 74.3%.Mass spectrum: 312 (M+1).

Step 2. adds compound 2 (2.18g, 7mmol), DCM (10ml), triethylamine (0.85g, 8.4mmol) and ethyl chloroacetate (0.857g, 7mmol) in reaction flask.Stir, be then warmed up to 40 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, and after reaction terminates, silicon bath soil filters, filter cake DCM washs, and merges DCM, washes three times, then separate DCM, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, and obtains pale brown oil thing 2.23g; Productive rate: 80%.Mass spectrum: 398 (M+1).

Step 3. adds compound 3 (1.985g, 5mmol), methyl alcohol (10mmol) and 80% hydrazine hydrate (0.937g, 15mmol) in reaction flask.Stir, then 60 DEG C of back flow reaction 8 hours are warmed up to, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, add DCM (50ml) in raffinate, tap water (80ml) washing once, separates DCM layer, water layer uses DCM (2*50ml) to wash secondary again, separate DCM layer, merge, anhydrous MgSO4 is dry, filter, the a small amount of DCM washing of filter cake, concentrate and obtain brown oil, oily matter silica column purification (eluent DCM: MeOH=10: 1 to DCM: MeOH=5: 1) obtains white solid 0.672g; Yield: 35%.Mass spectrum: 384 (M+1).

Step 4. adds compound 4 (0.574g, 1.5mmol), dehydrated alcohol (3ml) and 2-hydroxyl-3-allyl benzene formaldehyde (0.243g, 1.5mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete, after reaction terminates, drips normal hexane until muddiness, cooling crystallization.Filter, drain, EtOH/n-Hexane recrystallization used again by filter cake.Obtain white solid 2-(4-(4-morpholine base benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 6g, yield: 60%.Mass spectrum: 528 (M+1).

The preparation of embodiment 3,2-(4-(p-toluenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room-temperature water bath, in reaction flask, add piperazine (25.8g, 0.3mol) and DCM (50ml), stir and solid is dissolved gradually, form suspension.Then Tosyl chloride (25.5g is slowly dripped, DCM (50ml) 0.1mol), 30min is stirred again after dropwising, TLC monitoring reaction terminates, then tap water (50ml) washing is added once, separate DCM layer, water layer DCM (50ml) extraction, separates, merge DCM layer, revolve and boil off except DCM, separate out solid, solids with methanol (30ml) is substantially clearly molten, slowly drip tap water (100ml) afterwards, have a large amount of solid to separate out, filter, filter cake water rinses.Infrared drying, obtains white solid thing 24g; Productive rate: 80%.Mass spectrum: 241 (M+1).

Step 2. adds compound 1 (7.2g, 30mmol), DCM (30ml), triethylamine (3.64g, 36mmol) and ethyl chloroacetate (3.67g, 30mmol) in reaction flask.Stir, be then warmed up to 40 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, and after reaction terminates, silicon bath soil filters, filter cake DCM washs, and merges DCM, washes three times, then separate DCM, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, and obtains pale brown oil thing 8.8g; Productive rate: 90%.Mass spectrum: 327 (M+1).

Step 3. adds compound 2 (6.52g, 20mmol), methyl alcohol (20mmol) and 80% hydrazine hydrate (3.75g, 60mmol) in reaction flask.Stir, be then warmed up to 60 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, adds DCM (20ml) in raffinate, once, separate DCM layer, water layer uses DCM (2*10ml) to wash secondary again in tap water (30ml) washing, separate DCM layer, merge, anhydrous MgSO4 is dry, filters, the a small amount of DCM washing of filter cake, concentrates and obtains brown oil 5g; Yield: 80%.Mass spectrum: 313 (M+1).

Step 4. adds compound 3 (5g, 16mmol), dehydrated alcohol (15ml) and 2-hydroxyl-3-allyl benzene formaldehyde (2.6g, 16mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete, after reaction terminates, drips normal hexane until muddiness, cooling crystallization.Filter, drain, EtOH/n-Hexane recrystallization used again by filter cake.Obtain white solid 2-(4-(p-toluenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 6.2g, yield: 85%.

Mass spectrum: 457 (M+1).

The preparation of embodiment 4,2-(4-(benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room-temperature water bath, in reaction flask, add piperazine (25.8g, 0.3mol) and DCM (50ml), stir and solid is dissolved gradually, form suspension.Then benzene sulfonyl chloride (17.6g is slowly dripped, DCM (50ml) 0.1mol), 30min is stirred again after dropwising, TLC monitoring reaction terminates, then tap water (50ml) washing is added once, separate DCM layer, water layer DCM (50ml) extraction, separates, merge DCM layer, revolve and boil off except DCM, separate out solid, solids with methanol (30ml) is substantially clearly molten, slowly drip tap water (100ml) afterwards, have a large amount of solid to separate out, filter, filter cake water rinses.Infrared drying, obtains white solid thing 20g; Productive rate: 88%.Mass spectrum: 227 (M+1).

Step 2. adds compound 1 (11.3g, 50mmol), DCM (50ml), triethylamine (6.06g, 60mmol) and ethyl chloroacetate (6.13g, 50mmol) in reaction flask.Stir, be then warmed up to 40 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, and after reaction terminates, silicon bath soil filters, filter cake DCM washs, and merges DCM, washes three times, then separate DCM, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, and obtains pale brown oil thing 12g; Productive rate: 76.9%.Mass spectrum: 313 (M+1).

Step 3. adds compound 2 (9.39g, 30mmol), methyl alcohol (30mmol) and 80% hydrazine hydrate (5.63g, 90mmoD in reaction flask.Stir, be then warmed up to 60 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, adds DCM (20ml) in raffinate, once, separate DCM layer, water layer uses DCM (2*10ml) to wash secondary again in tap water (30ml) washing, separate DCM layer, merge, anhydrous MgSO4 is dry, filters, the a small amount of DCM washing of filter cake, concentrates and obtains brown oil 7.6g; Yield: 85%.Mass spectrum: 299 (M+1).

Step 4. adds compound 3 (5.96g, 20mmol), dehydrated alcohol (20ml) and 2-hydroxyl-3-allyl benzene formaldehyde (3.24g, 20mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete, after reaction terminates, drips normal hexane until muddiness, cooling crystallization.Filter, drain, EtOH/n-Hexane recrystallization used again by filter cake.Obtain white solid 2-(4-(benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 7.51g, yield: 85%.Hydrogen spectrum (400MHz, DMSO): 11.90 (s, 1H); 11.45 (s, 1H); 8.44 (s, 1H); (7.6-7.8 m, 5H); (7.1-7.3 m, 2H); (6.84 m, 1H); (5.95 m, 1H); (5.02 m, 2H); (3.34 d, 2H); (3.10 s, 2H); (2.91 s, 4H); (2.52 m, 4H).Mass spectrum: 443 (M+1).

The preparation of embodiment 5,2-(4-(to chlorobenzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room-temperature water bath, in reaction flask, add piperazine (25.8g, 0.3mol) and DCM (50ml), stir and solid is dissolved gradually, form suspension.Then parachloroben-zenesulfonyl chloride (21.1g is slowly dripped, DCM (50ml) 0.1mol), 30min is stirred again after dropwising, TLC monitoring reaction terminates, then tap water (50ml) washing is added once, separate DCM layer, water layer DCM (50ml) extraction, separates, merge DCM layer, revolve and boil off except DCM, separate out solid, solids with methanol (30ml) is substantially clearly molten, slowly drip tap water (100ml) afterwards, have a large amount of solid to separate out, filter, filter cake water rinses.Infrared drying, obtains white solid thing 24g; Productive rate: 85%.Mass spectrum: 261 (M+1).

Step 2. adds compound 1 (7.8g, 30mmol), DCM (30ml), triethylamine (3.64g, 36mmol) and ethyl chloroacetate (3.67g, 30mmol) in reaction flask.Stir, be then warmed up to 40 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, and after reaction terminates, silicon bath soil filters, filter cake DCM washs, and merges DCM, washes three times, then separate DCM, anhydrous magnesium sulfate drying, filters, and filtrate concentrates, and obtains pale brown oil thing 9.34g; Productive rate: 90%.Mass spectrum: 347 (M+1).

Step 3. adds compound 2 (6.92g, 20mmol), methyl alcohol (20mmol) and 80% hydrazine hydrate (3.75g, 60mmol) in reaction flask.Stir, be then warmed up to 60 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, adds DCM (20ml) in raffinate, once, separate DCM layer, water layer uses DCM (2*10ml) to wash secondary again in tap water (30ml) washing, separate DCM layer, merge, anhydrous MgSO4 is dry, filters, the a small amount of DCM washing of filter cake, concentrates and obtains brown oil 5.46g; Yield: 82%.Mass spectrum: 333 (M+1).

Step 4. adds compound 3 (5.3g, 16mmol), dehydrated alcohol (15ml) and 2-hydroxyl-3-allyl benzene formaldehyde (2.6g, 16mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete, after reaction terminates, drips normal hexane until muddiness, cooling crystallization.Filter, drain, EtOH/n-Hexane recrystallization used again by filter cake.Obtain white solid 2-(4-(to chlorobenzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 6.2g, yield: 80%.Hydrogen spectrum (400MHz, DMSO): 11.93 (s, 1H); 11.4 (s, 1H); 8.45 (s, 1H); (7.5-7.8 m, 4H); 7.12-7.35 (m, 2H); 6.86 (m, 1H); 5.91 (m, 1H); 5.02 (m, 2H); 3.34 (d, 2H); 3.10 (s, 2H); 2.91 (s, 4H); 2.52 (m, 4H).Mass spectrum: 477 (M+1).

The preparation of embodiment 6,2-(4-(4-((4-methylpiperazine-1-yl) methyl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room temperature ice-water bath, in reaction flask, add 4-((4-methylpiperazine-1-yl) methyl) Benzoyl chloride dihydrochloride (3.25g, 10mmol) and DCM (10ml), magnetic agitation is even.Then triethylamine (3.53g is slowly dripped, 3.5mol), solid dissolves gradually, finally form suspension, stirring reaction 30min is continued after dripping, then 2-(piperazine-1-base) ethyl acetate (1.72g is dripped in 30min, DCM (10ml) solution 10mol), stir 30min again after dropwising, TLC monitoring reaction terminates, and then adds tap water (2 × 50ml) and washs secondary, separate DCM layer, anhydrous magnesium sulfate drying, filter, filtrate revolving boils off except DCM obtains oily matter 3.5g; Productive rate: 90%.Mass spectrum: 289 (M+1).

Step 2. adds compound 1 (3.1g, 8mmol), methyl alcohol (10mmol) and 80% hydrazine hydrate (1.5g, 24mmol) in reaction flask.Stir, be then warmed up to 60 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, adds DCM (20ml) in raffinate, once, separate DCM layer, water layer uses DCM (2*10ml) to wash secondary again in tap water (10ml) washing, separate DCM layer, merge, anhydrous MgSO4 is dry, filters, the a small amount of DCM washing of filter cake, concentrates and obtains brown oil 2.09g; Yield: 70%.Mass spectrum: 375 (M+1).

Step 3. adds compound 2 (1.87g, 5mmol), dehydrated alcohol (15ml) and 2-hydroxyl-3-allyl benzene formaldehyde (0.81g, 5mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete; after reaction terminates; concentrated removal ethanol; debris silica column purification (elutriant: DCM: MeOH=10: 1) obtain pale brown oil thing 2-(4-(4-((4-methylpiperazine-1-yl) methyl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 1.29g, yield: 75%.Hydrogen spectrum (400MHz, DMSO): 11.82 (s, 1H); 11.35 (s, 1H); 8.36 (s, 1H); 7.51 (m, 2H); (7.0-7.25 m, 6H); (6.82 m, 1H); (5.97 m, 1H); (5.0 m, 2H); (3.62 s, 2H); (3.33 m, 8H); (3.15 s, 2H); (2.91 s, 4H); (2.1-2.4 m, 7H).Mass spectrum: 519 (M+1).

The preparation of embodiment 7,2-(4-(4-(4-methylpiperazine-1-yl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Reaction process is as follows:

Under step 1. room temperature, in reaction flask, add 4-(4-methylpiperazine-1 base) phenylformic acid (2.2g, 10mmol), DCM (10ml) and triethylamine (1.01g, 10mmol), magnetic agitation is even.Then DCC (2.47g is slowly added, 12mmol), magnetic agitation activates 2 hours, after priming reaction, be added dropwise to DCM (10ml) solution of 2-(piperazine-1-base) ethyl acetate (1.72g, 10mol), after dropwising, stirred overnight at room temperature, after TLC monitoring reaction terminates, filter, filtrate tap water (2 × 50ml) washs secondary, separate DCM layer, anhydrous magnesium sulfate drying, filter, filtrate revolving boils off except DCM obtains oily matter 3.5g, silica column purification obtains solid 2.4g, productive rate: 64.1%.Mass spectrum: 375 (M+1).

Step 2. adds compound 1 (1.87g, 5mmol), methyl alcohol (10mmol) and 80% hydrazine hydrate (0.94g, 15mmol) in reaction flask.Stir, be then warmed up to 60 DEG C of back flow reaction 8 hours, TLC monitoring reacts completely, after reaction terminates, concentrated removal methyl alcohol, adds DCM (20ml) in raffinate, once, separate DCM layer, water layer uses DCM (2*10ml) to wash secondary again in tap water (10ml) washing, separate DCM layer, merge, anhydrous MgSO4 is dry, filters, the a small amount of DCM washing of filter cake, concentrates and obtains brown oil 1.44g; Yield: 80%.Mass spectrum: 361 (M+1).

Step 3. adds compound 2 (1.44g, 4mmol), dehydrated alcohol (15ml) and 2-hydroxyl-3-allyl benzene formaldehyde (0.81g, 5mmol) in reaction flask, heats to 70 DEG C, isothermal reaction.TLC detection reaction is complete; after reaction terminates; concentrated removal ethanol; debris silica column purification (elutriant: DCM: MeOH=10: 1) obtain white solid 2-(4-(4-(4-methylpiperazine-1-yl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine 1.63g, yield: 81%.Hydrogen spectrum (400MHz, DMSO): 11.78 (s, 1H); 11.41 (s, 1H); 8.38 (s, 1H); 7.61 (m, 2H); (7.0-7.25 m, 6H); (6.80 m, 1H); (5.93 m, 1H); (4.97 m, 2H); (3.33 m, 8H); (3.20 s, 2H); (2.95 s, 4H); (2.1-2.4 m, 7H).Mass spectrum: 505 (M+1).

Experimental example 1, biological test

External activity screening adopts mtt assay to detect embodiment of the present invention compound to the impact of the inhibiting rate of National People's Congress cell lung cancer cell NCI-H460 and human colon cancer cell HCT-116, and compares experiment with PAC-1 (preparing according to patent WO2008134474A2 method) medicine.Concrete grammar is: the tumour cell in vegetative period of taking the logarithm, counts after conventional digestion, and be inoculated in 96 orifice plates with the density in 3000/hole, adherent growth is spent the night.Add the embodiment compound (mother liquor is dissolved in DMSO) of 10,20,40,60,80 μMs respectively, each concentration arranges 3 multiple holes, using the DMSO of maximum dose level as negative control, with the cis-platinum of 10 μMs, 20 μMs, 30 μMs, 40 μMs or 60 μMs for positive control.After processing 24,48,72 hours respectively, every hole adds 10 μ lMTT (5mg/ml), continues cultivation 2 ~ 4 hours.Nutrient solution is abandoned in suction, adds the DMSO of 100 μ l in every hole, and concussion dissolving 5 minutes, detects the light absorption value at 570nm place, according to light absorption value and the ratio contrasting light absorption value of each concentration, calculate the growth inhibition ratio of each concentration by microplate reader; Growth inhibition ratio calculation formula is as follows:

Inhibiting rate (%)=(1-is by prospect hole OD value/negative control hole OD value) × 100%; Adopt SPSS software, calculate the IC50 value of medicine further, the results are shown in Table 1 and table 2.

In addition, get BALB/C mice 30, be divided into 6 groups at random by body weight, sex, often organize 5.Fasting, after 12 hours, by PAC-1 and embodiment 1 compound solution of proportional diluted method preparation different concns, gives mouse 12.5mg/kg, 25mg/kg and 50mg/kg liquid of various dose by body weight tail vein respectively.4-5 at the uniform velocity injects in second.Animal reflection is observed: observe 24 hours after injection.Record reaction of animals situation and animal dead situation, the results are shown in Table 3.

Table 1 embodiment Compound ira vitro is to the IC50 value of NCI-H460

Embodiment sequence number	24 hours IC50 (μM)	48 hours IC50 (μM)	72 hours IC50 (μM)
				Embodiment 1	36.23	8.62	8.75
Embodiment 2	/	22.88	17.83
				Embodiment 3	135.50	15.64	9.53
Embodiment 4	/	7.89	11.05
				Embodiment 5	/	5.22	7.74
PAC-1	171.01	15.74	11.74

Can clearly be seen that from table 1 test-results, the claimed compound of the present invention has good anti tumor activity in vitro, and some compound is better than tumour medicine PAC-1.

Table 2 embodiment Compound ira vitro is to the IC50 value of HCT-116

Embodiment sequence number	24 hours IC50 (μM)	48 hours IC50 (μM)	72 hours IC50 (μM)
				Embodiment 1	30.99	7.12	1.23
Embodiment 6	87.58	15.54	2.18
				PAC-1	/	9.60	3.72

Can clearly be seen that from table 2 test-results, the claimed compound of the present invention has good anti tumor activity in vitro, and some compound is better than tumour medicine PAC-1.

Table 3PAC-1 and the administration of embodiment 1 compound intravenous injection are on the impact of mouse

PAC-1(mg/kg)	Neurotoxicity	XB-5(mg/kg)	Neurotoxicity
				12.5	Nothing	12.5	Nothing
25	Have	25	Nothing
				50	Have	50	Nothing

Mouse mainline administration experimental result shows (table 3): simultaneously all to the PAC-1 of 12.5mg/kg and embodiment 1 compound, and mouse reaction is normal, does not have toxic reaction and dead mouse phenomenon.When dosage is increased to 25mg/kg, PAC-1 group has occurred that jumping, trembling and the existing picture of astasia all appears in all mouse, and has a death, and all mouse of embodiment 1 compound group are all normal, do not have toxic reaction and the phenomena of mortality.When dosage is increased to 50mg/kg, PAC-1 group has four mouse dead at once, and embodiment 1 compound group mouse does not still have toxic reaction and the phenomena of mortality.Therefore, embodiment 1 compound acute toxicity is well below PAC-1 medicine.

Contriver also finds, the compound of other compound that the present invention relates to particularly other several embodiment also have with above-described embodiment 1 Compound Phase with or similar result.

Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.

Claims (18)

1. the compound of formula I or formula II:

Wherein,

A, B, C, D and E are carbon atom independently of one another; And

R1, R2, R3, R4 and R5 are selected from hydrogen atom, hydroxyl, C2-C6 alkenyl independently of one another,

R is selected from hydrogen atom, halogen, heterocycle amido, heterocycle amido straight chained alkyl, and the structure of described heterocycle amido is: wherein X is C, O, NH or alkyl replacement N, n is 0-3,

The structure of described heterocycle amido straight chained alkyl is: wherein X is that to replace N, n be 0-3, m is 1-6 for C, O, NH or alkyl,

Or its pharmacologically acceptable salts, steric isomer.

2. the compound of claim 1, it is following compound:

2-(4-(4-(4-methylpiperazine-1-yl) benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(4-morpholine base benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(benzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(to chlorobenzenesulfonyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine;

2-(4-(4-((4-methylpiperazine-1-yl) methyl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine; With

2-(4-(4-(4-methylpiperazine-1-yl) benzoyl) piperazine-1-base)-acetyl (3-allyl group-2-hydroxyl-methylene-benzene) hydrazine

Or its pharmacologically acceptable salts, steric isomer.

3. prepare the method for type I compound described in claim 1 or its pharmacologically acceptable salts, it comprises the following steps:

(1), under alkaline condition, make in organic solvent react with piperazine, generate with following formula Ι b compound:

(2) in the basic conditions, Ι b compound and ethyl chloroacetate are reacted, generate with following formula Ι c compound:

(3) in organic solvent, hydrazine hydrate and formula Ι c compound are reacted, generate with following formula Ι d compound:

(4) in organic solvent, make formula Ι d compound with reaction, generates with following formula Ι compound:

(5) make formula Ι compound and acid-respons, obtain the corresponding salt of formula Ι compound,

Wherein the definition of A, B, C, D, E, R, R1-R5 as claimed in claim 1.

4. prepare the method for formula II compound or its pharmacologically acceptable salts described in claim 1, it comprises the following steps:

(1), under alkaline condition, make in organic solvent with 2-(piperazine-1-base) acetic acid ethyl reaction, generate with following formula II b compound:

(2) in organic solvent, hydrazine hydrate and formula II b compound are reacted, generate with following formula II c compound:

(3) formula II c compound and formula in organic solvent, is made reaction, generates with following formula II compound:

(4) make formula II compound and acid-respons, obtain the corresponding salt of formula II compound,

Wherein the definition of A, B, C, D, E, R, R1-R5 as claimed in claim 1.

5. the compound of claim 1 or 2 is for the preparation of the purposes treated and/or prevented in the medicine of tumour and/or cancer.

6. the purposes of claim 5, wherein said tumour and/or cancer comprise malignant tumour.

7. the purposes of claim 6, wherein said malignant tumour comprises bladder cancer, mammary cancer, colorectal carcinoma, kidney liver cancer, lung cancer, head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma.

8. the purposes of claim 7, wherein said lung cancer is small cell lung cancer or nonsmall-cell lung cancer.

9. the purposes of claim 7, wherein said skin carcinoma is squamous cell carcinoma.

10. the purposes of claim 5, wherein said tumour and/or cancer comprise the hematopoetic tumor of lymphsystem or marrow system.

The purposes of 11. claims 10, the hematopoetic tumor of described lymphsystem or marrow system comprises leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myelomatosis and Burkitt`s lymphatic cancer and myelodysplastic syndrome.

The purposes of 12. claims 11, wherein, described leukemia comprises acute lymphoblastic leukemia, acute and chronic granulocytic leukemia and promyelocytic leukemia.

The purposes of 13. claims 5, wherein said tumour and/or cancer comprise the tumour of the interstitial origin cause of formation.

The purposes of 14. claims 13, the tumour of the wherein said interstitial origin cause of formation comprises fibrosarcoma and rhabdosarcoma.

The purposes of 15. claims 5, wherein said tumour and/or cancer comprise the tumour of maincenter and peripheral nervous system.

The purposes of 16. claims 15, wherein said maincenter comprises astrocytoma with the tumour of peripheral nervous system, becomes neurofibroma, neurospongioma and schwannoma.

The purposes of 17. claims 5, wherein said tumour and/or cancer comprise melanoma, spermocytoma, teratoma, osteosarcoma, exophytic look purple neck knurl (xenoderoma pigmentosum), Tiroidina filter capsule cancer and Kaposi's sarcoma.

18. 1 kinds of pharmaceutical compositions, it comprises compound and the acceptable thinner of optional pharmacy, carrier, vehicle, auxiliary material or the vehicle of the claim 1 or 2 treating and/or preventing significant quantity.