CN1989112A - Cancer treatment method - Google Patents

Abstract

The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and pharmaceutical compositions containing the same. In particular, the method relates to a methods of treating cancers which are mediated by the tyrosine kinases EGFR and/or erbB2 by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof.

Description

Cancer treatment method

Background of invention

The present invention relates to treat method for cancer by administration Mammals 4-quinazoline amine (quinazoline amine s) and the pharmaceutical composition that comprises it.Particularly, this method relates to by administration N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl (methanesulphonyl)) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine and its salt and solvate treat the method by Tyrosylprotein kinase EGFR and/or erbB2 cancers mediated.

At tumor area, effective chemotherapy of cancer therapy is continued treatment (continuinggoal).Usually, cancer is caused by the normal processes abnormality of control cell fission, differentiation and apoptotic cell death.Apoptosis (apoptosis) for example plays an important role in the morbidity of degenerative neuronal disease (degenerative neuronal diseases), cardiovascular disorder and cancer in fetal development and multiple disease.A path of common research, it relates to apoptotic kinases regulates, and is the cell signal transmission (Crews and Erikson, Cell, 74:215-17,1993) to nuclear of the growth factor receptors of cell surface.Noticeable especially path is the cell signal transmission from erbB family growth factor receptors.

Exist significantly in the erbB family to interact, it regulates these receptor-mediated cytosiies.Comprise that in conjunction with six of EGFR important parts EGF, transforming growth factor, the two-ways regulation factor, heparin are in conjunction with EGF, β cell regulin (betacellulin) and epiregulin (Alroy﹠amp; Yarden, FEBS Letters, 410:83-86,1997; Burden﹠amp; Yarden, Neuron, 18:847-855,1997; People such as Klapper, ProcNatiAcadSci, 4994-5000,1999).Heregulins, the part of another type is directly in conjunction with HER3 and/or HER4 (people such as Holmes, Science, 256:1205,1992; People such as Klapper, 1997, Oncogene, 14:2099-2109; People such as Peles, Cell, 69:205,1992).The combination of specific ligand comprises homologous dimerizationization (homodimerization) or different dimerization (the heterodimerization) (Carraway﹠amp in the erbB family member; Cantley, Cell, 78:5-8,1994; Lemmon﹠amp; Schlessinger, TrendsBiochemSci, 19:459-463,1994).Compare with other ErbB acceptor member, do not confirm that also soluble ligand can be in conjunction with HER2, it is behind different dimerization (transactivated) of transactivation seemingly.The different dimerization of erbB-2 acceptor and EGFR, HER3 or HER4 acceptor refers to homologous dimerizationization (people such as Klapper, 1999; People such as Klapper, 1997).Receptor dimerizationization causes ATP to be bonded to the activation, the autophosphorylation of the terminal tyrosine residues of C-of Tyrosylprotein kinase of catalytic site, the acceptor of acceptor.Then, the tyrosine residues of phosphorylation plays for example docking site of Grb2, Shc and Phospholipase C of protein, activate the signal path in downstream successively, comprise Ras/MEK/Erk and P13K/Akt path, other albumen that it is regulated transcription factor and participates in biological respinse, described biological respinse is propagation, cell mobility, vasculogenesis, cell survival and differentiation (Alroy﹠amp for example; Yarden, 1997; Burgering﹠amp; Coffer, Nature, 376:599-602,1995; People such as Chan, AnnRevBiochem, 68:965-1014,1999; People such as Lewis, AdvCanRes, 74:49-139,1998; People such as Liu, Genes and Dev, 13:786-791,1999; People such as Muthuswamy, Mol﹠amp; CellBio, 19,10:6845-6857,1999; Riese﹠amp; Stern, Bioessays, 20:41-48,1998).

Study some strategy that comprises monoclonal antibody (Mab), immunoconjugate, anti--EGF vaccine and tyrosine kinase inhibitor and come target erbB family receptors, (look back (people such as Sridhar, Lancet, 4 with their activation in cancer cell of blocking-up, 7:397-406,2003)).Because it is the most stable to comprise the erbB2 of heterodimer, therefore, the preferred startup incident of be used to send signal, blocking erbB2 and EGFR simultaneously is most interested therapeutic strategy.The dual erbB-2/EGFR TK of a series of 6-furans quinazolines inhibitor powerful in the treatment (people such as Cockerill, BiorgMedChemLett, 11:1401-1405,2001 have been synthesized before cancer clinical; People such as Rusnak, CanRes, 61:7196-7203,2001a; People such as Rusnak, MolCanTher, 1:85-94,2001b).GW572016 is a 6-furans quinazoline, Orally active, the dual kinase inhibitor of reversible EGFR and erbB2 proteolytic enzyme (people such as Rusnak, 2001b).In the research of human heterograft, GW572016 has shown the dose-dependent inhibition effect, and selectivity suppresses tumour cell and crosses expression EGFR or erbB2 (people such as Rusnak, 2001 b; People such as Xia, Oncogene, 21:6255-6263,2002).

At present; the inventor has had been found that new methods of treatment, comprises administration N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-([2-(methane sulfonyl) ethyl] aminomethyl)-the 2-furyl]-4-quinazoline amine (GW572016) and salt and/or solvate.

Summary of the invention

In one aspect of the invention, provide in a kind of treatment Mammals EGFR and/or erbB2 to cross the expression method for cancer, comprising: the formula of the described Mammals treatment of administration significant quantity (I ") compound

Aspect second of the present invention, provide that EGFR crosses the expression method for cancer in a kind of treatment Mammals, comprising: the described Mammals treatment of administration significant quantity formula (I ") compound

Aspect the 3rd of the present invention, provide that erbB2 crosses the expression method for cancer in a kind of treatment Mammals, comprising: the formula of the described Mammals treatment of administration significant quantity (I ") compound

Aspect the 4th of the present invention, provide that EGFR and erbB2 cross the expression method for cancer in the treatment Mammals, comprise formula (the I ") compound of the described Mammals treatment of administration significant quantity

Aspect the 5th of the present invention, the method for treatment Mammals carcinoma mesonephric is provided, comprising: the described Mammals treatment of administration significant quantity formula (I) compound or its solvate

Aspect the 6th of the present invention, a kind of method for the treatment of bladder cancer in the Mammals is provided, comprising: formula (I) compound or its solvate of the described Mammals treatment of administration significant quantity

Detailed Description Of The Invention

The supernormal growth of term " vegetation " phalangeal cell or tissue as used herein, can be regarded as comprise benign, that is, and non-cancerous growths, and virulent, i.e. cancerous growths.Term " excrescent " refers to vegetation or relevant with it.

Term " significant quantity " for example refers to draw biology or the medicine of medical response or the consumption of medicinal medicament by investigator or the appreciable tissue of clinicist, general, animal or human's body as used herein.And term " treatment significant quantity " refers to compare with the respective patient of not accepting this dosage, and this dosage produces treatment, healing, the prevention that improves or improves disease, illness or side effect, or the development rate of disease or illness reduces.This term is also included within its scope, can strengthen the consumption of normal physiological function effectively.

As known in the art, tumour often shifts, because first (primary) site of tumor growth can be spread to one or more anatomy dispersive site.As this paper and the patient that uses in term " tumour " not only comprise primary tumor, also comprise the metastatic tumo(u)r growth.

" EGFR " is also referred to as " erbB-1 " and " erbB-2 ", is albumen (matter) the Tyrosylprotein kinase transmembrane growth factor receptor of erbB family.Phosphorylation of specific tyrosine residues (A.F.Wilks, Progressin Growth Factor Research, 1990,2,97-111 in the range protein of protein tyrosine kinase catalysis participation adjusting cell growth and differentiation; S.A.Courtneidge, Dev.Supp.1,1993,57-64; J.A.Cooper, Semin.Cell Biol., 1994, 5 (6).377-387; R.F.Paulson, Semin.Immunol., 1995,7 (4), 267-277; A.C.Chan, Curr.Opin.Immunol., 1996,8 (3), 394-401).The ErbB family of I receptor Tyrosylprotein kinase comprises ErbB1 (being also referred to as epithelial growth factor receptor (EGFR or HER1)), erbB2 (being also referred to as Her2), erbB3 and erbB4.These receptor tyrosine kinases are wide expression in epithelium, a matter and neuronal tissue, and wherein they work vital role (Sibilia and Wagner, Science, the 269:234 (1995) that regulates cell proliferation, survival and differentiation; People such as Threadgill, Science, 269:230 (1995)).The expression of wild-type erbB2 or EGFR increases, or constitutes the expression of activated receptors mutant, makes cell in vitro change (people such as Di Fiore, 1987; People such as DiMarco, Oncogene, 4:831 (1989); People such as Hudziak, Proc.NatI.Acad.Sci.USA., 84:7159 (1987); People such as Qian, Oncogene, 10:211 (1995)).In some mammary cancer and multiple other malignant tumour, that the expression of erbB2 or EGFR increases is relevant with relatively poor clinical effectiveness (people such as Slamon, Science, 235:177 (1987); People such as Slamon, Science, 244:707 (1989); People such as Bacus, Am.J.Clin.Path, 102:S13 (1994)).

As used herein, cell " cross express " EGFR and/or erbB2 refer to compare with the average quantity of the acceptor found in the cell of the same type, and functional EGFR and/or erbB2 acceptor quantity that this cell has significantly increase.For example, confirmed that cross expressing of EGFR and/or erbB2 is present in the multiple cancer types, comprised mammary cancer (people such as Verbeek, FEBS Letters425:145 (1998); Colorectal carcinoma (people such as Gross, Cancer Research51:1451 (1991)); Lung cancer (people such as Damstrup, Cancer Research52:3089 (1992), renalcell (people such as Stumm, Int.J.Cancer 69:17 (1996), people such as Sargent, J.Urology 142:1364 (1989)) and bladder cancer (people such as Chow, Clin.Cancer Res.7:1957 (2001); People such as Bue, Int.J.Cancer, 76:189 (1998); (Mellon J, LunecJ., J Uro 1996; 155:321-6; Orlando C, Sestini R., J Urol1996; 156:2089-2093), people such as Turkeri, Urology 51:645 (1998)).Also can estimate crossing of ErbB2 and express, include but not limited to that quantity, protein expression and the mRNA of the cell receptor of imaging, gene amplification, existence expresses by any suitable method known in the art.Referring to, people such as Piffanelli for example, Breast Cancer Res.Treatment 37:267 (1996).

Term " solvate " refers to the variable stoichiometric complex compound by solute (in the present invention, being formula (I) compound or its salt) and solvent formation as used herein.The such solvent that is used for the object of the invention can not influence the biological activity of solute.The example of suitable solvent includes, but are not limited to water, methyl alcohol, ethanol and acetic acid.The preferred solvent that uses is acceptable solvent.The example of suitable acceptable solvent includes, but are not limited to water, ethanol or acetic acid.The solvent that most preferably uses is water.

Cancer treatment method disclosed herein comprises Medicine-feeding type (I) compound or its salt or solvate:

Implement in the diagram at another, described compound is formula (I ') compound or its dehydrate (anhydrate) or its hydrate forms.Formula (I ') compound is the xylenesulfonate (ditosylate) of formula (I) compound.

Implement in the diagram at one, compound is the anhydrous dimethyl benzene sulfonate of formula (I) compound.Implement in the diagram at another, compound is formula (the I ") compound of the monohydrate xylenesulfonate of formula (I) compound for it.

The monohydrate xylenesulfonate of formula (I) compound has chemical name N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine (GW572016) xylenesulfonate monohydrate, be also referred to as lapatinib.

Free alkali salt, HCI salt and the xylenesulfonate of formula (I) compound can be according to the international patent application No.PCT/EP99/00048 of application on January 8th, 1999, with the open WO 99/35146 in the world on July 15th, 1999, the international patent application No.PCT/US01/20706 that relates to the application of above-mentioned patent and June 28 calendar year 2001, with the method among the open WO 02/02552 in the world on January 10th, 2002, and prepare according to the method among the following suitable embodiment.A kind of method of such preparation formula (I) compound xylenesulfonate is listed in following diagram 1:

Scheme 1

In diagram 1, the preparation of formula (III) compound xylenesulfonate divides four-stage to carry out: the stage 1: the bicyclic compound of indication and amine reaction, the iodo quinazoline derivant that obtains indicating; Stage 2: prepare corresponding acetaldehyde salt; Stage 3: preparation quinazoline ditosylate salt; With the stage 4: preparation monohydrate xylenesulfonate.

Typically, salt of the present invention is pharmacologically acceptable salt.The salt that comprises in term " pharmacologically acceptable salt " refers to the non-toxic salt of The compounds of this invention.The salt of The compounds of this invention can comprise the acid addition salt derived from nitrogen on the The compounds of this invention substituting group.Representational salt comprises following salt: acetate, benzene sulfonate, benzoic ether, supercarbonate, hydrosulfate, bitartrate, borate, bromide, Ca-EDTA, camsilate, carbonate, muriate, Clavulanate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, glucoheptose salt, gluconate, glutaminate, glycollylarsanilate, Sucrets (hexylresorcinate), breathe out amine salt (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactic acid salt, Lactobionate, lauroleate, malate, mandelate, mesylate, monobromethane, the nitrated salt of methyl, Methylsulfate, toxilic acid one potassium, mucate, naphthalenesulfonate, nitrate, meglumin salt, oxalate, pamoate (embonate), palmitate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, sylvite, salicylate, receive salt, stearate, subacetate, succinate, tannate, tartrate, 8-Chlorotheophyline, tosylate, triethyl iodate thing, triethyl ammonium and valerate.Other non-pharmacologically acceptable salt can be used for preparing compound of the present invention, and these form another aspect of the present invention.

Although formula (I) compound of the treatment significant quantity of using in cancer treatment method of the present invention and its salt or solvate can be with unprocessed chemical administrations, it also can make pharmaceutical composition with activeconstituents.Therefore, the present invention also provide can administration in cancer treatment method of the present invention pharmaceutical composition.Described pharmaceutical composition comprises formula (I) compound and its salt or solvate and one or more pharmaceutically acceptable carrier, thinner or the vehicle for the treatment of significant quantity.Described carrier, thinner or vehicle be with other composition of preparation compatible and nontoxic to the recipient.

Pharmaceutical composition can exist with the unit dosage form that every dosage unit comprises the predetermined amount activeconstituents.Such unit can comprise, 0.5mg to 1g for example, preferred 1mg to 700mg, the more preferably formula of 5mg to 100mg (I) compound, depend on subject illness, route of administration and patient's age, body weight and physical appearance, perhaps pharmaceutical composition can exist with the unit dosage form that every dosage unit comprises the predetermined amount activeconstituents.Preferred unit dosage form is for comprising dosage or divided dose (sub-dose) is aforesaid or activeconstituents of its suitable part every day.And such pharmaceutical composition can be by the known any means preparation of pharmaceutical field.

The compound of formula (I) can be by any route of administration administration.That suitable route of administration comprises is oral, rectum, nasal cavity, part (comprising oral cavity or hypogloeeis), vagina and parenteral (comprising in subcutaneous, intramuscular, intravenously, intradermal, the film or epidural).Should be appreciated that preferred route of administration can change according to for example acceptor's the comprehensive of situation.

Method of the present invention also can be used other treatment method for cancer.Especially, comprise be different from the above-mentioned antineoplaston of mentioning, with combination, hormone, antibody medicament and the surgical intervention and/or the radiotherapy of other chemotherapy.Antineoplaston is for example described in the international application No.PCT US 02/01130 of application on January 14th, 2002, and its disclosed antineoplaston is incorporated herein by reference.Therefore, combination therapy according to the present invention comprises at least a formula of administration (I) compound and randomly uses other therapeutical agent that comprises antineoplastic agent.The combination of such medicament can be together or separate administration, when separate administration, can be simultaneously or in turn with random order, and at time administration close or that be separated by.The compound of the formula (I) of selection relative timing administration and the combination therapy effect of consumption to obtain wanting of other medical active reagent.

Be suitable for pharmaceutical composition for oral administration and can be isolating unit for example capsule or tablet; Pulvis or granule; Solution in the waterborne liquid or suspension; Edible foaming agent (foams) or whips; Or oil-in-water liq emulsion or or water-in-oil-type liquid emulsion.

For example, for the oral administration of tablet or capsule form, active medicine component can be united with oral, nontoxic pharmaceutically acceptable carrier, and described carrier is ethanol, glycerine, water etc. for example.Pulvis can by compound is smashed to pieces into suitable fine size and with similarly smash to pieces pharmaceutical carrier for example edible carbohydrates for example starch or N.F,USP MANNITOL are mixed with.Also can comprise seasonings, sanitas, dispersion agent and tinting material.

Capsule can prepare by the gelatin sheath for preparing aforesaid powdered mixture and be packed into shaping.Before the filling stage, can be to adding glidant and lubricant for example colloid silica, talcum, Magnesium Stearate, calcium stearate or solid polyethylene glycol in the powdered mixture.For example agar-agar, lime carbonate or yellow soda ash improve drug utilization degree when ingestible capsule also can to add disintegrating agent or solubilizing agent.

And when wanting or in case of necessity, suitable tackiness agent, lubricant, disintegrating agent and tinting material also can be incorporated in the mixture.Suitable tackiness agent comprises for example for example gum arabic, west yellow work glue or sodium alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax class etc. of glucose or beta lactose, corn sweetener, natural and synthetic gum of starch, gelatin, natural tree carbohydrate.The lubricant that uses in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium-acetate, sodium-chlor etc.Disintegrating agent includes, but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.Tablet add lubricant and disintegrating agent, and tablet forming prepares by preparation powdered mixture, granulation, precompressed.Powdered mixture is by with compound and aforesaid thinner or matrix, randomly with tackiness agent for example carboxymethyl cellulose, alginates, gelatin or polyvinylpyrrolidone, with delayer (retardant) solution paraffin for example, with absorption enhancer for example quaternary ammonium salt and/or absorption agent for example wilkinite, kaolin or Lin Suanergai mix, and suitably smash to pieces and prepare.Powdered mixture can by with tackiness agent for example the acadia mucilage or the solution-wet of syrup, starch paste, cellulosic or polymeric material, and the screen cloth that pressurizeed prepares.As another kind of method of granulating, powdered mixture can prepare with tabletting machine, and obtaining to become the pre-compressing tablet that particulate not exclusively forms.Can come lubricated granules to be clamminess by adding stearic acid, stearate, talcum or mineral oil to prevent the tablet shaping die.Then, in flakes with lubricated mixture compacting.Compound of the present invention also can mix with free-pouring inert support and directly suppress in flakes, does not need through granulating or the precompressed stage.Clear or the coating of opaque protective coating, sugar or polymeric material and the polishing coating of wax be made up of shellac can be provided.Dyestuff can be joined in these coatings to distinguish the different units formulation.

Liquid oral for example solution, syrup and elixir can be prepared into dosage device, so that given dosage comprises the compound of predetermined amount.Syrup can prepare by compound being dissolved in the suitable liquor that spices is arranged, and elixir can prepare by using the nontoxic pure vehicle that contains.Suspensoid can prepare by compound is dispersed in the non-toxic excipients.Also can add for example for example spearmint oil or natural sweeteners or asccharin or other artificial sweetening agent etc. of the isooctadecanol of ethoxyquin and polyoxyethylene sorbitan ester, sanitas, odor additive of solubilizing agent and emulsifying agent.

When suitable, the dosage unit formulation of oral administration can be by microencapsulation.Also can prepare said preparation delaying or continue to discharge, for example by dressing or with particulate matter be embedded in polymkeric substance, the wax class is medium.

Medicament used according to the invention also can liposome delivery be administered systemically, for example little unilamellar vesicle, big unilamellar vesicle and multilamellar vesicle.Liposome can for example cholesterol, stearylamide or phosphoric acid Yelkin TTS prepare by multiple phosphatide.

Medicament used according to the invention also can be sent as the separate carrier of compound molecule coupling wherein by using monoclonal antibody.Described compound also can with for example target medicine carrier coupling of soluble polymer.Such polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropylmethyl acrylamide-phenol, poly-hydroxyethyl amino-succinamic acid phenol or the polyethylene oxygen polylysine that replaces with the palmityl residue.And, compound can be used to obtain the Biodegradable polymeric coupling that medicine controlled releasing discharges with a class, and described polymkeric substance is the crosslinked or amphiphilic block copolymer of poly(lactic acid), polepsilon caprolactone, multi-hydroxybutyrate, polyorthoesters, poly-carboxylic aldehyde, poly-dihydropyrane class, polycyanoacrylate and hydrogel for example.

The pharmaceutical composition that is suitable for percutaneous dosing can be isolating patch, and its expection can keep directly contacting with recipient's epidermis the time period of prolongation.For example, activeconstituents can be sent by iontophoresis, as usually at Pharmaceutical Research, 3 (6), describe in (1986).

But the pharmaceutical composition preparation that is suitable for topical becomes ointment, emulsifiable paste, suspensoid, pulvis, solution, paste, gelifying agent, sprays, gaseous solvents or oil.

For example mouthful and for the skin, preparation is preferably with topical ointment or emulsifiable paste application for treatment eye or other outside organization.When preparation became ointment, activeconstituents can be used with paraffin tear or water miscibility emulsifiable paste matrix.In addition, activeconstituents can preparation becomes to contain the emulsifiable paste of water-in-oil-type emulsifiable paste matrix or oil-in-water-type matrix.

Be suitable for use in topical to the pharmaceutical composition of eye and comprise eye drops, wherein activeconstituents dissolving or be suspended in the suitable carrier is especially in the aqueous solution.

Be suitable for topical to mouthful pharmaceutical composition comprise lozenge, pastille and mouth wass.

The pharmaceutical composition that is suitable for rectal administration can be suppository or enema.

The wherein carrier that is suitable for intranasal administration is that the solid pharmaceutical composition comprises meal, and its particle diameter that has is 20 to 500 microns, and it promptly, sucks by nasal cavity from the close container that contains powder of nose fast to absorb the mode administration of wherein smelling agent.The suitable formulations that is used for wherein carrier with sprays or nasal drop administration and is liquid comprises the water or the oil solution of activeconstituents.

Be suitable for comprising fine particle pulvis or mist agent that it can produce by dosage pressurized aerosol, atomizer or the sucker of broad variety metering by the pharmaceutical composition of inhalation.

The pharmaceutical composition that is suitable for vagina administration can be vaginal suppository, tampon, emulsifiable paste, gelifying agent, paste, foaming agent or spray agent.

The pharmaceutical composition that is suitable for parenteral admin comprises moisture or not moisture aseptic parenteral solution, and it can comprise oxidation inhibitor, buffer reagent, fungistat and make preparation and the isoosmotic solute of the recipient of expection; With moisture or not moisture aseptic suspensoid, it can comprise suspending agent and thickening material.Said preparation can be packed in unitary dose or the multi-dose container, and for example Mi Feng ampoule and medicine bottle can be stored under lyophilize (lyophilized) condition, before using immediately, only needs to add sterile liquid carrier, for example water for injection.Interim injection solution or suspensoid can be by sterilized powder, particle and tablet preparation.

Should be appreciated that except mentioned component described preparation also can comprise other this area relevant with the preparation type of discussing medicament commonly used, for example be suitable for those comprised seasoningss of oral administration.

As noted, the specific compound administration Mammals of the formula (I) of significant quantity will be treated.Typically, a kind of treatment significant quantity of administration medicament of the present invention depends on multiple factor, comprises accurate situation, the severity of illness, the character of preparation, the route of administration of for example mammiferous age, body weight, needs treatment.In a word, the treatment significant quantity will be determined cautiously by care physician or animal doctor.

Typically, the administration scope of formula (I) compound was 0.1 to 100mg/ every kg recipient (Mammals) body weight every day, was more typically for 1 to 10mg/kg body weight every day.

Point out as above-mentioned; the present invention relates to the method for cancer therapy, it comprises administration N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine (GW572016) and salt and/or solvate.

In Europe, bladder cancer is modal the 5th kind of malignant tumour, and in the U.S., it is that (Jensen 0, Esteve J.Eur J Cancer 1990 for the 4th kind of malignant tumour; 26:1167-256; JemalA, Thomas A.Cancer Statistics, 2002.CA Cancer J Clin 2002; 52:23-47).Worldwide, the bladder cancer of the overwhelming majority is (TCC) of transitional cell type, and it comprises 90 to 95% urothelium tumour.These tumours can be present in any position morbidity of urinary tract, comprise renal plevis, ureter, bladder (90%) and near 2/3rds positions of urethra.In clinical localized patient, muscle aggressive TCC, 20 to 80% can cure with suitable topical therapeutic, comprise surgical operation or radiotherapy.Other patient will develop into possible local recurrence of very little healing or metastatic disease (de Mulder p, van der MeijdenA.Bladder cancer.In:Oxford Textbook of Oncolog.2nd ed.Oxford, NY:Oxford University Press; 2002).

In treatment of urinary tract epithelial tumor treatment applicating evaluating many cytotoxic agents, comprise MVAC (methotrexate, vinealeucoblastine(VLB), Dx and cis-platinum) and CMV, it is considered to gold standard (Loehrer P, the Einhorn L.JClin Oncol 1992 of first-line treatment respectively at US and European at present; 10:1066-1073); Von der Maase H, Hansen S., J ClinOncol 2000; 18:3068-3077).Gemcitabine/cis-platinum (GC) is the another kind of MVAC medication diagram with safer characteristic, and it more and more is much accounted of use, especially is proved to be a line medicine since gemcitabine.

Clearly the medicine of the TCC of the late period in the second line treatment urothelium road of Que Dinging or transfer seldom.Exist to be used for the treatment of the unratified medicament of suffering from recurrent bladder cancer and/or other urothelium cancer patient, described disease of patient be develop after with platinum base chemotherapy due to.The most conventional medicament that uses is taxanes, gemcitabine, mitomycin and anthracycline antibiotics.Response rate changes between 7% to 27%, and the progress time (time to progression) is (TTP) short usually, and OAS (OS) lacks usually.Because the prediction of bladder cancer is relatively poor and its available therapeutical agent deficiency, thereby this disease has been represented does not really have satisfied medical science needs, requires the further effective therapeutical agent of research.

Relevant (Mellon J, Lunec J., the J Uro 1996 of expression excessively of EGFR in bladder cancer (erbB1) and erbB2 with the tumour of late period and senior (highgrade); 155:321-6; OrlandoC, Sestini R., J Urol 1996; 156:2089-2093) .ErbB1 and erbB2 express in 72.2% and 44.5% primary bladder cancer example respectively.That finds erbB1 and erbB2 in 33.9% example unites expression (Chow N-H, Chan S-H., Clin Cancer Res2001; 7:1957-1962).GW572016, a kind of erbB1 and erbB2 effectively and the selectivity double inhibitor, therefore, can provide a kind of TCC patient who is used for the treatment of the local late period of suffering from the urothelium road or transfer effective, well tolerable property and treatment selection easily.

Implement to provide a kind of method for the treatment of urothelium cancer in the Mammals in the diagram at one of the present invention, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is the compound of formula (I '), the preferred formula (compound of I ").Implement in the diagram at one of the present invention, the method for bladder cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.Implement to provide the method for the bladder cancer of treatment Mammals middle and advanced stage or transfer in the diagram at of the present invention another, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at of the present invention another, the method for transitional cell bladder cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.

In the west, carcinoma of the pancreas is for being caused a kind of in dead preceding 10 kinds of causes of disease by cancer.Surgical excision improved should disease prospect, percent 10 Pancreas cancer patients is suitable to adopt this method although only have.Most treatment failure is because local recurrence, hepatic metastases or both have, and comes across surgical operation after one to two year.Advanced pancreatic cancer has treatment seldom to select and make us melancholy prognosis.Be lower than 2% Pancreas cancer patients and live through 5 years.The Pancreas cancer patients of suffering from local late period at present adopts chemoradiotherapy, is generally the medication diagram of Fluracil (FU) or gemcitabine-Ji, or uses gemcitabine separately.For the tumour of remote transfer (distant metastases), gemcitabine has become nursing standard, after small-sized random test, with compare with FU-base medication diagram, it demonstrates the appropriateness raising (the 5.6v4.4 month) that the related indication significance of cancer is improved (clinical useful the replying of 23.8%v4.8%) and OAS.In the survival rate of uniting or do not improve the Pancreas cancer patients of gemcitabine treatment by gemcitabine and FU with the up-to-date trial in the randomized controlled trial of BAY12-9566, marimastat or Farnesyltransferase inhibitor tipifarnib replacement gemcitabine.It is about 30% that ErbB1 is expressed as, and erbB2 is expressed as about 70%.

Implement in the diagram at one of the present invention, the method for carcinoma of the pancreas in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

The evaluation of prostate cancer sickness rate shows, has in the U.S. in 2003 to surpass 220,000 new diagnosed SARS case, causes surpassing 28,000 people's death.In Britain, Italy, Spain, France and German, diagnosis has 110, the 000 routine cases for prostate cancer of surpassing, and has to surpass 46,000 examples because this is died of illness and dies.And prostate cancer is the whole world male sex's the 4th a kind of modal cancer.Comprising that radiation or prostatectomy really after the foregone conclusion portion treatment, have the patients with prostate cancer recurrence near half to be terminal illness.Can remove method (androgen ablation) with male sex hormone and effectively treat although suffer from the patient of advanced prostate cancer, its effect to disease process is temporary.It is invalid that these patients finally can remove method to male sex hormone, finally is categorized as hormone refractoriness prostate cancer (HRPC) [Crawford, 1989; Eisenberger, 1994].The Standard Selection of suffering from HRPC patient comprises hormonotherapy for the second time or chemotherapy.Comprise that as if the combination chemotherapy medication diagram that influences microtubule integrity medicament have the activity of tolerable side effect.Yet,, mediumly reply the time length and be defined as approximately June although there is high prostate specific antigen (PSA) response rate.Survival benefit (Survival benefit) has obtained confirmation.Although obtained the development of remission and the raising of life treatment, but still need to improve the inventive process of survival rate with chemotherapy and steroid.The novel method of treatment prostate cancer comprises that use is to the survive target therapeutic agent of key path of tumour cell.For the treatment of transitivity HRPC, use mitoxantrone/prednisone or estramustine usually.And, ratified Docetaxel (75mg/m2, per 3 weeks) and the line medicament of prednisone associating on May 19th, 2004 as the transitivity HRPC of treatment.At present, multiple LHRH agonist and antiandrogen are used to the hormone-sensitive prostate cancer.Some uses a small amount of test well afoot of chemotherapeutic agent.Under this situation (setting), the erbB1/2 inhibitor can delay to use the male sex hormone blocker and with the xicity related ability of this therapy will be clinically important advantage.In prostate cancer, erbB1 and erbB2 express.Great majority research has shown to express in the prostate cancer process to be increased, because it is to the hormonotherapy of standard produce effects (41-100%erbB1 not; 20-80%erbB2).In prostate cancer, also hopeless with the clinical study of ErbB1 or ErbB2 targeted therapies.Because the expression of erbB1 and erbB2 is with relevant to the process of hormone refractoriness disease prostate cancer, the double inhibitor of erbB acceptor can provide the more effective treatment selection of medicine that suppresses arbitrary independent acceptor than specificity.

Implement in the diagram at one of the present invention, the method for prostate cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, preferred formula (I ") compound is implemented in the diagram at one of the present invention; the method that hormone in the treatment Mammals should (hormone refractory) prostate cancer is provided, comprises: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

Colorectal carcinoma is the 4th kind of main cancer types of Western society, is the second kind of cause of disease that causes the death of cancer dependency in North America.In the U.S., the sickness rate in colorectal carcinoma every year is about 148,300 examples (influencing 72,600 male sex and 75,700 women), by 56,600 examples dead (wherein 27,800 male sex and 28,800 women) are arranged.The lifetime risk of colorectal carcinoma is about percent 5 to 6 in general crowd.Those that suffer from that two or more one-levels of the patient of family's danger-have or second degree relative (or both) suffer from colorectal carcinoma one constitute all and suffer from colorectal carcinoma patients' about percent 20, yet about percent 5 to 10 of the annual total amount of colorectal carcinoma derives from the heredity of autosomal dominant mode.

Although independent surgical excision might be cured, but think and develop into part or remote many patients of recurring, should accept Fluracil based system assistant chemical therapy with those patients with high-risk recurrence, it has shown useful in a large amount of cooperation group tests and analysis.

In primary tumor, ErbB2 is that moderate to height indicator reaches.The vivoexpression of erbB2 is relevant to process, tumor stage, the initiation potential of cancer knurl sequence with adenoma, and it is the dependent/non-dependent prognosis factor of survival.ErbB1 expresses and is lower than erbB2 (40% to 60%), although its effect in growth may be more important than erbB2.The coexpression of erbB1 and erbB2 and erbB3 is～30% (all rank).

Implement in the diagram at one of the present invention, the method for colorectal carcinoma in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, preferred formula (I ") compound.Implement in the diagram at one, cancer is a colorectal carcinoma.Implement in the diagram at another, cancer is the rectum cancer.

The sickness rate of the annual lung cancer in the whole world is 1.24 million peoples.And, estimate that annual global 1.1 million peoples die from lung cancer [Parkin, 2001].These patients of about 3/4ths will suffer from nonsmall-cell lung cancer (NSCLC), and great majority suffer from local late period or metastatic disease with diagnosis.At present, these patients there is not curable therapy; Therefore, chemotherapeutic target is to improve the life treatment by slowing down symptom among the NSCLC patient.One line combination chemotherapy of advanced NSCLC can produce the response rate of 20-50%, and other patient has realized the stable of disease.The standard first-line treatment that is used for NSCLC at present comprises cisplatin combined vinorelbine or gemcitabine or carboplatin associating taxol or Docetaxel [Schiller, 2002; Fossella, 2003].People such as Schiller report the process time (TTP) of four platinum associating and total survival rate (OS), and are similar 4 months and 8 months respectively.People such as Fossella have reported 5 months and 9 months TTP and OS with carboplatin and Docetaxel associating.

Balance between the toxicity that the benefit (survival time prolongs or quality of life improves) of using the two wires chemotherapy to obtain to want is correlated with medicine.Docetaxel, vinorelbine, gemcitabine, irinotecan, taxol and premetrexed demonstrate activity as second line treatment to the patient who suffers from NSCLC.At present, the designated patient who is used for the treatment of the nonsmall-cell lung cancer of suffering from local late period or transfer of Docetaxel only, described patient are in advance with platinum base chemotherapy treatment failure.The EGFR inhibitor also is mentioned (looked at).In the U.S., Gefitinib (Iressa ) monotherapy has been approved for the patient of the NSCLC of local late period after two kinds of platinum bases of treatment and the failure of Docetaxel chemotherapy or transfer.The PRELIMINARY RESULTS of the three phases research of erlotinib in recurrent NSCLC patient (Tarceva ) shows the improvement that has realized total survival rate.Cetuximab (Erbitux ), target confirm to have found its activity to NSCLC recently in the monoclonal antibody of erbB1 in CRC and persistence (ongoing) test.

Implement in the diagram at one of the present invention, the method for lung cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.Implement in the diagram at one, cancer is a nonsmall-cell lung cancer.

In the U.S., annual about 14,300 women die from ovarian cancer.It is the 5th normal cancer among the women, is the cause of disease that causes reproductive system cancer (genital cancers) dead.Concerning the women who suffers from this local disease, suffering from the survival rate in 5 years of ovarian cancer is about 95%.Yet about 60% women suffers from ovarian cancer in late period (III/IV phase) when diagnosis, and the 5-annual survival rate of suffering from remote this disease only is 31%.Age and ethnic group influence the sickness rate and the survival rate of Age ovarian cancer.Age is that 65 years old or more old women have disease with high sickness rate (56.3/100ths, 000, by comparison, the age is less than being 11.2/100ths, 000 among 65 years old the women) and remarkable 5 low annual survival rates (32.9% to 65.8%).

In the U.S., the standard treatment that is used to suffer from the advanced ovarian cancer women (GOG) has been carried out a series of random tests at first by gynecological oncology group (Gynecologic Oncology Group) and has been studied.In 1996, the patient's of untreated III phase in late period and IV phase disease result before this group has been reported at random relatively and to have been suffered from cis-platinum and endoxan contrast cis-platinum and paclitaxel treatment.According to the following result of this test, it is more excellent to conclude that cis-platinum adds taxol medication diagram: improved whole response rate (73%v60%; P=.01); Increased clinical complete response rate (54%v32%); Improved non-carrying out property (progression-free) survival rate (PFS; 18.1v13.6 month; P＜.001); The most important thing is, improved all median survivals (38v24 month; P＜.001).Afterwards, the result of this test was by confirming the European-Canadian test of suffering from IIB to IV phase epithelium ovarian cancer patients, and described patient is appointed as cis-platinum equally at random and adds endoxan medication diagram contrast cis-platinum and add taxol.In test afterwards, cis-platinum and taxol are united at 3 hours drug administration by injection, and in the GOG test, taxol was at 24 hours drug administration by injection.Although the test design diagram is different, two researchs all confirm among the untreated advanced ovarian cancer patient, to add taxol with cis-platinum and just treat more excellent before suffering from.Carboplatin, the analogue of cis-platinum has littler non-hematotoxicity than parent compound cis-platinum, finds that also uniting of carboplatin and taxol is effective medication diagram.

ErbB1 generally expresses in the tumour example, and erbB-2 seldom expresses.

The coexpression of erbB1 and erbB2 is also very common.In heterograft animal model and patient's example, erbB1 is relatively poor survival rate and anti-chemotherapeutic dependent/non-dependent prognostic markers.ErbB1 crosses and is expressed as approximately 70%, and erbB2 crosses and is expressed as about 30-60%.The coexpression of erbB1 and erbB2 is also common: about 30-60%.In multivariate analysis, ErbB1 is expressed as the dependent/non-dependent prognostic factor of survival rate and DFS, yet the erbB2 prognosis values is more unreliable.In ovarian cancer cell line, there is erbB1 growth appurtenant evidence.

Implement in the diagram at one of the present invention, the method for ovarian cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

Carcinoma vulvae (Vulval cancer) is a cancer rare among the women, influences cysthus, and cysthus is the female sexual organ outside, more is common in middle age or the old women.The standard treatment that is used for carcinoma vulvae comprises surgery, radiation and/or chemotherapy, and typically at the early stage topical Fluracil of disease, for its late period or metastatic disease, administration of cisplatin is as monotherapy or other medicament.

Implement in the diagram at one of the present invention, the method for carcinoma vulvae in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

Cervical cancer is for being second kind of modal cancer in the Womankind Worldwide, is to cause in the under-developed country cause of disease of cancer dependency death among the women.The whole world, about 500, the 000 example cases of cervical cancer of annual diagnosis.In the U.S., the conventional underproduction has reduced the incidence of aggressive cervical cancer, and annual diagnosis about 13,000 routine aggressive cervical cancer cases and 50,000 routine original position neck carninomatosis examples (that is localized cancer).The aggressive cervical cancer is more common among middle age and old women and the women who differs from socioeconomics, and they are not easy to obtain clocklike inspection and early treatment.In American Women's Africa, America, Hispanic and local, also there is higher sickness rate.The standard treatment that is used for cervical cancer comprises surgery, radiation and/or chemotherapy, typically, points out that administration of cisplatin is as monotherapy or use other medicament, for example Fluracil.

Implement in the diagram at one of the present invention, the method for treatment Mammals cervical cancer is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

The erbB2 that relates in the Endometrial Carcinomas crosses expression, contains or do not contain gene amplification.Compare with the normal uterus intimal epithelium, 10 (10) to 15% carcinoma of endometrium showed expression, and was quantitative by immunohistochemistry.Some studies confirm that the erbB2 gene amplification in the carcinoma of endometrium of tumors subtypes (subset) demonstrated expression.If erbB2 crosses expression, think its be present in senior and/or the late tumor hypotype in.ErbB2 crosses the relation of expressing with clinical effectiveness and lacks clear and definite conclusion, expresses and the relevant trend of prognosis that worsens although observed. (Am J Obstet Gynecol 164:15-21,1991; Gynecol Oncol 47:179-185,1992; Gynecol Oncol 53:84-92,1994.)

Implement in the diagram at one of the present invention, the method for treatment Mammals carcinoma of endometrium is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

In the U.S., renal cell carcinoma (RCC) is the 6th kind and causes causing the dead cause of disease by cancer, accounts for about 3% adult malignant tumour.In 2000, in the U.S., there are about 31,200 routine diagnosed SARS cases, about 12,000 examples are dead.Other place in the world, M ﹠ M all are higher than 10 times.Sickness rate is the highest in the Scandinavia, but is lower than England and Wales in other place in Northern Europe.It is reported that minimum sickness rate is in India, China and Japanese and at the middle part or zone, southern America.In 25 years, sickness rate is stable to be increased in the past.ErbB1 crosses expression and rises to above 80% from 40%.It is relevant with survival rate with tumor stage to cross expression.Still disputable with the effect that the cytokine therapy of IL-2 and/or IFN-alpha suffers from patient's the survival time of late period and transitivity RCC in prolongation, reply speed and be about 15%, treat toxic basically.Replying the extended period is the 6-10 month.Anti-inherently chemotherapy of RCC and hormonotherapy be not because there is medicament can obtain surpassing replying of 10% patient consistently.

Implement in the diagram at one of the present invention, the method for treatment Mammals carcinoma mesonephric is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.Implement in the diagram at one, renal cell carcinoma (cancer) is renal cell carcinoma (carcinoma).

Mesothelioma is the cancer of pleura or peritonaeum internal layer.The expression of crossing of EGF-R ELISA (EGFR) generally is found in many solid knurls, comprising lung knurl, mastadenoma and mesothelioma.This is crossed expression and has demonstrated relevant with chemotherapy with anti-radiation with the prognosis of difference.Present evidence shows the just adjusting of EGFR and activates and can play key effect in the carcinogenic in early days incident.Carcinogenic fibrous magnesium silicate, the known mesothelioma cause of disease, the known expression of crossing that can just regulate EGFR.The MET5A cell causes activating nf-kB (NF-kB) to the exposure of asbestos, a kind of in a large amount of the adjusting in gene to inflammation, propagation and lung protects important transcription factor.Very important (Faaux in the new therapeutic strategy that is adjusted in research chemoprophylaxis and treatment malignant mesothe of the EGFR/NF-kB signal path of asbestos mediation, EGFR Induced Activation of NF-kB inMesothelial Cells by Asbestos Is Important in Cell Survival, Proceedings of the American Association for Cancer Research, AACR, Vol.42, March 2001).

Implement in the diagram at one of the present invention, the method for mesothelioma in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of giving the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

In the U.S., by the cancer that oesophagus causes, comprise stomach oesophagus joint, uncommon relatively, in 2003, report had 13,900 routine new cases, and 13,000 examples are dead.Danger increased with the age, and average diagnosis of age is 67 years old.The esophageal carcinoma is for causing the 7th the dead cause of disease by cancer among the American.In the whole world, the esophageal carcinoma is the 6th cause of disease that is caused death by cancer.Surpassing percent 90 the esophageal carcinoma is squamous cell carcinoma or gland cancer.About 3/4ths find and terminal oesophagus in all gland cancer, yet squamous cell carcinoma is for being evenly distributed in middle age and youngster (middle and lower third).In a word, when discovered, surpass percent 50 patient and suffer from and to excise or metastatic disease.All the survival rate variances in 5 years are percent 14 at present.Although the squamous cell carcinoma of oesophagus and gland cancer are all replied chemotherapy, there is not the medication diagram of approval at present.In suffering from carcinoma of esophagus patients, express ErbB1 (30% adenocarcinoid; 70% flaky), appear as prognostic indicator.In tip oesophagus and GE joint, ErbB2 is expressed as about 25%.

Implement in the diagram at one of the present invention, the method for esophoria cancer in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

Some clinical cases learn (clinicopathological) research used immunohistochemical detection in pernicious salivary gland tumor EGFR and crossing of erbB2 express.For adenoidcyctic carcinoma (ACC), the frequency shift that EGFR crosses expression is 0-85%, and same, the frequency shift that erbB2 crosses expression is 0-100%.These frequencies are usually based on the limited sample capacity of little series.For example dye and the selection of the different and antibody of scoring method by the laboratory for other factors, may cause result's unhomogeneity.(people such as Glisson in 137 routine salivary-gland carcinomas of nearest disclosed one big group, ClinCanRes, 10:944-46,2004), in whole histology hypotypes of salivary-gland carcinoma, all frequencies (at least 10% tumour cell, 2+ to the 3+ film dyeing completely of keeping the score is crossed expression as positivity) that erbB2 crosses expression are 17% (23/137ths).Discovery crossing of erbB2 in ACC expressed seldom (3/4%, 70), yet crossing in salivary duct carcinoma expressed and be generally (10/83%, 12).Feel the Aggression of this observations and typical high-level organization feature and salivary ducts hypotype and be similar to the tissue generation of mammary cancer consistent.

Implement in the diagram at one of the present invention, the method for salivary-gland carcinoma in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

Hepatocellular carcinoma (HCC) is modal cancer, and there is 1.2 hundred million cases every year in the whole world.Because the infectious wide-scale distribution of C type hepatitis, its sickness rate increases fast.In the U.S., 17,300 routine cases were arranged approximately in 2003,14,400 examples are dead.Surgical operation is that the treatment of suffering from the small number of patients that can excise disease is selected.The treatment of local HCC comprises surgical operation, radiofrequency ablation (radiofrequency ablation), injection ethanol or through the arterial chemotherapy embolism.There is not definite adjuvant therapy, most of tumor recurrences.The poor prognosis of recurrent or transitivity HCC, median survival are 6 months.Dx as single medicament or combined utilization, is generally used for treating HCC in late period; Yet it is low to reply speed, in this case, does not improve survival rate.Also normal enforcement forms with chemotherapeutic TAE (Chemoembolism) or through arterial thrombosis.Reported erbB1 expressing excessively in HCC, reported that also having crossing of multiple degree expresses.In tumour, ErbB1 expresses relevant with anti-chemotherapy with aggressive growth, poor prognosis.In hepatoma cell line, it is important growth regulator that ErbB1 and erbB2 express.

Implement in the diagram at one of the present invention, the method for hepatocellular carcinoma in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

EGFR cross to express people such as (, ClinCanRes, 8:3496-3502,2002) Heimberger usually in malignant brain tumor, described brain tumor comprises neurospongioma people such as (, ClinCanRes, 5:1786-1792,1999) Bredel.Therefore, GW572016, as effectively and dual erbB1 of selectivity and erbB2 inhibitor, can be provided for suffering from brain tumor comprise gliomatous patient effective, well tolerable and treatment selection easily.

Implement in the diagram at one of the present invention, the method for the cancer of the brain in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.Implement in the diagram at one, the cancer of the brain is a neurospongioma.

Melanoma is the skin carcinoma of very serious form.It is fallen ill in melanophore, and melanophore is referred to as melanic pigment for giving skin.Although only account for 4% of all skin carcinoma cases in melanoma, it causes the Cancer-Related death of topmost skin.Typically, adopt the surgical operation therapy melanoma, use immunotherapy to treat high-risk case, adopt for example Interferon Alpha-2b.

Implement in the diagram at one of the present invention, melanomatous method in the treatment Mammals is provided, comprising: formula (I) compound and its salt or the solvate of the described Mammals treatment of administration significant quantity.Implement in the diagram at another, compound is formula (I ') compound, and preferred formula (I ") compound.

In aforementioned cancer treatment method of the present invention, formula (I), (I ') and (I ") compound is aforesaid.

Following embodiment only is intended to be used for set forth, and the scope that is not meant to limit the present invention in any manner.

Embodiment

As used in this article, those that for example use among Journal of the American Chemical Society or the Journal of Biological Chemistry in the mark that uses in these methods, diagram and embodiment and convention and the current scientific literature are consistent.The single letter of standard or the abbreviation of three letters are generally used for representing amino-acid residue, except as otherwise noted, suppose that it is the L-configuration.Except as otherwise noted, all initial substances derive from the available commercial merchant, need not be further purified use.

Especially, can in embodiment and specification sheets, use following abbreviation:

G (gram); Mg (milligram);

L (liter); ML (milliliter);

μ L (microlitre) psi (pound/square inch);

M (mole); MM (mmole);

N (normally); Kg (kilogram);

I.v. (intravenous injection); Hz (hertz);

MHz (megahertz) mol (mole);

Mmol (mmole); RT (room temperature);

Min (minute) h (hour);

Mp (fusing point); TLC (thin-layer chromatography);

Tr (retention time); RP (anti-phase);

DCM (methylene dichloride); DCE (ethylene dichloride)

DMF (N, dinethylformamide); HOAc (acetic acid);

TMSE (2-(TMS) ethyl); TMS (TMS);

TIPS (triisopropyl silyl); TBS (t-butyldimethylsilyl);

HPLC (high pressure lipuid chromatography (HPLC));

THF (tetrahydrofuran (THF)); DMSO (methyl-sulphoxide);

EtOAc (ethyl acetate); DME (1, the 2-glycol dimethyl ether);

The EDTA ethylenediamine tetraacetic acid (EDTA);

The FBS foetal calf serum

IMDM Iscove ' s Modified Dulbecco ' s medium

IMS industry methylated spirits;

The PBS phosphate buffered saline;

RPMI Roswell Park Memorial Institute

RIPA damping fluid *

The RT room temperature

^*150mM NaCl, 50mM Tris-HCI, pH7.5,0.25% (w/v)-Septochol, 1%NP-40,5mM sodium orthovanadate, 2mM Sodium Fluoride and proteinase inhibitor cocktail.

Except as otherwise noted, all temperature with ℃ (degree centigrade) expression.Except as otherwise noted, all being reflected under inert conditions and the room temperature carried out.

GW572016F is lapatanib, its chemistry N-{3-chloro-4-[(3-fluorobenzene methyl by name) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine xylenesulfonate monohydrate.

Embodiment 1

The preparation of GW572016F

Stage 1

Under 20 to 25 ℃, use tri-n-butylamine (1.2 equivalent) to handle toluene (5 volume) suspension of the 3H-6-quinazoline-4-one (compd A) that stirs, then, be heated to 90 ℃.Add phosphorus oxychloride (Phosphorous oxychloride) (1.1 equivalent), heating reflux reaction mixture then.Reaction mixture is cooled to 50 ℃, adds toluene (5 volume).The Compound C (1.03 equivalent) that adds solid form, the heating slurries are back to 90 ℃, stir 1 hour.Slurries are transferred in second container; Wash first container and and reaction mixture with toluene (2 volume).Reaction mixture is cooled to 70 ℃, dripped 1.0M water-based sodium hydroxide solution (16 volume) in 1 hour to the slurries that stir, keeping the composition temperature is 68-72 ℃.Stirred 1 hour at 65-70 ℃, then at 1 hour internal cooling to 20 ℃.Stirred suspension 2 hours at 20 ℃, filter and collect product, continuous water (3 * 5 volume) and washing with alcohol are then 50-60 ℃ of vacuum-drying.The several quality according to the compd A that uses of volume are quoted (quoted) as proof.The yield percentage scope of actual measurement: 90% to 95%, white or yellow crystals.

Stage 2

With N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-iodo-4-quinazoline amine-Compound D (1wt), boric acid-compd E (0.37wt, 1.35 mixture homogenate in IMS (15 volume) of (0.028wt, 50% moisture) 10% palladium equivalent) and on the gac.The suspension that stirring obtains 5 minutes is handled with diisopropylethylamine (0.39 volume, 1.15 equivalents), be heated to then 70 ℃ about 3 hours, up to react completely (analyze with HPLC and determine).With tetrahydrofuran (THF) (THF, 15 volumes) diluted mixture thing, heat filters catalyzer then.Container washs (2 volume) with IMS.

In 5-10 minute, the aqueous solution (1.5 volume) of tosic acid monohydrate (1.5wt, 4 equivalents) is joined in the filtered solution, remain on 65 ℃.When 60-75 ℃ stir suspension crystallization in 1 hour after, at 1 hour internal cooling to 25 ℃, stirring at room is 2 hours once more.Solid collected by filtration, with IMS (3 volume) washing, then in about 50 ℃ of vacuum-dryings, the compound F 17-hydroxy-corticosterone that obtains wanting is orange crystalline solid (separating) from the alcohol solvent compound that comprises about 5%w/w EtOH.

Stage 3

With compound F 17-hydroxy-corticosterone ^#(1 weight) and 2-(methylsulfonyl) ethamine (0.4 weight, 1.62 equivalents) are suspended among the THF (10 volume).Add acetic acid (0.354 volume, 4 equivalents) and diisopropylethylamine (DIPEA, 1.08 volumes, 4.01 equivalents) continuously.About 1 hour of the solution that obtains 30-35 ℃ of stirring is cooled to 22 ℃.Then, in about 15 minutes, constantly filler adds triacetoxy boron hydride thing (0.66 weight, 2.01 equivalents) (can see some effervescence in this point).At about 22 ℃ of mixtures that stirring obtains, sampling is used for the HPLC analysis then.Add water-based sodium hydroxide (25%w/w, 3 volumes), and then add entry (2 volume) cancellation reaction, stir about 30 minutes (when beginning to add caustic soda, can see some effervescence).

Then, water phase separated.With THF (2 volume) extraction, use the watersoluble chlorinated ammonium solution of 25%w/v (2 * 5 volume) then ²Washing blended THF extract.The aqueous solution (1 volume) of preparation tosic acid monohydrate (p-TSA, 0.74wt, 2.5 equivalents) ¹, be heated to about 60 ℃, add (0.002wt) crystal seed (seeds) of GW572016F (compound G).

In at least 30 minutes, give to add in the free alkali THF solution of GW572016, keep batch temperature (batch temperature) simultaneously at 60 ± 3 ℃ to TSA solution.Obtain in about 60 ℃ of stirrings suspension 1-2 hour, at 1 hour internal cooling to 20-25 ℃, aging about 1 hour of this temperature.Solid collected by filtration, with 95: 5 THF: water (3 * 2 volume) washing in about 35 ℃ of vacuum-dryings, obtained GW572016F-compound G, glassy yellow crystalline solid.Expection productive rate 80%, theoretical yield 117%w/w.

¹About 1 volume of minimal reaction volume.

²Maximum reaction volume is about 17 volumes.

# analyzes rectification

Stage 4

With N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-tetrahydrofuran (THF) (THF of the xylenesulfonate monohydrate salt of 4-quinazoline amine-compound G (1wt); 14 volumes) and the suspension of water (6 volume) be heated to about 55-60 ℃; heated 30 minutes; obtain settled solution; filter; wash in the crystallisation vessel with THF/ water (7: 3 ratios, 2 volumes) drainage.The solution that reflux obtains under atmospheric pressure, steams and removes tetrahydrofuran (THF) (9vol is with the azeotropic mixture of water 95%w/w).

Described solution contains composition N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine xylenesulfonate monohydrate (0.002wt).Crystallization Once you begin adds entry (6 volume), keeps temperature of reaction to be higher than 55 ℃ simultaneously.In about 2 hours, cooling mixture is to 5-15 ℃.Solid collected by filtration; with tetrahydrofuran (THF)/water (3: 7 ratios; 2 volumes) washing; use tetrahydrofuran (THF)/water (19: 1 ratios then; 2 volumes); 45 ℃ of vacuum-dryings, obtain N-{3-chloro-4-[(3-fluorobenzene methyl) oxygen] phenyl }-6-[5-({ [2-(methane sulfonyl) ethyl] amino } methyl)-2-furyl]-4-quinazoline amine xylenesulfonate monohydrate, be the glassy yellow solid crystal.

Embodiment 2

Definite (the IC that suppresses the GW 572016F concentration of 50% cell growth ₅₀)

Human bladder clone HT-1197, HT-1376 and T24 and ovary cell line SKOV3 derive from American Type Culture Collection.Described cell is kept in the tissue culture flasks that contains RPMI1640 (Invitrogen#22400-089), contain among the RPMI1640 10% foetal calf serum (FBS, HyClone#SH30071.03), and at 37 ℃ in containing 5%CO ₂Atmosphere in cultivate, up to being used for determining IC ₅₀Plating.In order to determine IC ₅₀, cell is positioned over suitable in 96 hole tissue culture wares, in the substratum of every hole 5,000 cells, put back to incubator and spend the night.After introducing a fine variety about 24 hours at first, with cellular exposure in the dimethylbenzene sulphonyl salt form of GW572016, GW 572016F.Cell is in 50%RPMI and 50% low dextrose DMEM medium, and it comprises 5%FBS, 50 micrograms/ml gentamicin and 0.3%DMSO, gives the wherein GW 572016F of three times of serial dilutions of dosing.Ultimate density is 30 micromole to 0.00152 micromoles.After compound exposed three days, growth medium was removed in suction.(Sigma#M9140,50: 50 ethanol of 0.5%: the aqueous solution), incubated at room temperature was estimated cellular biomass at least in 30 minutes then with the methylene blue staining cell in the every hole of 0.1ml.The suction stain will be cultivated the people and be immersed in the deionized water and wash, then dry air.Make cell discharge stain by the solubilizing agent (the PBS solution of 1.0%N-l lauryl sarkosine, sodium salt, Sigma#L5121) that adds 0.1ml.Incubated at room temperature culture dish 40 minutes.With the TecanSpectra microplate reader in 620nM reading specific absorption.Calculating is with respect to the cell growth-inhibiting per-cent of untreated control cells.Use Levenberg and Marquardt method (Mager, 1972) and equation y=Vmax*[1-(x ⁿ/ (K ⁿ+ x ⁿ))] (wherein " K " equals IC ₅₀) calculate IC ₅₀Value.

The result of result and other clone is presented in the table 1.Prepare other clone according to being similar to the method for in embodiment 2, describing, and be exposed to GW 572016F.All clone derives from American Type Culture Collection, and the concentration of placement is for providing the concentration of compound exposure with the logarithmic growth of time length.

Table 1

Tissue-derived	Clone	Growth-inhibiting (IC50 μ M)
			Bladder	H1197	7.78
Bladder	H1376	3.34
			Bladder	T24	8.22
Adenocarcinoma of colon	SW480	6.86
			Colorectal carcinoma	Lovo	3.39
Colorectal carcinoma	HCT116	5.87
			Colon-caecum	NCI-H747	1.49
Adenocarcinoma of colon	LS174T	1.51
			Adenocarcinoma of colon	DLD-1	3.63
Adenocarcinoma of colon	HT29	5.24
			Adenocarcinoma of colon	SW620	6.75
Adenocarcinoma of colon	Colo205	7.70
			The rectum cancer	SW837	4.7
Colorectal carcinoma	RKO	5.48
			Carcinoma of the pancreas	B×PC3	1.41
Lung cancer	H157	5.98
			Lung carcinoid segmental bronchus	NCI-H727	7.59
Lung cancer	NCI-H2009	11.5
			Lung cancer	A549	4.98
Lung cancer	A427	5.95
			Lung cancer	NCI-H460	9.00
Lung cancer	CaLu3	0.057
			NSCLC	NCI-H322	0.92
The NSCLC-alveolar	NCI-H358	0.27
			The lung epiderm-like	Calu1	5.51
Melanoma	SKMEL28	5.90
			Normal breast	HMEC	1.34
Normal people's foreskin	HFF	6.45
			Ovarian cancer	SKOV3	1.25
Prostate cancer	PC3	7.15
			Prostate cancer	LNCaP	4.69
Kidney	786O	1.82
			The erbB2 of transfection	H16N2	0.03
The Vulval cancer	A431	0.23

Embodiment 3

The clinical study of the single medicament lapatinib of oral administration, it suffers from the local late period in urothelium road or transitivity transitional cell carcinoma patient's medicine for second line treatment

58 suffer from local late period or transitivity urothelium tumour patient, they are in platinum base treatment back development and cause, and accept 1250mg lapatinib once a day, increase the weight of or pathology disappears up to disease.Carry out security and validity mensuration (independent assessment) at the interval in 4 weeks and 8 weeks respectively.Also estimate the patient that disease disappears, per two weeks are measured until death.30 patient's data of intermediate value assay (in 16 weeks of research) are listed in this article.

Mean age is 62 years old.Most patients (67%) has visceral metastases.Confirmed that all patients express erbB1 and/or erbB2 (1+, 2+ or 3+ pass through immunohistochemistry).Only 19 patients (63%) accept lapatinib, and it is the second line treatment agent of expection.In initial test, three patients' (10%) tumour reduces, and is restricted to partial reaction (PR); Yet in the 8th week, only a PR obtains confirming.Eight patients (27%) have stable disease (SD), and writing down 5 has the cell reduction.In 3 patients (10%), find clinical benefit (SD in＞June).Five (17%) patients suffer from the progressivity disease, and 11 patients (37%) withdrawed from before 8 weeks, and 3 patients (10%) do not obtain to estimate.Progression of disease is the common cause that withdraws from.

Second line treatment with oral administration lapatinib demonstrates activity likely, and it has good tolerability usually in local late period or transitivity urothelium tumour.

Embodiment 3A

The II phase clinical study of the lapatinib of the single medicament of oral administration, it suffers from the local late period in urothelium road or transitivity transitional cell carcinoma patient's medicine for second line treatment

Method: initial end points is RECIST response rate (by independent radiology evaluation).Main criterion of acceptability comprises the IIIB of bladder or the expression (1+ of the TCC of IV phase (causing in the back development of line platinum base medication diagram), predictable disease, erbB1 and/or erbB2,2+ or 3+ pass through immunohistochemistry) and the Karnofsky performance status be 70 or higher.Oral administration lapatinib (1250mg, daily), up to progression of disease or unacceptable toxicity occurs.Respectively in per 8 weeks with carry out tumour or security mensuration 4 weeks.In baseline and per 8 weeks, detect heart function.With multiple biomarker analysis tumor tissues (TUNEL, p53, pAkt, Her3, pHer3, pErk, IGF-1R, Rb, pS6).

Result: the patient who has registered the TCC of 59 the local late periods of suffering from bladder or transfer.The investigator reports that 2 (3%) partly reply (PR), and 12 (20%) have stable disease (SD); Independent radiology evaluation report 1 (2%) PR and 18 (31%) SD.Based on the investigator with independently check, six and three patients have persistent SD, lasting 4 months and 6 months respectively.In the 8th week, 10 patient tumors growths have cytostasis up to 20%, 4 patient, and 10 patients have the cell reduction.It is short-term that most tumour is shunk; Yet a patient has kept＞56 weeks under study for action.Average T TP is 8.6 weeks (95%Cl, 8.00,11.29), and the intermediate value survival time is 17.9 weeks (95%Cl, 13.14,30.29).In being the patient of 2+ and 3+, rbB1 or erbB2 observe the trend that clinical benefit increases.The following measurable patient of biomarker of initial analysis revealed will have refractoriness to Lapatinib: high pHer3, high pErk and two kinds of mutant p53﹠amp; High pHer3.On the contrary, suffers from the patient of high pAkt and high IGF-1R to the lapatinib sensitivity.

Have 10% side reaction (AEs) for diarrhoea (39%), rash (32%), feel sick (27%), vomiting (22%), weak (12%) and fatigue (10%).The 3/4 grade of AEs that is present in more than a patient is vomiting (7%) and diarrhoea (3%).A patient does not have symptom, and 2 grades for having reduced cardiac ejection fraction.

Conclusion: in a word, to late period or transitivity TCC recurrence, bladder, lapatinib is well tolerable property, and shows single therapeutic activity, and investigator and observing separately estimates and confirms clinical benefit (CR+PR+SD 〉=16weeks) is respectively patient's 14% and 12%.Average T TP was 8.6 weeks, was equivalent to the report of various chemotherapeutics in the second line treatment.Immunohistochemistry shows in the patient of containing erbB1 or erbB2 2-3+ the trend that trends towards clinical benefit.

Embodiment 4

Oral administration suffers from the clinical study of the patient lapatinib of solid tumor

Handle 81 patients (pts) (27 colorectal carcinomas, 7 lung cancer, 6 unknown primary gland cancer (AUP), 5H﹠amp with lapatinib; N, other (referring to Table II) of 6 kidneys, 6 mammary cancer, 4 ovarian cancers and 15), (qd) or twice (bid) once a day, the dosage designs scale increases.40 patient 175-1800mg of administration qd, 41 patients 500,750 of administration or 900mg bid.Every month evaluate patient is up to progression of disease or insupportable side effect occurs.Per 8 weeks are measured clinical response.

Cross at erbB1 and to observe a CR (continuing the 16+ month) in the cancer of the brain of expression or the neck squamous cell carcinoma.24 patients suffer from kinds of tumors, cross expression erbB1 or erbB2 mainly, experience SD, and average duration is 4 months (scope is 1-13+ month).Administration patient lapatinib, dosage be 〉=1200mg/ days, and treatment is＞4 months continuously.In 22 SD patients, 2 have nonsmall-cell lung cancer and AUP to be transferred to lung, all former treatment are got along with, and divide to keep in addition the lapatinib12+ and the 8+ month.The case that does not have interstitial pneumonia.

In severe pretreat crowd, the clinical activity evidence shows that QD administration lapatinib has good tolerability.The result is presented in the Table II, comprises in the table 2 only accepting the patient that lapatinib surpasses 4 months.

Table 2

Tumor type	# patient	Clinical response
			Colorectal carcinoma	27	SD＝3
Mammary cancer	6	SD＝2
			AUP	6	SD＝1
NSCLC	7	SD＝3
			Kidney	6	SD＝2
The cancer of the brain and neck cancer	9	CR＝1；SD＝3
			Mesothelioma	3	SD＝1
Ovarian cancer	4
			Carcinoma of the pancreas	2
Cervical cancer	2	SD＝1
			Cancer of the stomach	1
Gastrointestinal cancer	1
			The bronchovesicular cancer	1
Prostate cancer	1
			The esophoria cancer	1
Neuroendocrine carcinoma	1
			Senior sarcoma	1
MLS	1
			The eye melanoma	1

CR-is defined as replying fully of target damage disappearance

PR-is defined as the part of at least 30% target damage minimizing and replys

SD-is defined as the stable disease that does not have growth or the damage of some target to reduce

Claims (32)

1. EGFR and/or erbB2 cross the expression method for cancer in the treatment Mammals, comprising: and the formula of the described Mammals treatment of administration significant quantity (I ") compound

2. the process of claim 1 wherein that cancer is a carcinoma of the pancreas.

3. the process of claim 1 wherein that cancer is a prostate cancer.

4. the process of claim 1 wherein that cancer is a hormone refractoriness prostate cancer.

5. the process of claim 1 wherein that cancer is a colorectal carcinoma.

6. the process of claim 1 wherein that cancer is a colorectal carcinoma.

7. the process of claim 1 wherein that cancer is the rectum cancer.

8. the process of claim 1 wherein that cancer is a nonsmall-cell lung cancer.

9. the process of claim 1 wherein that cancer is an ovarian cancer.

10. the process of claim 1 wherein that cancer is a carcinoma vulvae.

11. the process of claim 1 wherein that cancer is a cervical cancer.

12. the process of claim 1 wherein that cancer is a carcinoma of endometrium.

13. the process of claim 1 wherein that cancer is a mesothelioma.

14. the process of claim 1 wherein that cancer is the esophageal carcinoma.

15. the process of claim 1 wherein that cancer is a salivary-gland carcinoma.

16. the process of claim 1 wherein that cancer is a hepatocellular carcinoma.

17. the process of claim 1 wherein that cancer is the cancer of the brain.

18. the process of claim 1 wherein that cancer is a neurospongioma.

19. the process of claim 1 wherein that cancer is a melanoma.

20. EGFR crosses the expression method for cancer in the treatment Mammals, comprising: the formula of the described Mammals treatment of administration significant quantity (I ") compound

21. erbB2 crosses the forwarding method of expressing cancer in the treatment Mammals, comprising: the formula of the described Mammals treatment of administration significant quantity (I ") compound

22. EGFR and erbB2 cross the expression method for cancer in the treatment Mammals, comprising: the formula of the described Mammals treatment of administration significant quantity (I ") compound

23. the method for treatment Mammals carcinoma mesonephric comprises: formula (I) compound or its salt or the solvate of the described Mammals treatment of administration significant quantity:

24. the method for claim 23, its Chinese style (I) compound is formula (I ') compound formula or its anhydride or hydrate forms

25. the method for claim 23, its Chinese style (I) compound are formula (I ") compound

26. the method for claim 23, its carcinoma mesonephric are renal cell carcinoma.

27. the method for urothelium cancer in the treatment Mammals comprises: formula (I) compound or its salt or the solvate of the described Mammals treatment of administration significant quantity

28. the method for claim 27, its Chinese style (I) compound is formula (I ') compound or its anhydride or hydrate forms

29. the method for claim 27, its Chinese style (I) compound are formula (I ") compound

30. the method for claim 27, wherein said urothelium cancer is a bladder cancer.

31. the method for claim 27, wherein said urothelium cancer are late period or transitivity urothelium cancer.

32. the method for claim 27, wherein said urothelium cancer is a transitional cell carcinoma.