CN108024987A - Combination for the analog or derivative and platiniferous antitumor drug of the two to the water wei ling alcohol for the treatment of cancer - Google Patents

Abstract

The use of two to the water wei ling alcohol provides new therapeutic modality to treat the NSCLC for the brain metastes for including non-small cell lung cancer (NSCLC) and oophoroma and other types of malignant tumour.Two to the water wei ling alcohol is as generation N⁷The alkylating agent to methylate acts on DNA.Growth of the two to the water wei ling alcohol for suppressing cancer stem cell is effective, and has antitumor activity to Temozolomide, cis-platinum and tyrosine kinase inhibitor tumour difficult to treat；The medicine plays a role independently of MGMT repair mechanisms.Two to the water wei ling alcohol can be used together with other anti-tumor agents and have addition or an effect of super addition.

Description

Analog or derivative for the two to the water wei ling alcohol for the treatment of cancer resist swollen with platiniferous The combination of tumor medicine

Cross reference to related applications

This application claims enjoy J.A. bars examine et al. submitted on April 6th, 2015 it is entitled " using two to the water wei ling alcohol and The PCT Patent Application sequence number PCT/US2015/0244562's of its analogs and derivatives treatment non-small cell lung cancer and ovary " Rights and interests, which, which requires to enjoy J.A. bars, examines et al. submitted on April 4th, 2014 entitled and " uses two to the water wei ling alcohol And the like and derivatives for treatment non-small cell lung cancer " U.S. Provisional Patent Application sequence number 61/975,587 rights and interests and " two to the water wei ling alcohol and the like and derivative is used it is required that enjoying J. bars and examining et al. submitted on October 10th, 2014 entitled The rights and interests of the U.S. Consul patent application serial number 62/062,246 of thing treatment non-small cell lung cancer ".Above-mentioned PCT application and The content of the two US provisional patents is incorporated herein by reference.

Technical field

The present invention relates to the general domain of the proliferative disease including oncology, it is of the invention focus on being used for previously by The novel method of the improvement effectiveness of the chemical reagent, compound and the formulation that are limited to undesirable human treatment's effect and combination Thing, the chemical reagent, compound and formulation include substituted oneself such as two to the water wei ling alcohol and diacetyl two to the water wei ling alcohol The chemical reagent of sugar alcohol and other classifications.Especially, the present invention relates to remove water winged euonymus by two to the water wei ling alcohol, diacetyl two Alcohol or derivatives thereof or the like treats non-small cell lung cancer.It can be treated but usually resisted by platiniferous swollen by two to the water wei ling alcohol The tumour of tumor medicine treatment includes：The cervical carcinoma of common plus cisplatin in treatment, commonly uses the colorectal cancer of oxaliplatin treatment, commonly uses card The carcinoma of fallopian tube of the usually pipe cancer of platinum (carboplatin) treatment, and the carcinoma of urinary bladder of common plus cisplatin in treatment.

Background technology

Exploration and identification for the cure method of the disease of the threat to life of many afflicting humans are still an experience Property and sometimes accidental process.Although achieving many progress from basic scientific research to actual patient management aspect, The disorders such as cancers particularly for threat to life rationally and in terms of successfully finding useful therapy, inflammation, infection and its In terms of the therapy of his illness, however it remains huge sense of defeat.

Initiated from the National Cancer Institute (NCI) of early 1970s National Institutes of Health (NIH) Since " anticancer war ", various strategies and plans are formulated and have implemented, for preventing, diagnosing, treating and curing Cancer.It is most ancient and can be described as one of most successful project be synthesis and screening for anticancer bioactivity small chemistry Entity (<1500 molecular weight (MW)).Organize the project and be to improve and simplify chemically synthesis and biological screening to close Reason develops into the progress of the event of the preclinical study in human clinical trial, it is desirable to be able to finds the threat to life of many types Malignant tumour cure method.Except screening from prokaryotes all over the world, invertebrate, plant is collected and other Outside natural products and extract in source, from the synthesis of academic and industrial source and screen thousands of kinds of compounds into For and continue become be used for identify as potentially new active drug novel important feature main method.This be except Project outside other projects, other projects include being intended to the biological therapy medicine by boosting vaccine human immune system Thing, therapeutic antibodies, cell factor, lymphokine, tumor vascular development (angiogenesis) inhibitor or for changing cancer cell Genetic constitution Antisense gene therapy and other biological reaction control agent.

By National Cancer Institute, other government organs support real in academic or industrial research and exploitation both at home and abroad The work in room is tested, has generated the biology, chemistry and clinical information of incredible amount.In addition, giant chemical is founded Storehouse, and the in vitro and in vivo biological screening system of altitude feature has been successfully applied.However, pass through interior flower over the past thirty years Expense is accredited or finds result in preclinical with tens billion of dollars that are clinically supporting these to compare, only a few compounds The successful exploitation of useful treatment product.Even so, zooscopy, the body for ensureing further to cause clinical research Outer and internal biosystem and " decision tree " has been verified.By this work exploitation these projects, biological model, Clinical trial protocol and other information are still most important to finding and developing any new therapeutic agent.

Regrettably, the compound of many federal regulatory requirements for being successfully realized preclinical test and clinical assessment is in people Or it is unsuccessful or disappointed in class clinical test.For determining maximum tolerated dose (MTD) and secondary work With in Human clinical's I phase dose escalation studies of overview, it is found that many compounds have unfavorable or specific side effect.At certain In the case of a little, the size of these toxicity or its toxicity is not yet determined or predicted in preclinical toxicologic study.In other situations Under, wherein in vitro and in vivo research proposal for the potential unique activity of specific tumors type chemical agent, molecular target or Biological pathways are unsuccessful in mankind's II clinical trial phases, in the mankind II clinical trial phases, particular cancers indication Or the specificity of type checks (such as U.S.'s food and Drug Administration (FDA)) in government's accreditation, mechanism of U.S. Ethic review It is evaluated in the clinical test of the committee (IRB) approval.Additionally, there are certain situation, there is potential new drug in those situations Agent is assessed as not confirming significant clinical benefit in random III clinical trial phases；These situations be also it is depressing and The reason for disappointed.Finally, many compounds have been realized in being commercialized, but their final clinical efficacy is subject to bad work( Effect such as monotherapy (<25% response rate) and unfavorable dose-limiting side effect (III level and IV grades) (such as marrow suppression System, neurotoxicity, cardiac toxic, gastrointestinal toxicity or other great side effects) limitation.

In many cases, by by the compound of conceptual phase develop and be moved to human clinical trial it is a large amount of when Between and expense after, and in the case where clinical failure occurs, trend is to return to laboratory to create more preferable analogies, is sought The medicament with different structure but potentially relevant mechanism of action is looked for, or attempts other modifications of medicine.In some cases, Through making an effort to attempt other I phases or II clinical trial phases, it is intended to special with regard to side effect to selection patient or cancer indication Sign or therapeutic effect carry out some improvement.In these situations in many cases, as a result sufficiently large improvement is not realized, with Ensure the further clinical development towards equipment registration.Even commercially produced product, its final use nevertheless suffers from undesirable The limitation of effect.

Since so few therapeutic agent is approved for cancer patient, and due to recognizing that cancer is that have a variety of diseases The set of the disease of cause, and response and survival of the patient in Results are complicated, wherein with many in treatment The factor to work in success or failure, including it is disease indication, invasion and metastatic diffusion stage, Gender, the age, strong Health situation, previous treatment or other diseases, the genetic marker and other factors that can promote or delay therapeutic efficiency, are controlled in the recent period More chance still unpredictable.In addition, American Cancer Society predicts that the incidence of the cancer of 2003 may proceed to rise about 4%, so as to be estimated to be the cases of cancer new more than 1,300,000.In addition, as the mammography of such as breast cancer is with before The progress of the diagnosis such as PSA (Prostate-Specific Antigen, the prostate-specific antigen) tests of row gland cancer, more Patient be diagnosed young when.For the cancer that treatment is difficult, the therapeutic choice of patient would generally exhaust quickly, Cause that there is an urgent need to other therapeutic scheme.Even for most limited PATIENT POPULATION, any other therapy apparatus can be all by tool There is sizable value.The present invention focuses on the composition and method of invention, for improving the compound of undesirable administration Treatment benefit, the compound include substitution hexitol such as two to the water wei ling alcohol.

Non-small cell lung cancer (NSCLC) includes the lung cancer of several types, including squamous cell carcinoma, large cell carcinoma and gland cancer, And other types of lung cancer.Smoking is clearly the most common reason of squamous cell carcinoma, and when no any previously smoking history When lung cancer occurs for patient, the lung cancer is often gland cancer.In many cases, NSCLC is very difficult to what is controlled for chemotherapy, Therefore surgery excision tumor mass is common therapeutic choice, particularly if when malignant tumour is early diagnosed out.However, chemotherapy and Radiotherapy is usually attempted, especially if diagnosis is not when the early stage of malignant tumour carries out.Other treatment includes RF ablation and chemoembolization.A variety of embolic chemotherapies have been attempted for late period or metastatic NSCLC.Some are in EGFR bases Because have specific mutation patient have to the EGFR tyrosine kinase inhibitors of such as Gefitinib reaction (M.G. Chris, “How Today’s Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow ' s Standards of Care, "Oncologist10(Suppl.2):23-29 (2005), passes through It is incorporated herein by reference).Cis-platinum is often used as the auxiliary treatment of operation.About 7% NSCLC has EML4-ALK transpositions, and Such patient may benefit from ALK (anaplastic lymphoma kinase, anaplastic lymphoma kinase), and inhibitor is such as It is gram vertical to replace Buddhist nun.Other treatment method, including Erlotinib, pemetrexed, vaccine TG4010, motesanibdiphosphate, for it is fragrant he Lu Dankang, the trastuzumab of resistance to former times, vaccine GSK1572932A, storehouse department do not replace gloomy sodium for Buddhist nun, Belotecan, methanesulfonic acid eribulin, thunder (custirsensodium), the vaccine BLP25 based on liposome, Buddhist nun not monoclonal antibody, EMD531444, up to gram replacing Buddhist nun (dacomitinib) and quignet spy must (genetespib) be evaluated, especially for late period or metastatic NSCLC.

It remains desirable, however, that for effective treatment of NSCLC, especially for the treatment of late period or metastatic NSCLC.It is excellent Selection of land, such treatment should be well tolerable, and if side effect, it should it can be easy to control.It is in addition, excellent Selection of land, such therapy should be mutually compatible with other chemical therapeutic methods and operation or radiation.In addition, and preferably, so Therapy should can play other treatment mode synergistic effect.

The content of the invention

Application of the substituted hexose 01 derivatives in terms for the treatment of non-small cell lung cancer (NSCLC) provides being used for for improvement The treatment method of NSCLC and oophoroma, the treatment method produce increased survival rate and there is no side effect.It is logical Often, available for the substituted hexanol of the method according to the invention and composition include dulcitol (galactitols), substitution defend Lance alcohol, galactitol (dulcitols), the galactitol of substitution.Usually, the substituted hexose 01 derivatives are selected from by two Dianhydrogalactitol, two to the water wei ling alcohol derivative, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derive The group that thing, mitolactol and mitolactol derivative are formed.Particularly preferred substituted hexose 01 derivatives are two to remove water Dulcitol (DAG).Substituted hexose 01 derivatives can be used together with other therapeutic modalities for these malignant tumours.Two Treatment of the dianhydrogalactitol especially suitable for these malignant tumours, because it can suppress the growth of cancer stem cell (CSC), and And because of it to O⁶The drug inactivation of-methyl guanine-dnmt rna (MGMT) has resistance.The substituted hexose 01 derivatives produce the response rate improved and improve the quality of life of NSCLC and ovarian cancer patients.

Two to the water wei ling alcohol is that N is produced in DNA⁷- Novel alkyl the agent to methylate.Specifically, two water winged euonymus is removed The main mechanism of alcohol is attributed to the difunctional N via true or derivative epoxide group⁷DNA is alkylated, described difunctional N⁷DNA alkylations are crosslinked across DNA chain.

Therefore, an aspect of of the present present invention is to improve to be used to treat NSCLC and the substituted hexose 01 derivatives of oophoroma Efficacy and/or the method for reducing its side effect, the described method comprises the following steps：

(1) identification and the effect of the administration of the substitution hexose 01 derivatives for treating NSCLC or oophoroma and/or side effect Related at least one factor or parameter occurs；And

(2) factor or parameter are adjusted to improve applying for the substituted hexose 01 derivatives for treating NSCLC or oophoroma With the effect of and/or reduce its side effect.

In general, the factor or parameter are selected from by the following group formed：

(1) dosage is adjusted；

(2) method of administration；

(3) administration time table；

(4) indication is used；

(5) selection of disease stage；

(6) other indications；

(7) patient selection；

(8) patient or disease phenotype；

(9) patient or genotyping of diseases；

(10) prepare before or after treatment；

(11) toxicity management；

(12) pharmacokinetics or pharmacodynamics monitoring；

(13) drug regimen；

(14) chemical sensitization (chemosensitization)；

(15) Chemical enhancement (chemopotentiation)；

(16) patient manages after treating；

(17) substitute medicine or therapy is supported；

(18) bulk material medicine improved product；

(19) diluent system；

(20) solvent system；

(21) excipient；

(22) formulation；

(23) dosage kit and packaging；

(24) drug delivery system；

(25) drug conjugate form；

(26) compound analog；

(27) pro-drug；

(28) multiple drug system；

(29) (enhancement) is strengthened in biological therapy；

(30) biological therapy resistance is modulated；

(31) radiotherapy is strengthened；

(32) novel mechanism；

(33) selective target cell group therapy；

(34) it is used together with ionizing radiation；

(35) it is used together with resisting the medicament of bone marrow suppression；And

(36) and the hexitol substituted is increased by blood-brain barrier to treat the medicament of the ability of the brain metastes of NSCLC or oophoroma It is used together.

As described above, in general, the substituted hexose 01 derivatives be selected from spread out by two to the water wei ling alcohol, two to the water wei ling alcohol Biology, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, mitolactol and mitolactol spread out The group that biology is formed.Preferably, the substituted hexose 01 derivatives are two to the water wei ling alcohol.

Another aspect of the present invention is to be spread out for improving using the substituted hexitol for being used to treat NSCLC or oophoroma The effect of undesirable dispenser therapy of biology and/or reduce the composition of its side effect, the composition include being selected from by with The substitute of the group of lower composition：

(i) the modified substituted hexose 01 derivatives of therapeutically effective amount or substitution hexose 01 derivatives derivative or Analog or pro-drug or the modified substituted derivative of hexose 01 derivatives or the like or pro-drug, wherein Compared with unmodified substituted hexose 01 derivatives, the modified substituted hexose 01 derivatives or the substitution The derivative of hexose 01 derivatives or the like or pro-drug or the modified substituted hexose 01 derivatives The derivative or the like or pro-drug, the treatment NSCLC of therapeutic efficiency or reduction with increased treatment NSCLC Side effect；

(ii) composition, the composition include：

(a) the hexose 01 derivatives of therapeutically effective amount substitution or modified substituted hexose 01 derivatives or the hexose of substitution The derivative or similar of derivative of 01 derivatives or the like or pro-drug or modified substituted hexose 01 derivatives Thing or pro-drug；And

(b) at least one other therapeutic agent, by chemotherapeutic therapeutic agent, therapeutic agent, diluent, figuration by Chemical enhancement Agent, solvent system, drug delivery system or the medicament for resisting bone marrow suppression, wherein with unmodified substituted hexitol Derivative is compared, the side effect of the treatment NSCLC of therapeutic efficiency or reduction of the composition with increased treatment NSCLC；

(iii) therapeutically effective amount include the substituted hexose 01 derivatives into formulation, modified substituted hexitol derives Thing or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted hexitol derive Derivative of thing or the like or pro-drug, wherein compared with unmodified substituted hexose 01 derivatives, it is described to include The substituted hexose 01 derivatives, modified substituted hexose 01 derivatives or the substituted hexitol for entering formulation derive The derivative of described derivative of thing or the like or pro-drug or the modified substituted hexose 01 derivatives Or the like or pro-drug, with increased treatment NSCLC therapeutic efficiency or reduction treatment NSCLC side effect；

(iv) the substituted hexose 01 derivatives, modified substituted included into dosage kit and packaging of therapeutically effective amount Hexose 01 derivatives or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted Derivative of hexose 01 derivatives or the like or pro-drug, wherein with unmodified substituted hexose 01 derivatives phase Than, it is described include into dosage kit and packaging substituted hexose 01 derivatives, modified substituted hexose 01 derivatives, Or described substituted described derivative of hexose 01 derivatives or the like or pro-drug or modified substituted oneself Described derivative of sugar alcohol derivant or the like or pro-drug, therapeutic efficiency or reduction with increased treatment NSCLC Treatment NSCLC side effect；And

(v) the substituted hexose 01 derivatives, modified substituted for being subject to bulk material medicine product improvement of therapeutically effective amount Hexose 01 derivatives or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted Derivative of hexose 01 derivatives or the like or pro-drug, wherein with unmodified substituted hexose 01 derivatives phase Than, be subject to bulk material medicine product improvement substituted hexose 01 derivatives or modified substituted hexose 01 derivatives or Substituted derivative of hexose 01 derivatives or the like or pro-drug or modified substituted hexose 01 derivatives spread out Biology or the like or pro-drug, the secondary work of the treatment NSCLC of therapeutic efficiency or reduction with increased treatment NSCLC With.

As described above, in general, the substituted hexose 01 derivatives be selected from spread out by two to the water wei ling alcohol, two to the water wei ling alcohol Biology, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, mitolactol and mitolactol spread out The group that biology is formed.Preferably, the unmodified substituted hexose 01 derivatives are two to the water wei ling alcohol.

Another aspect of the present invention is a kind of method for treating NSCLC, and the described method includes to the trouble with malignant tumour Person applies the step of substituted hexose 01 derivatives of therapeutically effective amount.As described above, the substituted hexose 01 derivatives choosing Free two to the water wei ling alcohol, two to the water wei ling alcohol derivative, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol The group that derivative, mitolactol and mitolactol derivative are formed.Preferably, the substituted hexose 01 derivatives are two Dianhydrogalactitol.This method can be used for treatment to tyrosine kinase inhibitor (TKI) or the chemotherapy based on platinum such as cis-platinum Medicament produces the patient of drug resistance.This method can also be used together with TKI or chemotherapeutant based on platinum.Suitably it is based on The chemotherapeutant of platinum treatment includes but not limited to cis-platinum and oxaliplatin.

Another aspect of the present invention is a kind of method for treating oophoroma, and the described method includes to the patient with oophoroma Using therapeutically effective amount substituted hexose 01 derivatives the step of.The hexose 01 derivatives suitably substituted are as described above；It is special The hexose 01 derivatives not substituted preferably are two to the water wei ling alcohol.In a kind of alternative solution, the oophoroma is to cis-platinum Drug resistant wild type p53 cancer.

Another aspect of the present invention is that a kind for the treatment of is suffered from selected from by II phases non-small cell lung cancer (NSCLC), III phases The method of the patient of the malignant tumour of the group of NSCLC and IV phases NSCLC compositions, this method comprise the following steps：

(a) to a effective amount of two to the water wei ling alcohol of patient therapeuticallv to treat the malignant tumour；And

(b) to patient therapeuticallv it is a effective amount of based on the antitumor agent of platinum to treat the malignant tumour.

In the method, in a kind of alternative solution, two to the water wei ling alcohol is applied after surgery excision NSCLC and is based on The antitumor agent of platinum.In another alternative solution, two to the water wei ling alcohol is applied before surgery excision NSCLC and based on platinum Antitumor agent to make Tumor shrank before surgery.

Brain metastes may occur for patient.This method is especially effective to the NSCLC patient for having been acknowledged or suspecting brain metastes.

In a kind of alternative solution, the two to the water wei ling alcohol and it is described based on the antitumor agent of platinum single medicine combine Applied in thing, wherein described pharmaceutical composition includes：(i) two to the water wei ling alcohol；(ii) antitumor agent based on platinum；And (iii) at least one pharmaceutically acceptable carrier.In another alternative solution, the two to the water wei ling alcohol and described it is based on The antitumor agent of platinum is applied in two kinds of pharmaceutical compositions：(i) include two to the water wei ling alcohol and at least one is pharmaceutically acceptable Carrier the first pharmaceutical composition；And (ii) includes the antitumor agent based on platinum and at least one pharmaceutically acceptable load Second pharmaceutical composition of body.

Patient can have the genotype of wild type p53.In another alternative solution, patient can have mutation P53 genotype；As the example shows, the mutation in p53 causes the resistance of two to the water wei ling alcohol is less than to Temozolomide or contained The resistance of platinum antineoplastic medicine, therefore two to the water wei ling alcohol is particularly effective such patient.The work of p53 is further elucidated below With.

In another alternative solution, patient can have the genotype of Wild type EGFR.

In another alternative solution, patient is in target of the coding as at least one tyrosine kinase inhibitor (TKI) Protein gene in there is at least one mutation.In another alternative solution, patient is characterized in that thering is at least one A other gene in wild type or mutation status, the gene code are assigned to the therapeutic effect of at least one TKI The product of resistance.The coding in wild type or mutation status is assigned to the another of the resistance of at least one TKI therapeutic effects Outer gene is AHI-1.The mutation of AHI-1 can be caused by provirus is inserted into.

In another alternative solution, patient is characterized by having one of the BCR-ABL fusion proteins as TKI targets Mutation in partial ABL1 protein kinase domains.

In another alternative solution, patient is characterized by having assigning tyrosine kinase inhibitor (TKI) resistance Germline deletion polymorphism (germline deletion polymorphism).Usually, germline DNA deletion polymorphisms are positions In the germline DNA deletion polymorphisms of the 2903bp of BIM genes, germline DNA deletion polymorphisms cause spliced variants, the spliced variants Expression is caused to lack the isotype of the BIM albumen of BH3 domains, so as to suppress the induction of Apoptosis.

Usually, platiniferous antitumor agent is selected from by cis-platinum, carboplatin, oxaliplatin, satraplatin (satraplatin), pyrrole Platinum (picoplatin), Nedaplatin (nedaplatin), three platinum (triplatin), lobaplatin (lobaplatin), eptalatin (heptaplatin) and cisplatin liposome (lipoplatin) composition group.Preferably, platiniferous antitumor agent be selected from by cis-platinum, The group of carboplatin and oxaliplatin composition.Particularly preferred platiniferous antitumor agent is cis-platinum.

In another alternative solution, the dosage of two to the water wei ling alcohol and platiniferous antitumor agent cause two to the water wei ling alcohol and Platiniferous antitumor agent plays synergistic effect.

Another aspect of the present invention is pharmaceutical composition, including：

(1) two to the water wei ling alcohol of therapeutically effective amount；

(2) the platiniferous antitumor agent of therapeutically effective amount；And

(3) alternatively, at least one pharmaceutically acceptable carrier.

Described pharmaceutical composition can be prepared to be selected from by II phases non-small cell lung cancer (NSCLC), III phases for treatment The malignant tumour of the group of NSCLC and IV phases NSCLC compositions.Also described pharmaceutical composition can be prepared brain turn has occurred for treatment Malignant tumour move, selected from the group being made of II phases non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC.

In another alternative solution for being used for pharmaceutical composition, the dosage of two to the water wei ling alcohol and platiniferous antitumor agent makes Obtain two to the water wei ling alcohol and platiniferous antitumor agent plays synergistic effect.

It is usually described pharmaceutically acceptable when described pharmaceutical composition includes at least one pharmaceutically acceptable carrier Carrier be selected from by water-based and non-aqueous solvent, decentralized medium, coating, antibacterium and/or antifungal agent and isotonic and/or inhale Receive the group that delayed-action activator is formed.

Pharmaceutical composition can be formulated for parenteral administration, and other methods of administration are possible.

In another alternative, said composition can include at least one p53 analogies.It is set forth below and serves as The compound of p53 analogies.

Another aspect of the present invention be treatment suffer from be selected from by II phases non-small cell lung cancer (NSCLC), III phases NSCLC and The method of the patient of the malignant tumour of the group of IV phases NSCLC compositions, wherein the patient has the p53 genes of mutation, this method Comprise the following steps：

(1) propagation and/or evil of the presence of patient's body Mutation p53 gene, wherein Mutation p53 effect gene malignant tumour are determined Resistance of the property tumour at least one antitumor agent；

(2) to a effective amount of two to the water wei ling alcohol of patient therapeuticallv to treat malignant tumour, wherein the two to the water wei ling alcohol Therapeutically effective amount determined by the result of the cell line of the p53 genes with mutation；

(3) antitumor agent based on platinum a effective amount of to patient therapeuticallv to be to treat malignant tumour, wherein described based on platinum The therapeutically effective amount of antitumor agent is determined by the result of the cell line of the p53 genes with mutation；And

(4) alternatively, to a effective amount of p53 analogies of patient therapeuticallv to treat malignant tumour.

Usually, the presence of patient's body Mutation p53 gene passes through selected from more by gene sequencing, Restriction Fragment Length Sample and determine whether the p53 in the cell sample from patient is combined the method for formed group to determine with pGL3 carriers.

Many p53 analogies known in the art, include but not limited to following：(i) N '-[2- [2- (4- methoxyphenyls) second Alkenyl] -4- quinazolyls]-N, N- dimethyl -1,3- propane diamine dihydrochlorides hydrate) (CP-31398)；

(ii) compound of formula (P-1)：

Wherein：

(A)R¹And R⁴It is each independently selected from the group consisted of：Amino, cyano group, nitro, carboxyl, halogen, hydroxyl, SO₂、 C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₈Alkoxy, C₁-C₁₁Alkoxyalkyl, C₁-C₆Alkyl amino and C₁-C₆Amino alkane Base；

(B)R²And R³It is each independently selected from the group being made of CH and N；

(C)R⁵It is CH or O；

(D)R⁶Selected from the group consisted of：Halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated, C₁- C₁₀Alkyl, have side chain or unbranched, C₁-C₁₀Alkoxy, have side chain or unbranched, C₁-C₁₀Acyl group, have side chain or Unbranched, C₁-C₁₀Acyloxy, have side chain or unbranched, C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, Aryloxy group, aryl sulfonyl, heterocyclic aryl and heterocycle aryloxy group；

(E)R⁷Selected from the group consisted of：Hydrogen, halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain Or unbranched C₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, Aryloxy group, aryl sulfonyl, heteroaryl and heteroaryloxy；

(F)R⁸Selected from the group being made of nitro, hydroxyl and carboxyl；And

(G)R⁹For methyl；Or its pharmaceutically acceptable ester or salt；

(iii) has the compound of stable, internal constraint secondary protein structure, wherein the compound has formula (P-2)：

Wherein：

(A) B is C (R¹)₂, O, S, or NR¹；

(B) each R¹Independently be hydrogen, amino acid side chain, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or Aryl alkyl；

(C)R²It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, acyl group, peptide, targeting moiety or label), -- (CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkane independently of one another Base, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula The part of (P-2 (a))：

Wherein：

(1)R^2’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, targeting moiety or label), -- (CH₂)_0-1N(R⁵)₂(wherein R⁵Be independently of one another hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m ' is zero or any numeral；

(3) b is each independently 1 or 2；And

(4) c is 1 or 2；

(D)R³Be hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, peptide, Targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl Alkyl, acyl group, peptide, targeting moiety or label), -- N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, ring independently of one another Alkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (b)) part：

Wherein：

(1)R^3’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, targeting Part or label) or-N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, virtue independently of one another Base, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m " is zero or any numeral；And

(3) d is respectively 1 or 2；

(E)R⁴For each independent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aryl alkyl；

(F) m, n ', be each independently 0,1,2,3 or 4, wherein m, n with n " ' and n's " and be 2 to 6；

(G) m " ' is 0 or 1；

(H) a is 1 or 2；

(I) o is each independently 1 or 2；And

(J) p is 1 or 2；

, wherein it is desired to meet at least one in condition：(i) m is that 1,2,3 or 4 and at least one o is 2；(ii) p is 2；(iii) m " ' is that 1 and a is 2；(iv)R²It is beta amino acids；(v)R²The part of formula (P-2 (a)), wherein m ' be at least 1 and At least one b is 2；(vi)R²It is the part of formula (P-2 (a)), wherein c is 2；(vii)R²It is the part of formula (P-2 (a)), wherein R^2’It is beta amino acids；(viii)R³It is beta amino acids；(ix)R³It is the part of formula (P-2 (b)), wherein m " is at least 1 and at least One d is 2；And (x) R³It is the part of formula (P-2 (b)), wherein R^3’It is beta amino acids.

Suitable platiniferous antitumor agent is as described above.In a kind of alternative solution, two to the water wei ling alcohol and containing platinum antineoplastic The dosage of agent causes two to the water wei ling alcohol and platiniferous antitumor agent to play synergistic effect.

Brief description of the drawings

Reference explanation book, appended claims and attached drawing, are better understood with following invention, wherein：

Fig. 1 is the figure for showing weight of the female Rag2 mouse after 5,000,000 A549 NSCLC cells are subcutaneously injected.Implement The result of example is shown as weight on the y axis, and days post inoculation is shown as in x-axis.In Fig. 1-2 of embodiment, ● it is not locate The control of reason；■ is the cis-platinum control of 5mg/kg；▲ be 1.5mg/kg two to the water wei ling alcohol；▲ it is the two of 3.0mg/kg to remove water Dulcitol；And ◆ it is the two to the water wei ling alcohol of 6.0mg/kg.

Fig. 2 is the gross tumor volume (average value ± S.E.M. (marks for the female Rag2 mouse for showing to have A549 NSCLC tumours Standard by mistake)) figure, wherein embodiment result is gross tumor volume on the y axis, is days post inoculation in x-axis.The top sample group of Fig. 2 Represent all mouse during whole research.The bottom sample group of Fig. 2 represents survival, and by the 70th day, (untreated control group was most All mouse one day after).

Fig. 3 is that the In vivo model of A549 in female Rag2 mouse (TKI- sensitive) cell opens Pulan-Meyer (Kaplan- Meier) survivorship curve, the survivorship curve compared for the cis-platinum of 5mg/kg and the two to the water wei ling alcohol of 1.5mg/kg, 3.0mg/kg Act on the effect of A549 (TKI- is sensitive) NSCLC.

Fig. 4 be the In vivo model of H1975 in female Rag2 mouse (TKI- sensitive) cell to open Pulan-Meyer existence bent Line, which compared for 5mg/kg cis-platinums and the two to the water wei ling alcohol of 2mg/kg, 3mg/kg and 4mg/kg act on H1975 The effect of (TKI- is sensitive) NSCLC.

Fig. 5 A be show two to the water wei ling alcohol (DAG) alone or in combination cis-platinum (CDDP) interaction in vitro in A549 (TKI- It is sensitive) design sketch of NSCLC cells.Data are shown as average value ± standard error, N=7.Fig. 5 B are to show two to the water wei ling alcohol (DAG) alone or in combination oxaliplatin interaction in vitro in the design sketch of A549 (TKI- sensitive) NSCLC cells.Data are shown as flat Mean value ± standard error, N=7.

Fig. 6 is to show two to the water wei ling alcohol cis-platinum interaction in vitro is thin in H1975 (TKI- sensitive) NSCLC alone or in combination The design sketch of born of the same parents.Data are shown as average value ± standard error, N=4.

Fig. 7 is the agent shown in the ovarian tumor cell system sample sets handled in vitro with two to the water wei ling alcohol (DAG) The figure of amount-response curve, is shown as cell survival in y-axis, DAG concentration is shown as in x-axis.Ovarian tumor cell system sample Group is following：● represent A2780；■ represents 2780-CP16；▲ represent OVCAR-10；▼ represents HEY；And ◆ represent OVCA- 433.Using 5 days MTT (tetrazolium salts) colorimetric method for determining cell viabilities to draw dose-response curve.A2780 is shown with suitable Platinum-sensitive model, and other four kinds of cell lines then show cisplatin-resistance.

Fig. 8 is to show that two to the water wei ling alcohol (" DAG "), cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali-Pt ") exist The figure of vitro cytotoxicity in wild type p53 human ovarian tumor's cell sample group.Show two to the water wei ling alcohol, cis-platinum and Relative activity (IC50) of the oxaliplatin to wild type p53 ovarian tumor cell.

Fig. 9 is to show two to the water wei ling alcohol and platinum medicine cis-platinum and oxaliplatin wild type p53 human ovarian swells in vitro The figure of the resistant multiple of knurl sample sets；Resistant multiple is shown relative to A2780 (cisplatin-sensitive).Relative to sensitive A2780 moulds Type normalizes the activity of two to the water wei ling alcohol and platinum medicine.The bright resistant tumor model of the chart has 10 to 30 times to cis-platinum and resists Property, there is 2 to 5 times of resistance to oxaliplatin, and there is 4 to 7 times of resistance to two to the water wei ling alcohol.Therefore, resistance to cis-platinum Wild type p53 ovarian tumor model only show partial intersection resistance to oxaliplatin and dianhydrogalactitol.

Figure 10 is the external cytotoxicity and relevant antagonism for showing the cis-platinum in human body NSCLC tumor cells specimens groups Figure.Used cell line is H460, A549, H838 and H226 with wild type p53, has mutant p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.

Figure 11 is to show in human body NSCLC tumor cells specimens groups the external cytotoxicity of oxaliplatin and opposite The figure of resistance.Used cell line is H460, A549, H838 and H226 with wild type p53, has mutant p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.

Figure 12 is to show in human body NSCLC tumor cells specimens groups the external cytotoxicity of DAG and external opposite The figure of resistance.Used cell line is H460, A549, H838 and H226 with wild type p53, has mutant p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.

Figure 13 is to show two to the water wei ling alcohol (" DAG ") and platinum medicine cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali- Pt ") for transformation HCT-116 models vitro cytotoxicity figure.In order to preferably explore the dependence of activity and p53 states Relation, employs the colorectum HCT-116 models of molecular modification.These are homogenic, and model passes through molecular modification to knock out p53 (p53^-/-) or p21 (p21^-/-)。P53^+/+Or p21^+/+Represent corresponding control.Using these IC₅₀Value is opposite to determine knockout group In the resistance of corresponding control.

Figure 14 is to show two to the water wei ling alcohol (" DAG ") and platinum medicine cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali- Pt ") external resistant multiple in the HCT-116 models of transformation figure.It is anti-in the colorectum HCT-116 models of transformation Property multiple shows that the missing of p53 and p21 can cause twice or the stronger resistance to cis-platinum and oxaliplatin, but to DAG's Resistance can then decline (p53^-/-) or there is no resistance (p21^-/-)。

Figure 15 shows two to the water wei ling alcohol (" DAG ") with cis-platinum (CDDP) or with oxaliplatin in people's A549NSCLC moulds Combination index (combination index) in the external model of type.

Figure 16 be show two to the water wei ling alcohol (DAG) combination with cisplatin (CDDP) or oxaliplatin (OXT) interaction in vitro in The design sketch of A549NSCLC cells.Left sample sets show the result of DAG combination with cisplatin；Right sample sets show that DAG joints are difficult to understand The result of husky profit platinum.Data are shown as average value ± standard error, N=7.

Figure 17 is to show that two to the water wei ling alcohol (DAG) combination with cisplatin or oxaliplatin interaction in vitro are thin in H460NSCLC The design sketch of born of the same parents.Left sample sets show the result of DAG combination with cisplatin；Right sample sets show the knot of DAG joint oxaliplatins Fruit.Under the H460 cell independent studies of N=3, the almost significant super additivity (super- of drug combination of cis-platinum+DAG Additivity), and the drug combination of oxaliplatin+DAG then has super additivity.Data are shown as average value ± standard error, N =4.

Figure 18 be show two to the water wei ling alcohol (DAG) combination with cisplatin (CDDP) or oxaliplatin (OXT) interaction in vitro in The design sketch of H1975NSCLC cells.Left sample sets show the result of DAG combination with cisplatin；Right sample sets show that DAG combines The result of oxaliplatin.Under the H1975 cell independent studies of N=4, the drug combination of cis-platinum+DAG has additivity, and difficult to understand The drug combination of husky profit platinum+DAG reaches significant super additivity.Data are shown as average value ± standard error.

Figure 19 be show two to the water wei ling alcohol (DAG) combination with cisplatin (CDDP) or oxaliplatin (OXT) interaction in vitro in The design sketch of H157NSCLC cells.Top sample group shows the result of DAG combination with cisplatin；Bottom sample group shows that DAG joins Close the result of oxaliplatin.Data are shown as average value ± standard error, N=3.Shown in effective dose ED75, ED90 and ED95 Data.Compared to other cell lines, H157 shows the resistance of higher degree.

Embodiment

It has been shown that compound two to the water wei ling alcohol (DAG), which has, suppresses non-small cell lung cancer (NSCLC) cell growth Substantial utility.In the case of GBM, DAG is proved in terms of NSCLC cell growths in suppressing mouse model than current NSCLC chemotherapeutic selection --- cis-platinum is more effective.As described below, DAG can effectively suppress cancer stem cell (CSCs) Growth.DAG is acted on independently of MGMT repair mechanisms.

As described below, DAG also has effects that ovarian tumor cell.It is as follows suitable for the method and composition of ovarian cancer resistance It is described.It can be included by the tumour that two to the water wei ling alcohol is treated but usually treated by platiniferous antitumor drug：Common cis-platinum is controlled The cervical carcinoma for the treatment of, commonly uses the colorectal cancer of oxaliplatin treatment, and commonly use Carboplatin in patients is usually the carcinoma of fallopian tube of pipe cancer, with And the carcinoma of urinary bladder of common plus cisplatin in treatment.Thus, the method according to the invention and composition can be used for treating these malignant tumours, The method and composition include the drug combination of two to the water wei ling alcohol and platiniferous antitumor agent and are configured to treat these The pharmaceutical composition of malignant tumour.

The structure of two to the water wei ling alcohol (DAG) is shown in following formula (I).

As described below, other substituted hexitols can be used in the method according to the invention and composition.In general, it can be used for Substituted hexitol in the method according to the invention and composition include dulcitol (galactitols), substitution dulcitol, Galactitol (dulcitols), the galactitol of substitution, these include two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol, two Bromine dulcitol and two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol, mitolactol and their derivative and analog. Usually, the substituted hexose 01 derivatives are selected from by two to the water wei ling alcohol, two to the water wei ling alcohol derivative, diacetyl two The group that dianhydrogalactitol, diacetyl two to the water wei ling alcohol derivative, mitolactol and mitolactol derivative are formed.It is excellent Selection of land, the substituted hexose 01 derivatives are two to the water wei ling alcohol.

It is as further described below, these dulcitols, substitution dulcitol, galactitol, substitution galactitol either Alkylating agent, or the pro-drug of alkylating agent.

The derivative of two to the water wei ling alcohol is also within the scope of the invention, and the derivative of the two to the water wei ling alcohol is, for example, The derivative for the two to the water wei ling alcohol that one or two hydrogen atom in two hydroxyls of two to the water wei ling alcohol is replaced by low alkyl group The derivative for the two to the water wei ling alcohol that thing, the one or more hydrogen being connected on two epoxides rings are replaced by low alkyl group, Or present in two to the water wei ling alcohol and multiple methyl of identical multiple carbon atoms of carrying hydroxyl are connected by C₂-C₆It is rudimentary Alkyl is replaced or replaces the hydrogen of methyl by using such as halo groups come the two to the water wei ling alcohol that substitutes by such as halo groups Derivative.In the case of no further limitation, term " halo groups " used herein, refers to fluoro, chloro, bromo Or one in iodo.In the case of no further limitation, term " low alkyl group " used herein, refers to C₁-C₆Base Roll into a ball and including methyl.Term " low alkyl group " can be further restricted, such as not include the " C of methyl₂-C₆Low alkyl group ". Unless otherwise defined, term " low alkyl group " refers to straight chain and branched alkyl.These groups optionally can further be taken Generation, as described below.

The structure of diacetyl two to the water wei ling alcohol is shown in following formula (II).

The derivative of diacetyl two to the water wei ling alcohol is also within the scope of the invention, and the diacetyl two removes water winged euonymus The derivative of alcohol is, for example, one or two methyl of part acetyl group by C₂-C₆The diacetyl two that low alkyl group is replaced is gone The diacetyl that the derivative of water dulcitol, one or two hydrogen atom being connected on epoxides ring are replaced by low alkyl group Multiple methyl of the derivative of two to the water wei ling alcohol or identical multiple carbon atoms of connection carrying hydroxyl are replaced by low alkyl group Change or replace hydrogen atom by using such as halo groups come the diacetyl two to the water wei ling alcohol that substitutes by such as halo groups Derivative.

The structure of mitolactol is shown in following formula (III).Mitolactol can be by elevated temperatures The reaction of galactitol and hydrobromic acid and the crystallization of subsequent mitolactol and produce.The properties of mitolactol are retouched N.E. meter Shi Le et al. are set forth in, " Dibromoducitol ",Cancer Treat.Rev.6：191-204 (1979), passes through reference It is incorporated herein.Many similar medicines such as dibromannitol and sweet is enjoyed particularly as the mitolactol of dibromo hexitol Reveal the biochemistry and biological characteristics of alcohol busulfan.Activation of the mitolactol to diepoxy two to the water wei ling alcohol occurs in body Interior, two to the water wei ling alcohol represents the chief active form of the medicine；This means mitolactol has being permitted for pro-drug More properties.It is quick and quite complete to absorb mitolactol by oral route.Mitolactol is in melanoma, mammary gland leaching Bar knurl (Hodgkin lymphoma and non-Hodgkin lymphoma), colorectal cancer and acute lymphatic leukemia have known work Property, have been demonstrated that mitolactol can reduce central nervous system leukemia, non-small cell lung cancer, cervical carcinoma, carcinoma of urinary bladder and turn The incidence of shifting property hemangiopericytoma.

The derivative of mitolactol is also within the scope of the invention, for example, its hydroxyl one or more hydrogen by lower alkyl The derivative for the mitolactol that base is replaced, or one or both bromo is by another halo groups, such as chloro, fluoro Or the derivative of the mitolactol of iodo replacement.

Typically for the optional substituent on saturated carbon atom, wherein the saturated carbon atom is, for example, two to go water to defend Lance alcohol, the derivative of two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, two A part for the structure of the derivative of bromine dulcitol and mitolactol, can use following substituent：C₆-C₁₀Aryl, containing choosing From 1-4 heteroatomic heteroaryls, the C of N, O and S₁-C₁₀Alkyl, C₁-C₁₀Alkoxy, cycloalkyl, F, amino (NR¹R²), nitre Base ,-SR ,-S (O) R ,-S (O₂)R、—S(O₂)NR¹R²With-CONR¹R², they can alternatively be substituted again.It is presented below latent Optional substituent further describe.

Optional substituent within the scope of the present invention has no substantial effect on the active of derivative or derivative as described above The stability of thing, the particularly stability of derivative in aqueous.It can be used as many common groups of optional substituent It is defined as follows；Refer to that such group cannot act as optionally however, must not believe that and omit any group from these definition Substituent, as long as such group meets chemistry and the pharmacology requirement of optional substituent.

As used herein, term " alkyl " refers to unbranched, tool with alternatively substituted 1 to 12 carbon atom Have side chain or cyclic saturated hydrocarbon base residue or its combination；When unsubstituted, alkyl residue only contains C and H.In general, without branch Chain or be 1 to 6 carbon atom with the saturated hydrocarbyl residue of side chain, be referred to herein as " low alkyl group ".When alkyl is ring Shape and during including ring, it should be understood that hydrocarbyl residue includes at least three carbon atoms, third, forming the minimal amount of ring.Such as this paper institutes With term " alkenyl " refers to unbranched, with side chain the or cyclic hydrocarbon group residue with one or more carbon-to-carbon double bonds. As used herein, term " alkynyl " refers to unbranched, with side chain the or cyclic hydrocarbon with one or more carbon-to-carbon triple bonds Base residue；The residue can also include one or more double bonds.On the use of " alkenyl " or " alkynyl ", multiple double bonds are deposited Aromatic rings cannot produced.As used herein, term " hydroxyalkyl ", " hydroxy alkenyl " and " hydroxy alkynyl " represent to include respectively one or Alkyl, alkenyl or alkynyl of multiple hydroxyls as substituent；As described below, other substituents can alternatively be included.As herein Used, term " aryl " refers to the monocyclic or fused bicyclic moiety with known armaticity feature；Example includes can be by can The phenyl and naphthyl of selection of land substitution.As used herein, term " hydroxyaryl " refers to include one or more hydroxyls as substituent Aryl；As described in further detail below, other substituents can alternatively be included.As used herein, term " heteroaryl " is Refer to the monocyclic or fused bicyclic carbocycle with armaticity feature, and including one or more hetero atoms for being selected from O, S and N.It is miscellaneous The armaticity included in 5 yuan of rings of permission and 6 yuan of rings of atom.Typical heteroaromatic system includes monocyclic C₅-C₆Heteroaryl, Such as pyridine radicals, pyrimidine radicals, pyrazinyl, thienyl, furyl, pyrrole radicals, pyrazolyl, thiazolyl, oxazolyl, triazolyl, three Piperazine base, tetrazole radical, tetrazine base and imidazole radicals, and fused bicyclic moiety, wherein the fused bicyclic moiety is by condensing these One of bicyclic heteroaryl is formed with phenyl ring, or by condensing one of these bicyclic heteroaryls with any bicyclic heteroaryl to be formed C₈-C₁₀Bicyclic radicals are formed, the C₈-C₁₀Bicyclic radicals include such as indyl, benzimidazolyl, indazolyl, benzo three Oxazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolyl pyridine radicals, quinazolyl, quinoxalinyl, scold Quinoline base and other member ring systems known in the art.Include any monocyclic or fused rings bicyclic system in this definition, it is described monocyclic Or there is the feature of armaticity in terms of delocalized electron distribution of the fused rings bicyclic system in whole ring system.This definition further includes double Cyclic group, the ring being wherein at least directly connected to the remainder of molecule have the feature of armaticity, and the bicyclic radicals include Delocalized electron distribution with armaticity feature.Usual ring system includes 5 to 12 ring members atoms and at most 4 hetero atoms, its Middle hetero atom is selected from N, O and S.In general, bicyclic heteroaryl contains 5 to 6 ring members and the at most 3 miscellaneous originals for being selected from N, O and S Son；In general, bicyclic heteroaryl contains 8 to 10 ring members and at most 4 hetero atoms for being selected from N, O and S.In heteroaryl ring structure Heteroatomic number and location are related with known armaticity and stability, and wherein stability requirement heteroaryl is sufficiently stable with sudden and violent It is exposed in the water of physiological temp without fast degradation.As used herein, term " hydroxyl heteroaryl " refers to include one or more Heteroaryl of a hydroxyl as substituent；As described in further detail below, other substituents can alternatively be included.Such as this paper institutes The aryl and heteroaryl for referring to by least one halogen group be substituted respectively with, term " halogenated aryl " and " haloheteroaryl ", Wherein " halogen " refers to the halogen selected from fluorine, chlorine, bromine and iodine, in general, the halogen is selected from chlorine, bromine and iodine；As described below, Ke Yike Selection of land includes other substituents.As used herein, term " haloalkyl ", " haloalkenyl group " and " halo alkynyl " refer to respectively by Alkyl, alkenyl and the alkynyl of at least one halogen group substitution, wherein " halogen " refers to the halogen selected from fluorine, chlorine, bromine and iodine, lead to Often, the halogen is selected from chlorine, bromine and iodine；As detailed below, other substituents can alternatively be included.

As used herein, term " alternatively substituting " expression is referred to as the special groups alternatively substituted or multiple groups Can not have a non-hydrogen substituent, or the group or the plurality of group can have it is one or more with the chemistry of gained molecule and The consistent non-hydrogen substituent of pharmacological activity.If do not dictated otherwise, the sum for these substituents that there may be, which is equal to, to be existed In the hydrogen atom sum on the group of unsubstituted form；There may be the substituent of the maximum quantity less than substituent.When When optional substituent is connected by double bond, such as ketonic oxygen (C=O), the group are former in the carbon that optional substituent is connected Two available valencys are occupied on son, therefore the number for the substituent that can include is reduced according to the quantity of available valency.As herein It is used, term " substituted ", either be used as " alternatively substituting " a part or other, when for modify special groups, When part or free radical, term " substituted " refers to that one or more hydrogen atoms are each taken by identical or different independently of one another Substitute for base.

Substituent available for the saturated carbon atom in substitution special groups, part or free radical includes but not limited to：— Z^a,=O ,-OZ^b,-SZ^b,=S^-,-NZ^cZ^c,=NZ^b,=N-OZ^b, trihalomethyl ,-CF₃,-CN ,-OCN ,- SCN ,-NO ,-NO₂,=N₂,-N₃,-S (O)₂Z^b,-S (O)₂NZ^b,-S (O₂)O^-,-S (O₂)OZ^b,-OS (O₂)OZ^b,- OS(O₂)O^-,-OS (O₂)OZ^b,-P (O) (O^-)₂,-P (O) (OZ^b)(O^-) ,-P (O) (OZ^b)(OZ^b) ,-C (O) Z^b,-C (S) Z^b,-C (NZ^b)Z^b,-C (O) O^-,-C (O) OZ^b,-C (S) OZ^b,-C (O) NZ^cZ^c,-C (NZ^b)NZ^cZ^c,-OC (O) Z^b,- OC(S)Z^b,-OC (O) O^-,-OC (O) OZ^b,-OC (S) OZ^b,-NZ^bC(O)Z^b,-NZ^bC(S)Z^b,-NZ^bC(O)O^-,- NZ^bC(O)OZ^b,-NZ^bC(S)OZ^b,-NZ^bC(O)NZ^cZ^c,-NZ^bC(NZ^b)Z^b,-NZ^bC(NZ^b)NZ^cZ^c, wherein, Z^aIt is selected from Alkyl, cycloalkyl, miscellaneous alkyl, cycloheteroalkyl, aryl, aryl alkyl, heteroaryl and heteroaryl alkyl；Each Z^bIt is independently hydrogen Or Z^a；And each Z^cFor independent Z^b, or two Z^c4-, 5-, 6- or 7- are formed together with the nitrogen-atoms that can be bonded with them Membered cycloheteroalkyl group ring structure, the cycloheteroalkyl ring structure can alternatively include 1 to 4 and be selected from the identical or different of N, O and S Hetero atom.As another instantiation ,-NZ^cZ^cIt is intended to include-- NH₂,-NH- alkyl ,-N- pyrrolidinyls, and- N- morpholinyls, but it is not limited to those specific substitutes and including other substitutes known in the art.Similarly, as another One instantiation, substituted alkyl are intended to include-alkylene-O-aryl ,-alkylene-heteroaryl ,-alkylidenyl-heterocyclic Base ,-alkylidene-C (O) OZ^b,-alkylidene-C (O) NZ^bZ^bWith-CH₂-CH₂-C(O)-CH₃, but be not limited to these and specifically replace For thing, and including other substitutes known in the art.One or more substituents can be with together with the atom that they are bonded Cyclic rings are formed, include but not limited to cycloalkyl and cycloheteroalkyl.

Similarly, the substituent available for the unsaturated carbon atom in substitution special groups, part or free radical include but It is not limited to：—Z^a, halogen ,-O^-,-OZ^b,-SZ^b,-S^-,-NZ^cZ^c, trihalomethyl ,-CF₃,-CN ,-OCN ,- SCN ,-NO ,-NO₂,-N₃,-S (O)₂Z^b,-S (O₂)O^-,-S (O₂)OZ^b,-OS (O₂)OZ^b,-OS (O₂)O^-,-P (O) (O^-)₂,-P (O) (OZ^b)(O^-) ,-P (O) (OZ^b)(OZ^b) ,-C (O) Z^b,-C (S) Z^b,-C (NZ^b)Z^b,-C (O) O^-,-C (O)OZ^b,-C (S) OZ^b,-C (O) NZ^cZ^c,-C (NZ^b)NZ^cZ^c,-OC (O) Z^b,-OC (S) Z^b,-OC (O) O^-,-OC (O) OZ^b,-OC (S) OZ^b,-NZ^bC(O)OZ^b,-NZ^bC(S)OZ^b,-NZ^bC(O)NZ^cZ^c,-NZ^bC(NZ^b)Z^b, and-NZ^bC (NZ^b)NZ^cZ^c, wherein Z^a, Z^bAnd Z^cIt is as defined above.

Similarly, the substituent available for the nitrogen-atoms in substitution miscellaneous alkyl and cycloheteroalkyl includes but not limited to：—Z^a, Halogen ,-O^-,-OZ^b,-SZ^b,-S^-,-NZ^cZ^cTrihalomethyl ,-CF₃,-CN ,-OCN ,-SCN ,-NO ,-NO₂,-S (O)₂Z^b,-S (O₂)O^-,-S (O₂)OZ^b,-OS (O₂)OZ^b,-OS (O₂)O^-,-P (O) (O^-)₂,-P (O) (OZ^b)(O^-) ,-P (O)(OZ^b)(OZ^b) ,-C (O) Z^b,-C (S) Z^b,-C (NZ^b)Z^b,-C (O) OZ^b,-C (S) OZ^b,-C (O) NZ^cZ^c,-C (NZ^b)NZ^cZ^c,-OC (O) Z^b,-OC (S) Z^b,-OC (O) OZ^b,-OC (S) OZ^b,-NZ^bC(O)Z^b,-NZ^bC(S)Z^b,- NZ^bC(O)OZ^b,-NZ^bC(S)OZ^b,-NZ^bC(O)NZ^cZ^c,-NZ^bC(NZ^b)Z^b, and-NZ^bC(NZ^b)NZ^cZ^c, wherein Z^a, Z^b And Z^cIt is as defined above.

Compound as described herein can contain one or more chiral centres and/or double bond, therefore can be with three-dimensional different The form of structure body exists, such as double bond isomer (i.e. such as the geometric isomer of E and Z), enantiomer or diastereomer.Except non-designated Specific stereoisomer, the present invention include separated stereoisomer form (for example, the isomers of enantiomer-pure, E and Z Other substitutes of isomers and stereoisomer) in each and different degrees of chiral purity or difference E and Z hundred Divide the mixture of the stereoisomer of ratio, the mixture of the stereoisomer includes racemic mixture, diastereoisomer Mixture and E and Z isomers mixture.Therefore, chemical constitution described herein can including all of shown compound The enantiomer and stereoisomer and the mixture of enantiomer and stereoisomer of energy, it is pure that the compound includes alloisomerism Form (for example, geometry is pure, enantiomer-pure or diastereomer it is pure).Use separation skill well known to those skilled in the art Art or chiral synthesis techniques, enantiomer and stereoisomer mixture can resolve into their constituent enantiomers or alloisomerism Body.The present invention includes various separated stereoisomer forms and has the mixed of the stereoisomer of different degrees of chiral purity Compound, the mixture include racemic mixture.It further includes a variety of diastereoisomers.Other structures may be seen Get up to describe specific isomers, but this is used for the purpose of for the sake of convenience, it is not intended to limit the invention to described Isomers.When chemical name does not have the isomeric form of appointed compound, it represents the possible isomery of any type of compound The mixture of form or these isomeric forms.

Compound can also exist with several tautomeric forms, and a kind of dynamic isomer described herein is only side Just for the sake of, and other dynamic isomers of shown form are also understood to include.Therefore, chemical constitution described herein includes The all possible tautomeric form of shown compound.Term " dynamic isomer " used herein refers to be very easy to change For mutual isomers, so that they can be present in balance together；Depending on stability consideration, the balance may be strong It is partial to one kind in dynamic isomer in ground.For example, ketone and enol are a kind of two kinds of tautomeric forms of compound.

As used herein, term " solvate " refer to by solvation (molecule or ion of solvent molecule and solute Combination) compound that is formed or the aggregation that is made of solute ions or molecule, that is, there is the sheet of one or more solvent molecules The compound of invention.When water is solvent, corresponding solvate is " hydrate ".The example of hydrate includes but not limited to half Hydrate, monohydrate, dihydrate, trihydrate, hexahydrate and other hydrous matters.Those of ordinary skill in the art should Work as understanding, the pharmaceutically acceptable salt and/or pro-drug of the compounds of this invention can also exist with solvate forms.It is molten For agent compound usually by being hydrated (hydration) formation, it either a part for the preparation of the compounds of this invention or passes through this The anhydrous compound of invention absorbs moisture and is formed naturally.

As used herein, term " ester " refers to any-COOH functional groups of any ester of the compounds of this invention, wherein molecule Substituted by-COOR functional groups, the R-portion of the wherein ester is any carbon-containing group for being formed and stablizing ester moiety, and the R-portion includes But it is not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heterocyclic radical, cycloheteroalkylalkyl and its takes For derivative.The hydrolyzable ester of the compounds of this invention is its carboxyl compound existing in the form of hydrolyzable ester groups.Also It is to say, these esters are pharmaceutically acceptable, and can be hydrolyzed into corresponding carboxylic acid in vivo.

In addition to above-mentioned substituent, alkyl, alkenyl and alkynyl can be alternatively or in addition by C₁-C₈Acyl group, C₂-C₈It is miscellaneous Acyl group, C₆-C₁₀Aryl, C₃-C₈Cycloalkyl, C₃-C₈Heterocyclic radical or C₅-C₁₀Heteroaryl substitutes, the alkyl, alkenyl and alkynyl Each can be with optional substituted.And in addition, when two groups that can form the ring with 5-8 ring members are present in phase With or adjacent atom on when, described two groups being capable of the alternatively atom in substituent connected to them or multiple originals Son comes together to form such a ring.

" miscellaneous alkyl ", " miscellaneous thiazolinyl " and " miscellaneous alkynyl " with and the like with corresponding alkyl (alkyl, alkenyl and alkynyl) Similarly it is defined, but term " miscellaneous " refers to contain 1-3 O in backbone residue, S or N hetero atoms or its combination；Therefore it is corresponding Alkyl, alkenyl or alkynyl the appointed hetero atom of at least one carbon atom in a replacement, form miscellaneous alkyl, miscellaneous respectively Alkenyl or miscellaneous alkynyl.For the reason for the chemical stability, unless otherwise stated, not include more than two continuous for these groups Hetero atom, if unless on nitro or sulfonyl, wherein oxygen groups are present on N or S.

Although " alkyl " used herein includes cycloalkyl and cycloalkyl-alkyl, term " cycloalkyl " can use herein In the carbocyclic non-aromatic race group that description is connected by ring carbon atom, " cycloalkyl-alkyl " passes through alkyl linker available for description The carbocyclic non-aromatic race group being connected with the molecule.

Similarly, " heterocyclic radical " can be used for describing (to be generally selected from N, O containing at least one hetero atom as ring members And S) and be connected to via annular atom the non-aromatic cyclic group of the molecule, the annular atom can be that (carbon connects C ) or N (nitrogen connection)；And " cycloheteroalkylalkyl " can be used for description to be connected so with another molecule by connector Group.Heterocyclic radical can be fully saturated or fractional saturation, but be non-aromatic.Suitable for cycloalkyl, cycloalkanes The size and substituent of base alkyl, heterocyclic radical and cycloheteroalkylalkyl are identical with abovementioned alkyl group.Heterocyclic radical usually contain 1,2 or 3 hetero atoms for being selected from N, O and S are as ring members；And N or S can be sent out on these atoms usually in heterocyclic system Existing group substitution.As used herein, these terms further include the ring of the double bond containing one or two, as long as the ring connected It is not aromatic.The substituted cycloalkyl and heterocyclic radical also include cycloalkyl or the heterocycle condensed with aromatic ring or hetero-aromatic ring, Condition is that the tie point of the group is cycloalkyl ring or heterocyclic ring, rather than aromatic ring or hetero-aromatic ring.

As used herein, " acyl group " be included in the alkyl of two of carbonylic carbon atom available prices connections, alkenyl, alkynyl, The free radical of aryl or aryl alkyl, miscellaneous acyl group refer to carbon of the corresponding wherein at least one in addition to carbonyl carbon by selected from The group that the hetero atom of N, O and S are substituted.

Acyl group and miscellaneous acyl group are good for any group or molecule that are connected together in them by the open valency of carbonylic carbon atom.It is logical Often, the acyl group and miscellaneous acyl group are the C for including formoxyl, acetyl group, valeryl and benzoyl₁-C₈Acyl group and including first The C of epoxide acetyl group, ethoxy carbonyl and 4- pyridine radicals₂-C₈Miscellaneous acyl group.

Similarly, " aralkyl " and " heteroaryl alkyl " refers to be bonded to the aromatic ring of its tie point and miscellaneous by linking group Aromatic ring system, the linking group is for example including substituted or unsubstituted, saturation or the alkylene of undersaturated, ring-type or non-annularity Base.Usual connector is C₁-C₈Alkyl.These connectors can also include carbonyl, thus allow them to provide as acyl group or The substituent of miscellaneous acyl moiety.Aromatic ring or hetero-aromatic ring in aralkyl or heteroaryl alkyl can be taken by identical with above-mentioned aryl Substitute for base.Preferably, aralkyl include alternatively by the above-mentioned phenyl ring substituted to the group that aryl defines and it is unsubstituted or By one or two C₁-C₄Alkyl or the C of miscellaneous alkyl substitution₁-C₄Alkylidene, wherein the alkyl or miscellaneous alkyl can be alternatively Cyclisation forms such as ring of cyclopropane, dioxolanes or tetrahydrofuran.Similarly, heteroaryl alkyl preferably include alternatively by C as the above-mentioned group substitution of typical substituent on aryl₅-C₆Bicyclic heteroaryl and unsubstituted or by one or two C₁-C₄Alkyl or the C of miscellaneous alkyl substitution₁-C₄Alkylidene；Or the heteroaryl alkyl includes the phenyl ring or C that alternatively substitute₅-C₆ Bicyclic heteroaryl and unsubstituted or by one or two C₁-C₄Alkyl or the C of miscellaneous alkyl substitution₁-C₄Miscellaneous alkylidene, wherein alkane Base or miscellaneous alkyl can be alternatively cyclized to form such as ring of cyclopropane, dioxolanes or tetrahydrofuran.

When aralkyl or heteroaryl alkyl are described as alternatively substituting, substituent can the group alkyl or On miscellaneous alkyl part or on aryl or heteroaryl moieties.The substituent being optionally present on the alkyl or miscellaneous alkyl part It is usually identical with the substituent of abovementioned alkyl；Be optionally present in substituent on the aryl or heteroaryl moieties usually with it is upper The substituent for stating aryl is identical.

If " aryl alkyl " used herein is unsubstituted, " aryl alkyl " is alkyl, and is led to Ring is crossed with the total number of carbon atoms in alkylidene or similar connector to describe.Therefore benzyl is C7- aryl alkyls, and phenylethyl is C8- aryl alkyls.

" heteroaryl alkyl " refers to the part for including the aryl by linking group connection as described above, and described " miscellaneous Aryl alkyl " and the difference of " aryl alkyl " be, an original at least one annular atom or linking group of aryl moiety Son is the hetero atom for being selected from N, O and S.Total atom number in ring and the connector of combination describes heteroaryl alkyl, and institute State the aryl that heteroaryl alkyl includes connecting by miscellaneous alkyl connector；The heteroaryl connected by the alkyl connector of such as alkylidene Base；The heteroaryl connected with by miscellaneous alkyl connector.Thus, for example, C₇- heteroaryl alkyl can include pyridylmethyl, benzene Epoxide and N- pyrrolylmethoxies.

" alkylidene (alkylene) " used herein refers to bivalent hydrocarbon radical；Because it is divalence, it can be by two Other groups link together.In general, it refers to-(CH₂)_n-, wherein n is 1-8, and preferably n is 1-4, although in defined situation Under, alkylidene can also be substituted by other groups, and can be other length, and open valence state is needed not in the opposite of chain End.

In general, any alkyl, alkenyl, alkynyl, acyl group or aryl or aryl alkyl that substituent includes in itself can be optional Ground is substituted by other substituent.If without substituent is in addition described, the property of these substituents is similar to be substituted on uncle The property of those listed substituent of basic body.

" amino " used herein refers to-NH₂, but when amino is described as " substituted " or " alternatively substituting " When, which includes NR ' R ", wherein, each R ' and R " independently is H, or for alkyl, alkenyl, alkynyl, acyl group, aryl or Aryl alkyl, and each in the alkyl, alkenyl, alkynyl, acyl group, aryl or aryl alkyl is alternatively retouched by this paper The substituent suitable for corresponding group stated substitutes；R ' and R " groups and the nitrogen-atoms that they are connected can optionally form 3 To 8 yuan of rings, 3 to 8 yuan of rings can be saturations, undersaturated or aromatic, and containing 1-3 independently selected from N, The hetero atom as ring members of O and S, and 3 to 8 yuan of rings are alternatively substituted by the substituent suitable for alkyl, Or if NR ' R " are aromatic group, 3 to 8 yuan of rings are alternatively substituted by the substituent suitable for heteroaryl.

Term " carbocyclic ring ", " carbocylic radical " or " carbocyclic ring " used herein refers in ring the only ring containing carbon atom, and Term " heterocycle " or " heterocycle " refer to include heteroatomic ring.The carbocylic radical can be fully saturated or fractional saturation , but be non-aromatic.For example, the carbocylic radical includes cycloalkyl.The carbocyclic ring and heterocycle structure include have it is monocyclic, Bicyclic or polycyclic system compound；And such system can be with mixed aromatic ring, heterocycle and carbocyclic ring.According to it is described The ring of remainder connection of compound mixed methylcyclosiloxane system described.

As used herein, term " hetero atom " refer to be not carbon or hydrogen any atom, such as nitrogen, oxygen or sulphur.When described Hetero atom be chain or ring main chain or skeleton a part when, hetero atom must be at least divalence, and be generally selected from N, O, P and S.

As used herein, term " alkanoyl " refers to the alkyl being covalently attached with carbonyl (C=O).Term " lower alkyl acyl Base " refers to that the moieties of wherein alkanoyl are C₁-C₆Alkanoyl.The moieties of the alkanoyl can as above institute State and be alternatively substituted.Term " alkyl-carbonyl " can also be used.Similarly, term " alkenyl carbonyl " and " alkynylcarbonyl groups " difference Refer to the alkenyl or alkynyl being connected with carbonyl.

Term " alkoxy " used herein refers to the alkyl being covalently attached with oxygen atom；The alkyl, which may be considered that, to be taken For the hydrogen atom of hydroxyl.Term " lower alkoxy " refers to that the moieties of alkoxy are C₁-C₆Alkoxy.The alkoxy The moieties can alternatively be substituted as described above.As used herein, term " halogenated alkoxy " refers to alkyl portion Divide the alkoxy substituted by one or more halogen groups.

Term " sulfo group " used herein refers to sulfonic acid (- SO₃H) substituent.

As used herein, term " sulfamoyl " refers to there is-S (O₂)NH₂The substituent of structure, the wherein group NH₂Partial nitrogen can be optionally substituted as described above.

As used herein, term " carboxyl " refers to structure-C (O₂) H group.

As used herein, term " carbamyl " refers to structure-C (O₂)NH₂Group, the wherein group NH₂Part Nitrogen can be optionally substituted as described above.

Term " Mono-alkylaminoalkyl " used herein and " dialkyl aminoalkyl " refer to structural formula-Alk₁-NH- Alk₂With-Alk₁-N(Alk₂)(Alk₃) group, wherein Alk₁, Alk₂And Alk₃Refer to alkyl as described above.

Term " alkyl sulphonyl " used herein refers to structure-S (O)₂The group of-Alk, wherein Alk refer to as above institute The alkyl stated.Term " alkenylsufonyl " and " alkynylsulfonyl " similarly refer to respectively with alkenyl and the sulphonyl of alkynyl covalent bonding Base.Term " aryl sulfonyl " refers to structure-S (O)₂The group of-Ar, wherein Ar represent aryl as described above.Term " virtue Epoxide alkyl sulphonyl " refers to structure-S (O)₂The group of-Alk-O-Ar, wherein Alk are alkyl as described above, Ar be as The upper aryl.Term " aryl alkylsulfonyl " refers to structure-S (O)₂The group of-AlkAr, wherein Alk are as above institutes The alkyl stated, Ar are aryl as described above.

As used herein, term " alkoxy carbonyl " refers to the ester substituent for including alkyl, and wherein carbonyl carbon is that molecule connects Contact.One example is ethoxy carbonyl, it is CH₃CH₂OC(O)—.Similarly, term " allyloxycarbonyl ", " alkynyloxy group carbonyl Base " and " naphthene base carbonyl " represent the similar ester substituent for including alkenyl, alkynyl or cycloalkyl respectively.Similarly, term " fragrant oxygen Base carbonyl " refers to the ester substituent for including aryl, and wherein carbonyl carbon is the aryl of molecule tie point.Similarly, term " aryloxy group Alkyl-carbonyl " refers to the ester substituent for including alkyl, and wherein alkyl is substituted by aryloxy group in itself.

Other combinations of substituent are known in the art, and are described in the United States Patent (USP) 8,344 of such as Jung et al., In 162, it is incorporated herein by reference.For example, the combination of term " thiocarbonyl " and the substituent including " thiocarbonyl " includes Common double bond oxygen in carbonyl, wherein double bond sulphur substituted radical.Term " alkylidene radical (alkylidene) " and similar terms refer to Specific alkyl, alkenyl, alkynyl or cycloalkyl, the alkyl, alkenyl, two hydrogen atoms of alkynyl or cycloalkyl are former from single carbon Son removes so that the group is bonded with the remainder double bond of structure.

For the improved aspect being related in the treatment use of substituted hexose 01 derivatives discussed below, unless separately Have it is specified, in general, the substituted hexose 01 derivatives be selected from by two to the water wei ling alcohol, two to the water wei ling alcohol derivative, diethyl Acyl group two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, mitolactol and mitolactol derivative are formed Group.Unless otherwise specified, it is preferable that the substituted hexose 01 derivatives are two to the water wei ling alcohol.In some cases, such as Lower described, preferably such as compounds are like thing or the two to the water wei ling alcohol derivative of pro-drug.

One aspect of the present invention is the substituted hexose for treating such as two to the water wei ling alcohol of NSCLC or oophoroma Improvement on the treatment use of 01 derivatives, wherein described improve by varying applying the time of compound, using control chemical combination Dosage conditioning agent, normal structure protective agent and the other alternative solutions of the metabolic rate of thing obtains.General example includes：It is defeated The change (for example, single-bolus high-dose intravenous injection (bolusi.v.) and continuous infusion) of note timetable, uses lymphokine (example Such as, G-CSF (Granulocyte Colony-Stimulating Factor, granulocyte colony stimulating factor), GM-CSF (granulocyte-macrophage colony-stimulating factor, granular leukocyte macrophage stimulus factor), EPO (Erythropoietin, hematopoietin)) increase white blood cell count(WBC) to improve immune response or be pressed down with prevention by marrow Anaemia caused by preparation, or using rescue agent, controlled such as the rescue agent formyl tetrahydrofolic acid of fluorouracil (5-FU) or for cis-platinum The rescue agent thiosulfate for the treatment of.Such as derive for treating the hexitol that the two to the water wei ling alcohol of NSCLC or oophoroma substitute The specific invention example of thing includes：Continuous venoclysis a few hours to a couple of days；Dispenser once every two weeks；Dosage is more than 5mg/m²/ My god；Based on patient tolerability, dosage is from 1mg/m²/ day gradually rises；Dosage is less than 1mg/m within more than 14 days²；Use coffee Because adjusting metabolism；Metabolism is adjusted using isoniazid；Single and multidose are injected by heavy dose, the dosage from 5mg/m²/ day raises；Oral dose is less than 30 or in 130mg/m²More than；3 days up to 40mg/m of oral dose², it is then minimum Point/convalescence is 18-21 days；With reduced levels administration long period (such as 21 days)；It is administered with higher level；To be longer than 21 days The administration of minimum point/convalescence；Substituted hexose 01 derivatives using such as two to the water wei ling alcohol are used as single cell toxicity Agent, is usually 30mg/m²/ day × 5 day, are monthly repeated once；Dosage is 3mg/kg；Such as two are used in combination therapy The substituted hexose 01 derivatives of dianhydrogalactitol, are usually 30mg/m²/ day × 5 day；Or with 40mg/ days in adult patient It is administered within × 5 days, is repeated once every two weeks.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement obtains by varying the approach for applying compound.It is general real Example includes：Change from the approach taken orally to intravenous administration, vice versa；Or specific approach is used, it is such as subcutaneous, intramuscular, dynamic In arteries and veins, peritonaeum is interior, intralesional, lymph is interior, (intravesicular), encephalic in intra-tumor, intrathecal, bladder.For treating The specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of NSCLC or oophoroma includes：Part is given Medicine；It is oral；Release oral；Intrathecal drug delivery；Intraarterial delivery；Continuous transfusion；Intermittent infusion；Intravenously administrable；Or by it is longer when Between administered by infusion；Or it is administered by intravenous injection.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement obtains by varying administration time table.General example includes： It is administered daily, every two weeks administration or weekly administration.For treat NSCLC or oophoroma such as two to the water wei ling alcohol it is substituted The specific invention example of hexose 01 derivatives includes：It is administered daily, weekly administration or continuous weekly administration in three weeks；Give every two weeks Medicine；It is administered every two weeks within continuous three weeks, rest 1-2 weeks；Interval booster is administered；Or multiple all it is administered daily within one week.

Another aspect of the present invention also resides in substituted oneself for treating NSCLC or oophoroma such as two to the water wei ling alcohol Improvement on the treatment use of sugar alcohol derivant, wherein the improvement is by giving medical diagnosis on disease/advance stages of compound Change and obtain.General example includes：For the chemotherapeutic application of unresectable local disease, prophylactic use with Prevention metastatic diffusion suppresses progression of disease or is converted into the more pernicious stage.For treating NSCLC or oophoroma for example The specific invention example of the substituted hexose 01 derivatives of two to the water wei ling alcohol includes：Applied in the suitable of NSCLC or oophoroma Work as disease stage；Such as the substituted hexose 01 derivatives of two to the water wei ling alcohol and for example a kind of VEGF inhibitor Arastin (Avastin) combination of angiogenesis inhibitors, is spread with prevention or the restriction of transfer；Such as two for newly diagnosing the illness go The application of the substituted hexose 01 derivatives of water dulcitol；Substituted oneself for such as two to the water wei ling alcohol of recurrent disease The application of sugar alcohol derivant；Or the substituted hexose 01 derivatives for resistance or such as two to the water wei ling alcohol of refractory disease Application.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement is by varying most tolerable or benefit from using compound Patient class obtain.General example includes：Child dose is used gerontal patient, and obese patient uses the dosage changed；Profit With comorbidity illness, such as diabetes, hepatic sclerosis or other may uniquely utilize the illness of compound characteristic.For treating NSCLC Or the specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of oophoroma includes：With being characterized as height The patient of the disease states of the horizontal metabolic enzyme selected from the group being made of histon deacetylase (HDAC) and ornithine decarboxylase；It is right The patient low or high selected from the illness sensitiveness by thrombopenia and neutropenia；To gastrointestinal toxicity (GItoxicities) patient not tolerated；It is characterized as being selected from c-Jun, GPCR (g protein coupled receptor), signal transducer, The overexpression of gene of VEGF (vascular endothelial growth factor), prostate specific gene and protein kinase or the trouble of low expression Person；Prostate specific gene and protein kinase；It is characterized as the patient of the EGFR mutation of including but not limited to EGFR variations III； Receiving patient of the platinum medicine administration as therapeutic alliance；It is mutated and is therefore less likely to tyrosine-kinase without EGFR The patient that enzyme inhibitor (TKI) is reacted；There is drug-fast patient to TKI treatments；With BIM be total to deletion mutation and because This is less likely the patient to react to TKI treatments；There is drug-fast patient to platinum medicine treatment；Or brain metastes are suffered from Person.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein described improve by more accurately identification and the particular phenotype phase of patient Associated patient tolerance, metabolism and obtained using the ability used of compound.General example includes：Using diagnostic tool and Kit come preferably characterize patient processing or metabolic chemistry therapeutic agent ability or potential specific cell, metabolism or organ The sensitiveness of patient toxicity caused by system phenotype.Such as two to the water wei ling alcohol for treating NSCLC or oophoroma takes The specific invention example of the hexose 01 derivatives in generation includes：Use diagnostic tool, diagnostic techniques, diagnostic kit or diagnostic assay Method confirms the particular phenotype of patient；Using selected from by histone deacetylase enzyme, ornithine decarboxylase, VEGF, the base as jun Because of the assay method of the label of the group of protein and the protein kinase composition of product；Alternative compounds detect；Or enzyme state Low dosage is predicted.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein described improve by more accurately identification and the special gene type of patient Associated patient tolerance, metabolism and obtained using the ability used of compound.General example includes：Can also take and The biopsy specimen of tumour or normal structure (such as Deiter's cells or other cells of central nervous system) is analyzed with special Property adjust or monitor for gene target certain drug use；Study unique oncogene expression pattern；Or analysis SNP (single nucleotide polymorphism), with the normal tissue toxicity for improving effect or avoiding specific medicaments insensitive.For treating The specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of NSCLC or oophoroma includes：To true Recognize diagnostic tool, technology, kit and the determination method of the specific genotype of patient；Gene or protein expression chip and analysis；It is single Nucleotide polymorphisms (SNP) are assessed；Histone deacetylase enzyme, ornithine decarboxylase, GPCR enzymes, protein kinase, the Telomerase of SNP Or jun enzymes；The identification and measurement of metabolic enzyme and metabolin；PDGFRA gene mutations determine；IDH1 gene mutations determine； NF1 gene mutations determine；The copy number of EGFR gene determines；Mgmt gene promoter methylation state determines；For Disease characterized by the promoter region that do not methylate of mgmt gene；For characterized by the promoter region that methylates of mgmt gene Disease；Disease characterized by for being expressed by MGMT high；For the disease characterized by MGMT low expressions；Or for The disease that EML4-ALK transpositions are characterized.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein it is described improve by using before or after chemotherapeutant to suffering from The special of person prepares to obtain.General example includes：Induction suppresses metabolic enzyme, to the spy of sensitive normal structure or tract Opposite sex protection.The specific of substituted hexose 01 derivatives of such as two to the water wei ling alcohol for treating NSCLC or oophoroma sends out Bright example includes：Use colchicin or the like；Use diuretics such as probenecid；Use medicine for improving uric acid excretion；Use urine Sour enzyme；It is parenteral to use niacinamide；The sustained release form of niacinamide；Use poly- (ADP ribose) polymerase inhibitors；Use coffee Coffee because；Formyl tetrahydrofolic acid is rescued；Infection control；Drug for hypertension.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement is prevented or subtracted by using other medicine or program Few potential side effect or toxicity obtain.General example includes：Limited using antemetic, anti-nausea agent, hematology supporting agent Or prevention neutrophilic granulocytopenia, anaemia, thrombopenia, using vitamin, antidepressants, treatment of sexual dysfunctions and Other supportive technologies.Substituted hexose 01 derivatives for such as two to the water wei ling alcohol for the treatment of NSCLC or oophoroma Specific invention example includes：Use colchicin or the like；Use diuretics such as probenecid；Use medicine for improving uric acid excretion； Use uricase；It is parenteral to use niacinamide；Use the niacinamide of sustained release form；Suppressed using poly- ADP- ribose polymerases Agent；Use caffeine；Formyl tetrahydrofolic acid is rescued；Use sustained release allopurinol；It is parenteral to use allopurinol；Moved using marrow Plant；Use haemocyte excitant；Use blood or platelet transfusion；Use Filgrastim, granulocyte colony stimulating factor (G- ) or granulocyte-macrophage colony stimutaing factor (GM-CSF) CSF；Use pain management technology；Use anti-inflammatory agent；Use stream Body；Use corticosteroid；Medicine is controlled using insulin；Use antipyretic；Treated using nausea；Controlled using anti diar rhea Treat；Use N-acetylcystein；Or use antihistamine.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement passes through following acquisition：Levels of drugs is monitored upon administration To make great efforts to maximize the drug blood plasma level of patient, the generation of toxic metabolite is monitored, is monitored in drug-drug interactions side The possible beneficial or harmful ancillary drug in face.General example includes：Binding of drug to plasma proteins is monitored, and monitors other medicines generation Dynamics or pharmacodynamics variable.Substituted hexitol for such as two to the water wei ling alcohol for treating NSCLC or oophoroma The specific invention example of derivative includes：The multiple assay of drug blood plasma level；Or the metabolin in blood or urine is multiple Measure.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement passes through following acquisition：Using unique drug regimen, its The improvement of the remote super increase or collaboration of effect or side effect management aspect can be provided.For treating the example of NSCLC or oophoroma Specific invention example such as the substituted hexose 01 derivatives of two to the water wei ling alcohol includes：Make with together with topoisomerase enzyme inhibitor With；Use fraudulent nucleosides；Use fraudulent nucleotide；It is used together with thymidylate synthetase inhibitor；Press down with signal transduction Preparation is used together；It is used together with cis-platinum, oxaliplatin or other platinum analogs；With alkylating agent such as nitrosoureas (BCNU (carmustine), Ge Li get chips (Gliadelwafer), CCNU (lomustine), Nimustine (ACNU), benzene is not up to Department spit of fland (Treanda)) it is used together；It is used together with the alkylating agent for destroying DNA, wherein the alkylating agent is compared to DAG Destroying DNA in diverse location, (TMZ, BCNU, CCNU and other alkylating agents are all in the O of guanine⁶Place destroys DNA, and DAG is in N⁷ Place's crosslinking)；It is used together with monofunctional alkyl agent；It is used together with bifunctional alkylating agent；Together with antitublin Use；It is used together with antimetabolite；It is used together with jamaicin；It is used together with 4',5,7-trihydroxyflavone；Make with together with Amonafide With；It is used together with colchicin or the like；It is used together with genistein；It is used together with Etoposide；With arabinose born of the same parents Glycosides is used together；It is used together with camptothecine；It is used together with vinca alkaloids；Make with together with topoisomerase enzyme inhibitor With；It is used together with 5 FU 5 fluorouracil；It is used together with curcumin；It is used together with NF- kB inhibitors；Together with Rosmarinic acid Use；It is used together with mitoguazone；It is used together with hanfangchin A (tedrandrine)；With Temozolomide (TMZ)；With Such as Arastin (VEGF inhibitor), Mabthera (Rituxan), herceptin (Herceptin), Erbitux (Erbitux) etc. The biotherapy of antibody is used together；It is used together with EGF-R ELISA (EGFR) inhibitor；Press down with tyrosine kinase Preparation is used together；It is used together with poly- (ADP- ribose) polymerase (PARP) inhibitor；Or make together with cancer vaccine treatment With.Substituted hexose 01 derivatives and cis-platinum, oxaliplatin or other platiniferous chemotherapies for such as two to the water wei ling alcohol The combination of agent, the ability of its remote super addition or collaboration is especially significant.

When the method according to the invention be used for treat oophoroma when, drug regimen can include substitute as described above oneself Sugar alcohol derivant and with anti ovary tumour antitumor activity other medicament.Such medicament includes but is not limited to： Taxol, Docetaxel (docetaxel), cis-platinum, carboplatin, topotecan, gemcitabine, bleomycin, Etoposide, Ah Mycin (can be with Pegylated Liposomal form use), tamoxifen, Letrozole, olaparib, U.S. of department replace Buddhist nun, mTOR (mammal rapamycin target protein) inhibitor, PI3 (phosphatidylinositols 3) kinase inhibitors and Trichostatin A.

The other medicament of antitumor activity with anti-NSCLC is well known in the art.Medicine according to the present invention Combination includes these other medicaments of therapeutically effective amount and the hexose 01 derivatives substituted as described above of therapeutically effective amount. The one or more of these other medicaments can be used.These other medicaments can be as described above right with one or more The medicament of anti-NSCLC activity is used together in drug regimen, and the drug regimen includes such as two to the water wei ling alcohol or diethyl The substituted hexose 01 derivatives of acyl group two to the water wei ling alcohol.These medicaments are jointly referred to herein as " having anti-NSCLC The other assistant medicament of activity ".These medicaments include following：5- disclosed in the U.S. Patent number 8,841,277 of Nguyen et al. The use of AzGR.The use of inhibitors of gamma-secretase disclosed in the U.S. Patent number 8,741,889 of Boylan et al..Chen Et al. U.S. Patent number 8, pyrroloquinoline base-pyrroles -2,5- dione compounds and EGFR inhibitor one disclosed in 575,191 It is same to be used for drug regimen.Neurotensin receptor 1 (NTSR1) disclosed in the U.S. Patent number 8,529,900 of Alifano et al. The use of neurotensin activation inhibitor.14- or 15- yuan of rings disclosed in the U.S. Patent number 5,795,870 of Narita et al. The use of Macrocyclic lactone compounds such as clarithromycin or berythromycin.Disclosed in the U.S. Patent number 5,756,512 of Johnson et al. The use of water soluble camptothecin analogs.5- methyl -6- disclosed in the U.S. Patent number 4,853,221 of Elslager et al. The use of [[(3,4,5- trimethoxyphenyl) amino]-methyl] -2,4- quinazolines diamines (Trimetrexate).U.S. of Nie et al. The pyrazoles yl pyridines of the disclosed substitution of state's patent No. 8,987,461, the use of pyrazoles radical pyridazine and pyrazolyl pyrimidines derivative. Hydrogen bond disclosed in the U.S. Patent number 8,987,412 of Arora et al. substitutes the use of Macrocyclic peptides.The United States Patent (USP) of Reddy et al. The use of number folic acid-catharanthus roseus conjugate disclosed in 8,987,281.8,987,280 disclosure of U.S. Patent number of Dotson et al. Pyrazolopyrimidine PIK3 inhibitor use, including 4- (3,4- dimethoxy phenoxy group) -6- (1H- indazole -4- bases) -1- first Base -1H- pyrazolos [3,4-d] pyrimidine；6- (1H- indazole -4- bases) -1- methyl -4- (4- (methyl sulphonyl) phenoxy group) -1H- Pyrazolo [3,4-d] pyrimidine；N- (3- (6- (1H- indazole -4- bases) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine-4-yl) benzene Base) Methanesulfomide；6- (1H- indazole -4- bases) -4- (3- (methoxy) phenyl) -1- methyl isophthalic acid H- pyrazolos [3,4-d] are phonetic Pyridine；3- (6- (1H- indazole -4- bases) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine-4-yl) benzonitrile；3- (6- (1H- indazoles- 4- yls) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine-4-yl)-N-methyl-benzamide；6- (1H- indazole -4- bases) -4- (3- Methoxyphenyl) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine；N- (3- (6- (1H- indazole -4- bases) -1- methyl isophthalic acid H- pyrazoles And [3,4-d] pyrimidine-4-yl) phenyl) acetamide；6- (1H- indazole -4- bases) -1- methyl -4- (4- (methyl sulphonyl) benzene Base) -1H- pyrazolos [3,4-d] pyrimidine；6- (1H- indazole -4- bases) -4- (4- methoxyphenyls) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine；4- (3,4- Dimethoxyphenyl) -6- (1H- indazole -4- bases) -1- methyl isophthalic acid H- pyrazolos [3,4-d] are phonetic Pyridine；6- (1H- indazole -4- bases) -1- methyl -4- (pyridin-3-yl epoxide) -1H- pyrazolos [3,4-d] pyrimidine；6- (1H- indazoles- 4- yls) -4- (3- methoxyphenoxies) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine；And 6- (1H- indazole -4- bases)-N- (3- methoxyphenyls) -1- methyl isophthalic acid H- pyrazolos [3,4-d] pyrimidine -4- amine).The patent No. 8,987,267 of Reddy et al. is public The use of 2- substitutions -8- alkyl -7- oxos -7,8- dihydro pyrido [2,3-d] pyrimidine -6- formonitrile HCNs of cloth, including 8- cyclopenta - 2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -7,8- dihydro pyrido [2,3-d] pyrimidine -6- formonitrile HCNs；8- Cyclohexyl -2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) -7- oxos -7,8- dihydro pyrido [2,3-d] pyrimidine -6- Formonitrile HCN；8- cyclopenta -2- ((3,5- Dimethoxyphenyl) amino) -7- oxos -7,8- dihydro pyrido [2,3-d] pyrimidine -6- Formonitrile HCN；8- cyclopenta -7- oxos -2- ((3,4,5- trimethoxyphenyl) amino) -7,8- dihydro pyridos [2,3-d] pyrimidine - 6- formonitrile HCNs；And 8- cyclopenta -2- ((4- morpholinoes-phenyl) amino) -7- oxos -7,8- dihydro pyrido [2,3-d] pyrimidine - 6- formonitrile HCNs.2- (1H- indazole -4- bases) -6- (4- methyl sulphurs that the U.S. Patent number 8,987,260 of Chuckowree et al. is announced Acyl-piperazin -1- ylmethyls) -4- morpholines -4- bases-thieno [3,2-d] pyrimidine bis-mesylate use.Radetich etc. The use for the morpholinyl purine derivative that the U.S. Patent number 8,987,257 of people is announced, including 3- [2- ((2S, 6R) -2,6- bis- Methyl-morpholine -4- bases) -6- morpholine -4- base -9H- purine -8- bases]-phenol；2,6- double-((S) -3- Methyl-morpholine -4- bases) - 8- (1H- pyrrolo-es [2,3-b] pyridin-4-yl) -9H- purine；{ the fluoro- 5- of 2- [6- ((S) -3- methyl-morpholinyl -4- bases) -2- Morpholine -4- base -9H- purine -8- bases]-phenyl }-methanol；2- (4,4- difluoro-piperidin -1- bases) -8- (1H- indoles -4- bases) -6- ((S) -3- Methyl-morpholine -4- bases) -9H- purine；5- [2,6- double-((S) -3- Methyl-morpholine -4- bases) -9H- purine -8- Base] -1,3- dihydro-benzoimidazole -2- ketone；{ 5- [2,6- double-((S) -3- Methyl-morpholine -4- bases) -9H- purine -8- bases] -2- Methoxyl group-phenyl }-methanol；8- (1H- indoles -4- bases) -2- morpholine -4- bases -6- (8- oxa- -3- aza-bicyclos [3.2.1] Oct-3-yl) -9H- purine；2- methoxyl groups -5- [6- ((S) -3- Methyl-morpholine -4- bases) -2- morpholine -4- base -9H- purine -8- Base]-benzoic acid；{ the chloro- 3- of 4- [6- ((S) -3- Methyl-morpholine -4- bases) -2- morpholine -4- base -9H- purine -8- bases]-phenyl } - Methanol；3- (2,6- bis--morpholine -4- base -9H- purine -8- bases)-benzylamine；1- { 3- [6- ((S) -3- Methyl-morpholine -4- bases) -2- Morpholine -4- base -9H- purine -8- bases]-phenyl }-ethanol；2,6- bis--morpholine -4- bases -8- (1H- pyrrolo-es [3,2-b] pyridine - 6- yls) -9H- purine；8- (1H- indoles -6- bases) -2,6- pairs-((S) -3- Methyl-morpholine -4- bases) -9H- purine；8- (1H- Yin Diindyl -4- bases) -2,6- pairs-((R) -3- Methyl-morpholine -4- bases) -9H- purine；1- [8- (1H- indoles -4- bases) -6- ((S) -3- Methyl-morpholine -4- bases) -9H- purine -2- bases]-piperidines -4- alcohol；{ 3- [2,6- double-((S) -3- Methyl-morpholine -4- bases) -9H- Purine -8- bases] -5- methoxyl groups-phenyl }-methanol；And 8- (1H- indoles -4- bases) -2- ((R) -3- Methyl-morpholine -4- bases) - 6- ((S) -3- Methyl-morpholine -4- bases) -9H- purine.The U.S. Patent number 8,980,955 of Turchi et al. is disclosed to be included taking The use of the micromolecular inhibitor as replication protein A of the halogen ester isoborneol (haloester isoborneols) in generation. The disclosed Antitubulin as antimitotic agent of the U.S. Patent number 8,980,824 of Cong et al. (tubulysins) use.Containing zinc bound fraction based on quinoline disclosed in the U.S. Patent number 8,975,401 of Qian et al. The use of the EGFR inhibitor of oxazoline.The imidazo [1,2-a] of the disclosed substitution of the U.S. Patent number 8,975,265 of Ince et al. The use of pyrimidine and imidazo [1,2-a] pyridine of substitution.Conduct disclosed in the U.S. Patent number 8,975,260 of Currie et al. The use of the pyridazinone of Btk kinase inhibitors.7- tert-butoxies disclosed in the U.S. Patent number 8,975,248 of Zaknoen et al. Iminomethyl camptothecin and taxol, epothilone B, cis-platinum, carboplatin, { 6- [4- (4- ethyl-piperazin -1- ylmethyls)-benzene Base] -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl]-((R) -1- phenyl-ethyl groups)-amine, everolimus, Imatinib or boron replace assistant The use of the combination of rice.The U.S. Patent number 8,969,401 of Maier et al. discloses as hdac inhibitor that (histone goes second Deacerylase inhibitors) sulphonylpyrroles use, including (E)-N- hydroxyls -3- [1- (toluene -4- sulfonyls) -1-H- pyrroles - 3- yls]-acrylamide；N- hydroxyls -3- (1- Phenylmethylsulfonyls base (phenylmethanesulfonyl) -1H- pyrroles -3- Base)-acrylamide；(E) -3- [1- (4- dimethylaminos-benzenesulfonyl) -1H- pyrroles -3- bases]-N- hydroxy-acrylamides； (E)-N- (2- methanesulfonylamino-phenyls) -3- [1- (toluene -4- sulfonyls) -1H- pyrroles -3- bases]-acrylamide；(E)-N- (2- ammonia Base-phenyl) -3- (1- Phenylmethylsulfonyls base (phenylmethanesulfonyl) -1H- pyrroles -3- bases)-acrylamide； (E)-N- (2- methanesulfonylamino-phenyls) -3- [1- (4- dimethylaminos-benzenesulfonyl) -1H- pyrroles -3- bases]-acrylamide；(E)- N- hydroxyls -3- (1- [4- (([2- (1H- indoles -2- bases)-ethyl]-Methyl-amino)-methyl)-benzenesulfonyl] -1H- pyrroles - 3- yls)-acrylamide；(E) -3- [1- (4- dimethylaminomethyls-benzenesulfonyl) -1H- pyrroles -3- bases]-N- hydroxyls-propylene Acid amides；And (E)-N- hydroxyls -3- [1- (4- { [(pyridin-3-yl methyl)-amino]-methyl }-benzenesulfonyl) -1H- pyrroles - 3- yls]-acrylamide.(3- chloro- 4- (the cyclopropylamino carbonyls of 4- disclosed in the U.S. Patent number 8,969,379 of Furitsu et al. Base) amino-benzene oxygen) -7- methoxyl group -6- quinoline formyl amine use.The U.S. Patent number 8,969,372 of Huesca et al. is public 2 opened, the use of 4,5- trisubstituted aryl imidazoles.The U.S. Patent number 8,962,637 of McAllister et al. discloses work For the use of the aromatic bicyclic compound with pyrimidine and pyridine moiety of dual c-SRC/JAK inhibitor, including N- (4- first Base -3- { 2- [4- (4- thyl-piperazin -1- carbonyls)-phenyl amino] -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- Base }-phenyl) -3- triflooromethyl-benzamides；N- (4- methyl -3- 2- [4- (4- thyl-piperazin -1- bases)-phenyl amino] - 5- oxos -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- bases }-phenyl) -3- triflooromethyl-benzamides；5-{6-[2- Methyl -5- (3- Trifluoromethyl-phenacyls amino)-phenyl] -5,6,7,8- Tetrahydro-pyridines simultaneously [4,3-d] pyrimidine -2-base ammonia Base }-pyridine-2-carboxylic acids cyclopropyl amide；N- { 3- [2- (4- Cyclopropylsulfonyls-phenyl amino) -7,8- dihydro -5H- pyridines And [4,3-d] pyrimidine -6- bases] -4- methylphenyls -3- triflooromethyl-benzamides；N- (4- chloro- 3- 2- [4- (4- methyl- Piperazine -1- bases)-phenyl amino] -5- oxos -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- bases }-phenyl) -3- trifluoros Methyl-benzamide；4- trifluoromethylpyridin -2- carboxylic acids { the chloro- 3- of 4- [2- (4- methylcarbamoyls-phenylamino) -7,8- Dihydro -5H- pyridos [4,3-d] pyrimidine -6- bases]-phenyl }-acid amides；4,4,4- tri- fluoro- 3- methyl-N- [4- methyl -3- (2- { 4- [2- (4- thyl-piperazin -1- bases)-ethyoxyl]-phenyl amino } -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- Base)-phenyl]-butyramide；And 1- cyclopenta -3- (4- methyl -3- { 2- [4- (2- pyrrolidin-1-yls-ethyoxyl)-phenylaminos Base] -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- bases }-phenyl)-urea.The U.S. Patent number 8,962 of Kuntz et al., 620 disclose using 6, the 5- fused bicyclic heteroaryls compound of substitution to prevent abnormal H3-K27 histone methylated, including N- ((4,6- dimethyl -2- oxo -1,2- dihydropyridine -3- bases) methyl) -6- (2,5- thioxene -3- bases) -1- isopropyls Base -1H- pyrazolos [3,4-b] pyridine -4- acid amides；6- (2,3- dihydros-Isosorbide-5-Nitrae-benzodioxin -6- bases)-N- [(1,2- bis- Hydrogen -4,6- dimethyl -2- oxo -3- pyridine radicals) methyl] -1- (1- Methylethyls) -1H- pyrazolos [3,4-b] pyridine -4- acyls Amine；6- cyclopropyl-N- ((4,6- dimethyl -2- oxo -1,2- dihydropyridine -3- bases) methyl) -1,3- dimethyl -1H- pyrazoles And [3,4-b] pyridine -4- acid amides；N- [(1,2- dihydro -4,6- dimethyl -2- oxo -3- pyridine radicals) methyl] -1,3,6- front threes Base -1H- pyrazolos [3,4-b] pyridine -4- acid amides；N- [(1,2- dihydro -4,6- dimethyl -2- oxo -3- pyridine radicals) methyl] - 6- methyl isophthalic acids-(1- Methylethyls) -1H- pyrazolos [3,4-b] pyridine -4- acid amides；And 6- cyclopropyl-N- ((4,6- diformazans Base -2- oxo -1,2- dihydropyridine -3- bases) methyl) -1- isopropyl -1H- pyrazolos [3,4-b] pyridine -4- acid amides. The U.S. Patent number 8,962,619 of Ashwell et al. discloses making for substituted imidazopyridyl-aminopyridine compounds With.The U.S. Patent number 8,962,609 of Perrior et al. discloses pyrimidine compound as protein kinase IKK ε and/or TBK-1 Inhibitor use, including 5- (2- phenylamino-pyrimidin -4- bases) -2- pyrrolidin-1-yls-benzonitrile；5- [2- (pyridine- 4- bases amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；5- [2- (pyridine -2- bases amino)-pyrimidine-4-yl] -2- Pyrrolidin-1-yl-benzonitrile；2- pyrrolidin-1-yls -5- [2- (3- trifluoromethyl-phenylaminos)-pyrimidine-4-yl]-benzonitrile； 2- [4- (3- cyano group-4- pyrrolidin-1-yls-phenyl)-pyrimidine -2 --amino]-oxazole-5- carboxylic acid amides；5- [2- (5- methyl- Isoxazole -3- bases amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；2- [4- (3- cyano group -4- pyrrolidin-1-yls - Phenyl)-pyrimidine -2 --amino]-oxazole-4- carboxylic acid amides；5- [4- (3- cyano group -4- pyrrolidin-1-yls-phenyl)-pyrimidine -2- Base amino] -2- methyl -2H- pyrazoles -3- carboxylic acid amides；5- [2- (5- methYl-thiazol -2- bases amino)-pyrimidine-4-yl] -2- pyrroles Cough up alkane -1- bases-benzonitrile；5- [2- (oxazole -2- bases amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；5-[2- (4- methYl-thiazol -2- bases amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；4- [4- (3- cyano group -4- pyrrolidines - 1- bases-phenyl)-pyrimidine -2 --amino]-3- methyl-benzamides；5- [2- (3- fluoro-phenyls amino)-pyrimidine-4-yl] -2- Pyrrolidin-1-yl-benzonitrile；5- [2- (the fluoro- phenylaminos of 4-)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；5-[2- (3- Methoxy-phenylaminos)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile；5- [2- (pyridin-3-yl amino)-phonetic Pyridine -4- bases] -2- pyrrolidin-1-yls-benzonitrile；5- [2- (3- methyl-isoxazole -5- bases amino)-pyrimidine-4-yl] -2- pyrroles Alkane -1- bases-benzonitrile；5- [2- (2- methyl -2H- pyrazole-3-yls amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzene first Nitrile；And 5- [2- (1- methyl isophthalic acid H- pyrazole-3-yls amino)-pyrimidine-4-yl] -2- pyrrolidin-1-yls-benzonitrile. The U.S. Patent number 8,962,602 of Fernandez Rodriguez et al. discloses and bufadienolide class compound The use of related unsaturated steroid lactone derivatives.The U.S. Patent number 8,961,970 of Huang et al. is disclosed to be pressed down with MEK Preparation 6- (the bromo- 2- fluoroanilinos of 4-) the fluoro- 3- methyl -3H- benzimidazole-5-carboxylic acids of -7- (2- hydroxyl-oxethyls)-acid amides and Use as the Antibody Combination of IGFR1 inhibitor.The U.S. Patent number 8,952,151 of Chen et al. discloses substituted amino The use of pyridine or amino pyridazine derivative, they are Histone Demethylase inhibitor.The U.S. Patent Publication No. of Hu et al. 8,951,993 disclose the use of the aryl compound as ALK or the substitution of the phosphorus of c-Met kinase inhibitor, including 3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- dimethyl phosphorus phenyl) pyridine -2- amine；[(2,6- bis- chloro- 3- are fluoro- by 1- by 3- Phenyl) ethyoxyl] -5- [1- [1- (dimethyl phosphorus methyl) -4- piperidyls] pyrazoles -4- bases] pyridine -2- amine；3- [1- (2,6- bis- Chloro- 3- fluoro-phenyls) ethyoxyl] -5- [1- (dimethyl phosphorus methyl) pyrazoles -4- bases] pyridine -2- amine；5- [4- [(double (dimethyl Phosphorus methyl) amino) methyl] phenyl] -3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] pyridine -2- amine；3- [1- (2,6- bis- Chloro- 3- fluoro-phenyls) ethyoxyl] -5- [4- [(dimethyl phosphorus methylamino) methyl] phenyl] pyridine -2- amine；3- [1- (2,6- bis- Chloro- 3- fluoro-phenyls) ethyoxyl] -5- (5- dimethyl phosphorus -3- pyridine radicals) pyridine -2- amine；3- [1- (2, the 6- bis- chloro- fluoro- benzene of 3- Base) ethyoxyl] -5- [4- (solutions of dimethyl phosphoryl epoxide methyl) phenyl] pyridine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) Ethyoxyl] -5- (4- dimethyl phosphorus -2- methoxyl groups-phenyl) pyridine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethoxies Base] -5- (4- dimethyl phosphorus -1- naphthyls) pyridine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- diformazans The fluoro- 5- methoxyl groups-phenyl of base phosphorus -2-) pyridine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- diformazans Base phosphorus phenyl) pyrazine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- dimethyl phosphorus -3- methoxyl groups-benzene Base) pyridine -2- amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- dimethyl phosphorus -2- fluoro-phenyls) pyridine -2- Amine；3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- (4- dimethyl phosphorus -3- fluoro-phenyls) pyridine -2- amine；And 3- [1- (2,6- bis- chloro- 3- fluoro-phenyls) ethyoxyl] -5- [4- dimethyl phosphorus -2- (trifluoromethyl) phenyl] pyridine -2- amine. Use of the tetrahydro carbazole as VEGF synthetic inhibitors disclosed in the U.S. Patent number 8,946,444 of Lennox et al..Ortega The U.S. Patent number 8,946,296 of Munoz et al. discloses substituted heteroaryl-and aryl-cyclopropyl amine acetamide conduct The use of -1 inhibitor of lysine specific demethylase, including 2- ((t) -2- (4- (4- cyano benzyloxies) phenyl) cyclopropyl Amino) acetamide；2- ((t) -2- (4- (3- cyano benzyloxies) phenyl) cyclopropylamino) acetamide；2- ((t) -2- (4- (benzyls Epoxide) phenyl) cyclopropylamino) acetamide；2- ((t) -2- (4- (4 (benzyloxy) phenyl) cyclopropylamino) acetamides；2- ((t) -2- (4- (3- fluorine benzyloxy) phenyl) cyclopropylamino) acetamide；2- ((t) -2- (4- (3- benzyl chlorides epoxide) phenyl) rings Propylcarbamic) acetamide；2- ((t) -2- (4- (4- benzyl chlorides epoxide) phenyl) cyclopropylamino) acetamide；2-((t)-2-(4- (3- bromo-benzyloxys) phenyl) cyclopropylamino) acetamide；2- ((t) -2- (4- (3,5- difluoro benzyloxy) phenyl) cyclopropyl ammonia Base) acetamide；2- ((t) -2- (4- benzene ethoxyl phenenyl) cyclopropylamino) acetamide (2- ((t) -2- (4- phenethoxyphenyl)cyclopropylarnino)acetamide)；2- ((t) -2- (3 '-(trifluoromethyl) diphenyl - 4- yls) cyclopropylamino) acetamide；2- ((t) -2- (3 '-chlorodiphenyl base -4- bases) cyclopropylamino) acetamide；2-((t)-2- (6- (4- chlorphenyls) pyridin-3-yl) cyclopropylamino) acetamide；(R) -2- ((t) -2- (4- (3- fluorine benzyloxy) phenyl) rings Propylcarbamic) propionamide；(S) -2- ((t) -2- (4- (4- luorobenzyls epoxide) phenyl) phenycyclopropyl amino) propionamide；(R)- 2- ((t) -2- (4- (4- fluorine benzyloxy) phenyl) cyclopropylamino) propionamide；(S) -2- ((t) -2- (4- (4- fluorine benzyloxy) benzene Base) cyclopropylamino) propionamide；And (R) -2- ((t) -2- (4- (benzyloxy) phenyl) cyclopropylamino) propionamide. A kind of rigidin disclosed in the U.S. Patent number 8,946,246 of Magedov et al. (pyrrolopyrimidine alkaloid) analog makes With.The U.S. Patent number 8,946,235 of Butterworth et al. discloses 2- (2,4,5- substituted 2-znilino) pyrimidine compound Use as the inhibitor of mutation EGFR.The U.S. Patent number 8,946,213 of Crawford et al. discloses alkylated piperazine Use of the piperazine as Btk inhibitor, including (S) -2- (5- fluoro- 2- (methylol) -3- (1- methyl -5- (5- (2- methyl -4- (oxygen Heterocycle butyl- 3- yls) piperazine -1- bases) pyridine -2- bases amino) -6- oxo -1,6- dihydropyridine -3- bases) phenyl) -3,4,6,7, 8,9- hexahydropyridines simultaneously [3,4-b] indolizine -1 (2H) -one；(S)-the 5- [(1- methyl -5- (5- (2- of the fluoro- 2- of 5- (methylol) -3 Methyl -4- (oxa- ring butyl- 3- yls) piperazine -1- bases) pyridine -2- bases amino) -6- oxo -1,6- dihydropyridine -3- bases) benzene Base] -8- thias -4,5- diaza tricyclic [7.4.0.02,7] tridecane-[(9), 2 (7), 3- triolefin -6- ketone；(2S)-10-[5- Fluoro- 2- (methylol) -3- [1- methyl -5- ({ 5- [2- methyl -4- (oxa- ring butyl- 3- yls) piperazine -1- bases] pyridine -2- bases } ammonia Base) -6- oxo -1,6- dihydropyridine -3- bases] phenyl] -4,4- dimethyl -1,10- diaza tricyclic [6.4.0.02,6] 12 Alkane -2 (6), 7- diene -9- ketone；2- (3- (5- (5- ((2S, 5R) -2,5- dimethyl -4- (oxa- ring butyl- 3- yls) piperazine -1- Base) pyridine -2- bases amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -5- fluoro- 2- (methylol) phenyl) -3,4, 6,7,8,9- hexahydropyrazines simultaneously [1,2-a] indoles -1 (2H) -one；(S) -2- (3- (5- (5- (2- ethyls -4- (oxa- ring butyl- 3- Base) piperazine -1- bases) pyridine -2- bases amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- bases -5- fluoro- 2- (methylol) benzene Base) -3,4,6,7,8,9- hexahydropyrazines simultaneously [1,2-a] indoles -1 (2H) -one；(S) -2- (5- fluoro- 2- (hydroxymethyl) -3- (1- Methyl -5- (5- (2- methyl -4- (oxa- ring butyl- 3- yls) piperazine -1- bases) pyridine -2- bases amino) -6- oxo -1,6- dihydro pyrroles Pyridine -3- bases) phenyl) -3,4,6,7,8,9- hexahydropyrazines simultaneously [1,2-a] indoles -1 (2H) -one；(S) -2- (3- (5- (5- (3,4- Lupetazin -1- bases) pyridine -2- bases amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -5- fluoro- 2- (hydroxyl first Base) phenyl) -3,4,6,7,8,9- hexahydropyrazines simultaneously [1,2-a] indoles -1 (2H) -one；(R) -2- (3- (5- (5- (3,4- diformazans Base piperazine -1- bases) pyridine -2- bases amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -5- fluoro- 2- (methylol) benzene Base) -3,4,6,7,8,9- hexahydropyrazines simultaneously [1,2-c] indoles -1 (2H) -one；And (R) -2- (3- (5- (5- (2,4- dimethyl Piperazine -1- bases) pyridine -2- bases amino) -1- methyl -6- oxo -1,6- dihydropyridine -3- bases) -5- fluoro- 2- (methylol) benzene Base) -3,4,6,7,8,9- hexahydropyrazines simultaneously [1,2-a] indoles -1 (2H) -one.The U.S. Patent number 8,937,095 of Zahn et al. Disclose the use of aurora kinase/MEK double inhibitors, including 3- [3- [[4- (dimethyl oxygen is for amino methyl) anilino-]- Phenyl methyl subunit] -2- oxo -1H- indoles -6- bases]-N- ethyl -2- propine acid amides.The U.S. Patent application of Blake et al. Publication number 2015/0087664 discloses use of the quinazoline as serine/threonine kinase inhibitor, including ((4- is chloro- by N- 3- fluorophenyls) (1- methyl isophthalic acid H- pyrazoles -4- bases) methyl) -2- ((S) -1- hydroxy propane -2- bases amino) quinazoline -7- acid amides； 2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(the chloro- 3- fluoro-phenyls of 4-)-(1- methyl isophthalic acid H- pyrazoles -4- bases)-first Base]-acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(S)-(the fluoro- 4- trifluoromethyl-phenyls of 3-)-(S) - Pyrrolidin-2-yl-methyl]-acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(the chloro- 3- fluoro-phenyls of 4-) - (1- methyl isophthalic acid H- pyrazole-3-yls)-methyl]-acid amides；2- isopropylaminos-quinazoline -7- carboxylic acids [(S)-(fluoro- 4- trifluoros of 3- Methylphenyl)-(R)-pyrrolidin-2-yl-methyl]-acid amides；N- ((the chloro- 3- fluorophenyls of 4-) (1- methyl isophthalic acid H- pyrazole-3-yls) Methyl) -2- ((S) -1- hydroxy propane -2- bases amino) quinazoline -7- acid amides；2- (tetrahydropyran -4-base amino)-quinazoline- 7- carboxylic acids [(S)-(the fluoro- 4- trifluoromethyl-phenyls of 3-)-(R)-pyrrolidin-2-yl-methyl]-acid amides；2- (tetrahydropyran -4-bases Amino)-quinazoline -7- carboxylic acids [(R)-(the chloro- 4- fluoro-phenyls of 3-)-(R)-pyrrolidin-3-yl-methyl]-acid amides；2- (tetrahydrochysene pyrroles Mutter -4- bases amino)-quinazoline -7- carboxylic acids [(R)-(the chloro- 4- fluoro-phenyls of 3-)-(S)-pyrrolidin-3-yl-methyl]-acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(S)-(the chloro- 4- fluoro-phenyls of 3-)-(S)-pyrrolidin-3-yl-methyl] - Acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(S)-(the chloro- 4- fluoro-phenyls of 3-)-(R)-pyrrolidines -3- Base-methyl]-acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(S)-(the chloro- 3- fluoro-phenyls of 4-)-(1- first Base -1H- pyrazoles -4- bases)-methyl]-acid amides；2- (tetrahydropyran -4-base amino)-quinazoline -7- carboxylic acids [(R)-(chloro- 3- of 4- Fluoro-phenyl)-(1- methyl isophthalic acid H- pyrazoles -4- bases)-methyl]-acid amides；And 2- ((S) -2- hydroxyl -1- methyl-ethvlaminos) - Quinazoline -7- carboxylic acids.The U.S. Patent Application Publication No. 2015/0087630 of Chen et al. discloses the use of diaza carbazole. The U.S. Patent Application Publication No. 2015/0087628 of Ostrem et al. is disclosed including Switch-2 binding pockets part and energy Enough and K-Ras cysteine residues or K-Ras asparagicacid residues form the K-Ras activity of the electrophilic chemical part of covalent bond The use of conditioning agent.The U.S. Patent Application Publication No. 2015/0087600 of Popovici-Muller et al. discloses different lemon The use of the mutant inhibitor of acidohydrogenase 1 or isocitric dehydrogenase 2.The U.S. Patent Application Publication No. of Chen et al. 2015/0086551 discloses the use for the hydroxamic acid derivs for suppressing HDAC paths.The U.S. Patent application of Wang et al. is public The number of opening 2015/0080392 discloses use of the quinazoline derivant as kinase inhibitor, and the kinase inhibitor includes EGFR, VEGFR-2 (vascular endothelial growth factor receptor), c-erbB-2 (epithelial growth factor receptor 2), c-erbB-4 (epitheliums Growth factor receptors 4), c-met (hepatocyte growth factor receptor), tie-2, PDGFR (platelet derived growth factor receptor), C-src (proto-oncogenic tyrosine protein kinase Src), lck (Lymphocyte-specific protein-tyrosine kinase), Zap70 One kind or more of (the φt cell receptor Zeta chains related protein kinase of 70kDa) and fyn kinases (tyrosine protein kinase fyn) Kind, such as N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((4- hydroxybutyls) amino) methyl -2- furyls) -4- Amido quinazoline；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((3- phenyl propyls) amino) methyl) -2- furans Base) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((n- hexylaminos) methyl) -2- furans Base) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((ethylamino) methyl) -2- furans Base) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((N, N- diethyl) amino) methyl) - 2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2- cyclobutenyls) amino) first Base) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- ((2- (1,3- dihydroxy Propyl group) amino) methyl) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- ((5- ((cyclohexyl methyl) amino) methyl) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl)- 6- (5- (((2- (3- cyclohexenyl groups) ethyl) amino) methyl) -2- furyls) -4- amido quinazolines；N- (3- chloro- 4- ((3- fluorine Benzyl) oxygen) phenyl) -6- (5- ((((3- chlorine cyclohexyl) methyl) amino) methyl) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((4- methoxybutyls) amino) methyl) -2- furyls) -4- amino Quinazoline；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((3- chlorobenzyls) amino) methyl) -2- furyls) -4- Amido quinazoline；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2- (4- nitrobenzophenones) ethyl) amino) first Base) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2- (4- hydroxy benzenes Base) ethyl) amino) methyl) -2- furyls) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2- (3,5- Dimethoxyphenyl) ethylamino) methyl) -2- furyls) -4- amido quinazolines；N- (3- chloro- 4- ((3- fluorine Benzyl) oxygen) phenyl) -6- (5- (((2- (3- hydroxyl-5-fluorines phenyl) ethyl) amino) methyl) -2- furyls) -4- amino quinoline azoles Quinoline；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2- (the chloro- 5- fluorophenyls of 3-) ethyl) amino) methyl) -2- Furyl) -4- amido quinazolines；N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) -6- (5- (((2-, 6- dihydroxy hexyl) ammonia Base) methyl) -2- furyls) -4- amido quinazolines；And (5- is ((double by -6- by N- (the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) (2- hydroxyethyls) amino) methyl) -2- furyls) -4- amido quinazolines.The U.S. Patent Application Publication No. of Dotson et al. 2015/0079081 discloses the use of tricyclic PI3K inhibitor, including 1- [4- (3a, 8- dimethyl -7- morpholine -4- base -3, 3a, 8,8a- tetrahydrochysene -2H-1- oxa-s -4,6, tri- azepines of 8--cyclopenta [a] indenes -5- bases)-phenyl] -3- ethyls-urea；5- (6,6- dimethyl -4- morpholino -8,9- dihydros -6H- (Isosorbide-5-Nitrae) oxazines simultaneously [3,4-e] purine -2- bases) -4- methylpyrimidines -2- Amine；5- (6,6- dimethyl -4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -2- bases) pyrimidine -2- amine； 5- (6,6- dimethyl -4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -2- bases) -4- (trifluoromethyl) Pyridine radicals -2- amine；5- (4- morpholino -8,9- dihydros -7H- [1,3] oxazines simultaneously [2,3-e] purine -2- bases) pyrimidine -2- amine；5- (4- morpholinoes -6,7,8,9- tetrahydropyridines simultaneously [2,1-e] purine -2- bases) pyrimidine -2- amine；5- (4- morpholinoes -6,7,8,9- tetra- Pyridinium hydroxide simultaneously [2,1-e] purine -2- bases) pyridine -2- amine；(4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines is simultaneously [3,4-e] by 5- Purine -2- bases) -4- (trifluoromethyl) pyridine radicals -2- amine；5- (4- morpholinoes -7,8- dihydro -6H- pyrrolo-es [2,1-e] purine - 2- yls) pyrimidine -2- amine；6,6- dimethyl -4- morpholinoes -2- (1H- pyrrolo-es [2,3-b] pyridine -5- bases) -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine；(6,6- dimethyl -4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines are simultaneously [3,4-e] by 5- Purine -2- bases) pyridine -2- amine；5- (4- morpholino -8,9- dihydros spiral shell [[1,3] oxazines simultaneously [2,3-e] purine -7,1 '-ring third Alkane] -2- bases) pyrimidine -2- amine；5- (4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -2- bases) pyrimidine - 2- amine；5- (4- morpholino -8,9- dihydros spiral shell [[Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -6,3 '-oxetanes] -2- bases) is phonetic Pyridine -2- amine；5- (7,7- dimethyl -4- morpholino -8,9- dihydros -7H- [1,3] oxazines simultaneously [2,3-e] purine -2- bases) pyrimidine - 2- amine；5- (4- morpholinoes -6- (trifluoromethyl) -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -2- bases) pyridine -2- Amine；And 5- (6,6- (six is deuterated) dimethyl -4- morpholino -8,9- dihydros -6H- [Isosorbide-5-Nitrae] oxazines simultaneously [3,4-e] purine -2- Base) pyrimidine -2- amine.The U.S. Patent Application Publication No. 2015/0073054 of Strongin et al. discloses furin suppression Agent and the use of other proprotein convertases inhibitor.The U.S. Patent Application Publication No. 2015/0073003 of Dagan et al. is public The use of sphingolipid analog is opened.The U.S. Patent Application Publication No. 2015/065526 of Deng et al. is disclosed including chlorine nitre willow The use of the Stat3 inhibitor of amine.The U.S. Patent Application Publication No. 2015/0057309 of Vakkalanka et al. discloses 3, 5- bis- substitutes -3h- imidazos (4,5-b) pyridine and 3,5- bis- to substitute -3H- [1,2,3] triazol [4,5-B] pyridine compounds to make For the use of c-Met conditioning agents, including N- (2- amino -2- oxoethyls) -4- (3- (quinoline -7- ylmethyls) -3H- [1,2, 3]-triazol [4,5-b] pyridine -5- bases) benzamide:N- (2- (methylamino) -2- oxoethyls) -4- (3- (quinoline -6- Ylmethyl) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzamide:N- (3- amino -3- oxopropyls) -4- (3- (quinoline -6- ylmethyls) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzamide:N- (3- (methyl ammonia Base) -3- oxopropyls) -4- (3- (quinoline -6- ylmethyls) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzoyl Amine:The chloro- N- of 2- (2- (pyrrolidin-1-yl) ethyl) -4- (3- (quinoline -7- ylmethyls) -3H- [1,2,3]-triazols [4,5-b] Pyridine -5- bases) benzamide:The chloro- N- of 2- (2- hydroxyl-oxethyls) -4- (3- (quinoline -6- ylmethyls) -3H- [1,2,3]-triazole And [4,5-b] pyridine -5- bases) benzamide:The chloro- N- of 2- (2- hydroxyl-oxethyls) -4- (3- (quinoline -6- ylmethyls) -3H- [1, 2,3]-triazol [4,5-b] pyridine -5- bases) benzamide hydrochloride salt:The chloro- N- of 2- (2- hydroxyl-oxethyls) -4- (3- (quinoline - 6- ylmethyls) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzamide 4- toluenesulfonates；Chloro- N- (the 2- of 2- Hydroxyl-oxethyl) -4- (3- (quinoline -6- ylmethyls) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzamide hydrogen Bromic acid；And sodium (the chloro- 4- of 2- (3- (quinoline -6- ylmethyls) -3H- [1,2,3]-triazol [4,5-b] pyridine -5- bases) benzene first Acyl group) (2- hydroxyl-oxethyls) acid amides.The U.S. Patent Application Publication No. 2015/0057295 of Reiser et al. disclose including Use as the 6- alkynyl pyridine derivates of SMAC analogies.The U.S. Patent Application Publication No. 2015/ of Angibaud et al. 0057293 discloses the use of 7-naphthyridine derivatives.2015/0057286 disclosure of U.S. Patent Application Publication No. of Reiser et al. Include the use of the double amidopyridines as SMAC analogies.The U.S. Patent Application Publication No. 2015/ of Bock et al. 0051209 discloses the use of the mek inhibitor with imidazoquinoline or imidazoquinolie part, including 1- ((3S, 4S) -4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazos [4, the 5-c] quinoline -1- bases of -7-) - 3- fluorine resources -1- bases) -2- hydroxyethanones；((8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) -7- is fluoro- by (3R, 4R) -4- by 1- 2- methyl isophthalic acid H- imidazos [4,5-c] quinoline -1- bases) -3- fluorine resources -1- bases) -2- hydroxyethanones；8- (the chloro- 4- of 2- (pyrimidine- 2- bases epoxide) phenyl) the fluoro- 1- of -7- (1- (2- methoxy ethyls) piperidin-4-yl) -2- methyl isophthalic acid H- imidazos [4,5-c] quinoline promise Ketone；2- (4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazos [4,5-c] quinoline -1- of -7- Base) piperidin-1-yl) ethanol；8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids of -7--(1- ((3- methyl oxygen Azetidine -3- bases) methyl) piperidin-4-yl) -1H- imidazos [4,5-c] quinolone；8- (2- chloro- 4- (pyrimidine -2-base oxygen Base) phenyl) the fluoro- 2- methyl isophthalic acids of -7--(1- (methyl sulphonyl) piperidin-4-yl) -1H- imidazos [4,5-c] quinolone；1-(4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazos [4, the 5-c] quinoline -1- bases of -7-) piperidines -1- Base) -2- hydroxy propane -1- ketone；1- (4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazoles of -7- And [4,5-c] quinoline -1- bases) piperidin-1-yl) propane -2- alcohol；8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) -1- (1- (Cyclopropylsulfonyl) piperidin-4-yl) fluoro- 2- methyl isophthalic acids H- imidazos [4, the 5-c] quinolones of -7-；8- (the chloro- 4- of 2- (pyrimidine- 2- bases epoxide) phenyl) the fluoro- 1- of -7- (1- (isopropelsulfonyl) piperidin-4-yl) -2- methyl isophthalic acid H- imidazos [4,5-c] quinoline promise Ketone；4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazos [4, the 5-c] quinoline -1- bases of -7-) - N, N- lupetidine -1- sulfonamide；4- (8- (2- chloro- 4- (pyrimidine-2-yloxy) phenyl) fluoro- 2- methyl isophthalic acids H- imidazoles of -7- And [4,5-c] quinoline -1- bases)-N, N- lupetidine -1- acid amides；And 1- (4- (8- (the chloro- 4- of 2- (pyrimidine-2-yloxy) Phenyl) fluoro- 2- methyl isophthalic acids H- imidazos [4, the 5-c] quinoline -1- bases of -7-) piperidin-1-yl) ethyl ketone.U.S. of Bencherif et al. State's patent application publication number 2015/0045386 discloses (2S, 3R)-N- (2- ((3- pyridine radicals) methyl) -1- azabicyclos [2.2.2] oct-3-yl) benzofuran -2- acid amides use.The U.S. Patent Application Publication No. 2015/0045324 of Cha et al. The use of fused pyrimidine derivative is disclosed, including (((furans is simultaneously by 2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) by 3- by N- [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N- (3- ((2- ((4- (4- isopropyl piperazine -1- bases) phenyl) ammonia Base) furans simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N- (3- ((2- ((4- morphlinophenyls) amino) furans Mutter simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N- (3- ((2- ((4- ((dimethylamino) methyl) phenyl) Amino) furans simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N- (3- ((2- ((4- ((4- (dimethylamino) Piperidin-1-yl) methyl) phenyl) amino) furans simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N-(3-((2- ((the fluoro- 4- of 3- (1- methyl piperazine -4- bases) phenyl) amino) furans simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acryloyl Amine；N- (3- ((2- ((4- (2- dimethylaminos) ethyl) amino) -3- fluorophenyls) amino) furans simultaneously [3,2-d] pyrimidine -4- Base) epoxide) phenyl) acrylamide；N- (3- ((2- ((the fluoro- 4- of 3- ((1- methyl piperidine -4- bases) amino) phenyl) amino) furans And [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide；N- (3- (2- (3- methoxyl groups -4- (4- thyl-piperazin -1- bases) - Phenyl amino)-furans simultaneously [3,2-d] pyrimidine-4-yl epoxide)-phenyl)-acrylamide；And N- (3- ((2- ((4- amine sulphonyl Base phenyl) amino) furans simultaneously [3,2-d] pyrimidine-4-yl) epoxide) phenyl) acrylamide.The U.S. Patent application of Nacro et al. Publication number 2015/0038506 discloses the Imidazopyrazines as MNK1 or MNK2 inhibitor, imidazopyridine, and imidazo is rattled away The use of piperazine and imidazolo-pyrimidine compounds.The U.S. Patent Application Publication No. 2015/0038430 of Nash et al. disclose including The use of the peptidomimetic macrocyclic compound combined with MCL-1.The U.S. Patent Application Publication No. 2015/ of Woodhead et al. 0031669 discloses the use of the benzopyrazines including the inhibitor as FGFR kinases.The United States Patent (USP) Shen of Allwein et al. Please publication number 2015/0011561 disclose as dual ALK and the condensed-bicyclic of Fak inhibitor 2,4- diamino-pyridines derive The use of thing.The U.S. Patent Application Publication No. 2015/0011506 of Olhava et al. discloses boracic proteasome inhibitor Use, such as [(1R) -1- ({ [(2,3- difluoro benzoyl) amino] acetyl group } amino) -3- methyl butyls] boric acid； [(1R) -1- ({ [(the chloro- 2- fluoro benzoyls of 5-) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R)-1- ({ [(3,5- difluoro benzoyl) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2,5- difluorobenzenes Formoxyl) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2- benzoyl bromides) amino] acetyl Base } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2- fluoro benzoyls) amino] acetyl group } amino) -3- methyl fourths Base] boric acid；[(1R) -1- ({ [(the chloro- 5- fluoro benzoyls of 2-) amino] acetyl group } amino) -3- methyl butyls] boric acid； [(1R) -1- ({ [(4- fluoro benzoyls) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(3,4- bis- Fluoro benzoyl) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(3- chlorobenzene formacyls) amino] second Acyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2,5- dichloro-benzoyl base) amino] acetyl group } amino) -3- Methyl butyl] boric acid；[(1R) -1- ({ [(3,4- dichloro-benzoyl base) amino] acetyl group } amino) -3- methyl butyls] boric acid； [(1R) -1- ({ [(3- fluoro benzoyls) amino] acetyl group } amino) -3- methyl butyls] boric acid；[({ [(2- is chloro- by (1R) -1- 4- fluoro benzoyls) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2,3- dichloro-benzoyl base) Amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2- chlorobenzene formacyls) amino] acetyl group } amino) - 3- methyl butyls] boric acid；[(1R) -1- ({ [(2,4- difluoro benzoyl) amino] acetyl group } amino) -3- methyl butyls] boron Acid；[(1R) -1- ({ [(the chloro- 2- fluoro benzoyls of 4-) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R)-1- ({ [(4- chlorobenzene formacyls) amino] acetyl group } amino) -3- methyl butyls] boric acid；[(1R) -1- ({ [(2,4- dichloro-benzoyls Base) amino] acetyl group } amino) -3- methyl butyls] boric acid；And [(1R) -1- ({ [(3,5- dichloro-benzoyl base) amino] second Acyl group } amino) -3- methyl butyls] boric acid.The U.S. Patent Application Publication No. 2015/0011461 of Crawford et al. discloses As the use of the heteroaryl pyridines ketone and azepine-pyridine ketoamide compounds of Btk (tumor of breast kinases) inhibitor, including N- [5- [2- (7,7- dimethyl -4- oxos -1,2,6,8- tetrahydro cyclopentyl diene simultaneouslies (1,2,4,8- Tetrahydrocyclopenta) [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) -3- (hydroxymethyl) -4- pyridine radicals] -1- first Base -2- oxo -3- pyridine radicals] cyclobutane acid amides；N- [5- [2- (7,7- dimethyl -4- oxos -1,2,6,8- tetrahydro cyclopentyl diene And [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) -3- (hydroxymethyl) -4- pyridine radicals] -1- methyl -2- oxo -3- pyridine radicals] Cyclopropane acid amides；2- cyclopropyl-N- [5- [2- (7,7- dimethyl -4- oxos -1,2,6,8- tetrahydro cyclopentyl diene simultaneouslies [3,4] pyrrole Cough up simultaneously [3,5-b] pyrazine -3- bases) -3- (hydroxymethyl) -4- pyridine radicals] -1- methyl -2- oxo -3- pyridine radicals] acetamide；N- [5- [2- (7,7- dimethyl -4- oxos -1,2,6,8- tetrahydro cyclopentyl diene simultaneouslies [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) - 3- (hydroxymethyl) -4- pyridine radicals] -1- methyl -2- oxo -3- pyridine radicals] oxetanes -3- formamides；N- [5- [2- (7, 7- dimethyl -4- oxos -1,2,6,8- tetrahydro cyclopentyl diene simultaneouslies [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) -3- (hydroxyl first Base) -4- pyridine radicals] -1- methyl -2- oxo -3- pyridine radicals] -2- morpholinoes-acetamide；N- [5- [2- (7,7- dimethyl -4- Oxo -1,2,6,8- tetrahydro cyclopentyl diene simultaneouslies [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) -3- (hydroxymethyl) -4- pyridines Base] -1- methyl -2- oxo -3- pyridine radicals] -2- methyl-cyclopropane acid amides；And N- [5- [2- (7,7- dimethyl -4- oxos - 1,2,6,8- tetrahydro cyclopentyl diene simultaneously [3,4] pyrrolo- [3,5-b] pyrazine -3- bases) -3- (hydroxymethyl) -4- pyridine radicals] -1- Methyl -2- oxo -3- pyridine radicals] propionamide.2015/0005309 disclosure of U.S. Patent Application Publication No. of Barfacker et al. As the use of the substituted Imidazopyrazines of PI3K/Akt inhibitor, including 2- [4- (1- Aminocyclobutyls) phenyl] -3- Phenylimidazole simultaneously [1,2-a] pyrazine -8- alcohol；1- [4- (6,8- dimethyl -3- phenylimidazoles simultaneously [1,2-a] pyrazine -2- bases) benzene Base]-ring butylamine；1- [4- (the bromo- 8- methoxyl groups -3- phenylimidazoles of 6- simultaneously [1,2-a] pyrazine -2- bases) phenyl] ring butylamine；1-[4- (6- ethyl -8- methoxyl group -3- phenylimidazoles simultaneously [1,2-a] pyrazine -2- bases) phenyl]-ring butylamine；Ethyl 2- [4- (1- amino rings Butyl) phenyl] -3- phenylimidazoles simultaneously [1,2-a] pyrazine -6- carboxylates；2- [4- (1- Aminocyclobutyls) phenyl] -3- phenyl miaows Azoles simultaneously [1,2-a] pyrazine -6- acid amides；2- [4- (1- Aminocyclobutyls) phenyl] -8- methoxyl group -3- phenylimidazoles simultaneously [1,2-a] - Pyrazine -6- carboxylic acids first salt/ester；And -8- methoxyl group -3- phenylimidazoles are simultaneously [1,2-a] by 2- [4- (1- Aminocyclobutyls) phenyl] Pyrazine -6- acid amides.The U.S. Patent Application Publication No. 2015/0378466 of Maderna et al. is disclosed as mek inhibitor The use of N- (arylamino) sulfamide derivative.2014/0371254 disclosure of U.S. Patent Application Publication No. of Leung et al. Include the use of the morphinane alkaloid of sanguinarine.The U.S. Patent Application Publication No. 2014/0371158 of Chadli et al. is public The use of the beauvericin and analog and derivative as Hsp90 companion's pathway inhibitors is opened.The U.S. of Gavai et al. is special Sharp application publication number 2014/0357605 discloses double-(fluoroalkyl)-Isosorbide-5-Nitrae-benzodiazepines as Notch receptor inhibitor The use of ketone compound, including (2R, 3S) -- N- ((3S) -1- methyl -2- oxo -5- phenyl -2,3- dihydro -1H-1,4- benzos Diazepine -3- bases) double (3,3, the 3- trifluoro propyl) succinamides of -2,3-；(2R, 3S)-N- ((3S) -2- oxo -5- phenyl - 2,3- dihydro -1H-1,4- benzodiazepine -3- bases) double (3,3, the 3- trifluoro propyl) succinamides of -2,3-；(2R, 3S)-N- ((3S) -1- methyl -2- oxo -5- phenyl -2,3- dihydro -1H-1,4- benzodiazepine -3- bases) -2- (2,2,2- trifluoro second Base) -3- (3,3,3- trifluoro propyl) succinamide；(2R, 3S)-N- ((3S) -1- methyl -2- oxo -5- phenyl -2,3- dihydro - 1H-1,4- benzodiazepine -3- bases) -3- (2,2,2- trifluoroethyl) -2- (3,3,3- trifluoro propyl) succinamide；(2R, 3S)-N-((3S)-1-(2H₃) methyl -2- oxo -5- phenyl -2,3- dihydro -1H-1,4- benzodiazepine -3- bases) -2,3- Double (3,3,3- trifluoro propyl) succinamides；(2R, 3S)-N- (chloro- 1- methyl -2- oxos -5- phenyl -2,3- bis- of (3S) -7- Hydrogen -1H-1,4- benzodiazepine -3- bases) double (3,3, the 3- trifluoro propyl) succinamides of -2,3-；(2R, 3S)-N- ((3S)- 8- methoxyl group -1- methyl -2- oxo -5- phenyl -2,3- dihydro -1H-1,4- benzodiazepine -3- bases) -2,3- pairs (3,3, 3- trifluoro propyls) succinamide；(2R, 3S)-N- (fluoro- 1- methyl -2- oxos -5- phenyl -2, the 3- dihydro -1H-1 of (3S) -8-, 4- benzodiazepine -3- bases) double (3,3, the 3- trifluoro propyl) succinamides of -2,3-；And (2R, 3S)-N- ((3S) -7- first Oxy-1-methyl-2- oxo-5- phenyl-2,3- dihydro-1H-1,4- benzodiazepine-3- bases)-2,3- double (3,3,3- tri- Fluoropropyl) succinamide.The U.S. Patent Application Publication No. 2014/0357594 of Hendrickson et al., which discloses, suppresses DNA The use of the purine-containing base heteroaryl compound of transmethylase.The U.S. Patent Application Publication No. 2014/ of Yang et al. 0350096 discloses the use of Android good fortune (antrocin).

The other medicament of antitumor activity with ovarian cancer resistance is well known in the art.Medicine according to the present invention Combination includes these other medicaments of therapeutically effective amount and the hexose 01 derivatives substituted as described above of therapeutically effective amount. The one or more in these other medicaments can be used.These other medicaments can be as described above with one or more The medicament of ovarian cancer resistance activity is used together in drug regimen, the drug regimen includes such as two to the water wei ling alcohol or two The substituted hexose 01 derivatives of acetyl group two to the water wei ling alcohol.These medicaments are jointly referred to herein as " having anti-ovum The other assistant medicament of nest cancer activity ".These medicaments include following：The U.S. Patent number 8,981,131 of Bhedi et al. discloses The use of tricyclic compound, such as (5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -3- ((4- methylpiperazine-1-yls) methyl) - 3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans -2 (9bH) -one hydrochlorides；4- (((5aR, 9bS) -3a- hydroxyls - 5a, 9- dimethyl -2- oxos -2,3,3a, 4,5,5a, 6,7,8,9b- decahydro naphtho- [1,2-b] furans -3- bases) methyl) piperazine - 1- carboxylate hydrochlorides；(5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -3- ((4-o- tolyl piperazine -1- bases) methyl) - 3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans -2 (9bH) -one hydrochlorides；Or (5aR, 9bR) -3a- hydroxyls -3- ((((5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -2- oxos -2,3,3a, 4,5,5a, 6,7,8,9b- decahydro naphtho-s [1,2- B] furans -3- bases) methylamino) methyl) -5a, 9- dimethyl -3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans - 2 (9bH) -one hydrochlorides).The U.S. Patent number 8,981,094 of Bongartz et al. is disclosed as DGAT inhibitor especially The use of the piperidine/piperazine derivatives of DGAT1 inhibitor.The U.S. Patent number 8,981,085 of Le Huerou et al. discloses The use of the pyrrolopyrimidine of CHK1 or CHK2 inhibitor.The U.S. Patent number 8,981,084 of Balogu et al. discloses evil two The use of azoles hdac inhibitor.The U.S. Patent number 8,980,955 of Turchi et al. is disclosed to be derived as halogen ester isoborneol The use of the replication protein A inhibitor of thing.The U.S. Patent number 8,980,934 of Pauls et al. discloses the Yin of TTK protein kinases The use of azoles inhibitor.The U.S. Patent number 8,980,933 of Schobert et al. discloses Kang Purui fourths (combretastatin) use of analog.The U.S. Patent number 8,980,909 of Chen et al. discloses the happiness for suppressing HDAC Set the application of alkali derivant.The U.S. Patent number 8,980,902 of Brown et al. discloses piperazinyl phenyl formamide PARP inhibitor Use.The U.S. Patent number 8,980,879 of Liu et al. people discloses the use of BET bromine domain inhibitor, including 5- (rings third Ylmethyl) -2,4,5,11- tetrahydrochysene -1H-2 of -11- methyl -8- ((methyl sulphonyl) methyl), 5,11- tri- azepine dibenzo [cd, H] Azulene -1- ketone；5- (4- fluorophenyls) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- Three azepine dibenzo [cd, h] Azulene -1- ketone；5- (2,4- difluorophenyl) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4, 5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -1- ketone；5- (cyclopropane carbonyl) -11- methyl -8- ((methyl Sulfonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -1- ketone；5- (4- fluorophenyls)- 4- (2- methoxy ethyls) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepines Dibenzo [cd, h] Azulene -1- ketone；3- (5- (4- fluorophenyls) -11- methyl -8- ((methyl sulphonyl) methyl) -1- oxos -2,4, 5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -4- bases) methyl propionate；N- (5- (4- fluorophenyls) -11- first Base -1- oxos -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) ethyl sulfonamide；8- is fluoro- 5- (4- fluorophenyls) -11- methyl -2,4,5,11- tetrahydrochysene -1H-2,5,6,11- tetra- azepine dibenzo [cd, h] Azulene -1- ketone；N- (5- (4- fluorophenyls) -11- methyl isophthalic acids-oxo -2,4,5,11- tetrahydrochysene -1H-2,5,6,11- tetra- azepine dibenzo [cd, h] Azulene - 8- yls) -2- (1- methyl isophthalic acid H- pyrazoles -4- bases) acetamide；8- amino -5- (4- fluorophenyls) -11- methyl -2,4,5,11- tetra- Hydrogen -1H-2,5,11- tri- azepines-dibenzo [cd, h] Azulene -1- ketone；N- (5- (4- fluorophenyls) -11- methyl isophthalic acids-oxo -2,4,5, 11- tetrahydrochysenes -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) benzsulfamide；N- (4- (N- (5- (4- fluorophenyls)- 11- methyl isophthalic acids-oxo -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) sulfamic) benzene Base) acetamide.The U.S. Patent number 8,980,875 of Mailliet et al. discloses the use of platinum N- heterocyclic carbene derivatives. The U.S. Patent number 8,980,850 of Smith et al. disclose NEDD8 activation enzyme inhibitor use, such as ((1S, 2S, 4R)- 4- (4- ((1S) -2,3- dihydro -1H- indenes -1- bases amino) -7H- pyrrolo-es [2,3-d] pyrimidin-7-yl) -2- hydroxycyclopents base) Methylsulfamic acid ester or { (1S, 2S, 4R) -4- [(6- { [chloro- 2- methoxyl groups -2,3- dihydro -1H- indenes -1- of (1R, 2S) -5- Base] amino } pyrimidine-4-yl) epoxide] -2- hydroxycyclopents base } methylsulfamic acid ester.The U.S. Patent number 8 of Wang et al., 980,838 disclose the use of the cyclic peptidomimetic inhibitor of WDR5/MLL1 interactions.The U.S. Patent number of Lowy et al. 8,980,268 disclose the use of anti-Ang-2 antibody.The anti-TGFα antibody of U.S. Patent number 8,980,257 of Kaneda et al. Use.The U.S. Patent number 8,975,398 of Hansen et al. discloses the use of NAMPT inhibitor, such as N- { 4- [1- (2- first Base propiono) piperidin-4-yl] phenyl }) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2- chlorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- [4- ({ 1- [(2S) -2- methyl Bytyry] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (1,3-thiazoles -2- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- Base)-N- (4- { [1- (tetrahydrochysene -2H- pyrans -4- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；N- [4- ({ 1- [difluoro (phenyl) acetyl group] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides； N- [4- ({ 1- [(4,4- difiuorocyclohexyl) carbonyl] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine - 3- acid amides；N- (4- { [1- (2- methyl -2- phenylpropionyl) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azacyclo- Butane -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (1,3-thiazoles -4- bases carbonyl) piperidin-4-yl] epoxide } phenyl) nitrogen Azetidine -3- acid amides；N- [4- ({ 1- [(5- methylthiophene -2- bases) carbonyl] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine - 3- yls) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- 4- [(1- { [4- (trifluoromethyl) phenyl] acetyl group } piperidines - 4- yls) epoxide] phenyl } azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (tetrahydrofuran -2- bases carbonyl) piperazines Pyridine -4- bases] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- [4- ({ 1- [3- (trifluoromethyl) benzene first Acyl group] piperidin-4-yl } epoxide) phenyl] azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (thiene-3-yls Carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- [4- ({ 1- [3- (fluoroforms Epoxide) benzoyl] piperidin-4-yl } epoxide) phenyl] azetidine -3- acid amides；N- (4- { [1- (3- methylbutyryls) piperazines Pyridine -4- bases] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (four Hydrogen furans -3- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；N- [4- ({ 1- [(3- fluorophenyls) second Acyl group] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2- fluorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2,4- difluorobenzene first Acyl group) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (4- fluorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；And N- (4- { [1- (3- fluorobenzene first Acyl group) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides.The United States Patent (USP) of Blein et al. Numbers 8,975,376 disclose anti-α₂The use of-integrin antibody.The U.S. Patent number 8,975,287 of Karp et al. discloses 1, The use of 2,4- oxadiazoles benzoic acid compounds.The U.S. Patent number 8,975,267 of Caldarelli et al. discloses tricyclic pyrrole Cough up the use of derivative, such as N- (2,6- diethyl phenyl) -9- (methoxy) -2- { [2- methoxyl groups -4- (4- methyl piperazines Piperazine -1- bases) phenyl] amino } -8- methyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, 2- [(the bromo- 2- of 4- Methoxyphenyl) amino]-N- (2,6- diethyl phenyl) -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinoline azoles Quinoline -7- acid amides, N- (2,6- diethyl phenyl) -2- ({ 2- methoxyl groups -4- [4- (pyrrolidin-1-yl) piperidin-1-yl] phenyl } ammonia Base) -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, N- (2,6- diethyl phenyl) -2- ({ 4- [4- (dimethylamino) piperidin-1-yl] -2-m- ethoxyl phenenyls } amino) -8,9- dimethyl -6,9- dihydro -5H- pyrroles Cough up simultaneously [3,2-h] quinazoline -7- acid amides, N- (2,6- diethyl phenyl) -2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) Phenyl] amino } -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, N- (2,6- diethylbenzenes Base) -2- ({ 4- [4- (2- hydroxyethyls) piperazine -1- bases] -2- methoxyphenyls } amino) -8,9- dimethyl -6,9- dihydro - 5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, 2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -8,9- Dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, and 2- [(the bromo- 2- methoxyphenyls of 4-) ammonia Base]-N- (2,6- diethyl phenyl) -9- methyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides.Bauer etc. The U.S. Patent number 8,974,781 of people discloses the use of anti-P- cadherin antibodies.The U.S. Patent number 8 of Abraham et al., 969,587 disclose the use of BRAF kinases (serine/threonine protein kitase) inhibitor, such as 1- (3- (6,7- dimethoxies Base quinazoline -4- bases epoxide) phenyl) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3- bases) urea.Maier Et al. U.S. Patent number 8,969,401 disclose sulphonylpyrroles as HDAC (histon deacetylase (HDAC)) inhibitor Use.The U.S. Patent number 8,969,396 of Du et al. discloses the BRAF including Hsp90 (heat shock protein 90) inhibitor and suppresses The use of agent, such as 3- (2,4- dihydroxy -5- isopropyl-phenyls) -4- (1- Methvl-indole -5- bases) -5- hydroxyls-[1,2,4] Triazole.The U.S. Patent number 8,969,395 of Ribeiro Salvador et al. discloses the use of triterpene compound derivative. The U.S. Patent number 8,969,381 of Wilson et al. discloses the use of Chemokines CC XCR4 conditioning agents, such as N¹-(((S)- 1,2,3,4- tetrahydroisoquinoline -3- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-diamines；N¹- (((R) -1,2,3,4- tetrahydroisoquinoline -3- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-two Amine；N¹- (((S) -4- benzyl diethylenediamine -2- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-diamines； And N¹- (((R) -4- benzyl diethylenediamine -2- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-two Amine.(3- chloro- 4- (cyclopropylaminocarbonyl) the aminobenzene oxygen of 4- disclosed in the U.S. Patent number 8,969,379 of Furitsu et al. Base) -7- methoxyl group -6- quinoline amides use.The U.S. Patent number 8,969,375 of Lai et al. discloses CDK9 kinase inhibitions The use of agent, such as 4- [1- (3- luorobenzyls) -2,3- dihydro -1H- indoles -6- bases] -2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridine；1- (3- luorobenzyls) -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- benzos Imidazoles；1- benzyls -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- indoles -3- nitriles；1- (3- fluorine Benzyl) -6- { 2- [1- (methyl sulphonyl) piperidin-4-yl] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1H- benzimidazoles； 6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1- (tetrahydrochysene -2H- pyrans -4- ylmethyls) -1H- benzos Imidazoles；6- { 2- [1- (methyl sulphonyl) piperidin-4-yl] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1- (tetrahydrochysene -2H- pyrroles Mutter -4- ylmethyls) -1H- benzimidazoles；5- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -3- (tetrahydrochysene - 2H- pyrans -4- ylmethyls) -3H- imidazos [4,5-b] pyridine；1- (3- luorobenzyls) -6- [2- (piperidin-4-yl) -1H- pyrroles And [2,3-b] pyridin-4-yl] -1H- indoles -3- nitriles；4- [the fluoro- 1- of 5- (3- luorobenzyls) -1H- indoles -6- bases] -2- (piperidines - 4- yls) -1H- pyrrolo-es [2,3-b] pyridine；6- { 2- [1- (2,3- dihydroxypropyl) piperidin-4-yl] -1H- pyrrolo-es [2,3- B] pyridin-4-yl } -1- (3- luorobenzyls) -1H- indoles -3- nitriles；1- (3- luorobenzyls) -6- 2- [1- (methyl sulphonyl) piperidines - 4- yls] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1H- indoles -3- nitriles；And 1- [(5- fluorine pyridin-3-yl) methyl] -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- benzimidazoles.The U.S. of Marchionni et al. is special Profit number 8,969,366 discloses the use of substituted pyrimidine radicals pyrrolopyridinone derivatives.The U.S. of Charrier et al. is special Profit number 8,969,360 discloses the use of ATR kinase inhibitors.The U.S. Patent number 8,969,335 of Hoelzemann et al. is public The use of IKK ε and the TBK1 inhibitor including benzonitrile derivative is opened.The U.S. Patent number 8,969,313 of Yu discloses The use of DACT protein activators.The U.S. Patent number 8,962,855 of Chen et al. discloses the application of nitrogen mustard derivatives.Wang Et al. U.S. Patent number 8,962,679 disclose the uses of the daidzein derivatives including alkoxy benzopyran-4-one ketone. The U.S. Patent number 8,962,663 of Mahadevan et al. discloses pleckstrin (pleckstrin) homology structure The use of domain inhibitor.The U.S. Patent number 8,962,642 of Mortimore et al. discloses 5- cyano group -4- (pyrrolo-es [2,3- B] pyridin-3-yl) pyrimidine derivatives use.The U.S. Patent number 8,962,637 of McAllister et al. is disclosed as c- The use of the substituted aromatic bicyclic compound of SRC/JAK inhibitor.8,962,630 disclosure of U.S. Patent number of Brain et al. As CDK kinases inhibitors include 7- cyclopenta -2- (5- piperazines -1- bases-pyridine -2- bases amino) -7H- pyrrolo-es The use of the Pyrrolopyrimidine compounds of [2,3-d] pyrimidine -6- carboxylic acid dimethylamides.The U.S. Patent number 8 of Kuntz et al., 962,620 disclose the use of substituted 6,5- fused bicyclic aryl compounds.The U.S. Patent number 8,962 of Ashwell et al., 619 disclose the use of substituted imidazopyridyl-aminopyridine compounds.The U.S. Patent number of Christopher et al. 8,962,611 disclose the use of the substituted imidazopyridine as HDM2 inhibitor.The United States Patent (USP) of Brubaker et al. Numbers 8,962,608 disclose the use of the cycloalkyl nitrile pyrazole amide as janus kinase inhibitors.Schoeberl's et al. U.S. Patent number 8,961,966 discloses the use of anti-ERBB3 (receptor tyrosine protein kinase) antibody.Heaton's et al. U.S. Patent number 8,957,109 discloses the use of chroman derivatives.The U.S. Patent number 8 of Dannhardt et al., 957,103 disclose conjugation 3- (indyl)-and 3- (azaindolyl) -4- aryl maleimide compounds.Kim's et al. U.S. Patent number 8,957,102 discloses the use of c-Met inhibitor, including 1,5- dimethyl -3- oxo -2- phenyl -2,3- Dihydro-1 h-pyrazole -4- carboxylic acids [the fluoro- 4- of 3- (2- phenyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide)-phenyl]-acid amides； 2- (4- fluoro-phenyls) -1,5- dimethyl -3- oxo -2,3- dihydro-1 h-pyrazole -4- carboxylic acid [the fluoro- 4- of 3- (2- phenyl -1H- pyrroles Cough up simultaneously [2,3-b] pyridin-4-yl epoxide]-phenyl]-acid amides；2- (4- fluoro-phenyls) -1,5- dimethyl -3- oxos -2,3- bis- Hydrogen -1H- pyrazoles -4- carboxylic acids [the fluoro- 4- of 3- (3- phenyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide)-phenyl]-acid amides；N- (the fluoro- 4- of 3- (2- (thiophene -2- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide) phenyl) -2- (4- fluorophenyls) -1,5- Dimethyl -3- oxo -2,3- dihydro-1 h-pyrazole -4- acid amides；And N- (the fluoro- 4- of 3- (2- (thiene-3-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide) phenyl) -2- (4- fluorophenyls) -1,5- dimethyl -3- oxo -2,3- dihydro-1 h-pyrazoles -4- Acid amides.The U.S. Patent number 8,957,078 of Brenchley et al. discloses the pyrazolopyrimidine as ATR kinase inhibitors Use.The U.S. Patent number 8,957,068 of Caferro et al. discloses 3- pyrimidine-4-yls-evil as mutation IDH inhibitor The use of oxazolidine -2- ketone.The U.S. Patent number 8,957,056 of Danishefsky et al. discloses Charles McGrath statin (Migrastatin) use of analog.The U.S. Patent number 8,956,613 of Wu et al. discloses making for gemcitabine prodrug With.The U.S. Patent number 8,952,163 of Blackburn et al. is disclosed as HDAC6 (histone deacetylase 6) inhibitor The use of substituted hydroxamic acid.The U.S. Patent number 8,952,161 of Beaton et al. discloses gonadotropin-releasing hormone (GRH) The use of receptor antagonist.The U.S. Patent number 8,952,157 of Ding et al. discloses making for anti-apoptotic Bcl-2 protein inhibitors With, such as 4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2,3- bis- Fluorophenoxy)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；2- (4- amino- 3- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；4- (4- [2- (4- chlorphenyls) -4, 4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2,5- dichlorophenoxy)-N- ({ 4- [(3- morpholine -4- bases Propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；N- (4- ((4- amino tetrahydrochysene -2H- pyrans -4- bases) methyl ammonia Base) -3- nitrophenylsulfonyls) -2- (3- chlorophenoxies) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene Base) methyl) piperazine -1- bases) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases) -2- (3- fluorophenoxies)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzene Formamide；2- (2- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine - 1- yls)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；2- (the chloro- 4- fluorobenzene of 2- Epoxide) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases)-N- ({ 4- [(3- Morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyl Hexamethylene -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2- fluorophenoxies)-N- (4- [(3- morpholine -4- bases propyl group) amino] - 3- nitrobenzophenones } sulfonyl) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases) -2- (2- fluorophenoxies)-N- ({ 4- [(2- morpholine -4- bases ethyl) amino] -3- nitrobenzophenones } sulfonyl) benzene Formamide；And 2- (3- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide.Kufe et al. U.S. Patent number 8,952,054 disclose MUC1 oligomerizations micromolecular inhibitor such as chromocor derivative use. The U.S. Patent number 8,952,043 of Blaquiere et al. discloses Ben Bing Evil heptan makes because of (benzoxepin) PI3K inhibitor With.The U.S. Patent number 8,951,987 of Hamilton et al. discloses the use of tetrahydrouridine derivative.U.S. of Combs et al. State's patent No. 8,951,536 discloses making for the N- hydroxyamidines heterocyclic compounds of the conditioning agent as indoleamine 2,3-dioxygenase With.The U.S. Patent number 8,946,445 of Wang et al. discloses the use of heterocycle apoptosis inhibitor, such as (Z) -5- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thienos [3,2-b] pyrroles (Z) the chloro- 5- of -2- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thiophenes Fen simultaneously [3,2-b] pyrroles；(Z) -5- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles - 5- yls) -2- methyl -4H- thienos [3,2-b] pyrroles；(Z) (((3,5- dimethyl -1H- pyrroles -2- bases) is sub- by 2- by the bromo- 5- of -2- Methyl) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thienos [3,2-b] pyrroles；(Z) -5- (2- ((3,5- dimethyl -1H- pyrroles Cough up -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -6H- thienos [2,3-b] pyrroles；And (Z) -5- (2- ((3, 5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -2- methyl -6H- thienos [2,3-b] Pyrroles.The U.S. Patent number 8,946,413 of Hughes et al. discloses the 3- amino cyclopentyls as chemokine receptor anagonists The use of alkane formamide.The U.S. Patent number 8,946,409 of Becker et al. discloses the use of polycyclic beta-lactam derivatives. The U.S. Patent number 8,946,289 of Hong et al. discloses the Ma Nishating for blocking HIF (hypoxia inducible factor) path (Manassatin) use of compound.The U.S. Patent number 8,946,278 of Seefeld et al. discloses as AKT that (albumen swashs Enzyme B) inhibitor Heterocyclylcarboxamderivatives use, such as N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } second Base) the chloro- 4- of -5- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) Phenyl] methyl } ethyl) -4- (the bromo- 1- methyl isophthalic acids H- pyrazoles -5- bases of 4-) -5- methyl -2- thenoyl amines；N- ((1S) -2- ammonia Base -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -4- (the chloro- 1-- methyl isophthalic acids H- pyrazoles -5- bases of 4-) -5- methyl -2- thiophenes Fen formamide；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) chloro- 4- of -5- (the chloro- 1- methyl of 4- - 1H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -4- (the bromo- 1- methyl isophthalic acids H- pyrazoles -5- bases of 4-) chloro- 2- thenoyl amines of -5-；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) Phenyl] methyl } ethyl) -5- methyl -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) the chloro- 4- of -5- (1- ethyl -1H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) the chloro- 4- of -5- (Isosorbide-5-Nitraes-dimethyl -1H- pyrazoles -5- Base) -2- thenoyl amines；N- { (1S) -2- amino -1- [(3- fluorophenyls) methyl] ethyl } the chloro- 4- of -5- (1- methyl isophthalic acid H- pyrroles Azoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -5- ethyls - 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；And N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] Methyl } ethyl) -4- (Isosorbide-5-Nitrae-dimethyl -1H- pyrazoles -5- bases) -5- methyl -2- thenoyl amines.The United States Patent (USP) of Curd et al. Numbers 8,946,205 disclose the use of anoxic activation prodrug, including N, N '-bis- (2- bromoethyls) phosphatide amic acid (phosphorodamidic acid) (1- methyl -2- nitro -1H- imidazoles -5- bases) methyl esters.The United States Patent (USP) of Gangjee et al. Numbers 8,946,239 disclose substituted pyrrolo--, furans simultaneously-, and the use of cyclopenta pyrimidine dicyclic compound. The U.S. Patent number 8,946,235 of Butterworth et al., which discloses 2- (2,4,5- substituted 2-znilino) pyrimidine compound, to be made With.The U.S. Patent number 8,946,224 of Craighead et al. discloses making for substituted [1,2,4] triazol [4,3-a] pyrazine With.The U.S. Patent number 8,946,216 of Deng et al. discloses the use of the indazole derivative as ERK inhibitor, including N- [3- [6- (1- methyl ethoxies) -3- pyridine radicals] -1H- indazole -5- bases] -4- (phenyl methyl) -2- morpholine formamides；N-[3- [6- (1- methyl ethoxies) -3- pyridine radicals] -1H- indazole -5- bases] -2- morpholine formamides；N- [3- (4- pyridine radicals) -1H- Yin Azoles -5- bases] -4- (4- benzothiazolylmethyls) -2- morpholine formamides；N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -4- (3- thiophenes Fen ylmethyl) -2- morpholine formamides；4- [(2- fluorophenyls) methyl]-N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -2- Quinoline formamide；N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -4- (2- pyridylmethyls) -2- morpholine formamides；N-[3-(4- Pyridine radicals) -1H- indazole -5- bases] -4- (2- pyridylmethyls) -2- morpholine formamides；And 4- [(2- bromophenyls) methyl]-N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -2- morpholine formamides.The U.S. Patent number 8,940,936 of Lee et al. discloses virtue The use of epoxide phenoxy group acyclic compound.The U.S. Patent number 8,940,760 of Page et al. is disclosed to be aoxidized as NADPH The use of the pyrazolo pyridine derivatives of enzyme inhibitor.The U.S. Patent number 8,940,756 of Flynn et al. is disclosed as c- The use of the dihydronaphthridine of Kit inhibitor.The U.S. Patent number 8,940,737 of Wang et al. discloses cell death inducer Use, such as 6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- (1- benzyls Base -1H- pyrazoles -4- bases) pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro isoquinolines Quinoline -2 (1H)-yl] -3- [1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1,3- benzo thiophenes Azoles -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (pyridin-3-yl methyl) -1H- pyrazoles -4- Base] pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (4- hydroxybenzyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) - - 2 (1H)-yl of 3,4- dihydro-isoquinoline] -3-- [1- (1- phenylethyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1, 3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- (1- { 4- [2- (dimethylamino) second Epoxide] benzyl } -1H- pyrazoles -4- bases) pyridine-2-carboxylic acids；{ [(5,6- bis- is fluoro- by 8- by -6- by 3- (1- benzyl -1H- pyrazoles -4- bases) 1,3- benzothiazole -2- bases) carbamoyl] -3,4- dihydro-isoquinolines -2 (1H)-yl } pyridine-2-carboxylic acids；6- [8- (1,3- Benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- { 1- [2- (4- fluorophenyls) ethyl] -1H- Pyrazoles -4- bases } pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (3- chlorobenzyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；And 3- (1- benzyl -1H- pyrazoles -4- Base) -6- { 8- [(fluoro- 1, the 3- benzothiazoles -2- bases of 6-) carbamoyl] -3,4- dihydro-isoquinolines -2 (1H)-yl } pyridine -2- Carboxylic acid.The U.S. Patent number 8,940,733 of Howard et al. discloses making for asymmetric Pyrrolobenzodiazepines dimer Zhuo With.The U.S. Patent number 8,940,726 of Duncan et al. discloses the use of PRMT5 inhibitor.U.S. of Pellecchia et al. State's patent No. 8,937,193 discloses the use of ApoG2 (Apogossypolone) derivative.Burlison et al. U.S. Patent number 8,937,094 disclose the uses of Hsp90 conditioning agents, including 5- (4- ethyoxyl -2- hydroxy phenyls) -4- (4- (morpholinomethyl) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- methoxyphenyls) -4- (4- ( Quinoline is for methyl) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- propoxyphenyls) -4- (4- (morpholino first Base) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- isopropyl phenyls) -4- (4- (morpholinomethyl) benzene Base) -4H-1,2,4- triazole -3- formamides；5- (2,4- Dimethoxyphenyl) -4- (4- (morpholinomethyl) phenyl) -4H-1, 2,4- triazole -3- formamides；5- (2- hydroxyl -4- isopropyl phenyls) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- first Acid amides；5- (2- hydroxy-4-methyls phenyl) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；5- (4- hydroxyls- 3- isopropyl phenyls) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；5- (3- tertiary butyl-4-hydroxy benzene Base) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；And 5- (4- hydroxyl -3- propyl group phenyl) -4- (4- first Phenyl) -4H-1,2,4- triazole -3- formamides.The U.S. Patent number 8,937,068 of Seipelt et al. discloses pyrido The use of pyrazine compound.The U.S. Patent number 8,933,212 of Fayard et al. discloses to reduce the protease of transfer The use of nexin1 inhibitor.The U.S. Patent number 8,933,116 of Wu et al. discloses inhibitors of gamma-secretase.Ohki et al. U.S. Patent number 8,933,103 disclose Pyridione derivatives Axl inhibitor use, including N- { 4- [2- amino -5- (3,4- Dimethoxyphenyl) pyridin-3-yl] phenyl } -5- (4- fluorophenyls) -4- oxos -1- (2,2,2- trifluoroethyl)-Isosorbide-5-Nitrae - Dihydropyridine -3- carboxamide hydrochlorides.The U.S. Patent number 8,933,084 of Andrews et al. is disclosed as Trk inhibitor The use of macrocyclic compound, such as fluoro- 2,11,15,19,20,23- six azepine five rings [15.5.2.1 of (6R) -9-^7,11.0^{2, 6}.0^20,24] pentacosane -1 (23), 7,9,17 (24), 18,21- hexene -16,25- diketone.The U.S. Patent number of Singh et al. 8,933,080 disclose the use of the triazole of the bridging bicyclic heteroaryl substitution as Axl inhibitor.U.S. of McGuigan et al. State's patent No. 8,933,053 discloses the use of the Phosphoramidate derivatives of the fluoro- 2 '-BrdUs of 5-.Sasaki et al. U.S.s State's patent No. 8,927,718 discloses the use of the condensed heterocyclic derivates as Smo (transmembrane protein) inhibitor, including 3,6- Diethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1- methyl -4- oxos -5- (2- oxo -2- phenylethyls) -4,5- bis- Hydrogen -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide；3- vinyl -6- ethyls-N- [1- (hydroxyacetyl) piperidin-4-yl] - 1- methyl -4- oxos -5- (2- oxo -2- phenylethyls) -4,5- dihydro -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide；With And 6- ethyls -3- (ethylamino)-N- [1- (hydroxyacetyl) piperidin-4-yl] -1- methyl -4- oxos -5- (2- oxos -2- Phenylethyl) -4,5- dihydro -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide.Huang et al. U.S. Patent numbers 8,927,717 Disclose the use of thiochromene simultaneously [2,3-c] quinoline -12- ketone derivatives, including 3- ((4- chlorphenyls) is thio) -2- hydroxyl quinolines Quinoline -4- carboxylic acids, 6,9- bis- chloro- 12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- hydroxyls -12H- thiochromenes of 10- simultaneously [2, 3-c] quinoline -12- ketone, the chloro- 6- methoxyl groups -12H- thiochromenes of 10- simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- dimethylaminos of 10- Base -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- of 10- (piperazine -1- bases) -12H- thiochromenes simultaneously [2,3-c] quinoline - 12- ketone, the chloro- 6- of 10- (4- methylpiperazine-1-yls) -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, 10- chloro- 6- (4- ethyls Piperazine -1- bases) -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- of 10- (4- (2- hydroxyethyls) piperazine -1- bases) - 12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, and 6- (4- benzyl diethylenediamine -1- bases) chloro- 12H- thiochromenes of -10- simultaneously [2,3- C] quinoline -12- ketone.Abraham et al. U.S. Patent numbers 8,927,711 disclose the use of quinazoline JAK inhibitor, including (3- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinazoline -2- bases) ketone；(4- (1H- pyrazole-3-yls amino) Quinazoline -2- bases) (3- fluorophenyls) ketone；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinazoline -2- bases) Ketone；(4- (1H- pyrazole-3-yls amino) quinazoline -2- bases) (4- fluorophenyls) ketone；(4- (1H- pyrazole-3-yls amino) quinoline Oxazoline -2- bases) (2- methoxyphenyls) ketone；(4- (1H- pyrazole-3-yls amino) quinazoline -2- bases) (4- fluorophenyls) methanol； 2- (fluorine (4- fluorophenyls) methyl)-N- (1H- pyrazole-3-yls) quinazoline -4- amine；2- (difluoro (4- fluorophenyls) methyl)-N- (5- Methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine；2- (difluoro (4- fluorophenyls) methyl)-N- (1H- pyrazole-3-yls) quinazoline- 4- amine；N- (5- cyclopropyl -1H- pyrazole-3-yls) -2- (difluoro (4- fluorophenyls) methyl) quinazoline -4- amine；3- (2- (4- fluorobenzene Formoxyl) quinazoline -4- bases amino) -1H- pyrazoles -5- nitriles；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinoline Oxazoline -2- bases) methanol；2- ((4- fluorophenyls) (methoxyl group) methyl)-N- (5- methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine； 2- (amino (4- fluorophenyls) methyl)-N- (5- methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine；3- (2- ((4- fluorophenyls) (hydroxyls Base) methyl) quinazoline -4- bases amino) -1H- pyrazoles -5- nitriles；(the fluoro- 4- of 5- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinoline azoles Quinoline -2- bases) (4- fluorophenyls) methanol；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) -7- (trifluoromethyl) quinoline Oxazoline -2- bases) ketone；And (4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) -7- (trifluoromethyl) quinazoline - 2- yls) methanol.The U.S. Patent number 8,927,580 of Richardson et al. discloses such as two -2- pyridyl ketone 4- ethyls -4- The use of double pyridine radicals thiosemicarbazones of methyl -3- thiosemicarbazones.8,927,562 disclosure of U.S. Patent number of Meng et al. The use of mTOR fused tricyclic inhibitor.The U.S. Patent number 8,927,560 of Ahmed et al. discloses 4- azepines -2,3- bis- The use of dehydrogenation podophyllotoxin compounds.Ying et al. U.S. Patent numbers 8,927,548 disclose the triazole of Hsp90 inhibitor The use of compound.The U.S. Patent number 8,927,538 of Kamal et al. disclose using carbazole connect pyrrolo- [2,1-c] [1, 4] benzodiazepine heterocomplex as with DNA react with formed N2- guanine adducts reagent use, the N2- birds Purine adduct is located in the ditch of duplex DNA, and parent is incorporated at N10-C11 by acid amides unstable under acid condition Electronics imines.Giannini et al. U.S. Patent numbers 8,927,533 disclose lactams substitution contain sulfur derivatives.Flynn etc. People's U.S. Patent number 8,921,565 discloses the use of the pyridine keto-amide as c-Met kinase inhibitor, such as N- (4- ((2- acetylaminos pyridin-4-yl) epoxide) -2,5- difluorophenyls) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxos -1,2- bis- Pyridinium hydroxide -3- formamides；N- (2,5- bis- fluoro- 4- ((2- propionamidos pyridin-4-yl) epoxide) phenyl) -4- ethyoxyl -1- (4- Fluorophenyl) -2- oxo -1,2- dihydropyridine -3- formamides；N- (4- (2- (cyclopropanecarbonyl amino) pyridin-4-yl) epoxide)- 2,5- difluorophenyls) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides, (2,5- bis- is fluoro- by N- 4- ((2- trimethyl-acetyls pyridin-4-yl) epoxide) phenyl) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxos -1,2- bis- Pyridinium hydroxide -3- formamides, N- (2,5- bis- fluoro- 4- ((2- isobutyrimide yl pyridines -4- bases) epoxide) phenyl) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides.The U.S. Patent number 8,921,522 of Kamal et al. discloses The use of benzothiazole derivant, including the alkene being connected with 2- phenylbenzothiazols, chalcone, pyrazoline, pyrazoles, isoxazole Quinoline, and isoxazole.The U.S. Patent number 8,921,546 of Chao et al. discloses the use of Imidazothiazole, such as 7- (2- Quinoline -4- bases-ethyoxyl) -2- (4- nitro-phenyls) imidazo [2,1-b] [1,3] benzothiazole and 4- (7- (2- morpholino second Epoxide) benzo [d] imidazo [2,1-b] thiazol-2-yl) aniline.8,921,414 disclosure of U.S. Patent number of Reddell et al. The use of spiroketal.The U.S. Patent number 8,921,407 of Ying et al. discloses the pyrazoles chemical combination as Hsp90 conditioning agents The use of thing.The U.S. Patent number 8,921,367 of Friberg et al. discloses the AMG900 (N- as aurora kinase inhibitors (4- (3- (2- aminopyrimidine -4- bases) pyridine -2- bases epoxide) phenyl) -4- (4- methylthiophene -2- bases) phthalazines -1- amine) make With.The U.S. Patent number 8,920,799 of Graham et al. discloses the Axl ligand binding moieties of Axl tyrosine kinase receptors Use.The U.S. Patent number 8,778,340 of Dupont et al. discloses the use of the anti-angiogenic agent including antibody. The U.S. Patent number 8,748,470 of Lengyel et al. discloses the use of fatty acid binding protein inhibitor, including carbazole fourth Acid, aryl sulfonic acid amides, sulfonyl thiophene, 4- hydroxy pyrimidines, 2,3- dimethyl indoles, Benzoylbenzene, xenyl-alkanoic acid, 2- oxazoles-alkanoic acid, tetrahydro pyrimidine ketone, pyridone, pyrazinones, aryl carboxylic acid, tetrazolium, triazolopyrimidones, indoles, BMS480404 ((2S) -2- [2,3- double [(2- chlorphenyls) methoxyl group] phenyl] -2- hydroxyacetic acids), or BMS309403 (2- [[2 '-(5- ethyl -3,4- diphenyl -1H- pyrazol-1-yls) [1,1 '-xenyl] -3- bases] epoxide]-acetic acid]).Clozel etc. The U.S. Patent number 8,541,433 of people discloses the use of macitentan.The U.S. Patent number 8,362,072 of Jensen et al. is public The use of BRCA1 (mammary cancer 1 albumen) generation reinforcing agents is opened.The U.S. Patent number 8,268,889 of Kloog et al. discloses The use of farnesyl- thiosalicylic acid and the like.The U.S. Patent number 7,968,514 of Coelingh Bennink et al. is public The use of immunogenic peptide is opened.The U.S. Patent number 7,323,164 of Chandrasekher et al. discloses interleukin 24 Use.The U.S. Patent number 7,074,575 of Chandrasekher et al. discloses the use of interleukin 19.Miller Et al. U.S. Patent number 6,237,307 disclose 2- phenyl -1- [4- (2- amino ethoxies)-benzyl]-indole derivatives Use.The U.S. Patent number 5,597,798 of Howell et al. discloses the use with the combination of taxol and epidermal growth factor. The U.S. Patent Application Publication No. 2014/0336150 of Frederick discloses karenitecin (7- [(2 '-trimethyl first silicon Alkyl) ethyl] -20 (S) camptothecines) and use.The U.S. Patent Application Publication No. 2014/0315959 of Moore et al. discloses The use of benzylidenei benzo hydrazides.The U.S. Patent Application Publication No. 2014/0309184 of Rocconi et al. discloses Smo suppressions The use of preparation and other drug regimens including the medicine containing platinum medicine.The U.S. Patent Application Publication No. of Chan et al. 2014/0302174 disclose with gemcitabine, cis-platinum or carboplatin and 5- [the 2- tert-butyl groups -5- (4- fluoro-phenyls) -1H- imidazoles - 4- yls] -3- (2,2- Dimethyl-propyl) -3H- imidazos [4,5-b] pyridine -2- base amine therapeutic alliance.U.S. of Moore et al. State's patent application publication number 2014/0275174 discloses the use of 2- amino -4H- naphtho-s [1,2-b] pyrans -3- nitriles. The U.S. Patent Application Publication No. 2014/0134169 of Kuhnert et al. discloses the use of Dll4 antagonists.The U.S. of Chen Patent application publication number 2013/0231286 discloses the use of prolactin receptor antagonist.The U.S. Patent application of Liu et al. people Publication number 2013/0203861 discloses the use of pimelie kelone compounds.The U.S. Patent Application Publication No. of Whiteman et al. 2012/0269827 discloses the use with the conjugate of CD56.The U.S. Patent Application Publication No. 2012/ of Darnowski 0237502 discloses the use of 17,20- lyase inhibitor examples, such as 3 β-acetoxyl group -17- (3- pyridine radicals) androstane -5, 16- diene, 6- [(7S) -7- hydroxyls -6,7- dihydro -5H- pyrrolo-es [1,2-c] imidazoles -7- bases]-N- methyl -2- naphthalenecarboxamides, 3 beta-hydroxyl-17s-(1H- benzimidazole -1- bases) androstane -5,16- diene, or 6- [(7S) -7- hydroxyl -6,7- dihydro -5H- pyrroles And [1,2-c] imidazoles -7- bases]-N- methyl -2- naphthalenecarboxamides.The U.S. Patent Application Publication No. 2012/ of Weinreich 0183546 discloses the use of angiopoietin-2 inhibitor.The U.S. Patent Application Publication No. 2010/ of Sherman et al. 0009330 discloses the use of the PARP inhibitor including 4- iodo -3- nitrobenzamides.The United States Patent (USP) of Umeda et al. Application publication number 2009/0118271 discloses the use of water-soluble prodrug, such as (9S) -1- butyl -9- ethyl -9- hydroxyls Base -1H, 12H- pyrans simultaneously [3 ', 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketone；(9S) -9- ethyl -9- hydroxyls -1- [2- (4- morpholinoes) ethyl] -1H, 12H- pyrans simultaneously [3 ", 4 ": 6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S)-1- [3- (dimethylamino) propyl group] -9- ethyl -9- hydroxyls -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6, 5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -9- ethyl -9- hydroxyl -1- phenethyls - 1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketone；(9S) -9- ethyl -9- hydroxyls -1- [2- (pyridine -2- bases) ethyl] -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -9- second Base -1- heptyl -9- hydroxyls -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] Quinazoline -2,10,13 (3H, 9H, 15H)-triketones；And (9S) -9- ethyl -9- hydroxyl -1- propyl group -1H, 12H- pyrans are simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones. The use of ginkgolides disclosed in the U.S. Patent Application Publication No. 2009/0099102 of Ye et al., including ginkalide A and Ginkolide B.The U.S. Patent Application Publication No. 2007/0299020 of Zeldis discloses -2 (2,6- dioxos of 4- (amino) The use of (3- piperidyls)-isoindoline -1,3- diketone.The U.S. Patent Application Publication No. 2006/0058217 of White et al. The use of disclosed anti-aramine (antialamin).The U.S. Patent Application No. 2005/0272766 of Koya et al. discloses 1- The use of acetaldehyde amide indolizine (1-glyoxylamide indolizine).

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement passes through following acquisition：By the use of being used as chemical sensitizer Such as the substituted hexose 01 derivatives of two to the water wei ling alcohol, its when being used alone not it is observed that measurable activity, but It is with combination with other therapeutic agents in use, the remote super increase being able to observe that in effect or the improvement cooperateed with.For treating NSCLC Or the specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of oophoroma includes：As different with topology The chemical sensitizer of structure enzyme inhibitor combination；As the chemical sensitizer with fraudulent nucleoside combinations；As with fraudulent nucleosides The chemical sensitizer of acid combination；As the chemical sensitizer combined with thymidylate synthetase inhibitor；Press down as with signal transduction The chemical sensitizer of formulation compositions；As the chemical sensitizer combined with cis-platinum, oxaliplatin or other platinum analogs；As alkane Base agent such as BCNU, BCNU chips, Ge Li get (Gliadel), CCNU, bendamustine (Treanda) or Temozolomide (Temodar) chemical sensitizer of combination；As the chemical sensitizer combined with antitublin；As with antimetabolite The chemical sensitizer of combination；As the chemical sensitizer combined with jamaicin；As the chemical sensitizer combined with 4',5,7-trihydroxyflavone；Make For the chemical sensitizer combined with Amonafide；As the chemical sensitizer combined with colchicin or the like；As with dye Expect the chemical sensitizer of lignin combination；As the chemical sensitizer combined with Etoposide；As the change combined with cytarabine Learn sensitizer；As the chemical sensitizer with camptothecin combination；As the combination with vinca alkaloids；As with topoisomerase The chemical sensitizer of enzyme inhibitor combination；As the chemical sensitizer combined with 5 FU 5 fluorouracil；As what is combined with curcumin Chemical chemotherapeutic sensitizer；As the chemical chemotherapeutic sensitizer combined with NF- kB inhibitors；As the chemistry combined with Rosmarinic acid Sensitizer；As the chemical sensitizer combined with mitoguazone；Chemical sensitizer as hanfangchin A combination；As with junket The chemical chemotherapeutic sensitizer of histidine kinase inhibitor combination；As the chemical sensitizer combined with EGFR inhibitor；Or as with The chemical sensitizer of the inhibitor combination of poly- (ADP- ribose) polymerase (PARP).

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein the improvement passes through following acquisition：By the use of being used as chemical intensifier Such as the substituted hexose 01 derivatives of two to the water wei ling alcohol, it can hardly observe therapeutic activity when being used alone, but It is with combination with other therapeutic agents in use, the remote super increase being able to observe that in effect or the improvement cooperateed with.For treating NSCLC Or the specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of oophoroma includes：As different with topology The chemical intensifier of structure enzyme inhibitor combination；As the chemical intensifier with fraudulent nucleoside combinations；Synthesized as with thymidylic acid The chemical intensifier of enzyme inhibitor combination；As the chemical intensifier combined with signal transduction inhibitor；As husky with cis-platinum, Austria Sharp platinum or the chemical intensifier of other platinum analogs combination；As alkylating agent such as BCNU, BCNU chips, Ge Li get (Gliadel), or bendamustine (Treanda) combination chemical intensifier；As the chemistry combined with antitublin Reinforcing agent；As the chemical intensifier combined with antimetabolite；As the chemical intensifier combined with jamaicin；As with celery The chemical intensifier of flavine combination；As the chemical intensifier combined with Amonafide；As with colchicin or the like group The chemical intensifier of conjunction；As the chemical intensifier combined with genistein；As the chemical intensifier combined with Etoposide； As the chemical intensifier combined with cytarabine；As the chemical intensifier with camptothecin combination；As with Vinca alkaloid The combination of alkali；As the chemical intensifier combined with topoisomerase enzyme inhibitor；Increase as the chemistry combined with 5 FU 5 fluorouracil Strong agent；As the chemical chemotherapy reinforcing agent combined with curcumin；As the chemical chemotherapy reinforcing agent combined with NF- kB inhibitors； As the chemical intensifier combined with Rosmarinic acid；As the chemical intensifier combined with mitoguazone；As hanfangchin A The chemical intensifier of combination；As the chemical chemotherapy reinforcing agent combined with tyrosine kinase inhibitor；As with EGFR inhibitor The chemical intensifier of combination；Or the chemical intensifier combined as the inhibitor with poly- (ADP- ribose) polymerase (PARP).

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein described improve by allow to have most the patient of compounds for treating The medicine of big benefit, treats and diagnoses to obtain.General example includes：Pain management, nutritional support, antemetic, nausea Treatment, anti-anemia action treatment, anti-inflammatory agent.Substituted hexitol for such as two to the water wei ling alcohol for treating NSCLC or oophoroma The specific invention example of derivative includes：It is used together with the relevant treatment of pain management；Nutritional support；Antemetic；Nausea Treatment；Anti-anemia action is treated；Anti-inflammatory agent；Antipyretic；Immunostimulant.

Another aspect of the present invention also resides in the substituted of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of hexose 01 derivatives, wherein described improve by using complementary therapeutic agent or method to improve effectively Property or reduce side effect and obtain.The substituted hexitol of such as two to the water wei ling alcohol for treating NSCLC or oophoroma spreads out The specific invention example of biology includes：Hypnosis；Acupuncture；Meditation；Including NF- kB inhibitors (such as parithenolide, curcumin, fan Repeatedly fragrant acid) pass through synthesis or by extracting the herbal drug produced；Natural anti-inflammatory agent (including Rhein, parithenolide)； Immunostimulant (immunostimulant as found in Echinacea purpurea)；Antimicrobial (such as jamaicin)；Flavonoids, isoflavones and Huang (such as 4',5,7-trihydroxyflavone, genistein, genistin, 6 "-O- malonyl-genistins, 6 "-O- acetyl colors wood glucosides, soybean are yellow for ketone Element, daidzin, 6 "-O- malonyl daidzins, 6 "-O- acetyl colors wood glycosides, Glycitein, glycitin, 6 "-O- malonyl Huangs Beans xanthosine and 6-O- acetyl glycitin)；Using kinematics.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein described improve is obtained by the change of medical bulk material medicine.It is general real Example includes：The formation of salt, uniform crystal structure, pure isomer.For treating such as two to the water wei ling alcohol of NSCLC or oophoroma The specific invention examples of substituted hexose 01 derivatives include：The formation of salt；Uniform crystal structure；Pure isomer；It is increased Purity；Less residual solvent；Or less heavy metal.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein described improve the change for passing through and being used to dissolve and transmit or present for being administered The change of the diluent of compound and obtain.General example includes：Emulsifier EL-60 (Cremophor-EL), for water solubility The cyclodextrin of the compound of difference.The substituted hexitol of such as two to the water wei ling alcohol for treating NSCLC or oophoroma derives The specific invention example of thing includes：The use of emulsion；Dimethyl sulfoxide (DMSO) (DMSO)；N-METHYLFORMAMIDE (NMF)；Dimethyl formyl Amine (DMF)；Dimethylacetylamide (DMA)；Ethanol；Phenmethylol；Water for injection containing glucose；Emulsifier EL-60；Ring Dextrin；Polyethylene glycol (PEG).

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein it is described improve by using with dissolve for be administered compound or into One step dilutes the change of required or required solvent and obtains.General example Bao Kuo ︰ ethanol, dimethylacetylamide (DMA). Specific invention example bag for the substituted hexose 01 derivatives of such as two to the water wei ling alcohol for the treatment of NSCLC or oophoroma Include：Use emulsion；Dimethyl sulfoxide (DMSO) (DMSO)；N-METHYLFORMAMIDE (NMF)；Dimethylformamide (DMF)；Dimethylacetylamide (DMA)；Ethanol；Phenmethylol；Water for injection containing glucose；Emulsifier EL-60；Cyclodextrin；PEG.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement is appropriate by being carried out for stablizing and presenting compound Administration needed for material or excipient, buffer or preservative change and obtain.General example includes：Mannitol, albumin, Ethylenediamine tetra-acetic acid (EDTA), sodium hydrogensulfite, phenmethylol.For treating such as two to the water wei ling alcohol of NSCLC or oophoroma The specific invention examples of substituted hexose 01 derivatives include：Use mannitol；Albumin；Ethylenediamine tetra-acetic acid (EDTA)； Sodium hydrogensulfite；Phenmethylol；Carbonate buffer solution；Phosphate buffer.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：According to route of administration, hold time, The change of the potential formulation of the compound of required blood plasma level, the side effect exposed to normal structure and metabolic enzyme.General example Including：Tablet, capsule, external-use gel, creme, patch, suppository.Such as two for treating NSCLC or oophoroma remove water winged euonymus The specific invention example of the substituted hexose 01 derivatives of alcohol includes：Use tablet；Capsule；External-use gel；External-application cream；Patch Agent；Suppository；Lyophilized dosage filling.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein described improve by formulation, container or closed system, mixing and dosimetric system It is standby and present accuracy change and obtain.General example includes：It is protected from the amber bottle of light, there is special coating Plug.The specific of substituted hexose 01 derivatives of such as two to the water wei ling alcohol for treating NSCLC or oophoroma is invented Example includes：Use the amber bottle for being protected from light；With special coating to improve the plug of the stability of shelf-life.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement improves drug products for example by using Transmission system Convenience, effect duration, the inherent nature of toxicity reduction obtain.General example includes：Nanocrystal, can bio-digestion Polymer, liposome, release injectable gel, microballoon.Substitution for such as two to the water wei ling alcohol for treating NSCLC or oophoroma The specific invention examples of hexose 01 derivatives include：Use nanocrystal；Can bio-digestion polymer；Liposome；Sustained release Injected gel；Microballoon.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement is by varying with covalent bond, ionic bond or Hydrogenbond Partial parent molecule is obtained with changing effect, toxicity, pharmacokinetics, metabolism or method of administration.General example includes：Such as Polyethylene glycol, polylactic acid (polylactides), polyglycolide, amino acid, the polymeric system of polypeptide or multivalence connector.With Include in the specific invention example for the treatment of NSCLC or the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of oophoroma： Use such as polyethylene glycol；Polylactic acid；Polyglycolide；Amino acid；The polymeric system of polypeptide or multivalence connector.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Change molecule so that passing through work Property molecule variation obtain improved pharmaceutical properties, wherein after introducing in vivo, the part of molecule is cut preferred to show Bioactive molecule.General example includes：Enzyme sensitivity ester, dimer, schiff bases.For treating such as the two of NSCLC or oophoroma The specific invention example of the substituted hexose 01 derivatives of dianhydrogalactitol includes：Use enzyme sensitivity ester；Dimer；Schiff bases； Pyridoxal compound；Caffeine complex.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Use other compound and biology Medicament, when being administered in a suitable manner, can realize the effect of unique useful.General example includes：Multidrug resistance inhibitor, it is special Different in nature medicament-resistant inhibitor, the specific inhibitor of selective enzyme, signal transduction inhibitor, Repair inhibition.For treat NSCLC or The specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of oophoroma includes：Use multidrug resistance Inhibitor；Specific drug resistance inhibitor；The specific inhibitor of selective enzyme；Signal transduction inhibitor；Repair inhibition；Have The topoisomerase enzyme inhibitor of non-overlapped side effect.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein described improve is used as enhanced sensitivity by using being combined with biological response modifier The substituted hexose 01 derivatives of such as two to the water wei ling alcohol of agent or reinforcing agent and obtain.General example includes：Should with biology Answer conditioning agent, cell factor, lymphokine, therapeutic antibodies, antisense therapy medicine, gene therapy medicament combination be used as sensitizer Or reinforcing agent uses.Tool for the substituted hexose 01 derivatives of such as two to the water wei ling alcohol for the treatment of NSCLC or oophoroma Body invention example includes：With biological response modifier；Cell factor；Lymphokine；Such as Arastin, Mabthera, herceptin, Erbitux therapeutic antibodies；Antisense therapy medicine；Gene therapy medicament；Ribozyme；RNA is disturbed or vaccine combination is as sensitizer Or reinforcing agent uses.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Utilize such as two to the water wei ling alcohol The selectivity of substituted hexose 01 derivatives uses developing or complete to efficiently using for biotherapeutics to overcome The resistance to the action of a drug.General example includes：It is the tumour of antibiont answer-reply regulator effect, cell factor, lymphokine, therapeutic anti- Body, antisense therapy medicine, gene therapy medicament.For treat NSCLC or oophoroma such as two to the water wei ling alcohol it is substituted The specific invention example of hexose 01 derivatives includes：Use the tumour acted on for antibiont answer-reply regulator；Cell factor；Leaching Ba Yinzi；Therapeutic antibodies；Antisense therapy medicine；Such as Arastin, Mabthera, herceptin, Erbitux medicine；Gene Medicine；Ribozyme；RNA is disturbed；And vaccine.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Utilize they and ionizing radiation, phototherapy Method, heat therapy or radio frequency produce therapy and are applied in combination.General example includes：Hypoxic cell sensitizer, radiosensitizer or protection Agent, photosensitizer, radiates repair inhibitors.Substituted hexose for such as two to the water wei ling alcohol for treating NSCLC or oophoroma The specific invention example of 01 derivatives includes：It is applied in combination with ionizing radiation；It is combined with hypoxic cell sensitizer；With radiosensitization Agent or protective agent are applied in combination；It is applied in combination with photosensitizer；It is applied in combination with radiation repair inhibitors；Combined with sulfydryl depletor Use；Used with blood-vessels target drug regimen；It is applied in combination with radioactive seed；It is applied in combination with radionuclide；With radiation Property labelled antibody is applied in combination；It is applied in combination with brachytherapy.This is useful, because radiotherapy is frequently used for controlling NSCLC or oophoroma are treated, is particularly used to treating terminal illness, and by by radiotherapy and such as two to the water wei ling alcohol The effect of substituted hexose 01 derivatives administration is combined to improve this radiotherapy or the ability for playing synergistic effect are weights Want.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Determine the various effect machines of compound System or biological target optimize its effectiveness so as to more understanding and accurately better profit from the effectiveness of molecule.For treating The specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of NSCLC or oophoroma includes：Respectively with It is used together below：Poly- ADP ribose polymerases inhibitor is used；Influence vascular system or vasodilative medicament；Carcinogenic targeting Agent；Signal transduction inhibitor；EGFR suppresses；Protein kinase C suppresses；Phospholipase C is lowered；Jun is lowered；Histone gene；VEGF； Ornithine decarboxylase；Ubiquitin C；junD；v-jun；GPCRs；Protein kinase A；Telomerase, prostate specific gene；Albumen swashs Protein kinase beyond enzyme A；Histone deacetylase enzyme；And tyrosine kinase inhibitor.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：More accurately identify compound and incite somebody to action Compound can maximally utilise exposed to selection cell mass, the wherein effect of compound, particularly NSCLC tumour cells Or ovarian cancer tumor cell.Substituted hexose 01 derivatives for such as two to the water wei ling alcohol for treating NSCLC or oophoroma Specific invention example include：For the use of radiation sensitive cell；For the use of Radiation tolerance cell；Or consumed for energy Exhaust the use of cell.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein described improve is obtained by the change of medical bulk material medicine.For controlling Treating the specific invention example of the substituted hexose 01 derivatives of such as two to the water wei ling alcohol of NSCLC or oophoroma includes：Use Dithiocar-bamate resists bone marrow suppression.

Another aspect of the present invention is substituted oneself of such as two to the water wei ling alcohol for treating NSCLC or oophoroma Improvement on the treatment use of sugar alcohol derivant, wherein the improvement passes through following acquisition：Hexitol using increase substitution leads to Cross the medicament of the ability of blood-brain barrier.Substituted hexitol for such as two to the water wei ling alcohol for treating NSCLC or oophoroma The specific invention example of derivative includes：Chimeric peptide；It is affine including being bonded with biotinylated substituted hexose 01 derivatives The composition of plain or affine plain fusion protein；Neutral liposome, it is by Pegylation and mixes substituted hexitol derivative Thing, and wherein described polyglycol chain can transport peptide with least one or targeting agent is conjugated；It is attached to by Avidin-biology The humanized murine's body for actrapid monotard's acceptor that the connection of element is connected with the hexose 01 derivatives substituted；With pass through Avidin-life Fusion protein of the thing element connecting key key connection to hexitol.

Therefore, one aspect of the present invention is to improve to be used to treat NSCLC or the substituted hexose 01 derivatives of oophoroma Such as efficacy and/or the method that reduces its side effect of two to the water wei ling alcohol, comprise the following steps：

(1) identification and the administration of the substituted hexose 01 derivatives such as two to the water wei ling alcohol for treating NSCLC or oophoroma The effect of and/or side effect the related at least one factor or parameter of generation；And

(2) factor or parameter are adjusted with improve for treat NSCLC or oophoroma substituted hexose 01 derivatives for example The effect of administration of two to the water wei ling alcohol and/or reduce its side effect.

In a kind of alternative solution, the method improve the substituted hexose 01 derivatives for treating NSCLC to The effect of medicine and/or reduce side effect.In an another kind alternative solution, the method is improved for treating taking for oophoroma The effect of administration of the hexose 01 derivatives in generation and/or reduce side effect.

In general, the factor or parameter are selected from by the following group formed：

(1) dosage is adjusted；

(2) method of administration；

(3) administration time table；

(4) indication is used；

(5) selection of disease stage；

(6) other indications；

(7) patient selection；

(8) patient or disease phenotype；

(9) patient or genotyping of diseases；

(10) prepare before or after treatment；

(11) toxicity management；

(12) pharmacokinetics or pharmacodynamics monitoring；

(13) drug regimen；

(14) chemical sensitization (chemosensitization)；

(15) Chemical enhancement (chemopotentiation)；

(16) patient manages after treating；

(17) substitute medicine or treatment is supported；

(18) bulk material medicine improved product；

(19) diluent system；

(20) solvent system；

(21) excipient；

(22) formulation；

(23) dosage kit and packaging；

(24) drug delivery system；

(25) drug conjugate form；

(26) compound analog；

(27) pro-drug；

(28) multiple drug system；

(29) (enhancement) is strengthened in biological therapy；

(30) biological therapy resistance is modulated；

(31) radiotherapy is strengthened；

(32) novel mechanism；

(33) selective target cell group therapy；

(34) it is used together with ionizing radiation；

(35) it is used together with resisting the medicament of bone marrow suppression；And

(36) and the hexitol substituted is increased by blood-brain barrier to treat the medicine of the ability of NSCLC brain metastes or treatment oophoroma Agent is used together.

As described above, in general, include winged euonymus available for the substituted hexitol in the method according to the invention and composition Alcohol, substitution dulcitol, galactitol, substitution galactitol, glycol and further include two to the water wei ling alcohol, diacetyl two removes water Dulcitol, mitolactol and two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol, the derivative of mitolactol and similar The substituted glycol of thing.Usually, the substituted hexose 01 derivatives are selected from and are spread out by two to the water wei ling alcohol, two to the water wei ling alcohol Biology, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, mitolactol and mitolactol spread out The group that biology is formed.Preferably, the substituted hexose 01 derivatives are two to the water wei ling alcohol.

When improvement is changed by dosage, dosage change can be but not limited to, selected from by following dosage change structure Into group at least one dosage change：

(a) single-bolus high-dose intravenous injection (bolusi.v.) and continuous infusion；

(b) it is administered once every two weeks；

(c) dosage is more than 5mg/m²/ day；

(d) it is based on patient tolerability, dosage is from 1mg/m²/ day gradually rises；

(e) metabolism is adjusted using caffeine；

(f) metabolism is adjusted using isoniazid；

(g) selective interval booster administration；

(h) single and multidose are applied, the multidose is injected from 5mg/m by heavy dose²/ day gradually rises；

(i) oral dose is less than 30mg/m²；

(j) oral dose is in 130mg/m²More than；

(k) oral dose is up to 40mg/m for three days on end², then minimum point or convalescence are 18-21 days；

(l) with reduced levels administration long period (such as 21 days)；

(m) it is administered with higher level；

(n) it is administered with the minimum point or convalescence that are longer than 21 days；

(o) it is usually 30mg/ as single cell toxic agents to use the substituted hexose 01 derivatives of such as two to the water wei ling alcohol m²/ day × 5 day, are monthly repeated once；

(p) dosage is 3mg/kg；

(q) the substituted hexose 01 derivatives of such as two to the water wei ling alcohol are used in combination therapy, are usually 30mg/m²/ day × 5 days；And

(r) it is administered with the dosage of 40mg/ days × 5 days in adult patient, is repeated once every two weeks.

When improvement is changed by dosage, dosage change can be but not limited at least one be selected from by following dosage Change the group formed：

(a) local administration；

(b) it is administered orally；

(c) release oral；

(d) intrathecal drug delivery；

(e) intraarterial delivery；

(f) continuous infusion；

(g) intermittent infusion；

(h) intravenously administrable, such as intravenously administrable 30 minutes；

(i) administered by infusion of longer time is passed through；And

(j) it is administered by intravenous injection.

When improvement is changed by dosage, dosage change can be but not limited to, selected from by following dosage change structure Into group at least one dosage change：

(a) it is administered daily；

(b) weekly administration；

(c) continuous weekly administration in 3 weeks；

(d) it is administered once every two weeks；

(e) it is administered every two weeks within continuous three weeks, rest 1-2 weeks；

(f) interval booster is administered；And

(g) continuously it is administered daily multiple weeks Monday.

When obtained by the selection of disease stage improve when, the selection of the disease stage can for but be not limited to, be selected from By the selection of at least one disease stage of the following group formed：

(a) the use of appropriate disease stage is non-small cell lung cancer or oophoroma；

(b) it is used together with angiogenesis inhibitors to prevent or the restriction of transfer spreads through sex intercourse；

(c) it is used for the disease newly diagnosed；

(d) it is used for recurrent disease；With

(e) it is used for drug resistance or refractory disease.

When select to obtain by patient improve when, patient selection can but be not limited to, by selected from being made of following Group at least one standard perform patient selection：

(a) selection, which has, is characterized as the high-caliber generation selected from the group being made of histon deacetylase (HDAC) and ornithine decarboxylase Thank to the patient of the disease states of enzyme；

(b) selection is to selected from the low or high patient of the illness sensitiveness by thrombopenia and neutropenia；

(c) patient not tolerated to gastrointestinal toxicity is selected；

(d) selection is characterized as being selected from c-Jun, GPCR, signal transducer, VEGF, prostate specific gene and protein kinase The overexpression of gene or the patient of low expression；

(e) selection is characterized as carrying the patient of the unnecessary copy of the EGFR gene of NSCLC；

(f) selection is characterized as the patient of the missing that methylates or methylate of mgmt gene promoter；

(g) selection is with MGMT (O⁶- methyl guanine methyl transferase) the patient that is characterized of the promoter region that do not methylate；

(h) patient of the selection characterized by the promoter region that methylates of MGMT；

(i) patient of the selection characterized by high expression MGMT；

(j) patient of the selection characterized by low expression MGMT；

(k) selection is characterized as the patient of the EGFR mutation of including but not limited to EGFR variations III；

(l) selection is characterized as receiving patient of the platinum medicine administration as therapeutic alliance；

(m) selection is characterized as being mutated and be therefore less likely to react to tyrosine kinase inhibitor (TKI) without EGFR Patient；

(n) selection is characterized as thering is drug-fast patient to TKI treatments；

(o) selection is characterized by BIM and is total to deletion mutation and is therefore less likely to the patient to react to TKI treatments；

(p) selection is characterized as thering is drug-fast patient to platinum medicine treatment；And

(q) selection is characterized as brain metastes patient.

Cellular proto-oncogene c-Jun codings combine the albumen to form AP-1 early stage response transcription factors with c-Fos.This original Oncogene plays a crucial role in transcription, and with largely influencing the protein-interactings of transcription and gene expression.It is also participated in carefully The propagation and apoptosis of born of the same parents, the cell form a part for many tissues, including the cell of endometrium and glandular epithelium.G G-protein linked receptor (GPCR) is important signal transduction acceptor.The superfamily of g protein coupled receptor includes substantial amounts of acceptor.This A little acceptors are the overall memebrane proteins characterized by the amino acid sequence including seven hydrophobic domains, be predicted represent albumen across Film area.They are found in extensive organism, and are participated in due to their interactions with heterotrimeric G protein Signal is transmitted to cell interior.They have reaction to various reagents and various stimulus to the sense organ, and the reagent includes The small molecule of fat analog, such as amino acid derivativges, adrenaline and dopamine.The property of many known GPCR is summarized in S.Watson and S.Arkinstall, " The G-Protein Linked Receptor Facts Book " (Academic Press, London, 1994), it is incorporated herein by reference.GPCR acceptors include but not limited to acetylcholinergic receptor, β-adrenal gland Plain energy acceptor, β₃- adrenergic receptor, serotonin (serotonin) acceptor, dopamine receptor, adenosine receptor, vasotonia Plain II receptors, bradykinin receptor, calcitonin receptor, calcitonin gene associated receptor, Cannabined receptor, cholecystokinin receptor, Chemokine receptors, cytokine receptor, gastrin-receptor, endothelin receptor, γ-aminobutyric acid (GABA) acceptor, galanin Acceptor, glucagon receptor, glutamate receptor, metakentrin acceptor, human chorionic gonadotropin receptor, follicle-stimulating hormone (FSH) Acceptor, thyrotropin receptor, gonadotropin-releasing hormone receptor, leukotriene receptor, neuropeptide Y receptor, opium Acceptor, parathyroid hormone receptor, Platelet Activating Factor Receptor, prostaglandin (prostanoid, prostaglandin) by Body, somatostatin receptor, trh receptor, pitressin and ocytocin receptor.

EGFR mutation can be related to the sensitiveness to therapeutic agent such as Gefitinib, this is described in J.G.Paez etc., " EGFR Mutationsin Lung Cancer:Correlation with Clinical Response to Gefitinib, "Science304:1497-1500 (2004), is incorporated herein by reference.With the relevant EGFR of tyrosine kinase inhibitor resistance In a specific mutations be referred to as EGFR variation III, this is described in C.A.Learn etc., " Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor VariantIII Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme, "Clin.Cancer Res.10：3216-3224 (2004), is incorporated herein by reference.EGFR variations III is characterized in that from thin Consistent and tumour-specific 801bp missings in the frame of extracellular domain, the missing segmentation codon are simultaneously merging Junction produces new glycine.Albumen of the mutation coding with structural active thymidine kinase, the albumen enhancing are taken The oncogenicity of cell with the mutation.The protein sequence of this mutation is not present in the normal tissue.

Nearest research it has been determined that be at least partly to the chemotherapeutic resistances of TKI (tyrosine kinase inhibitor) by Genetic polymorphism in influence to the apoptotic response of TKI.

Specifically, these polymorphisms include but is not limited to the polymorphism in gene BCL2L11 (also referred to as BIM), The gene BCL2L11 encodes the BH3-only proteins as BCL-2 family members.BH3-only proteins by with BCL2 families (BCL2, BCL2 sample 1 (BCL-XL, also referred to as BCL2L1), myelocytic leukemia sequence 1 (MCL1) and BCL2 phases Close albumin A 1 (BCL2A1)) the growth-promoting person of being saved as confrontation or pass through combine promote apoptosis BCL2 family member's (BCL2 correlation X proteins (BAX) and BCL2 antagonists 1 (BCL2-antagonist/killer1, BAK1)) and directly activate its apoptotic function to activate Cell death；The activation of apoptotic function will cause cell death (" the The BCL-2 of R.J.Youle and A.Strasser Protein Family:Opposing Activities that Mediate Cell Death, "Nat.Rev.Mol.Cell.Biol.9：47-59 (2008), is incorporated herein by reference.

The cancer of several kinases driving is also had shown that before, such as chronic myelocytic leukemia (CML) and EGFR NSCLC, Can be by suppressing BIM transcriptions and by being targeted by mitogen-activated protein kinase 1 (MAPK-1) dependence phosphorylation BIM albumen for proteasome degraded is come the advantage of surviving.In all these malignant tumours, BIM up-regulations are TKI inductions Necessary to cancer cell-apoptosis, BIM expression inhibitings are enough to assign external resistance (J.Kuroda etc., " Bimand Bad to TKI Mediate Imatinib-Induced Killing of Bcr/Abl⁺Leukemic Cells,and Resistance Due to Their Lossis Over come by a BH3Mimetic,”Proc.Natl.Acad.Sci.USA 103:14907- 14912(2006)；" the Low-Level Expression of Proapoptotic Bcl-2- of K.J.Aichberger et al. Interacting Mediator in Leukemic Cells in Patients with Chronic Myeloid Leukemia:Role of BCR/ABL,Characterization of Underlying Signaling Pathways, and Reexpression by Novel Pharmacologic Compounds,”Cancer Res.65:9436-9444 (2005)；" the Roles of Bimin Apoptosis of Normaland Bcl-Abr- of R.Kuribara et al. Expressing Hema to poietic Progenitors,”Mol.Cell.Biol.24:6172-6183(2004)； " the Gefitinib-Induced Killing of NSCLC Cell Lines Expressing of M.S.Cragg et al. Mutant EGFR Requires BIM and Can Be Enhanced by BH3Mimetics,”PLoS Med.4:1681- 1689(2007)；Y.Gong's et al., " Induction of BIM Is Essential for Apoptosis Triggered by EGFR Kinase Inhibitors in Mutant EGFR-Dependent Lung Adenocarcinomas,”PLoS Med.4:e294(2007)；" the BIM Mediates EGFR of D.B.Costa et al. Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations,”PLoS Med.4:1669-1679 (2007), all these to be incorporated herein by reference).

Nearest one is the discovery that the deletion polymorphism found in BIM genes, it causes the alternative splicing hypotype of BIM (isoform) generation, the alternative splicing hypotype of the BIM lack the key BH3 domains for being related to and promoting apoptosis.It is this more State property has far-reaching influence to the TKI sensitiveness of CML and EGFRNSCLC cells so that the equipotential base of the missing of a copy Because being enough to make cell itself that there is TKI resistances.This polymorphism has the TKI sensitiveness of CML and EGFRNSCLC cells far-reaching Influence so that the allele of missing of a copy is enough to make cell itself have TKI resistances.Therefore, this polymorphism Worked with dominant mode so that this cell is resistant to TKI chemotherapy.The discovery further include with polymorphism individual with The individual for not having polymorphism is compared, and the reaction to TKI is significantly poor.Particularly, the presence of polymorphism with it is white to chronic granulocyte TKI in blood disease, the relatively low extent of reaction of Imatinib and shorter the getting nowhere for the treatment of of EGFR TKI in EGFR NSCLC Life cycle (PFS) correlation (" the A Common BIM Deletion Polymorphism Mediates of K.P.Ng et al. Intrinsic Resistance and Inferior Responses to Tyrosine Kinase Inhibitors in Cancer,”Nature Med.Doi10.138/nm.2713 (March 18,2012), is incorporated herein by reference.)

When this method is intended to treat NSCLC, prognosis or by stages special other biomarkers for NSCLC are It is knowing and can use.For NSCLC predictive biomarker F.R.Hirsch et al. " Molecular Predictors of Outcome With Gefitinib in a Phase III Placebo-Controlled Study in Advanced Non-Small-Cell Lung Cancer,”J.Clin.Oncol.24：It is public in 5034-5042 (2006) Open, be incorporated herein by reference.These biomarkers include：(i) EGFR gene copy number；(ii) presence of EGFR mutation, Including exons 1 8G719A, the deletion of exons 19, exons 1 9A743S, and exon 2 1L858R/L861Q；(iii) EGFR protein expressions；(iv) p-Akt protein expressions；(v) presence of KRAS mutation；And the presence of (vi) BRAF mutation.It is other Biomarker be described in " the Customizing Cisplatin Based on Quantitative of M.Cobo et al. Excision Repair Cross-Complementing 1 mRNA Expression:A Phase III Trial in Non-Small-Cell Lung Cancer,”J.Clin.Oncol.25：2747-2754 (2006), includes the mRNA water of ERCC1 It is flat, it is incorporated herein by reference.

Other biomarkers of NSCLC are well known in the art.The U.S. Patent number 8,969 of Buckingham, 001 discloses the DNA methylation as NSCLC biomarkers.The U.S. Patent number 8,940,302 of Amler et al. discloses Presence as the low HER3 of NSCLC biomarkers.The U.S. Patent number 8,911,940 of Weiss et al. discloses conduct The expression of the miRNA of NSCLC biomarkers.The U.S. Patent number 8,828,657 of Rafnar et al. is disclosed gives birth to as NSCLC Multiple genetic variants of substance markers thing, including rs1051730 allele T, rs16969968 allele A, Ss107794645 allele Cs and rs8034191 allele Cs.The U.S. Patent number 8,768,629 of Von Hoff et al. is public The TOP1 (topoisomerase I) as NSCLC biomarkers, TYMS (thymidylate synthetase), MGMT (O are opened⁶Methyl bird is fast Purine dnmt rna), PTEN (No. 10 homology of chromosome lacks acid phosphatase-tensin gene), ERBB2, and SPARC (is rich in cystein-type acidic protein).The U.S. Patent number 8,741,587 of Roessler et al. discloses conduct That is shifted in a kind of infantile tumour of NSCLC biomarkers is rich in arginic albumen (ARMET).The U.S. of Lam et al. is special Profit number 8,728,823 is disclosed as the relevant biomarkers of the CTAP-III of NSCLC biomarkers.Von Hoff et al. U.S. Patent number 8,700,335 disclose ERBB2, ESR1, PGR, KIT, EGFR, PTGS2 as NSCLC biomarkers And AR.The U.S. Patent number 8,632,592 of Schoeberl discloses the pErbB3 as NSCLC biomarkers；pErbB3 Determined by measurement indirectly, the measurement indirectly includes:Gross protein and (i) in measurement sample be selected from ErbB1, ErbB2 with The level and the level of at least one of (ii) heregulin and β cytokines of at least one acceptor of ErbB3.Showe's et al. U.S. Patent number 8,476,420 discloses the gene expression profile as NSCLC biomarkers.The United States Patent (USP) of Costa et al. Numbers 8,377,888 disclose the methylation state of the nucleic acid of the coding 14-3-3 Sigmas as NSCLC biomarkers.Tsao Et al. U.S. Patent number 8,211,643 disclose as NSCLC biomarkers polygenes signature.The U.S. of Jove et al. The patent No. 8,133,692 discloses the expression of the phosphorylation Stat and survivin (survivin) as NSCLC biomarkers. The U.S. Patent number 7,655,414 of Brennscheidt et al. discloses the phosphorylated AKT protein as NSCLC biomarkers And/or the overexpression of phosphorylated MAPK protein.These biomarkers and other biomarkers known in the prior art It may be used to patient selection.

When this method is intended to treat oophoroma, prognosis or by stages special biomarker for oophoroma are known And can use.For oophoroma biomarker B.Zhang et al. " An Overview of Biomarkers for the Ovarian Cancer Diagnosis,”Eur.J.Obstet.Gynecol.Reprod.Biol.2：119-123 (2011) it is disclosed, is incorporated herein by reference in.These biomarkers include the mutation in BRCA1 or BRCA2；BRCA1, The hyper-methylation of RASSF1A, APC, p14ARF, p16INK4a, or DAP kinases, oophoroma expression of specific gene spectrum；From pair The spectrum of the serial analysis of the gene expression (SAGE) of CLDN3, HE4, FOLR1, COL18A1, CCND1 or FLJ12988；M- α-pancreas The cutting fragment of protease inhibitors heavy chain H4；Transferrins；Afamin albumen；Apolipoprotein A-IV；With miRNA express spectras. Another biomarker for being usually used in oophoroma is CA125 albumen.CA125 is typically 1890 amino measured in serum The heavy glycosylated protein of acid.Another biomarker for being usually used in oophoroma is DF3 albumen, which is also typically in blood Measure in clear.

Other biomarkers of oophoroma are well known in the art.The U.S. Patent number 8 of Inazawa et al., 741,641 disclose gene as oophoroma biomarker, being present in chromosomal region：2q14.2,3p24.1, 3q26.2,3q29,4q34.2,6q23,9p21 3,11q13.3,13q22.1,13q33.1,13q33.3,15q12,15q15.1, 17p12,17p13.1,17p13.3,18q21.1,18q21.2,18q21.31,18q21.32,18q21.33,18q23, 20q13.13,20q13.2,20q13.31,20q13.33, Xp11.23, Xp13.1, Xp13.3, Xp26.2, Xp26.3, or Xq28 Change.The U.S. Patent number 8,682,591 of Chan et al. discloses the biomarker for oophoroma, including：Modification ApoA1, and selected from by cysteine transthyretin, sulfonation transthyretin, what CysGly was modified turns first shape The transthyretin of one or more modifications of the group of parathyrine albumen and glutathione transthyretin composition. The U.S. Patent number 8,664,358 of Mansfield et al. discloses many biomarkers for being used for oophoroma, including CA- 125, CRP, EGF-R, CA-19-9, Apo-AI, Apo-CIII, IL-6, IL-18, MIP-1a, tenascin C and myoglobins and Its fragment.The U.S. Patent number 8,652,777 of Kamalakaran et al. discloses the CpG bis- as oophoroma biomarker The methylation state of nucleotide.The U.S. Patent number 8,642,347 of Ye et al. disclose as oophoroma biomarker by The peptide that the CA125 degradeds being present in urine produce.The U.S. Patent number 8,476,026 of Alex et al. discloses many antigens Antibody is the biomarker of oophoroma；The antigen includes Casein kinase 1.The U.S. Patent number 8,465 of Fung et al., 929 disclose many biomarkers for being used for oophoroma, including calcyclin, calgranulin C, hepcidin, ApoC1, ApoAII, ApoCII, calgranulin A, and transthyretin.8,404,829 disclosure of U.S. Patent number of Gray et al. Rise expression as the PVT1 of oophoroma biomarker.The U.S. Patent number 8,323,906 of Veiby et al. discloses work Used for the LIV-1 of oophoroma biomarker.The U.S. Patent number 8,192,935 of Al-Murrani is disclosed as oophoroma The expression of the MetAP2 of the biomarker of middle cisplatin.The U.S. Patent number 8,030,060 of Guo is disclosed as pre- Survey the gene signature of the biomarker of the recurrence and transfer in oophoroma, including 15 gene signatures, 23 gene signatures and 28 bases Because of signature.The U.S. Patent number 7,910,314 of Frackelton, Jr. et al. are disclosed as oophoroma biomarker The Shc of p66-Shc and phosphorylation.The U.S. Patent number 7,700,280 of Al-Murrani is disclosed as cis-platinum in oophoroma The expression of the S100A10 and S100A11 of the biomarker of resistance.The U.S. Patent number 7 of van Ommen et al., 507,800 disclose the germline missing as the BRCA1 of oophoroma biomarker.The U.S. of Van Kriekinge et al. is special Profit number 7,507,536 discloses the gene silencing of the epigenetics of multiple genes as oophoroma biomarker, including Gene code plasmolipin, TNFRSF10B tumor necrosis factor receptor super family (member 10b), RUNX3 runt are related to be turned Record the factor 3, ACTN1 actinine (α 1), and FANCG Fanconi Fanconi anemias (supplementation group G).Lancaster etc. The U.S. Patent Application Publication No. 2015/0080249 of people discloses the participation O- glycan paths as oophoroma biomarker Many genes elevated expression level use, these genes include B3GALT1, B3GALT2, B3GALT4, B3GALT5, B3GNT6,B4GALT1,B4GALT2,B4GALT3,C1GALT1,GALNT1,GALNT10,GALNT11,GALNT12, GALNT13,GALNT14,GALNT2,GALNT3,GALNT4,GALNT5,GALNT6,GALNT7,GALNT8,GALNT9, GALNTL1, GALNTL2, GALNTL4, GALNTL5, GCNT1, GCNT2, GCNT3, ST3GAL1, ST3GAL2, ST6GALN, with And the U.S. Patent Application Publication No. 2015/0031561 of WBSCR17.Bertenshaw et al. discloses and many is used as oophoroma Biomarker, including CA125, HE4, IL-2R α, α -1- antitrypsins, C reactive protein, YKL-40, the fine even egg of cell In vain, prostatein, TIMP-1, IL-8, IL-6, VEGF-B, MMP-7, calcium sozin, IGFBP-2, LOX-1, neural cilium Albumen -1, TNFR2, MPIF-1, and CA-72-4.The U.S. Patent Application Publication No. 2014/ of Bertenshaw et al. 0364341 discloses many biomarkers for oophoroma, including CA 15-3 (MUC-1), Her2/Neu (erbB-2), Kallikrein -5, macrophage inhibition factor (MIF), osteopontin, TAG-72, IGF-II, HE4, IL6-R, IL18-R, IL-18BP, VCAM-1, IP-10 (interferon-gamma induction type 10kD protein), SMRP, Tgll (tissue transglutaminases Enzyme), exotoxin -1 (exotaxin-1), Cyfra 21-1 (cytokeratin 19 fragment), IGF2BP3, TIMP-1, alpha-1 Antitrypsin, MMP7, IL-8, IL-6, sortillin albumen, CD40, Alpha 1- antichymotrypsins, VEGF, Yi Jijie Close globin.The U.S. Patent Application Publication No. 2014/0017703 of Lancaster et al. discloses cell death pathway albumen The phosphorylation levels of BCL2 antagonists may be used as treatment of cancer of the prediction based on platinum, the treatments of taxanes or endoxan The biomarker of the clinical effectiveness for the treatment of, wherein the BCL2 antagonists of the cell death pathway albumen are BAD, Bax, BcL- XL, PP2C/PPM1A, AKT, EGFR, IRS-1, Shc, H-Ras, CDK1, G- protein alpha-s, G- albumen β/γ, PI3K (phosphatidyl Inositol 3-kinase) cat class 1A, c-Raf-1, p90Rsk, MEK2 (MAP2K2), PKA-cat, or PKA-reg.

When obtained by the analysis of patient or disease phenotype improve when, the analysis of the patient or disease phenotype can be but It is not limited to, selected from by the patient performed by the method for the following group formed or the analysis method of disease phenotype：

(a) particular phenotype of patient is confirmed using diagnostic tool, diagnostic techniques, diagnostic kit or diagnostic assay method；

(b) use selected from by histone deacetylase enzyme, ornithine decarboxylase, VEGF, as jun gene outcome protein and The detection method of the label for the group that protein kinase is formed；

(c) alternative compounds dosed administration；And

(d) low dosage of enzyme state is tested in advance.

When the analysis by patient or genotyping of diseases, which obtains, to be improved, the analysis of the patient or genotyping of diseases can For but be not limited to, selected from by the patient performed by the method for the following group formed or the analysis method of genotyping of diseases：

(a) particular phenotype of patient is confirmed using diagnostic tool, diagnostic techniques, diagnostic kit or diagnostic assay method；

(b) genetic chip is utilized；

(c) gene expression analysis is used；

(d) analyzed using single nucleotide polymorphism (SNP)；

(e) the horizontal measurement of metabolin or metabolic enzyme；

(f) copy number of EGFR gene is definite；

(g) mgmt gene promoter methylation state is definite；

(h) the existing measure of the non-promoter region that methylates of mgmt gene；

(i) mgmt gene methylates the existing measure of promoter region；

(j) high the existing of expression MGMT determines；

(k) the existing of low expression MGMT determines；And

(l) it is used for the confirmation of the p53 genotypic states of oophoroma.

The use of genetic chip is described in " the DNA Microarrays in of A.J.Lee and S.Ramaswamy Biological Discovery and Patient Care”in Essentials of Genomic and Personalized Medicine(G.S.Ginsburg and H.F.Willard, eds., Academic Press, Amsterdam, 2010), ch.7, pp.73-88, are incorporated herein by reference.

When the method is analyzed using single nucleotide polymorphism (SNP), to selected from histone deacetylase enzyme, ornithine Gene in the group that decarboxylase, VEGF, prostate specific gene, c-Jun and protein kinase are formed performs the snp analysis. Snp analysis is described in " the DNA Sequencing for the Detection of of S.Levy and Y.-H.Rogers Human Genome Variation”in Essentials of Genomic and Personalized Medicine (G.S.Ginsburg and H.F.Willard, eds., Academic Press, Amsterdam, 2010), ch.3, pp.27-37, It is incorporated herein by reference.

Also other genome-based technologies, such as copy number analysis of variance and DNA methylation analysis can use.Copy base Factor analysis of variance is described in " the Copy Number Variation and Human Health " of C.Lee et al.in Essentials of Genomic and Personalized Medicine(G.S.Ginsburg and H.F.Willard, Eds., Academic Press, Amsterdam, 2010), ch.5, pp.46-59, are incorporated herein by reference.DNA methylation Analysis is described in " the DNA Methylation Analysis of S.Cottrell et al.:Providing New Insight into Human Disease”in Essentials of Genomic and Personalized Medicine (G.S.Ginsburg and H.F.Willard, eds., Academic Press, Amsterdam, 2010), ch.6, pp.60-72, It is incorporated herein by reference.This is especially important for NSCLC, because the effect due to mgmt gene in drug resistance is promoted, NSCLC prognosis can change as the promoter methylation degree of mgmt gene changes.

When preparing to obtain improvement before or after by treatment, prepare be but be not limited to before or after the treatment, be selected from Method by preparing before or after the treatment of the following group formed：

(a) using colchicin or the like；

(b) diuretics is used；

(c) medicine for improving uric acid excretion is used；

(d) uricase is used；

(e) it is parenteral to use niacinamide；

(f) niacinamide of sustained release form is used；

(g) poly- (ADP ribose) polymerase inhibitors is used；

(h) caffeine is used；

(i) folinic acid is rescued；

(j) infection control；And

(k) drug for hypertension.

Medicine for improving uric acid excretion includes, but not limited to probenecid, Benzbromarone and Sulfinpyrazone.Particularly preferred uricosuric It is probenecid to drain medicine.Medicine for improving uric acid excretion including probenecid, it is also possible to have diuretic activity.Other diuretics are in ability It is known in domain, and include but not limited to, Hydrochioro, carbonic anhydrase inhibitor, frusemide, ethacrynic acid, amiloride, spiral shell Lactone.

Poly ADP-ribose polymerase inhibitor is described in the " Poly (ADP-Ribose) of G.J.Southan and C.Szab ó Inhibitors,”Curr.Med.Chem.10：321-240 (2003), is incorporated herein by reference, and including niacinamide, 3- Aminobenzamide, (2H) -one of 3,4- dihydro-isoquinolines -1 of substitution and isoquinolin -1 (2H) -one, benzimidazole, indoles, phthalein Piperazine -1 (2H) -one, quinazolinone, isoindoline, phenanthridone and other compounds.

Folinic acid rescue include to apply methotrexate (MTX) patient apply folinic acid (folinicacid, leucovorin).Folinic acid is the reduction form of folic acid, and the folinic acid can bypass dihyrofolate reductase, and recover hematopoiesis Function.Folinic acid can pass through vein or oral administration.

In an alternative solution, wherein, it is to use medicine for improving uric acid excretion to be handled before or after described, the uricosuric excretion Medicine is probenecid or its analog.

When obtained by toxicity management improve when, the toxicity management can be but be not limited to, selected from being made of following The method of the toxicity management of group：

(a) using colchicin or the like；

(b) diuretics is used；

(c) medicine for improving uric acid excretion is used；

(d) uricase is used；

(e) it is parenteral to use niacinamide；

(f) niacinamide of sustained release form is used；

(g) poly- (ADP ribose) polymerase inhibitors is used；

(h) caffeine is used；

(i) folinic acid is rescued；

(j) using sustained release allopurinol；

(k) it is parenteral to use allopurinol；

(l) bone-marrow transplantation is used；

(m) haemocyte excitant is used；

(n) blood or platelet transfusion are used；

(o) Filgrastim, granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimutaing factor are used (GM-CSF)；

(p) pain management technology is applied；

(q) anti-inflammatory agent is applied；

(r) application of fluid；

(s) corticosteroid is applied；

(t) administration of insulin control medicine；

(u) antipyretic is applied；

(v) nausea is applied to treat；

(w) anti diar rhea is applied to treat；

(x) N-acetylcystein is applied；And

(y) antihistamine is applied.

Filgrastim is granulocyte colony stimulating factor (G-CSF) analog produced by recombinant DNA technology, described non- Geseting is used for the propagation for stimulating granulocyte and differentiation and for treating neutrophilic granulocytopenia；G-CSF can be with similar Mode use.GM-CSF is granulocyte macrophage colony stimulating factor, and stimulates stem cell to produce granulocyte (acidophil granules Cell, neutrophil cell and basophilic granulocyte) and monocyte；It is administered available for prevention or treatment infection.

Antiinflammatory is it is well known in the art that and including corticosteroid and non-steroidal anti-inflammatory agent (NSAID).Have The corticosteroid of anti-inflammatory activity includes but not limited to, hydrocortisone, cortisone, beclomethasone dipropionate, betamethasone, Sai meter Song, metacortandracin, methylprednisolone, fluoxyprednisolone, fluocinolone and fludrocortison.Non-steroidal anti-inflammatory agent includes but unlimited In, acetylsalicylic acid (aspirin), sodium salicylate, choline magnesium trisalicylate, salsalate, Diflunisal, sulfasalazine, Olsalazine, acetaminophen, Indomethacin, sulindac, tolmetin, Diclofenac, ketorolac, brufen, naproxen, fluorine compare Lip river Sweet smell, Ketoprofen, fenoprofen, olsapozine, mefenamic acid, Meclofenamic Acid, piroxicam, Meloxicam, Nabumetone, sieve It is non-examine former times, celecoxib, Etodolac, aulin, Aceclofenac, alclofenac, alminoprofen, amfenac, Ampiroxicam, Apazone (Apazone), Araprofen, azapropazone (Azapropazone), Bendazac, Benoxaprofen, benzydamine, Bai Mo Ibuprofen, benzpiperilone, Bromfenac, bucloxic acid, bumadizone, butibufen, Carprofen, cimicoxib, cinmetacin, Xin Nuoxi Health, clidanac, clofezone, Clonixin, Clopirac, darbufelone, deracoxib, Droxicam, eltenac, benzene second ammonia fennel Acid, epirizole, Esflurbiprofen, Ethenzamide, etofenamate, etoricoxib, felbinac, fenbufen, fenclofenac, funk Lip river acid, fragrant chlorine piperazine (Fenclozine), fendosal, Fentiazac, feprazone, filenadol, flobufen, florifenine, fluorine relax Amine, methanesulfonic acid fluorine rupee star (flubichinmethanesulfonate), Flufenamic acid, Flufenisal, Flunixin, Flunoxaprofen, Fluprofen, Fluproquazone, Furofenac, ibufenac, imrecoxib, indoprofen, isofezolac, Isoxepac, Yi Suoxi Health, Licofelone, Lobuprofen, Lornoxicam, lonazolac, loxoprofen, lumiracoxib (lumaricoxib), Ma Buluo Sweet smell, miroprofen, mofebutazone, Mofezolac, morazone, nepafenac (Nepafenac), niflumic acid, nitrofen (nitrofenac), nitroflurbiprofen, (S) -2- (6- methoxyl group -2- naphthyls) propionic acid 4- nitroxide butyl esters (nitronaproxen), Orpanoxin, Oxaceprol, Oxindanac, Losec product sour (Oxpinac), Oxyphenbutazone, Pamicogrel, Parcetasal, SC 69124, Parsalmide, pelubiprofen, Pemedolac, phenylbutazone, pirazolac, pirprofen, pranoprofen, water Benzasalicin, salicylamide, disalicylic acid, Satigrel, Sudoxicam, suprofen, Talmetacin, Talniflumate, Tazofelone, Tebufelone, Tenidap, tenoxicam, Tepoxalin, Tiaprofenic Acid, tiaramide, examine for horse former times, Tinoridine, sulphur are put down Acid, sulphur ibuprofen, Tolfenamic Acid, Triflusal, Indomethacin tropeine (tropesin), ursolic acid, valdecoxib, Xi Moluo The U.S. acid of sweet smell, Zaltoprofen, zidometacin, assistant and their salt, solvate, analog, congener (congeners), life Thing isostere, hydrolysate, metabolin, presoma and pro-drug.

The Clinical practice of corticosteroid is described in B.P.Schimmer's and K.L.Parker “Adrenocorticotropic Hormone；Adrenocortical Steroids and Their Synthetic Analogs；Inhibitors of the Synthesis and Actions of Adrenocortical Hormones”in Goodman and Gilman’s The Pharmacological Basis of Therapeutics(L.L.Brunton, ed.,11^thEd., McGraw-Hill, New York, 2006), ch.59, pp.1587-1612, are incorporated herein by reference.

Nausea treatment include, but not limited to Ondansetron, Metoclopramide, fenazil, Cyclizine, hyoscine, Dronabinol, dramamine, diphenhydramine, hydroxyzine, medizine, Dolasetron, Granisetron, palonosetron, Lei Mosi Fine jade, domperidone, haloperidol, chlorpromazine, fluphenazinum, perphenazine, prochlorperazine, betamethasone, dexamethasone, Laura west Dissolve and tietylperazine.

Anti diar rhea treatment includes, but not limited to diphenoxylate, Fen Nuoxin, Loperamide, codeine, racecadotril, Austria Bent peptide (octreoside) and berberine.

N-acetylcystein is a kind of antioxidant and mucolytic agent, and the N-acetylcystein also provides life Sulphur obtained by thing (biologicallyaccessiblesulfur).

Poly ADP-ribose polymerase (PARP) inhibitor includes but not limited to：(1) such as by Duncan et al. in U.S. Patent number Tetracycline derivant described in 8,338,477；(2) as Gerson et al. described in U.S. Patent number 8,324,282 3,4- dihydro -5- methyl isophthalic acids (2H)-isoquinolin, 3-AB, 6-aminonicotinamide and 8- hydroxy-2-methyls -4- (3H) quinazolinone；(3) such as 6- (the 5H)-phenanthridone and 1,5- by Yuan et al. described in U.S. Patent number 8,324,262 Isoquinolin；(4) as by Fujio et al. described in U.S. Patent number 8,309,573 (R) -3- [2- (2- hydroxymethyl pyrrolidines - 1- yls) ethyl] -5- methyl -2H- isoquinoline-1-ketones；(5) such as retouched by Vialard et al. in U.S. Patent number 8,299,256 The 2- quinolinones of 6- alkenyls substitution, the quinolinone of 6- phenylalkyls substitution, 2- quinokysalines, the 6- phenyl of the substitution of 6- alkenyls stated The 2- quinolines that 2- quinolinones, the 6- cyclohexylalkyls that alkyl-substituted 2- quinokysalines, the 6- cyclohexylalkyls of substitution substitute substitute Quinoline ketone, pyridone, Quinazol derivative, phthalazine derivatives, quinazolinedione derivatives and the substituted 2- alkyl of substitution Quinazol derivative；(6) such as the 5- bromo-isoquinolines by Mateucci et al. described in U.S. Patent number 8,299,088；(7) Such as 5- pairs-(2- chloroethyls) amino by Gallagher et al. described in U.S. Patent number 8,227,807] -1- methyl -2- The fluoro- 5- of benzimidazole butyric acid, 4-iodo-3-nitrobenzamide, 8- (4- ((methylamino) methyl) phenyl) -3,4- dihydros -2H- Azepine simultaneously [5,4,3-cd] indoles -1 (6H) -one phosphoric acid and N- [3- (3,4- dihydro -4- oxo -1- phthalazinyls) phenyl] -4- Morpholine butyramide methanesulfonates；(8) as derived by pyridazinones of the Branca et al. described in U.S. Patent number 8,268,827 Thing；(9) such as 4- [3- (the 4- cyclopropane carbonyls-piperazine -1- carbonyls by Menear et al. described in U.S. Patent number 8,247,416 Base) -4- luorobenzyls] -2H- phthalazines -1- ketone；(10) as by Menear et al. described in U.S. Patent number 8,236,802 four Azepine benzo naphthalene -3- ketone compounds；(11) as by Menear et al. described in U.S. Patent number 8,217,070 2- substitution- 1H- h-benzimidazole-4-carboxamides；(12) as substituted described in U.S. Patent number 8,188,103 by VanderAa et al. 2- alkyl quinazolinones；(13) such as the 1H- benzimidazoles -4- by Penning et al. described in U.S. Patent number 8,183,250 Formamide；(14) such as the indenoisoquinoline ketone by Jagtap et al. described in U.S. Patent number 8,119,654 (indenoisoquinolinone) analog；(15) such as the benzo by Chu et al. described in U.S. Patent number 8,088,760 Azoles carboxylic acid amides；(16) as closed by diaza benzo (de-) anthracene -3- assimilations of the Xu et al. described in U.S. Patent number 8,058,075 Thing；(17) such as the dihydro pyrido phthalazone by Wang et al. described in U.S. Patent number 8,012,976 (dihydropyridophthalazinones)；(18) as Jiang et al. described in U.S. Patent number 8,008,491 Substituted azaindole；(19) such as the fused tricyclic compounds by Chua et al. described in U.S. Patent number 7,956,064； (20) such as by Gangloff et al. in U.S. Patent number 7, the substituted 6a described in 928,105,7,8,9- tetrahydropyridines simultaneously [3, 2-e] pyrrolo- [1,2-a] pyrazine -6 (5H) -one；(21) such as the thieno [2,3- described in U.S. Patent number 7,825,129 C] isoquinolin, all above patents are both incorporated herein by reference.Other PARP inhibitor are known in the art.

Obtained when by pharmacokinetics or pharmacodynamics monitoring when improving, the pharmacokinetics or pharmacodynamics Monitoring can be but be not limited to, selected from the method by the following group formed：

(a) blood plasma level is repeatedly measured；And

(b) at least one of blood or urine metabolin are repeatedly measured.

In general, it is metabolized by immunoassay to measure blood plasma level or measure at least one of blood or urine Thing.The method for carrying out immunoassays is well known in the art, including radioimmunoassay, ELISA (enzyme linked immunosorbent assay (ELISA)s Method), competitive immunoassay method, immunoassay and other assay methods using lateral flow test strips.

When obtained by drug regimen improve when, the drug regimen can be, but be not limited to, selected from being made of following The drug regimen of group：

(a) it is used together with topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides is used；

(c) fraudulent nucleotide is used；

(d) it is used together with thymidylate synthetase inhibitor；

(e) it is used together with signal transduction inhibitor；

(f) it is used together with cis-platinum, oxaliplatin or other platinum analogs；

(g) it is used together with monofunctional alkyl agent；

(h) it is used together with bifunctional alkylating agent；

(i) with destroy DNA alkylating agent be used together, wherein the alkylating agent compared to two to the water wei ling alcohol in different positions Put and destroy DNA；

(j) it is used together with antitublin；

(k) it is used together with antimetabolite；

(l) it is used together with jamaicin；

(m) it is used together with 4',5,7-trihydroxyflavone；

(n) it is used together with Amonafide；

(o) it is used together with colchicin or the like；

(p) it is used together with genistein；

(q) it is used together with Etoposide；

(r) it is used together with cytarabine；

(s) it is used together with camptothecine；

(t) it is used together with vinca alkaloids；

(u) it is used together with 5 FU 5 fluorouracil；

(v) it is used together with curcumin；

(w) it is used together with NF- kB inhibitors；

(x) it is used together with Rosmarinic acid；

(y) it is used together with mitoguazone；

(z) it is used together with hanfangchin A；

(aa) it is used together with Temozolomide；

(ab) it is used together with VEGF inhibitor；

(ac) it is used together with cancer vaccine；

(ad) it is used together with EGFR inhibitor；

(ae) it is used together with tyrosine kinase inhibitor；

(af) it is used together with poly- (ADP- ribose) polymerase (PARP) inhibitor；And

(ag) it is used together with ALK inhibitor.

Topoisomerase enzyme inhibitor includes, but not limited to Irinotecan, Hycamtin, camptothecine, Lamellarin D, peace a word used for translation Pyridine, Etoposide, etoposide phosphate, Teniposide, Doxorubicin and ICRF-193.

Fraudulent nucleosides includes, but not limited to cytarabine, gemcitabine and fludarabine；Other fraudulent nucleosides are It is as known in the art.

Fraudulent nucleotide includes, but not limited to tenofovir disoproxil fumarate and Aldoforwe ester；Other fraudulent nucleosides Acid is known in the art.

Thymidylate synthetase inhibitor include, but not limited to Raltitrexed, pemetrexed, nolatrexed, ZD9331, GS7094L, fluorouracil and BGC945.

Signal transduction inhibitor is described in the Lee et al. of A.V.Lee etc., " New Mechanisms of Signal Transduction Inhibitor Action:Receptor Tyrosine Kinase Down-Regulation and Blockade of Signal Transactivation,”Clin.Cancer Res.9：516s (2003), by quoting it It is integrally incorporated herein.

Alkylating agent includes but not limited to, salt open country justice 254-S (Shionogi 254-S), aldehyde-phosphamide analog, pregnancy Melamine, Anaxirone, Bao Lingman BBR-2207 (Boehringer Mannheim BBR-2207), bendamustine, beta cloth Pungent (bestrabucil), Budotitane, gush CA-102 (Wakunaga CA-102), carboplatin, Carmustine (BCNU), covenant forever Because -139 (Chinoin-139), covenant are because of -153 (CHINOIN-153), Chlorambucil, cis-platinum, endoxan, american cyanamide Company CL-286558, Sai Nuofei CY-233, western Alexandre Desplat (Cyplatate), Degussa D-19-384, Sumitomo DACHP (Myr)₂、(Sumimoto DACHP(Myr)₂), diphenyl spiromustine (diphenylspiromustine), two platinum cells life Long inhibitor, the distamycin derivatives of Erba companies, China and foreign countries (Chugai) DWA-2114R, ITIE09, elmustine, The FCE-24517 of Erbamont companies, estramustine phosphate sodium, Fotemustine, step especially G-6-M (stepping G-6-M especially), covenant because GYKI-17230 (CHINOINGYKI-17230), super sulfanilamide (SN) (Hepsulfam), ifosfamide, iproplatin, lomustine (CCNU), Mafosfamide, melphalan, mitolactol, Nimustine (ACNU), Japanese chemical drug NK-121, NCI NSC- 264395th, NCI NSC-342215, oxaliplatin, the PCNU of general strong (Upjohn) company, pennisetum mustard, Proter companies PTT-119, Ranimustine, Semustine, SmithKline SK＆F-101772, the SN-22 of Yakult Honsha companies, spiral shell Mo Siting, the pharmacy of field side (Tanabe Seiyaku) TA-077, tauromustine, Temozolomide, teroxirone, four platinum and front three Close alcohol, above alkylating agent in U.S. Patent number 7, described in 446,122, are incorporated herein by reference such as by Chao et al.. Temozolomide, BCNU, CCNU and ACNU are all in the O of guanine⁶Locate damage dna, and in N⁷Locate DAG crosslinkings；Therefore it is a kind of to substitute Scheme is the combination using DAG and alkylating agent, wherein the alkylating agent compared to DAG in diverse location damage dna.Alkyl Agent can be monofunctional alkyl agent or bifunctional alkylating agent.As in N.Kondo incorporated herein by reference Et al. " DNA Damage Induced by Alkylating Agents and Repair Pathways, "J.Nucl.Acidsdoi:Described in 10.4061/2010/543531 (2010), monofunctional alkyl agent includes but unlimited In Carmustine, lomustine, Temozolomide and Dacarbazine；As incorporated herein by reference J.M.Walling and I.J.Stratford, " Chemosensitization by Monofunctional Alkylating Agents,”Int.J.Radiat.Oncol.Biol.Phys.12：Described in 1397-1400 (1986), monofunctional alkyl Agent further includes such as following reagent methyl mesylate, ethyl methane sulfonate and N- methyl-N-nitroso guanidines.Difunctional alkylation Agent includes, but not limited to mustargen, Chlorambucil, endoxan, busulfan, Nimustine, Carmustine, lomustine, good fortune Mo Siting and double (2- chloroethyls) thioethers (N.Kondo et al. (2010), ibid).Significant a kind of bifunctional alkylating agent's bag Include, targeting DNA guanines O⁶Alkylating agent.Another notable class alkylating agent includes cis-platinum and other platiniferous agent, including, but not It is limited to, cis-platinum, carboplatin, iproplatin, oxaliplatin, four platinum, Satraplatin, picoplatin, Nedaplatin, three platinum.These reagents cause DNA to hand over Connection, the DNA crosslinkings and then inducing cell apoptosis.Combined with cis-platinum, oxaliplatin or other platiniferous reagents is that standard platiniferous is double The potential part of medication.In addition, substituted hexose 01 derivatives and cis-platinum, sand difficult to understand for such as two to the water wei ling alcohol The combination of sharp platinum or other platiniferous chemotherapeutants and other chemotherapeutants as described herein, its remote super addition or collaboration Ability is especially significant.

Antitublin include, but not limited to vinca alkaloids, taxanes, podophyllotoxin, halichondrin B and Homologous halichondrin B (homohalichondrin B).

Antimetabolite includes, but are not limited to：Methotrexate, pemetrexed, 5 FU 5 fluorouracil, capecitabine, arabinose born of the same parents Glycosides, gemcitabine, Ismipur and Pentostatin, Alanosine, AG2037 (Pfizer), 5-FU- fibrinogens, spine leaf Sour (Acanthifolic Acid), chiral lactones, brequinar sodium, Carmofur, the CGP- of vapour Ba-Jia Ji (Ciba-Geigy) 30694th, cyclopenta cytimidine, stearic acid cytarabine phosphate, A acyl cytosine arabinoside conjugate, Li Lai companies DATHF, Merrill Lynch Tao Shi DDFC, dezaguanine (deazaguanine), dideoxycytidine, dideoxyguanosine, more this (Didox), Yoshitomi DMDC, doxifluridine, Wei Kang (Wellcome) company EHNA, Merck ＆ Co., Inc. (Merck and Co.) EX-015, fazarabine, fluorine Uridine, fludarabine phosphate (fludarabine phosphate), N- (2 '-furan alkyls) -5 FU 5 fluorouracil, Daiichi Seiyaku companies FO-152, isopropyl pyrroles piperazine, LillyLY-188011, Lilly LY-264618, the general woods of toluene (Methobenzaprim), methotrexate (MTX), prestige health MZPES, Northey ripple pyrimidine (Norspermidine), NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert (Warner-Lambert) PALA, pyrrole Qu Kexin, plicamycin, Asahi Chemical Industry (Asahi Chemical) PL-AC, force field (Takeda) TAC-788, thioguanine, thiophene Azoles furan woods, Erbamont TIF, three Mei Site (Trimetrexate), tyrosine kinase inhibitor, tyrosine protein kinase suppression Preparation, Taiho UFT and excellent Li Xiding (uricytin).

Jamaicin has antibacterial activity, and prevents and suppress pro-inflammatory cytokine and E-selectin E-Selectin (E-selectin) expression, and the expression of increase adiponectin.

4',5,7-trihydroxyflavone is the flavones for the adverse effect that can reverse cyclosporine, and individually has chemoprotective activity, or with Sugared derivative and chemoprotective activity.

Amonafide is the topoisomerase enzyme inhibitor and DNA intercalators for having antitumor activity.

Curcumin is considered to have antitumor, anti-inflammatory, anti-oxidant, anti-ischemic, Antiarthritic and anti-amyloid properties, And also there is liver-protecting activity.

NF- kB inhibitors include but not limited to, bortezomib.

Rosmarinic acid is a kind of naturally occurring phenol antioxidant, it also has anti-inflammatory activity.

Mitoguazone is the inhibitor by the polyamines biosynthesis of the Reverse transcriptase of S adenosylmethionine decarboxylase.

Hanfangchin A has 6,6 ', 7,12- tetramethoxy-2, the chemical constitution of the β of 2 '-dimethyl-1-berbamine, and It is with anti-inflammatory, immune and anti-allergic effects, and the calcium channel blocker of the antiarrhythmic effect similar to quinindium.It It has been located away from Fourstamen Stephania Root and other Asian herbals.

VEGF inhibitor includes bevacizumab (Avastin), and bevacizumab is the monoclonal antibody of anti-vegf, is further included Itraconazole and suramin and Batimastat and Marimastat, the VEGF inhibitor are that matrix metalloproteinase suppresses Agent, Cannabinoids and their derivative.

Have begun to research and development cancer vaccine.In general, cancer vaccine is immune response based on albumen or based on not normal The immune response of the albumen present in cancer cell occurred in cell.Cancer vaccine is included before being used for metastatic hormone refractory The vaccine for prostate cancer Provenge of row gland cancer, kidney vaccine Oncophage, the CimaVax- for lung cancer for kidney EGF, MOBILAN, for such as breast cancer, colon cancer, the cancer of the expression of the Her2/neu of carcinoma of urinary bladder and oophoroma Neuvenge, Stimuvax and other cancer vaccines for breast cancer.Cancer vaccine be described in S.Pejawar-Gaddy and " the Cancer Vaccines of O.Finn:Accomplishments and Challenges,”Crit.Rev.Oncol.Hematol.67：93-102 (2008), is incorporated herein by reference.

EGF-R ELISA (EGFR) exists on the cell surface of mammalian cell, and is matched somebody with somebody by its specificity Body and acceptor with reference to and activate, it includes but not limited to epidermal growth factor and transforming growth factor α.When by being attached to its life During long factor ligand activation, EGFR experience is from the transition that nonactive monomeric form is active homodimer, although being pre-formed Active dimeric can exist before ligand binding.Except forming active homodimer after ligand binding, EGFR can be with Another member of ErbB receptor family, such as ErbB2/Her2/neu pairings, the heterodimer activated with generation.Also on evidence Show, the cluster for activating EGFR is formed, although not can determine that whether such cluster is important or so in itself to activation still at present Cluster whether appear in the activation of single dimer after.EGFR dimerizations stimulate its intrinsic intracellular protein tyrosine kinase Activity.As a result, several tyrosine residue autophosphorylations in the carboxy-terminal domain of EGFR occur.These residues include Y992, Y1045, Y1068, Y1148 and Y1171.Such autophosphorylation causes activated downstream and letter by several other oroteins Number conduction, the phosphotyrosine combination SH2 domains and the tyrosine residue phase of phosphorylation that the other oroteins pass through oneself Association.Then these pass through the phosphotyrosine combination SH2 domains of oneself egg associated with the tyrosine residue of phosphorylation White signal transduction can start several signal transduction cascades, and cause DNA synthesis and cell Proliferation.The kinase domain of EGFR Cross phosphorylation, and the kinase domain of the EGFR occur for the tyrosine residue for other acceptors that domain can also polymerize it Itself it can be activated by this way.EGFR is encoded by c-erbB1 proto-oncogenes, and the molecular weight with 170kDa.It It is a kind of carry rich in the extracellular region of cysteine, the intracellular domain containing continual tyrosine kinase sites, Yi Jiru The upper transmembrane glycoprotein in multiple autophosphorylation sites of carboxy-terminal tail cluster.Extracellular portion has been subdivided into four Domain：Domain I and III with 37% sequence identity are that cysteine is poor, and include ligand in conformation (EGF and transforming growth factor α (TGFα)) binding site.The glycosyl that domain II rich in cysteine is connected with IV including N- Change site and disulfide bond, the domain II and IV determine the three-level conformation of the extracellular portion of protein molecule.It is thin in many people Born of the same parents are that TGFα expression is with the strong correlation being overexpressed with EGFR, and therefore, TGFα is considered as that autocrine mode works, thorn Swash the propagation of its cell produced by the activation by EGFR.The combination of irritation ligand and EGFR extracellular domains cause by The beginning of body dimerization and intracellular signal transduction, its first step are the activation of tyrosine kinase.Kinase activation it is earliest The result is that the phosphorylation (autophosphorylation) of the tyrosine residue of its own as described above.Followed by causing have silk The association of the activation of the signal transduction of division.Cause EGFR express or overactivity mutation with many malignant tumours, including Glioblastoma is associated.The specific mutations of the EGFR of EGFR variations III are known called often by spongioblastoma In observe (" the EGF Mutant Receptor VIII as a Molecular Target in of C.T.Kuan et al. Cancer Therapy,”Endocr.Relat.Cancer8:83-96 (2001), is incorporated herein by reference.EGFR is considered It is oncogene.The inhibitor of EGFR includes, but not limited to Erlotinib, Gefitinib, Lapatinib, Lapatinib diformazan Benzene sulfonate, Afatinib, Canertinib, come that Buddhist nun, CP-724714, WHI-P154, TAK-285, AST-1306, ARRY- 334543rd, ARRY-380, AG-1478, tyrphostin 9, up to gram for Buddhist nun (dacomitinib), go to first strategic point Lip river to replace Buddhist nun, OSI-420, AZD8931, AEE788, Pei Li, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035 hydrochloric acid, BMS-599626, BIBW2992, CI1033, CP724714, OSI420 and Vande Thani (vandetinib).Particularly preferred EGFR inhibitor includes Erlotinib, Afatinib and Lapatinib.

Tyrosine kinase inhibitor includes, but not limited to Imatinib, Gefitinib, Tarceva, Sutent, rope La Feini, N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N ' - (4- fluorophenyls) cyclopropane -1,1- diformamides (foretinib), cederinib, Axitinib, card it is rich for Buddhist nun, BIBF1120, N- [the fluoro- 4- of 2- [[2- [[[4- (4- methylpiperazine-1-yls) piperidin-1-yl] carbonyl] amino] pyridin-4-yl] oxygen Base] phenyl]-N '-(4- fluorophenyls) cyclopropane -1,1- diformamides (golvatinib), more Weis for Buddhist nun, ZM306416, ZM323881 hydrochloric acid, SAR131675,1,3- dihydro -3- [(3,5- dimethyl -1H- pyrroles -2- bases) methylene] -2H- indoles - 2- ketone (semaxinib), Telatinib, pazopanib, Ponatinib Ke Lailani, tivanitib, wood profit are for Buddhist nun, Da Lushe Replace, Bu Linibu, fingomode, saracatinib, N- [the 3- tert-butyl groups -1- (quinoline -6- bases) -1H- pyrazoles -5- bases]-N '-[2- Fluoro- 4- [(2- (methylcarbamoyl) pyridin-4-yl) oxygen] phenyl] urea (rebastinib), Kui prick for Buddhist nun, Tandutinib, N- (1,3- benzodioxolane -5- ylmethyls) -4- benzofurans simultaneously [3,2-D] pyrimidine-4-yl -1- piperazine thioformamides (amuvatinib), Buddhist nun, Fox imatinib (fostamatinib), (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and linsitinib are replaced in Yiluo.It is such Tyrosine kinase inhibitor can suppress the tyrosine kinase associated with one or more following acceptors：VEGFR,EGFR, PDGFR,c-Kit,c-Met,Her-2,FGFR,FLT-3,IGF-1R,ALK,c-RET,and Tie-2.Epidermal growth factor receptor The activity of body (EGFR) is related to the activity of tyrosine kinase, the classification of tyrosine kinase inhibitor and the classification weight of EGFR inhibitor It is folded.Many tyrosine kinase inhibitors suppress the activity of EGFR and at least one other tyrosine kinase.In general, tyrosine kinase Inhibitor can be worked by four kinds of different mechanism：Compete with atriphos (ATP), carried out by tyrosine kinase use Phosphorylation reaction competes；With substrate competition；At the same time with ATP and substrate competition；Or allosteric suppresses.The activity of these inhibitor is draped over one's shoulders It is exposed to " the Blocking of EGF-Dependent Cell Proliferation by EGF of P.Yaish et al. Receptor Kinase Inhibitors,”Science242:933-935(1988)；A.Gazit's et al. “Tyrphostins.2.Heterocyclic andα-Substituted Benzylidenemalononitrile Tyrphostins as Potent Inhibitors of EGF Receptor and ErbB2/neu Tyrosine Kinases,”J.Med.Chem.34：1896-1907(1991)；" the Selective Inhibition of N.Osherov et al. of the Epidermal Growth Factor and HER2/neu Receptors by Tyrphostins,”J.Biol.Chem.268：11134-11142(1993)；And " the Tyrphostins and of A.Levitzki and E.Mishani Other Tyrosine Kinase Inhibitors,”Annu.Rev.Biochem.75：93-109 (2006), all of the above is led to Cross and be incorporated herein by reference.

ALK inhibitor is with change (ALK) such as EML4-ALK metathesises of anaplastic lymphoma kinase in tumour.ALK Inhibitor includes but not limited to：(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (3- [(1R) -1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl] -5- (1- piperidines - 4- yls) pyrazoles -4- bases) pyridine -2- amine)；AP26113 ((2- ((the chloro- 2- of 5- ((4- (4- (dimethylamino) piperidin-1-yl)- 2- methoxyphenyls) amino) pyrimidine-4-yl) amino) phenyl) dimethyl phosphine)；ASP-3026 (N2- [2- methoxyl groups -4- [4- (4- methyl isophthalic acids-piperazinyl) -1- piperidyls] phenyl]-N4- [2- [(1- Methylethyls) sulfonyl] phenyl] -1,3,5- three Piperazine -2,4- diamines)；Ai Le replaces Buddhist nun (9- ethyl -6,6- dimethyl -8- (4- morpholinyl -4- phenylpiperidines -1- bases) -11 oxo -5H- Benzo [b] carbazole -3- formonitrile HCNs)；NMS-E628 (N- (5- (3,5- difluorobenzyls) -1H- indazole -3- bases) -4- (4- methyl piperazines - 1- yls) -2- ((tetrahydrochysene -2H- pyrans -4- bases) amino) benzamide)；Ceritinib；PF-06363922；TSR-011；CEP- 37440 (2- [[the chloro- 2- of 5- [[(6S) -6- [4- (2- ethoxys) piperazine -1- bases] -1- methoxyl group -6,7,8,9- tetrahydrochysene -5H- benzene And [7] annulene -2- bases] amino] pyrimidine-4-yl] amino]-N- methyl-benzamides)；And X-396 (R) -6- amino -5- (1- (the chloro- 3- fluorophenyls of 2,6- bis-) ethyoxyl)-N- (4- (4- methyl piperazine -1- carbonyls) phenyl) pyridazine -3- formamides).

These above-mentioned other medicines can be used for drug regimen to treat NSCLC together with substituted hexose 01 derivatives Or oophoroma.Other medicament to be included is known with anti-treated cancer types (NSCLC or oophoroma) activity Compound, it is related with the known compound with anticancer type activity or a kind of compound in structure, or can known to it Path is adjusted, the adjusting has been demonstrated effective to the cancer types treated.As used herein, term " adjusting " can include The activation or suppression of involved path, but typically refer to suppress path.

When the method according to the invention be used for treat oophoroma when, drug regimen can include substitute as described above oneself Sugar alcohol derivant and with anti ovary tumour antitumor activity other medicament.Such medicament includes but is not limited to： Taxol, Docetaxel (docetaxel), cis-platinum, carboplatin, topotecan, gemcitabine, bleomycin, Etoposide, Ah Mycin (can be with Pegylated Liposomal form use), tamoxifen, Letrozole, olaparib, U.S. of department replace Buddhist nun, mTOR suppressions Preparation, PI3 kinase inhibitors and Trichostatin A.

The other medicament of antitumor activity with anti-NSCLC is well known in the art.Medicine according to the present invention Combination includes these other medicaments of therapeutically effective amount and the hexose 01 derivatives substituted as described above of therapeutically effective amount. The one or more of these other medicaments can be used.These other medicaments can resist as described above with one or more The medicament of NSCLC activity is used together in drug regimen, and the drug regimen includes such as two to the water wei ling alcohol or diacetyl The substituted hexose 01 derivatives of base two to the water wei ling alcohol.These medicaments are jointly referred to herein as " there is anti-NSCLC to live Property other secondary medicament ".

The other medicament of antitumor activity with ovarian cancer resistance is well known in the art.Medicine according to the present invention Combination includes these other medicaments of therapeutically effective amount and the hexose 01 derivatives substituted as described above of therapeutically effective amount. The one or more of these other medicaments can be used.These other medicaments can resist as described above with one or more The medicament of oophoroma activity is used together in drug regimen, and the drug regimen includes such as two to the water wei ling alcohol or diacetyl The substituted hexose 01 derivatives of base two to the water wei ling alcohol.These medicaments are jointly referred to herein as " having ovarian cancer resistance The other secondary medicament of activity ".

When by chemical sensitization obtain improve when, the chemical sensitization can include but not limited to, using with selected from by with The substituted hexose 01 derivatives as chemical sensitizer of the reagent combination of the group of lower composition：

(a) topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides；

(c) fraudulent nucleotide；

(d) thymidylate synthetase inhibitor；

(e) signal transduction inhibitor；

(f) cis-platinum, oxaliplatin or other platinum analogs；

(g) alkylating agent；

(h) antitublin；

(i) antimetabolite；

(j) jamaicin；

(k) 4',5,7-trihydroxyflavone；

(l) Amonafide；

(m) colchicine or the like；

(n) genistein；

(o) Etoposide；

(p) cytarabine；

(q) camptothecine；

(r) vinca alkaloids；

(s) topoisomerase enzyme inhibitor；

(t) 5 FU 5 fluorouracil；

(u) curcumin；

(v) NF- kB inhibitors；

(w) Rosmarinic acid；

(x) mitoguazone；

(y) hanfangchin A；

(z) tyrosine kinase inhibitor；

(aa) EGFR inhibitor；And

(ab) poly- (ADP- ribose) polymerase (PARP) inhibitor.

When by Chemical enhancement obtain improve when, the Chemical enhancement can include but not limited to, using with selected from by with The substituted hexose 01 derivatives as chemical sensitizer of the reagent combination of the group of lower composition：

(a) topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides；

(c) fraudulent nucleotide；

(d) thymidylate synthetase inhibitor；

(e) signal transduction inhibitor；

(f) cis-platinum, oxaliplatin or other platinum analogs；

(g) alkylating agent；

(h) antitublin；

(i) antimetabolite；

(j) jamaicin；

(k) 4',5,7-trihydroxyflavone；

(l) Amonafide；

(m) colchicine or the like；

(n) genistein；

(o) Etoposide；

(p) cytarabine；

(q) camptothecine；

(r) vinca alkaloids；

(s) 5 FU 5 fluorouracil；

(t) curcumin；

(u) NF- kB inhibitors；

(v) Rosmarinic acid；

(w) mitoguazone；

(x) hanfangchin A；

(y) tyrosine kinase inhibitor；

(z) EGFR inhibitor；And

(aa) PARP inhibitor.

Being managed when management obtains improvement after by treatment, after the treatment can be but be not limited to, selected from by following structure Into group method：

(a) with the relevant therapy of pain management；

(b) antemetic is applied；

(c) nausea therapy；

(d) anti-inflammatory agent is applied；

(e) antipyretic is applied；And

(f) immunostimulant is applied.

When management supports to obtain improvement after by the medicine of replacement or treatment, managed after the medicine of the replacement or treatment It can be but be not limited to, selected from the method by the following group formed：

(a) hypnosis；

(b) acupuncture；

(c) meditate；

(d) by synthesis or by extracting the herbal drug produced；And

(e) kinematics is applied.

It is described to pass through conjunction when this method is the herbal drug by synthesizing or extracting generation in an alternative solution Into or extraction produce herbal drug can be selected from by the following group formed method：

(a) NF- kB inhibitors；

(b) natural anti-inflammatory agent；

(c) immunostimulant；

(d) antiseptic；And

(e) flavonoids, isoflavones or flavones.

When the herbal drug by synthesizing or extracting generation is NF- kB inhibitors, the NF- kB inhibitors can be selected from The group being made of parithenolide, curcumin and Rosmarinic acid.When by synthesizing or extracting the herbal drug of generation to be natural anti- During scorching medicine, the natural anti-inflammatory agent can be selected from the group being made of Rhein and parithenolide.When by synthesizing or extracting production When raw herbal drug is immunostimulant, the immunostimulant can be product found from Echinacea purpurea or separated. When the herbal drug by synthesizing or extracting generation is antiseptic, the antiseptic can be jamaicin.When by synthesis or It is flavonoids or flavones by extracting the herbal drug produced, the flavonoids, isoflavones or flavones can be selected from by 4',5,7-trihydroxyflavone, Genistein, 4',5,7-trihydroxyflavone (apigenenin), genistein, genistin, 6 "-O- malonyl wood glycosides, 6 "-O- acetyl dyes The wooden glycosides of material, Daidezin, daidzin, 6 "-O- malonyl daidzins, 6 "-O- acetyl daidzin, Glyciteins, glycitin, 6 " group that-O- malonyl glycitin and 6-O- acetyl glycitin are formed.

When obtained by the product improvement of bulk material medicine improve when, the bulk material medicine product improvement can be but unlimited In selected from the bulk material medicine product improvement by the following group formed：

(a) formation of salt；

(b) it is prepared as uniform crystal structure；

(c) it is prepared as pure isomer；

(d) purity is increased；

(e) prepared with less residual solvent levels；And

(f) prepared with less residual content of beary metal.

Being managed when management obtains improvement after by treatment, after the treatment can be but be not limited to, selected from by following structure Into group method：

(a) emulsion；

(b) dimethyl sulfoxide (DMSO) (DMSO)；

(c) N-METHYLFORMAMIDE (NMF)；

(d) dimethylformamide (DMF)；

(e) ethanol；

(f) phenmethylol；

(g) water for injection containing glucose；

(h) Emulsifier EL-60；

(i) cyclodextrin；And

(j)PEG。

When the use by dicyandiamide solution, which obtains, to be improved, the dicyandiamide solution can be but be not limited to, selected from by following The dicyandiamide solution of the group of composition：

(a) emulsion；

(b) dimethyl sulfoxide (DMSO) (DMSO)；

(c) N-METHYLFORMAMIDE (NMF)；

(d) dimethylformamide (DMF)；

(e) ethanol；

(f) phenmethylol；

(g) water for injection containing glucose；

(h) Emulsifier EL-60；

(i) cyclodextrin；And

(j)PEG。

When obtained by the use of excipient improve when, the excipient can be but be not limited to, selected from being made of following Group excipient：

(a) mannitol；

(b) albumin；

(c) ethylenediamine tetra-acetic acid；

(d) sodium hydrogensulfite；

(e) phenmethylol；

(f) carbonate buffer solution；And

(g) phosphate buffer.

When the use by formulation, which obtains, to be improved, the formulation can be but be not limited to, selected from by the following group formed Formulation：

(a) tablet；

(b) capsule；

(c) external-use gel；

(d) external-application cream；

(e) patch；

(f) suppository；And

(g) dosage filler is freezed.

Preparation of the pharmaceutical composition in tablet, capsule and external-use gel, external-application cream or suppository be it is well known in the art, And it is described in the U.S. Patent Application Publication No. 2004/0023290 of the Griffin being for example incorporated herein by reference et al. In.

Pharmaceutical composition is well known in the art as the preparation of patch such as transdermal patch, and is described in and for example passes through In the United States Patent (USP) No.7,728,042 of the Eros being incorporated herein by reference et al..

Lyophilized dosage filler is also well known in the art.Be used to prepare suitable for two to the water wei ling alcohol and its derivative and The conventional method of the lyophilized dosage filler of diacetyl two to the water wei ling alcohol and its derivative comprises the following steps：

(1) medicine is dissolved in pre- be cooled to below in 10 DEG C of water for injection.Final volume is diluted to cold water for injection, is obtained 40mg/mL solution.

(2) aseptically, original solution is filled into by 0.2- μm of filter and received in container.Preparation and filtering should be 1 Completed in hour.

(3) aseptically, the nominal 1.0mL filtrates in the range of control targe are filled into sterile glass bottle.

(4) after filling, all bottles are placed with the rubber stopper of insertion " lyophilized position ", and are fitted into the freeze dryer of precooling.It is right In freeze dryer, when shelf temperature is set in+5 DEG C and small holding 1；Then by shelf temperature adjust to -5 DEG C and keep 1 it is small when, and The condenser for being arranged to -60 DEG C is started.

(5) and then by bottle when being refrigerated to 30 DEG C or lower, and keeping small no less than 3, when being usually 4 small.

(6) and then start vacuum, shelf temperature is adjusted to -5 DEG C, when drying 8 is small for the first time；Shelf temperature is adjusted to -5 again DEG C, and it is dry at least 5 it is small when.

(7) redrying is started after condenser (being set in -60 DEG C) and vacuum start.In redrying, by shelf temperature Degree control at+5 DEG C 1 to 3 it is small when, when being usually 1.5 small, then control at 25 DEG C 1 to 3 it is small when, when being usually 1.5 small, Finally control at 35-40 DEG C at least 5 it is small when, when being usually 9 small, or until product is completely dried.

(8) vacuum is destroyed with filtered inert gas (such as nitrogen).Bottle in refrigerator is clogged.

(9) bottle is taken out from refrigerator room and is sealed with aluminium flip seal.Visually inspect all bottles and with by criticizing Accurate label is into row label.

When obtained by using dosage kit and packaging improve when, the dosage kit and packaging can not be, but not It is limited to, selected from by for being protected from the amber bottle of light and for improving the plug with special coating of shelf life stability The dosage kit and packaging for the group that son is formed.

When the use by drug delivery system, which obtains, to be improved, the drug delivery system can be, but be not limited to, choosing The freely drug delivery system of the following group formed：

(a) nanocrystal；

(b) can bio-digestion polymer (bioerodible polymers)；

(c) liposome；

(d) release injectable gel；With

(e) microballoon.

Nanocrystal is described in the U.S. Patent number 7,101,576 of the Hovey being incorporated herein by reference et al..

Can the polymer of bio-digestion be described in the U.S. Patent number 7 of Okumu et al., 318,931, it is incorporated by reference into Herein.When can the polymer of bio-digestion be placed in organism when, can the polymer of bio-digestion can decompose, as measured The molecular weight of polymer decline with the time.Polymer molecular weight can be determined by a variety of methods, including size exclusion color Spectrometry (SEC), is typically expressed as average weight or par.If when in the phosphate-buffered that pH7.4 and temperature are 37 DEG C When in brine (PBS), measured by SEC, its weight average molecular weight reduces at least 25% within the time of 6 months, then polymer is Can bio-digestion.It is useful can the polymer of bio-digestion include polyester, such as poly- (caprolactone), poly- (glycolic), poly- (breast Acid) and it is poly- (butyric ester)；Polyanhydride, for example, it is poly- (adipic anhydride) and poly- (maleic anhydride)；Polydioxanone；Polyamines； Polyamide；Polyurethane；Polyesteramide；Polyorthoesters；Polyacetals；Polyketals；Makrolon；Poly- orthocarbonic ester (polyorthocarbonates)；Polyphosphazene；Poly- (malic acid)；Poly- (amino acid)；Polyvinylpyrrolidone；Poly- (ethylene methacrylic Base ether)；Poly- oxalic acid alkylene ester (poly (alkyleneoxalate))；Poly- (alkylene succinates) (poly (alkylenesuccinate))；Poly- hydroxylated cellulose；Chitin；Chitosan；And their copolymer and mixture.

Liposome is well-known drug delivery vehicle.The preparation of liposome is described in what is be incorporated herein by reference The European patent application publication No. EP1332755 of Weng et al..

Release injectable gel is well known in the art, and is described in for example, being incorporated herein by reference " the Drug Release from Biodegradable Injectable Thermosensitive of B.Jeong et al. Hydrogel of PEG-PLGA-PEG Triblock Copolymers,”J.Controlled Release 63:155-163 (2000)。

Microballoon is known in the art in the application of medicine delivery, and is described in what is be for example incorporated herein by reference " the Biodegradable Microspheres in Drug Delivery, " of H.Okada and H.TaguchiCrit Rev.Ther.Rev.Ther.12：1-99(1995).

When obtaining improvement by using drug conjugate form, the drug conjugate form can be, but be not limited to, and be selected from By the following group formed：

(a) polymeric system；

(b) it is polylactic acid-based；

(c) polyglycolide；

(d) amino acid；

(e) peptide；And

(f) multivalence connector.

Polylactic acid-based conjugate is known in the art, and is described in for example, being incorporated herein by reference " the Controlled Synthesis of Camptothecin-Polylactide Conjugates of R.Tong and C.Cheng and Nanoconjugates,”Bioconjugate Chem.21：111-121(2010).

Polyglycolide conjugate is also known in the art, and is described in for example, being incorporated herein by reference The PCT Patent Application publication number WO2003/070823 of Elmaleh et al..

Multivalence connector is known in the art, and is described in for example, Silva being incorporated herein by reference et al. PCT Patent Application number 2007/0207952.For example, multivalence connector can contain the close sulphur with the reaction of reactive cysteine Group, and allow the multiple nucleophilic groups (such as NH or OH) or electrophilic multiple biologically-active moieties being connected on connector Group (such as Acibenzolar).

Suitable agent for being crosslinked many combination of functional groups is known in the art.For example, electrophilic group can be with being permitted Polyfunctional group reacts, including the functional group being present in protein or polypeptide.Various groups of reactive amino acid and electrophilic reagent Conjunction is known in the art and can use.For example, the N-terminal cysteine containing sulfydryl can be with halogen or maleimide Amine reacts.Known thiol group has reactivity, such as alkyl halide, haloacetyl radical derivative, horse with a large amount of coupling agents Come acid imide, aziridine, acryl derivatives, the arylating agent of such as aryl halide.The above is described in logical Cross the G.T.Hermanson that is incorporated herein by reference " Bioconjugate Techniques " (Academic Press, SanDiego,1996),pp.146-150.Cysteine residues can be optimized by proper choice of adjacent amino acid residue Reactivity.For example, the histidine residues adjacent with cysteine residues will increase the reactivity of cysteine residues.Reactivity Other combinations of amino acid and electrophilic reagent are known in the art.For example, maleimide can be with amino such as lysine The epsilon-amino reaction of side chain, particularly in higher pH scopes.Aryl halide can also be reacted with such amino.Halogen acetyl Radical derivative can be anti-with the epsilon-amino of the imidazoyl side chain nitrogen of histidine, the thioether group of methionine side chain and lysine side-chain Should.Known many other electrophilic reagents will be reacted with the epsilon-amino of lysine side-chain, include but not limited to isothiocyanates, isocyanide Acid esters, acyl azide, N-hydroxy-succinamide ester, sulfonic acid chloride, epoxides, ethylene oxide, carbonic ester, imidic acid Ester, carbodiimide and acid anhydrides.These are described in " the Bioconjugate for the G.T.Hermanson being incorporated herein by reference Techniques”(Academic Press,San Diego,1996),pp.137-146.Furthermore it is known that electrophilic reagent will be with carboxylic The carboxylic acid side chain reaction of sour side chain such as aspartic acid and glutamic acid, such as diazoparaffins and diazonium acetyl compound, two miaow of carbonyl Azoles and carbodiimide.The above is described in the " Bioconjugate for the G.T.Hermanson being incorporated herein by reference Techniques”(AcademicPress,SanDiego,1996),pp.152-154.Furthermore it is known that electrophilic reagent will be with hydroxyl Such as the hydroxyl reaction in the side chain of serine and threonine, including reactive haloalkane derivative.The above is described in logical Cross the G.T.Hermanson that is incorporated herein by reference " Bioconjugate Techniques " (Academic Press, SanDiego,1996),pp.154-158.In another alternate embodiment, electrophilic body and nucleophile (that is, with electrophilic precursor reactant Molecule) relative position be reversed so that albumen has with amino acid residue with the electrophilic group of nucleophilic precursor reactant, and And targeted molecular includes nucleophilic group therein.This includes the reaction of aldehyde (electrophilic body) and azanol (nucleophile) described above, But than the reaction more commonly；Other groups can be used as electrophilic body and nucleophile.Suitable group is many institute's weeks in organic chemistry Know, it is not necessary to be described in further detail.

Other combinations for crosslinked reactive group are known in the art.For example, amino can be with isothiocyanic acid Ester, isocyanates, acyl azide, n-hydroxysuccinimide (NHS) ester, sulfonic acid chloride, aldehyde, glyoxal, epoxides, ring Oxidative ethane, carbonic ester, alkyl agent, imino-ester, carbodiimide and anhydride reaction.Thiol group can be by aoxidizing and being formed The disulphide of mixing and haloacetyl halide derivative or alkyl halide derivative, maleimide, aziridine, Acryl derivatives, acylating agent or the reaction of other thiol groups.Carboxyl can be with diazonium paraffin, diazonium acetyl compound, carbonyl Base diimidazole, carbodiimide reaction.Hydroxyl can be with epoxides, ethylene oxide, carbonyl dimidazoles, the succinimide of N, N '-two Base carbonic ester, n-hydroxysuccinimide base chloro-formate, periodate (oxidation), alkyl halide or isocyanates reaction. Aldehyde and ketone groups can react to form schiff bases with hydrazine reagent, and with its in reductive amination process or mannich condensation reaction Its radical reaction.Other reactions also suitable for cross-linking reaction are also known in the art.Such cross-linking reagent and reaction It is described in " Bioconjugate the Techniques " (Academic for the G.T.Hermanson being incorporated herein by reference Press, San Diego, 1996) in.

When obtaining improvement by using compound analog, the compound analog can be, but be not limited to, and be selected from By the following group formed：

(a) side chain is changed to increase or decrease lipophilicity；

(b) other chemical functionality is added to change the group for selecting free reactive, electron affinity and binding ability to be formed Property；And

(c) salt form is changed.

When obtaining improvement by using pro-drug system, the pro-drug system can be, but be not limited to, and be selected from By the pro-drug system of the following group formed：

(a) enzyme sensitivity ester is used；

(b) dimer is used；

(c) schiff bases is used；

(d) pyridoxal compound is used；And

(e) caffeine complex is used.

The use of pro-drug system is described in the T. being incorporated herein by referenceEt al. " Design and Pharmaceutical Applications of Prodrugs”in Drug Discovery Handbook (S.C.Willard,eds.,Academic Press,Amsterdam,2005),ch.17,pp.733-796.This part of publication Describe use of the enzyme sensitivity ester as pro-drug.Dimer is described in as the application of pro-drug is incorporated by reference into this In the U.S. Patent number 7,879,896 of the Allegretti of text et al..Peptides are described in by drawing as the application of pro-drug With " the Delivering Multiple Anticancer Peptides as a of the S.Prasad being incorporated herein et al. Single Prodrug Using Lysyl-Lysine as a Facile Linker,”J.Peptide Sci.13：458- 467(2007).The U.S. that schiff bases is described in the Epstein being incorporated herein by reference et al. as the application of pro-drug is special In profit number 7,619,005.Caffeine is described in the Epstein's being incorporated herein by reference et al. as the application of pro-drug In U.S. Patent number 6,443,898.

When obtaining improvement by using multiple drug system, the multiple drug system can be, but be not limited to, and be selected from By the multiple drug system of the following group formed：

(a) multidrug resistant inhibitor is used；

(b) using specific medicament-resistant inhibitor；

(c) using the special inhibitor of selective enzyme；

(e) signal transduction inhibitor is used；

(e) Repair inhibition is used；And

(f) using the topoisomerase enzyme inhibitor with nonoverlapping side effect.

Multidrug resistant inhibitor is described in the U.S. Patent number 6,011 of the Inomata being incorporated herein by reference et al., In 069.

Specific medicament-resistant inhibitor is described in the " The of the T.Hideshima being incorporated herein by reference et al. Proteasome Inhibitor PS-341 Inhibits Growth,Induces Apoptosis,and Overcomes Drug Resistancein Human Multiple Myeloma Cells,”Cancer Res.61:3071-3076 (2001)。

Repair inhibition is described in " the DNA Repair Inhibition for the N.M.Martin being incorporated herein by reference and Cancer Therapy,”J.Photochem.Photobiol.B63:162-170(2001)。

When strengthening acquisition improvement by using biological therapy, the biological therapy is strengthened by being used as sensitizer or enhancing Agent is applied in combination with therapeutic agent or treatment technology to carry out, and the therapeutic agent or treatment technology can be, but be not limited to, selected from by The therapeutic agent or treatment technology of the group formed below：

(a) cell factor；

(b) lymphokine；

(c) therapeutic antibodies；

(d) antisense therapy；

(e) gene therapy；

(f) ribozyme；

(g) RNA is disturbed；And

(h) vaccine.

Antisense therapy is described in " the Antisense RNA Gene of the B.Weiss being for example incorporated herein by reference et al. Therapy for Studying and Modulating Biological Processes,”Cell.Mol.Life Sci.55：334-358(1999).

Ribozyme is described in the S.Pascolo's that is for example incorporated herein by referenceDrug Discovery HandbookIn " RNA-Based Therapies " (S.C.Gad, editor, Wiley-Interscience, Hoboken, NJ, 2005), ch.27,pp.1273-1278。

RNA interference is described in the S.Pascolo's that is for example incorporated herein by referenceDrug Discovery Handbook In " RNA-Based Therapies " (S.C.Gad, editor, Wiley-Interscience, Hoboken, NJ, 2005), ch.27,pp.1273-1283。

As described above, it is generally the case that immune response of the cancer vaccine based on albumen or based on not sent out in normal cell The immune response of the raw albumen present in cancer cell.Cancer vaccine is included for metastatic hormone-refractory prostate cancer Vaccine for prostate cancer Provenge, for the kidney vaccine Oncophage of kidney, for the CimaVax-EGF of lung cancer, MOBILAN, for such as breast cancer, colon cancer, the Neuvenge of the cancer of the expression of the Her2/neu of carcinoma of urinary bladder and oophoroma, is used Stimuvax and other cancer vaccines in breast cancer.Cancer vaccine is described in above-mentioned S.Pejawar-Gaddy and O.Finn, (2008), as above.

When being applied in combination by using biological therapy reinforcing as sensitizer or reinforcing agent with therapeutic antibodies, institute Stating therapeutic agent or treatment technology can be, but be not limited to, selected from by bevacizumab (Arastin Avastin), Rituximab (Rituxan), group that Herceptin (Trastuzumab Herceptin) and Cetuximab (Erbitux Erbitux) are formed is controlled The property treated antibody.

Improved when by using the modulation of biological therapy resistance, the biological therapy resistance, which is modulated, to be, but unlimited In for being used selected from the resistant NSCLC of the therapeutic agent or treatment technology by the following group formed：

(a) biological response modifiers；

(b) cell factor；

(c) lymphokine；

(d) therapeutic antibodies；

(e) antisense therapy；

(f) gene therapy；

(g) ribozyme；

(h) RNA is disturbed；And

(i) vaccine.

When for being modulated to the resistant tumour of therapeutic antibodies using biological therapy resistance, the therapeutic antibodies energy Enough it is, but is not limited to, selected from by bevacizumab (Arastin Avastin), Rituximab (Rituxan), Herceptin The therapeutic antibodies for the group that (Trastuzumab Herceptin) and Cetuximab (Erbitux Erbitux) are formed.

When strengthened by radiotherapy obtain improve when, the radiotherapy, which is strengthened, to be, but is not limited to, selected from by with The radiotherapy hardening agent or radiotherapy reinforcement technique of the group of lower composition：

(a) anoxic cell sensitizer；

(b) radiosensitizer or protective agent；

(c) photosensitizer；

(d) repair inhibitors are radiated；

(e) sulfydryl depletor；

(f) blood-vessels target medicine；

(g) DNA repair inhibitors；

(h) radioactive seed；

(i) radionuclide；

(j) radioactively labelled substance antibody；And

(k) brachytherapy.

As described above, the substituted hexose 01 derivatives of such as two to the water wei ling alcohol can be used in combination with radiation to treat NSCLC or to treat oophoroma.

Anoxic cell sensitizer is described in " the The Effect of of the C.C.Ling being incorporated herein by reference et al. Hypoxic Cell Sensitizers at Different Irradiation Dose Rates,”Radiation Res.109：396-406(1987).Radiosensitizer is described in the T.S.Lawrence's that is incorporated herein by reference “Radiation Sensitizers and Targeted Therapies,”Oncology 17(Suppl.13)23-28 (2003).Radioprotector is described in " the Evaluation of D- of the S.B.Vuyyuri being incorporated herein by reference et al. Methionine as a Novel Oral Radiation Protector for Prevention of Mucositis,”Clin.Clin.Cancer Res.14：2161-2170(2008).Photosensitizer is described in what is be incorporated herein by reference " the Oncologic Photodynamic Therapy Photosensitizers of R.R.Allison and C.H.Sibata:A Clinical Review,”Photodiagnosis Photodynamic Ther.7：61-75(2010).Radiate Repair inhibition Agent and DNA repair inhibitors are described in " the Evaluation of of the M.Hingorani being incorporated herein by reference et al. Repair of Radiation-Induced DNA Damage Enhances Expression from Replication- Defective Adenoviral Vectors,”Cancer Res.68：9771-9778(2008).Sulfydryl depletor is described in " the Postirradiation Sensitization of Mammalian of the K.D.Held being incorporated herein by reference et al. Cells by the Thiol-Depleting Agent Dimethyl Fumarate,”Radiation Res.127：75-80 (1991).Blood-vessels target medicine is described in " the Tumor Necrosis Factor α Mediates of A.L.Seynhaeve et al. Homogeneous Distribution of Liposomes in Murine Melanoma that Contributes to a Better Tumor Response,”Cancer Res.67：9455-9462(2007).As described above, using radiotherapy To treat NSCLC, it is of great significance so radiotherapy is strengthened for such malignant tumour.

When by using novel mechanism obtain improve when, the novel mechanism can be, but be not limited to, with selected from by The novel mechanism of the therapeutic effect of target or the mechanism interaction of the group formed below：

(a) poly- ADP ribose polymerases inhibitor；

(b) vascular system or vasodilative reagent are influenced；

(c) cancer target agent；

(d) signal transduction inhibitor；

(e) EGFR suppresses；

(f) protein kinase C suppresses；

(g) phospholipase C is lowered；

(h) Jun is lowered；

(i) histone gene；

(j)VEGF；

(k) ornithine decarboxylase；

(l) ubiquitin C；

(m)JunD；

(n)v-Jun；

(o)GPCR；

(p) protein kinase A；

(q) protein kinase beyond protein kinase A；

(r) prostate specific gene；

(s) Telomerase；

(t) histone deacetylase enzyme；And

(u) tyrosine kinase inhibitor.

EGFR suppresses to be described in " the EGFR of the G.Giaccone being incorporated herein by reference and J.A.Rodriguez Inhibitors:What Have We Learned from the Treatment of Lung Cancer,”Nat.Clin.Pract.Oncol.11：554-561(2005).Protein kinase C suppresses to be described in what is be incorporated herein by reference " the Protein Kinase C Inhibitors, " of H.C.Swannie and S.B.KayeCurr.Oncol.Rep.4：37-46 (2002).Phospholipase C lowers the " Phosphoinositide of the A.M.Martelli for being described in and being incorporated herein by reference et al. Signaling in Nuclei of Friend Cells:Phospholipase CβDownregulation Is Related to Cell Differentiation,”Cancer Res.54：2536-2540(1994).Jun lowers (particularly c-Jun) and retouches It is set forth in " the Downregulation of c-Jun Expression and of the A.A.P.Zada being incorporated herein by reference et al. Cell Cycle Regulatory Molecules in Acute Myeloid Leukemia Cells Upon CD44Ligation,”Oncogene22:2296-2308(2003).Work of the histone gene as the target of therapeutic intervention With " the Altered Expression of G1-Specific Genes in Human for being described in B.Calabretta et al. Malignant Myeloid Cells,”Proc.Natl.Acad.Sci.Sci.1495-1498(1986).VEGF is as treatment The effect of the target of property intervention is described in the " VEGF-Mediated of the A.Zielke being incorporated herein by reference et al. Angiogenesis of Human Pheochromocytomas Is Associated to Malignancy and Inhibited by anti-VEGF Antibodies in Experimental Tumors,”Surgery 132:1056- 1063(2002).Ornithine decarboxylase is described in what is be incorporated herein by reference as the effect of the target of therapeutic intervention " the Targeting Ornithine Decarboxylase in Myc-Induced of J.A.Nilsson et al. Lymphomagenesis Prevents Tumor Formation,”Cancer Cell7:433-444(2005).Ubiquitin C makees " the A Phase I of the C.Aghajanian being incorporated herein by reference et al. are described in for the effect of the target of therapeutic intervention Trial of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies,”Clin.Cancer Res.8：2505-2511(2002).Works of the JunD as the target of therapeutic intervention " the JunD Is Involved in the of the M.M.Caffarel being incorporated herein by reference with being described in et al. Antiproliferative Effect ofΔ⁹-Tetrahydrocannibinol on Human Breast Cancer Cells,”Oncogene27:5033-5044(2008).V-Jun is described in as the effect of the target of therapeutic intervention to be passed through " the Differential and Antagonistic Effects of v-Jun and of the M.Gao being incorporated herein by reference et al. c-Jun,”Cancer Res.56：4229-4235(1996).Protein kinase A is described as the effect of the target of therapeutic intervention In " the Elevation of Protein Kinase A and of the P.C.Gordge being incorporated herein by reference et al. Protein Kinase C in Malignant as Compared With Normal Breast Tissue,”Eur.J.Cancer12:2120-2126(1996).Telomerase is described in by drawing as the effect of the target of therapeutic intervention With " the Telomerase as a Novel and Potentially of the E.K.Parkinson being incorporated herein et al. Selective Target for Cancer Chemotherapy,”Ann.Med.35：466-475(2003).Histone goes second Acyl enzyme is described in the A.Melnick's being incorporated herein by reference and J.D.Licht as the effect of the target of therapeutic intervention “Histone Deacetylases as Therapeutic Targets in Hematologic Malignancies,”Curr.Opin.Hematol.9：322-332 (2002), is incorporated herein by reference.

When obtaining improvement by using selective target cell group's therapy, the application of selective target cell group therapeutic agent can For, but be not limited to, selected from the application by the following group formed：

(a) it is directed to the application of radiation sensitive cell；

(b) it is directed to the application of Radiation tolerance cell；And

(c) it is directed to the application of energy exhaustion cell.

Also can be combined by using substituted hexose 01 derivatives with above-mentioned ionizing radiation to carry out the improvement.

When by using resistance bone marrow suppression reagent be improved when, it is described resistance bone marrow suppression reagent can be, But it is not limited to, dithiocar-bamate or ester.

The U.S. Patent number 5,035,878 of the Borch being incorporated herein by reference et al. is disclosed for treating marrow suppression The dithiocarbamates or esters of system；The dithiocarbamates or esters are formula R¹R²NCS (S) M or R¹R²NCSS-SC(S)N R³R⁴Compound, wherein R¹, R², R³And R⁴It is identical or different, R¹, R², R³And R⁴Be it is unsubstituted or by Aliphatic, the alicyclic or heterocycloaliphatic groups of hydroxyl substitution；Or wherein R¹And R²One of and R³And R⁴In one can be Hydrogen；Or wherein R¹、R²、R³And R⁴It can be substituted with together with nitrogen-atoms as 5 yuan or 6 yuan of N- heterocycles, one pair of which R group, institute It is aliphatic series or the aliphatic series interrupted by epoxy or the second ring nitrogen to state N- heterocycles, and M is hydrogen or with the pharmaceutically acceptable of equal charge number Cation, in this case, the remainder of the molecule is negatively charged.

The U.S. Patent number 5,294,430 of the Borch being incorporated herein by reference et al., which discloses, other to be used to treat The dithiocarbamates or esters of bone marrow suppression.In general, these are the compounds of formula (D-I)：

Wherein：

(i)R¹And R²It is identical or different C₁-C₆Alkyl, C₃-C₆Cycloalkyl or C₅-C₆Heterocyclylalkyl；Or

(ii)R¹And R²One of be H, but cannot be H at the same time；Or

(iii)R¹And R²With that can be 5 yuan or 6 yuan of N- heterocycles together with nitrogen-atoms, the N- heterocycles be aliphatic series or by epoxy or the The aliphatic series that two ring nitrogen interrupt；And

(iv) M is hydrogen or the pharmaceutically acceptable cation with equal charge number, in this case, the remainder of molecule It is negatively charged；Or

(v) M is the part of formula (D-II)：

Wherein R³And R⁴With with R₁And R²Identical mode limits.When the group defined by formula (D-I) is anion, cation It can be ammonium cation, or unit price or divalent metal such as alkali or alkaline earth metal can be derived from, such as Na⁺、K⁺Or Zn^{2 +}.In the case of aminodithioformic acid, the group limited by formula (D-I) is connected with ionizable hydrogen atom；In general, hydrogen is former Son will dissociate under greater than about 5.0 pH.What can be used in dithiocarbamates or esters has：Dithiocarbamates What can be used in formiate or esters has：N- methyl, N- diethyldithiocar bamic acids salt or ester, two sulphur of hexa-methylene For carbamic acid, two (beta-hydroxyethyl) nabams, various dipropyl, dibutyl and diamyl disulfide for amino first Hydrochlorate or ester, N- methyl, N- cyclobutylmethyls nabam, N- pi-allyl-N- Cvclopropvlmethvl dithiocarbamates Sodium formate, Cyclohexylamino dithiocar-bamate or ester, dibenzyl aminodithioformic acid salt or ester, two sulphur of dimethylene For carbamic acid sodium, various pentamethylene dithiocar-bamates, two sodium sulphate of pyrrolidines-N- carbon, two sulfuric acid of piperidines-N- carbon Sodium, two sodium sulphate of morpholine-N- carbon, α-difurfuryl disulbide are for carbaminate or ester and imidazoline dithiocar-bamate or ester. Another alternative solution is the R of wherein formula (D-I)¹It is the chemical combination of the low alkyl group of the hydroxyl substitution with most 6 carbon atoms Thing, or preferably, for the compound of the low alkyl group of (double to five alkyl) polyhydroxy substitution with most 6 carbon atoms.Example Such as, R¹Can be HO-CH₂-CHOH-CHOH-CHOH-CHOH-CH₂-.In these compounds, R²Can be H or low alkyl group (unsubstituted or substituted by one or more hydroxyls).Work as R²When being H, methyl or ethyl, space problem (stericproblem) It can minimize.Therefore, such particularly preferred compound is N-METHYL-ALPHA-L-GLUCOSAMINE dithiocar-bamate, these Most preferred cation is sodium or potassium in salt.Other preferable dithiocar-bamates or ester include alkali or alkaline earth metal Salt, wherein anion are second, n-butyl dithiocarbamate root, diη-propyl aminodithioformic acid root, two sulphur of pentamethylene For carbamic acid root or tetramethylene aminodithioformic acid root.

When by being used together with increasing the substituted hexitol by the reagent of blood-brain barrier ability to treat NSCLC Or the brain metastes of oophoroma to obtain improvement when, reagent energy that the increase substituted hexitol passes through blood-brain barrier ability Enough it is, but is not limited to, selected from the reagent by the following group formed：

(a) structural formula is the chimeric peptide of (D-III)：

Wherein：(A) A be Somat, it is thyrotropin-releasing hormone (TRH) (TRH), vasopressing, alpha interferon, interior Deltorphin delta, muramyl dipeptide or ACTH4-9 analogs；And (B) B is insulin, IGF-I, IGF-II, transferrins, cation Change (alkalescence) albumin or prolactin；Or the chimeric peptide that structural formula is (D-III), two sulphur conjugated bridge quilts between wherein A and B The bridge of formula (D-III (a)) substitutes：

A-NH(CH₂)₃S-S-B (cleavable key) (D-III (a))

Wherein described bridge is to be used as bridge reagent by cysteamine and EDAC to be formed；Or the chimeric peptide that structural formula is (D-III), Two sulphur conjugated bridges between wherein A and B are substituted by the bridge of minor (D-III (b))：

A-NH=CH (CH₂)₃CH=NH-B (non-cleavable key) (D-III)

Wherein described bridge is to be used as bridge reagent by glutaraldehyde to be formed；

(b) Avidin that is combined with biotinylated substituted hexose 01 derivatives or affine plain fusion protein are included to form parent With the composition of element-biotin-reagent complex, the affine plain fusion protein including selected from by insulin, turn iron egg In vain, the albumen for the group that anti-acceptor monoclonal antibody, cationized proteins and agglutinin are formed；

(c) neutral liposome, it is by Pegylation and including entering the substituted hexose 01 derivatives, wherein the poly- second two Alcohol chain can transport peptide with least one or targeting agent is conjugated；

(d) humanized murine's body of actrapid monotard's acceptor, the company that actrapid monotard's acceptor passes through Avidin-Biotin are incorporated into Connect and be connected with the substituted hexose 01 derivatives；And

(e) fusion protein of the first section and the second section is included：First section includes the antigen on identification cell surface Antibody variable region, the antigen after being combined with the variable region of the antibody through go through antagonist-receptor mediation endocytosis, And first section alternatively further comprises the domain of the constant region of at least one antibody；And secondth area Section includes being selected from affine by Avidin derivative, Streptavidin, the strepto- of Avidin, Avidin mutain, chemical modification The protein domain for the group that plain mutain and the Streptavidin derivative of chemical modification are formed, wherein fusion protein pass through Covalent attachment with biotin is connected with the substituted hexitol.

Improve " the That the reagent that blood-brain barrier penetrates is disclosed in the W.M.Pardridge being incorporated herein by reference Blood-Brain Barrier:Bottleneck in Brain Drug Development,”NeuroRx 2:3-14 (2005)。

These a kind of reagents are disclosed in the U.S. Patent number 4 for the Pardridge being incorporated herein by reference, and 801,575, its Disclose the chimeric peptide for the reagent delivering across blood-brain barrier.These chimeric peptides include the peptide that formula is formula (D-IV)：

Wherein：

(i) A be Somat, thyrotropin-releasing hormone (TRH) (TRH), vasopressing, alpha interferon, endorphin, Muramyl dipeptide or ACTH4-9 analogs；And

(ii) B is insulin, IGF-I, IGF-II, transferrins, cationization (alkalescence) albumin or prolactin.At another In alternative solution, the disulfide bond conjugation between A and B is replaced with the bridge of minor (D-IV (a))：

A-NH(CH₂)₂S-S-B (cleavable key) (D-IV (a))；

When cysteamine and EDAC are used as bridge reagent, minor (D-III (a)) bridge is formed.In a further alternative, A and B it Between disulfide bond conjugation replaced with the bridge of minor (D-IV (b))：

A-NH=CH (CH₂)₃CH=NH-B (non-cleavable key) (D-IV (b))；

When glutaraldehyde is used as bridge reagent, minor (D-III (b)) bridge is formed.

The U.S. Patent number 6,287,792 of the Pardridge being incorporated herein by reference et al. is disclosed across blood-brain barrier Reagent delivering method and composition, the method and composition include the affinity prime combined with biotinylation reagent or Affine plain fusion protein, to form Avidin-Biotin-reagent complex.Affine plain fusion protein can include such as insulin Or amino acid sequence, anti-acceptor monoclonal antibody, cationized proteins or the agglutinin of the protein of transferrins.

The U.S. Patent number 6,372,250 of the Pardridge being incorporated herein by reference et al., which discloses, is used for across blood brain The method and composition of barrier delivery of agents, the method and composition use liposome.Liposome is neutral liposome.It is neutral The surface of liposome is by Pegylation.Polyglycol chain is conjugated with that can transport peptide or other targeting agents.Suitable targeting agent bag Include insulin, transferrins, insulin-like growth factor or leptin.Alternatively, the surface of liposome can be different from two kinds Peptide can be transported to be conjugated, the peptide of one kind targeting endogenous BBB (blood-brain barrier) acceptor, another kind targeting endogenous BCM (brain cell matter Film) peptide.The latter is probably the specific cells specific to intracerebral, such as neuron, Deiter's cells, perithelial cells, smooth muscle Cell or microglia cell.Targeting peptides can be the endogenous peptide ligand of acceptor, the analog of endogenic ligand or combination The peptidomimetic MAb (monoclonal antibody) of the same receptor of endogenous ligands.TfR specificity peptidomimetic monoclonal antibody can use Work can transport peptide.The monoclonal antibody of actrapid monotard's acceptor can be used as that peptide can be transported.For blood barrier targeting agent to be conjugated to The conjugated agent of surface of liposome can be any known polymeric conjugation agent, such as sphingomyelins, polyethylene glycol (PEG) or other Organic polymer, preferably PEG.Liposome preferably has less than 200 nanometers of diameter.A diameter of 50 to 150 nanometers of liposome It is preferable.Liposome or other nano containers particularly preferably with about 80 nanometers of outside diameter.The lipid of suitable type Body is to use such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), two phosphatidyl phosphocholines, distearyl Made of the neutral phospholipid or cholesterol of base phosphatidyl-ethanolamine (DSPE).Peptide can be transported and be connected to liposome as follows：It can transport Defeated peptide such as insulin or HIRMAb be Thiolation and end with a small amount of PEG chains on dimaleoyl imino be conjugated；Or peptide can be transported As the surface carboxyl groups on transferrins or TfRMAb pass through carboxyl activator group such as N- methyl-N ' -3 (dimethylaminopropyl) Carbodiimide hydrochloride (EDAC) and hydrazides (Hz) moiety conjugation in PEG chain ends；Peptide thiol can be transported and by two Sulfide linkage connector is conjugated with the liposome with N- succinimides 3- (2- pyridines two are thio) propionic esters (SPDP) reaction；Or The surface that peptide is conjugated to liposome by Avidin-Biotin technology can be transported, such as it is single biotinylated that can transport peptide, and And combined with Avidin or Streptavidin (SA), the Avidin or Streptavidin are connected to the surface of PEG chains.

The U.S. Patent number 7,388,079 of the Pardridge being incorporated herein by reference et al. is disclosed with reference to people's pancreas islet The application of humanized murine's body of plain acceptor；Humanized murine's body can by Avidin-Biotin connection with it is to be delivered Reagent connects.

The U.S. Patent number 8,124,095 of the Pardridge being incorporated herein by reference et al. discloses can be with reference to interior Therefore the receptor-mediated transportation system of source property blood-brain barrier simultaneously can act as the monoclonal for being used for across BBB transport therapeutic agent for carrier Antibody.Monoclonal antibody can be that the antibody of actrapid monotard's acceptor is specifically bound for example on people BBB.

The U.S. Patent Application Publication No. 2005/0085419 of the Morrison being incorporated herein by reference et al. discloses For plurality of reagents to be delivered to the fusion protein of cell, the fusion protein bag via the endocytosis that antagonist-receptor mediates Include the first section and the second section：First section includes the variable region of the antibody of the antigen on identification cell surface, described The endocytosis that antigen mediates after being combined with the variable region of the antibody through going through antagonist-receptor, and first section can Selection of land further comprises the domain of the constant region of at least one antibody；And second section includes being selected from by affine Element, Avidin mutain, the Avidin derivative of chemical modification, Streptavidin, Streptavidin mutain and chemistry The protein domain for the group that the Streptavidin derivative of modification is formed.In general, antigen is albumen.In general, on cell surface Proteantigen be acceptor, such as TfR or insulin receptor.Present invention additionally comprises the antibody including fusion protein Construct, the antibody construct are to form the heavy chain of complete antibody molecule or light chain together with complementary light chain or heavy chain. Therapeutic agent can be non-proteinaceous molecule, and can be covalently attached with biotin.

Another aspect of the present invention is to be spread out for improving using the substituted hexitol for being used to treat NSCLC or oophoroma The effect of undesirable dispenser therapy of biology and/or reduce the composition of its side effect, the composition include being selected from by with The substitute of the group of lower composition：

(i) the modified substituted hexose 01 derivatives of therapeutically effective amount or substitution hexose 01 derivatives derivative or Analog or pro-drug or the modified substituted derivative of hexose 01 derivatives or the like or pro-drug, wherein Compared with unmodified substituted hexose 01 derivatives, the modified substituted hexose 01 derivatives or the substitution The derivative of hexose 01 derivatives or the like or pro-drug or the modified substituted hexose 01 derivatives The derivative or the like or pro-drug, the treatment NSCLC of therapeutic efficiency or reduction with increased treatment NSCLC Side effect；

(ii) composition, the composition include：

(a) the hexose 01 derivatives of therapeutically effective amount substitution or modified substituted hexose 01 derivatives or the hexose of substitution The derivative or similar of derivative of 01 derivatives or the like or pro-drug or modified substituted hexose 01 derivatives Thing or pro-drug；And

(b) at least one other therapeutic agent, by chemotherapeutic therapeutic agent, therapeutic agent, diluent, figuration by Chemical enhancement Agent, solvent system, drug delivery system, the medicament for resisting bone marrow suppression or increase substitution hexitol pass through blood-brain barrier The medicament of ability, wherein compared with unmodified substituted hexose 01 derivatives, the composition has increased treatment The treatment NSCLC of the therapeutic efficiency or reduction of NSCLC or oophoroma or the side effect of oophoroma；

(iii) therapeutically effective amount include the substituted hexose 01 derivatives into formulation, modified substituted hexitol derives Thing or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted hexitol derive Derivative of thing or the like or pro-drug, wherein compared with unmodified substituted hexose 01 derivatives, it is described to include The substituted hexose 01 derivatives, modified substituted hexose 01 derivatives or the substituted hexitol for entering formulation derive The derivative of described derivative of thing or the like or pro-drug or the modified substituted hexose 01 derivatives Or the like or pro-drug, there is increased treatment NSCLC or the therapeutic efficiency of oophoroma or the treatment NSCLC or ovum of reduction The side effect of nest cancer；

(iv) the substituted hexose 01 derivatives, modified substituted included into dosage kit and packaging of therapeutically effective amount Hexose 01 derivatives or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted Derivative of hexose 01 derivatives or the like or pro-drug, wherein with unmodified substituted hexose 01 derivatives phase Than, it is described include into dosage kit and packaging substituted hexose 01 derivatives, modified substituted hexose 01 derivatives, Or described substituted described derivative of hexose 01 derivatives or the like or pro-drug or modified substituted oneself Described derivative of sugar alcohol derivant or the like or pro-drug, have increased treatment NSCLC or the treatment work(of oophoroma Effect or the treatment NSCLC of reduction or the side effect of oophoroma；And

(v) the substituted hexose 01 derivatives, modified substituted for being subject to bulk material medicine product improvement of therapeutically effective amount Hexose 01 derivatives or the derivative of hexose 01 derivatives of substitution or the like or pro-drug or modified substituted Derivative of hexose 01 derivatives or the like or pro-drug, wherein with unmodified substituted hexose 01 derivatives phase Than, be subject to bulk material medicine product improvement substituted hexose 01 derivatives or modified substituted hexose 01 derivatives or Substituted derivative of hexose 01 derivatives or the like or pro-drug or modified substituted hexose 01 derivatives spread out Biology or the like or pro-drug, have increased treatment NSCLC or the therapeutic efficiency of oophoroma or the treatment NSCLC of reduction Or the side effect of oophoroma.

As described above, in general, the unmodified substituted hexose 01 derivatives be selected from gone by two to the water wei ling alcohol, two Water winged euonymus 01 derivatives, diacetyl two to the water wei ling alcohol, diacetyl two to the water wei ling alcohol derivative, mitolactol and two The group that bromine winged euonymus 01 derivatives are formed.Preferably, the unmodified substituted hexose 01 derivatives are two to the water wei ling alcohol.

In an alternative solution, composition according to the present invention has to NSCLC and the increased treatment work(of oophoroma Effect or the treatment side effect of reduction.In a further alternative, composition according to the present invention has control increased to NSCLC Treat the side effect of effect or reduction.In a further alternative, composition according to the present invention has increased to oophoroma Therapeutic efficiency or the side effect of reduction.

In an alternative solution, the composition includes including following drug regimen：

(i) the hexose 01 derivatives of substitution；And

(ii) other therapeutic agent is selected from by the following group formed：

(a) topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides；

(c) fraudulent nucleotide；

(d) thymidylate synthetase inhibitor；

(e) signal transduction inhibitor；

(f) cis-platinum, oxaliplatin or other platinum analogs；

(g) monofunctional alkyl agent；

(h) and bifunctional alkylating agent；

(i) alkylating agent of DNA is destroyed, the alkylating agent destroys DNA compared to two to the water wei ling alcohol in diverse location；

(j) antitublin；

(k) antimetabolite；

(l) jamaicin；

(m) 4',5,7-trihydroxyflavone；

(n) Amonafide；

(o) colchicine or the like；

(p) genistein；

(q) Etoposide；

(r) cytarabine；

(s) camptothecine；

(t) vinca alkaloids；

(u) 5 FU 5 fluorouracil；

(v) curcumin

(w) NF- kB inhibitors；

(x) Rosmarinic acid；

(y) mitoguazone；

(z) hanfangchin A；

(aa) Temozolomide；

(ab) VEGF inhibitor；

(ac) cancer vaccine；

(ad) EGFR inhibitor；

(ae) tyrosine kinase inhibitor；

(af) with poly- (ADP- ribose) polymerase (PARP) inhibitor；And

(ag) ALK inhibitor.

These above-mentioned extra medicines can together be used for the combination for including drug regimen with substituted hexose 01 derivatives To treat NSCLC or oophoroma in thing.Other medicament to be included is that known have anti-treated cancer types (NSCLC Or oophoroma) activity compound, its in structure with the known compound with anticancer type activity or one kind compound It is related, or its known adjustable path, the adjusting has been demonstrated effective to the cancer types treated.As used herein, art Language " adjusting " can include the activation or suppression of involved path, but typically refer to suppress path.

When composition according to the present invention is used to treat oophoroma, being included in the drug regimen in composition can include The other medicament of the hexose 01 derivatives substituted as described above and the antitumor activity with anti ovary tumour.Such medicine Agent includes but is not limited to：Taxol, Docetaxel (docetaxel), cis-platinum, carboplatin, topotecan, gemcitabine, wins Bleomycin, Etoposide, adriamycin (can be with Pegylated Liposomal form use), tamoxifen, Letrozole, Aura pa Buddhist nun, U.S. of department replace Buddhist nun, mTOR inhibitors, PI3 kinase inhibitors and Trichostatin A.

The other medicament of antitumor activity with anti-NSCLC is well known in the art.Include according to the present invention These other medicaments of the composition of drug regimen including therapeutically effective amount and therapeutically effective amount substitute as described above Hexose 01 derivatives.One kind or more than one in these extra medicaments can be included in drug regimen in composition.This A little other medicaments can be with the active of the one or more anti-NSCLC as described above in drug regimen including such as The medicament of the substituted hexose 01 derivatives of two to the water wei ling alcohol or diacetyl two to the water wei ling alcohol is included in composition together In.These medicaments are jointly referred to herein as " the other secondary medicament with anti-NSCLC activity ".

The other medicament of antitumor activity with ovarian cancer resistance is well known in the art.Include according to the present invention These other medicaments of the composition of drug regimen including therapeutically effective amount and therapeutically effective amount substitute as described above Hexose 01 derivatives.One kind or more than one in these extra medicaments can be included in drug regimen in composition.This A little other medicaments can with drug regimen one or more ovarian cancer resistances as described above it is active, such as two remove water The medicament of dulcitol or the substituted hexose 01 derivatives of diacetyl two to the water wei ling alcohol is included in composition together.These Medicament is jointly referred to herein as " the other secondary medicament with ovarian cancer resistance activity ".

In the scheme that another kind substitutes, the composition includes：

(i) the hexose 01 derivatives of substitution；And

(ii) selected from the group consisted of through chemotherapeutic therapeutic agent：

(a) topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides；

(c) fraudulent nucleotide；

(d) thymidylate synthetase inhibitor；

(e) signal transduction inhibitor；

(f) cis-platinum, oxaliplatin or other platinum analogs；

(g) alkylating agent；

(h) antitublin；

(i) antimetabolite；

(j) jamaicin；

(k) 4',5,7-trihydroxyflavone；

(l) Amonafide；

(m) colchicine or the like；

(n) genistein；

(o) Etoposide；

(p) cytarabine；

(q) camptothecine；

(r) vinca alkaloids；

(s) topoisomerase enzyme inhibitor；

(t) 5 FU 5 fluorouracil；

(u) curcumin；

(v) NF- kB inhibitors；

(w) Rosmarinic acid；

(x) mitoguazone；

(y) hanfangchin A；

(z) tyrosine kinase inhibitor；

(aa) EGFR inhibitor；And

(ab) poly- (ADP- ribose) polymerase (PARP) inhibitor；The hexose 01 derivatives wherein substituted are used as chemical sensitizer.

In the scheme that another kind substitutes, the composition includes：

(i) the hexose 01 derivatives of substitution；And

(ii) therapeutic agent through Chemical enhancement selected from the group consisted of：

(a) topoisomerase enzyme inhibitor；

(b) fraudulent nucleosides；

(c) fraudulent nucleotide；

(d) thymidylate synthetase inhibitor；

(e) signal transduction inhibitor；

(f) cis-platinum, oxaliplatin or other platinum analogs；

(g) alkylating agent；

(h) antitublin；

(i) antimetabolite；

(j) jamaicin；

(k) 4',5,7-trihydroxyflavone；

(l) Amonafide；

(m) colchicine or the like；

(n) genistein；

(o) Etoposide；

(p) cytarabine；

(q) camptothecine；

(r) vinca alkaloids；

(s) 5 FU 5 fluorouracil；

(t) curcumin；

(u) NF- kB inhibitors；

(v) Rosmarinic acid；

(w) mitoguazone；

(x) hanfangchin A；

(y) tyrosine kinase inhibitor；

(z) EGFR inhibitor；And

(aa) PARP inhibitor；

The hexose 01 derivatives wherein substituted are used as chemical intensifier.

In another alternative solution, substituted hexose 01 derivatives pass through bulk material medicine improved product, wherein described dissipate The selection of bulk pharmaceutical chemicals improved product is filled by the following group formed：

(a) formation of salt；

(b) it is prepared as uniform crystal structure；

(c) it is prepared as pure isomer；

(d) purity is increased；

(e) prepared with less residual solvent levels；And

(f) prepared with less residual content of beary metal.

In an also alternative solution, the composition includes the hexose 01 derivatives and diluent of substitution, described dilute Agent is released to be selected from by the following group formed：

(a) emulsion；

(b) dimethyl sulfoxide (DMSO) (DMSO)；

(c) N-METHYLFORMAMIDE (NMF)；

(d) dimethylformamide (DMF)；

(e) ethanol；

(f) phenmethylol；

(g) water for injection containing glucose；

(h) Emulsifier EL-60；

(i) cyclodextrin；And

(j)PEG。

In an also alternative solution, the composition includes the hexose 01 derivatives and solvent system of substitution, described Solvent system is selected from by the following group formed：

(a) emulsion；

(b) dimethyl sulfoxide (DMSO) (DMSO)；

(c) N-METHYLFORMAMIDE (NMF)；

(d) dimethylformamide (DMF)；

(e) ethanol；

(f) phenmethylol；

(g) water for injection containing glucose；

(h) Emulsifier EL-60；

(i) cyclodextrin；And

(j)PEG。

In an also alternative solution, the composition includes the hexose 01 derivatives and excipient of substitution, the tax Shape agent is selected from by the following group formed：

(a) mannitol；

(b) albumin；

(c) ethylenediamine tetra-acetic acid；

(d) sodium hydrogensulfite；

(e) phenmethylol；

(f) carbonate buffer solution；And

(g) phosphate buffer.

In an also alternative solution, the substituted hexose 01 derivatives are incorporated into selected from by the following group formed Formulation：

(a) tablet；

(b) capsule；

(c) external-use gel；

(d) external-application cream；

(e) patch；

(f) suppository；And

(g) dosage filler is freezed.

In an also alternative solution, the substituted hexose 01 derivatives are merged in selected from by for being protected from light Amber bottle and for improve the dosage kit for the group that the plug with special coating of shelf life stability is formed and Packaging.

In an also alternative solution, the composition includes the hexose 01 derivatives and drug delivery system of substitution, Wherein described drug delivery system is selected from by the following group formed：

(a) nanocrystal；

(b) can bio-digestion polymer (bioerodible polymers)；

(c) liposome；

(d) release injectable gel；With

(e) microballoon.

In an also alternative solution, the substituted hexose 01 derivatives are present in selected from by the following group formed Composition in drug conjugate form：

(a) polymeric system；

(b) it is polylactic acid-based；

(c) polyglycolide；

(d) amino acid；

(e) peptide；And

(f) multivalence connector.

In an also alternative solution, wherein the therapeutic agent is modified substituted hexose 01 derivatives, it is described Modification is selected from by the following group formed：

(a) side chain is changed to increase or decrease lipophilicity；

(b) other chemical functionality is added to change the group for selecting free reactive, electron affinity and binding ability to be formed Property；And

(c) salt form is changed.

In an also alternative solution, the substituted hexose 01 derivatives are the forms of pro-drug system, wherein The pro-drug system is selected from by the following group formed：

(a) enzyme sensitivity ester is used；

(b) dimer is used；

(c) schiff bases is used；

(d) pyridoxal compound is used；And

(e) caffeine complex is used.

In an also alternative solution, the composition includes hexose 01 derivatives and at least one other therapeutic agent To form multiple medicine body system, the other therapeutic agent of wherein at least one is selected from by the following group formed：

(a) multidrug resistant inhibitor；

(b) specific medicament-resistant inhibitor；

(c) selective enzyme special inhibitor；

(d) signal transduction inhibitor；

(e) enzyme inhibitor is repaired；And

(f) topoisomerase enzyme inhibitor of nonoverlapping side effect is carried.

In a further alternative, the composition includes the hexose 01 derivatives of substitution and resistance bone as described above The reagent that marrow suppresses.Usually, the reagent of the resistance bone marrow suppression is dithiocar-bamate or ester.

In a further alternative, the composition includes the hexose 01 derivatives of substitution and increase institute as described above State reagent of the substituted hexitol by blood-brain barrier ability.Usually, the increase substituted hexitol passes through blood brain The reagent of barrier ability is the reagent being selected from by the following group formed：

(a) structural formula is the chimeric peptide of (D-III)：

Wherein：(A) A be Somat, it is thyrotropin-releasing hormone (TRH) (TRH), vasopressing, alpha interferon, interior Deltorphin delta, muramyl dipeptide or ACTH4-9 analogs；And (B) B is insulin, IGF-I, IGF-II, transferrins, cation Change (alkalescence) albumin or prolactin；Or the chimeric peptide that structural formula is (D-III), two sulphur conjugated bridge quilts between wherein A and B The bridge of formula (D-III (a)) substitutes：

A-NH(CH₂)₂S-S-B (cleavable key) (D-III (a))

Wherein described bridge is to be used as bridge reagent by cysteamine and EDAC to be formed；Or the chimeric peptide that structural formula is (D-III), Two sulphur conjugated bridges between wherein A and B are substituted by the bridge of minor (D-III (b))：

A-NH=CH (CH₂)₃CH=NH-B (non-cleavable key) (D-III (b))

Wherein described bridge is to be used as bridge reagent by glutaraldehyde to be formed；

(b) Avidin that is combined with biotinylated substituted hexose 01 derivatives or affine plain fusion protein are included to form parent With the composition of element-biotin-reagent complex, the affine plain fusion protein including selected from by insulin, turn iron egg In vain, the albumen for the group that anti-acceptor monoclonal antibody, cationized proteins and agglutinin are formed；

(c) neutral liposome, it is by Pegylation and comprising the substituted hexose 01 derivatives are entered, wherein the poly- second two Alcohol chain can transport peptide with least one or targeting agent is conjugated；

(d) humanized murine's body of actrapid monotard's acceptor, the company that actrapid monotard's acceptor passes through Avidin-Biotin are incorporated into Connect and be connected with the substituted hexose 01 derivatives；And

(e) fusion protein of the first section and the second section is included：First section includes the antigen on identification cell surface Antibody variable region, the antigen after being combined with the variable region of the antibody through go through antagonist-receptor mediation endocytosis, And first section alternatively further comprises the domain of the constant region of at least one antibody；And secondth area Section includes being selected from affine by Avidin derivative, Streptavidin, the strepto- of Avidin, Avidin mutain, chemical modification The protein domain for the group that plain mutain and the Streptavidin derivative of chemical modification are formed, wherein fusion protein pass through Covalent attachment with biotin is connected with the substituted hexitol.

When pharmaceutical composition according to the present invention includes the active generation of a kind of pro-drug, a variety of pro-drugs and compound When thanking to thing, routine techniques as known in the art can be used to identify.See, for example, everybody J.Med.Chem. such as Bertolini, 40,2011-2016 (1997)；The J.Pharm.Sci. of Shan et al., 86 (7), 765-767；Bagshawe, Drug Dev.Res., 34,220-230 (1995)；The Advances in Drug Res. of Bodor, 13,224-331 (1984)； Bundgaard, Design of Prodrugs (Elsevier Press 1985)；The Design and of Larsen Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers, 1991)；The J.Chromatogr.B of Dear et al., 748,281-293 (2000)；The J.Pharmaceutical＆Biomedical Analysis of Spraul et al., 10,601-605 (1992)；And The Xenobiol. of Prox et al., 3,103-112 (1992)

When the pharmacologically active chemical compounds in pharmaceutical composition according to the present invention have enough acid functional groups, foot Enough alkaline functional groups, or be respectively provided with acid enough and alkaline enough functional group, these groups can correspondingly with it is any The inorganic or organic base and inorganic and organic acid reaction of number, to form pharmaceutically acceptable salt.Exemplary pharmaceutically may be used The salt of receiving includes those salt prepared by the reaction of pharmacologically active chemical compounds and inorganic acid or organic acid or inorganic base, such as Including following salt：Sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, dibasic alkaliine, Dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, octanoic acid Salt, acrylates, formates, isobutyrate, caproate, heptan fat, propiolate, oxalates, malonate, succinate is pungent Diacid salt, sebacate, fumarate, maleate, butine-Isosorbide-5-Nitrae-diacid, hexin -1,6- diacid, benzoate, containing chlorobenzene Acid compounds, methylbenzoic acid ethyl ester, ethyl nitrobenzoate, hydroxy benzoate, methoxy benzoic acid salt, O-phthalic Hydrochlorate, sulfonate, xylenesulfonate, phenylacetic acid, phenpropionate, phenyl butyrate class, citrate, lactate, beta-hydroxy fourth Acid esters, glycolate, tartrate, methane sulfonates, propane sulfonate, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt and almond Hydrochlorate.If pharmacologically active chemical compounds have one or more basic functionalities, desired pharmaceutically-acceptable salts can lead to The available any appropriate method in this area is crossed to prepare, for example, with mineral acid treatment free alkali, the inorganic acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.；Or with organic acid treatment free alkali, the organic acids such as acetic acid, maleic acid, amber Acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic, salicylic acid, pyranose thuja acid such as glucuronic acid or gala Uronic acid, 'alpha '-hydroxy acids such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or Cinnamic acid, sulfonic acid such as p-methyl benzenesulfonic acid or ethyl sulfonic acid etc..If pharmacologically active chemical compounds have one or more acid functionals Group, then desired pharmaceutically acceptable salt can be prepared by the available any appropriate method in this area, for example, with inorganic or Organic alkali process free acid, described inorganic or organic bases such as amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline-earth metal hydrogen Oxide etc..Organic salt such as glycine and arginine of the illustrative example of suitable salt including being derived from amino acid, ammonia, Primary, secondary and tertiary aminess, and cyclammonium, such as piperidines, morpholine and piperazine, and derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium With the organic salt of lithium.

In the case where medicament is solid, by it will be appreciated by persons skilled in the art that invention compound and salt can be with Exist with different crystal or polymorphic forms, it is all these to be intended within the scope of of the invention and specified formula.

It is included in a given pharmacological activity reagent in the unit dose of pharmaceutical composition according to the present invention Amount, will vary depending on a number of factors, such as specific compound, disease condition and its seriousness, the body of subject in need for the treatment of Part (for example, weight), but still can routinely be determined by those skilled in the art, the pharmacological activity reagent is for example such as The substituted hexose 01 derivatives of such as two to the water wei ling alcohol described above or two to the water wei ling alcohol analog or derivative spread out Biology.Typically, the pharmacological activity reagent of this pharmaceutical composition including therapeutically effective amount and inert pharmaceutically acceptable Carrier or diluent.Typically, these compositions are to be adapted to selected method of administration such as oral administration or parenteral administration It is prepared by unit dosage form.Pharmacological activity reagent as described above can be administered with conventional dosage form, by that will treat A effective amount of such pharmacological activity reagent appropriate pharmaceutical carrier as active ingredient and according to conventional methods or dilution Agent is combined to prepare the pharmacological activity reagent.These steps can be related to mixing, granulation and compression or dissolving is suitable required Preparation each component.The pharmaceutical carrier of use can be solid or liquid.The example of solid carrier is lactose, sucrose, talcum, Gelatin, agar, pectin, Arabic gum, magnesium stearate, stearic acid etc..Typical liquid-carrier is syrup, peanut oil, olive oil, Water etc..Similarly, carrier or diluent can include time delay known in the art or time controlled released material, such as monostearate Glyceride or individually or together with wax, ethyl cellulose, hydroxypropyl methyl cellulose, methyl methacrylate etc..

Various medicament forms can use.Therefore, if using solid carrier, preparation can be tablet, be placed in hard Powder or pellets in gelatine capsule or in the form of lozenge (troche or lozenge).The amount of solid carrier can become Change, but be typically from about 25mg to about 1g.If during using liquid-carrier, preparation will be syrup, lotion, Perle, nothing Bacterium injects the form of solution or suspension or water-free suspension in ampoule bottle or bottle.

In order to obtain stable water-soluble dose form, by the pharmaceutically acceptable of pharmacological activity reagent as described above Salt be dissolved in the aqueous solution of organic or inorganic acid, such as the butanedioic acid or citric acid solution of 0.3M.If soluble-salt shape Formula is disabled, which can be dissolved in the combination of suitable cosolvent or cosolvent.The example bag of suitable cosolvent Include, but be not limited to, alcohol, propane diols, Liquid Macrogol, polysorbate80, glycerine etc., its concentration range is the 0- of cumulative volume 60%.In an exemplary embodiment, the compound of Formulas I is dissolved in DMSO and is diluted with water.Said composition can be with It is the solution form of the salt form of the active ingredient in suitable aqueous vehicles, the suitable aqueous vehicles such as water Or isotonic saline solution or glucose solution.

It should be appreciated that the actual dose of the reagent used in the composition of the present invention will be according to spy currently in use Fixed complex, the specific composition of preparation, mode of administration and privileged site, host being treated and disease and/or disease Disease and change.The actual dose level of active ingredient can change in the pharmaceutical composition of the present invention, in order to effectively real Amount, composition and the administering mode of the active ingredient of the desired therapeutic response of existing special object, and there is no toxicity to subject. Selected dosage level depends on multi-medicament dynamic metabolism factor, including the activity of specific therapeutic agent, method of administration, Administration time, the discharge rate of used specific compound, the order of severity of the state of an illness, other health factors of influence subject And the state and renal function of the liver of subject.Also depend on the duration for the treatment of, combined with the specific therapeutic agent used Other medicines, compound and/or the material used, and the age of subject being treated, weight, situation, general health Medical history before and similar factor.Method for determining optimal dose is described in the art, for example, Remington:The Science and Practice of Pharmacy, Mack Publishing Co., 20^thEd., The optimal dose of 2000. one group of condition for giving can use conventional dosage determination tests by those skilled in the art Determined based on the experimental data of reagent.For being administered orally, the exemplary daily dose of generally use is about the 0.001 of weight To about 3000mg/kg, coordinate the treatment course repeated with appropriate interval.In some embodiments, daily dose is weight About 1 to 3000mg/kg.Other dosage are as described above.

Typical daily dosage can be about 500mg to any dosage between about 3000mg in patients, give one daily It is secondary or twice, for example, for 6000mg accumulated doses, 3000mg can be given once daily twice.In one embodiment, dosage exists About 1000 between about 3000mg.In another embodiment, dosage about 1500 between about 2800mg.In another reality Apply in scheme, dosage is about 2000 between about 3000mg.Typically, dosage is from about 1mg/m²To about 40mg/m².Preferably, agent Amount is from about 5mg/m²To about 25mg/m².As described above, the timetable and dosage on administration improve, the other of dosage are described Alternative solution.Dosage can change according to therapeutic response.As being discussed in further detail below, when two to the water wei ling alcohol and platiniferous When antitumor agent was applied or is closely administered in time under the same time, can select two to the water wei ling alcohol and platiniferous resist it is swollen The dosage of knurl agent with provide collaboration or super addition effect.

The plasma concentration of subject can be between about 100 μM about 1000 μM.In some embodiments, plasma concentration can With between about 200 μM to about 800 μM.In other embodiments, concentration is about 300 μM to about 600 μM.Other other In embodiment, plasma concentration can be between about 400 μM to about 800 μM.In another alternative solution, plasma concentration can be Between about 0.5 μM to about 20 μM, typically between 1 μM to about 10 μM.The dosage of pro-drug is usually according to weight water Flat, this is equal to the weight level of fully active form in chemistry.

The composition of the present invention can use the commonly known technology for being used to prepare pharmaceutical composition to manufacture, for example, logical Routine techniques is crossed as mixed, dissolves, granulation, prepares sugar-pill, suspension (levitating), emulsification, encapsulating, embedding or lyophilized work Skill.Pharmaceutical composition can be prepared using one or more physiologically acceptable carriers in a usual manner, and the carrier can To be made choice from excipient and the auxiliary agent for promoting reactive compound to be processed into pharmaceutically workable preparation.

Appropriate preparation depends on the method for administration of selection.For injection, reagent of the invention can be configured to aqueous solution, It is preferred that compatible buffer solution such as Hunk (Hanks ' s) solution, Ren Shi (Ringer ' s) solution or physiological saline in a physiologically Prepared in buffer solution.For mucosal, the bleeding agent for being suitable for barrier to be infiltrated is used in preparation.Such infiltration Agent is commonly known in the art.

For being administered orally, the compound can be easily by using pharmaceutically acceptable carrier known in the art Prepared with active compound.Such carrier enables the compound of the present invention to be configured to tablet, pill, sugar-coat Ball, capsule, liquid, gel, syrup, slurries, solution, suspension etc., are orally ingested for patient to be treated.It can use mixed The solid excipient of conjunction and active ingredient (medicament), alternatively grinding gained mixture, and while needing, add suitable auxiliary agent Post-processing granulate mixture is to obtain tablet or sugar-coat capsule core, to obtain pharmaceutical preparations for oral use.Suitable figuration Agent includes：Filler, such as sugar, including lactose, sucrose, mannitol, or sorbierite；Cellulose preparation, for example, cornstarch, Wheaten starch, rice starch, farina, gelatin, natural gum, methylcellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose Plain sodium, or polyvinylpyrrolidone (PVP).It can add disintegrant, such as crosslinked polyvinylpyrrolidone when needing, agar, or Alginic acid or its salt such as mosanom.

Sugar-coat capsule core possesses suitable coating.For this purpose, can use concentration sugar juice, its can it is optional containing Arabic gum, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, paint solution and suitable organic molten Agent or solvent mixture.Dyestuff or pigment can add tablet or dragee coatings are used to recognize or the difference of identified activity reagent Combination.

The pharmaceutical preparation that can be administered orally includes the sucking fit formula capsule made of gelatin, and by gelatin and plasticising Agent soft seal capsule as made of glycerine or D-sorbite.Sucking fit formula capsule can include mixing active ingredient with such as The adhesive of the filler of lactose, such as starch, and/or the lubricant of such as talcum powder or magnesium stearate, and it is optional steady Determine agent.In soft capsule, active agent can be dissolved or suspended in suitable liquid, such as fat oil, atoleine, or liquid Body polyethylene glycol.Furthermore it is possible to add stabilizer.The all formulations of oral administration should be the dosage suitable for this administration.It is right In oral administration, composition can take the form of the tablet prepared in a usual manner or lozenge.

Pharmaceutical preparation for parenteral may include aqueous solution or suspension.Suitable lipophilic solvent or medium bag Include the fat oil of such as sesame oil, or the Acrawax of such as ethyl oleate or triglycerides.Water injection suspension liquid can Material containing increase suspension viscosity, such as sodium carboxymethylcellulose, sorbierite, or glucan.Alternatively, suspension can be with Dissolubility or dispersiveness containing suitable stabilizer or the increase composition are to allow the adjusting for preparing highly enriched solution Agent, or suspending agent or dispersant can be contained.Pharmaceutical preparations for oral use can by by pharmaceutically active agents with Solid excipient combines, and suitable auxiliary agent post-processing granulate mixture is added when alternatively grinding gained mixture, and needing, To obtain tablet or sugar-coat capsule core.Suitable excipient is particularly such as sugared filler, including lactose, sucrose, sweet dew Alcohol, or sorbierite；Such as, for example, cornstarch, wheaten starch, rice starch, farina, gelatin is yellow for cellulose preparation Alpine yarrow glue, methylcellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).If If needing, disintegration conditioning agent, such as crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt such as mosanom can be added.

Other components of such as stabilizer can be used, for example, antioxidant, such as sodium citrate, ascorbic acid palm Acid esters, propyl gallate, reducing agent, ascorbic acid, vitamin E, sodium hydrogensulfite, Yoshinox BHT, BHA, half Guang of acetyl Propylhomoserin, monothioglycerol, phenyl-α-naphthylamine, or lecithin.In addition it is possible to use chelating agent such as EDTA.Medicine group can be used Other components of compound and formulation art routine, such as the lubricant in tablet or pill, colouring agent or flavouring.In addition, Conventional drug excipient or carrier can be used.Drug excipient may include, but be not necessarily limited to, calcium carbonate, calcium phosphate, respectively Plant sugared or various types of starch, cellulose derivative, gelatin, vegetable oil, polyethylene glycol and physiologically compatible solvent. Other medicines excipient is well known in the art.Exemplary pharmaceutically acceptable carrier include, but not limited to it is any and/ Or all solvents, including water-based and non-aqueous solvent, decentralized medium, coating, antibacterial and/or antifungal agent, penetration enhancer and/or suction Receive delayed-action activator, and/or analog etc..It is known in the art to be used for pharmaceutically active substance using these media and/or reagent 's.If unless any conventional medium, carrier or reagent are incompatible with active ingredient or component, otherwise can be expected it in root According to the use in the composition of the present invention.The active ingredient supplemented as described above can be also included in composition, particularly such as In the upper composition.Administration for any compound being used in the present invention, preparation should meet biological agent mark Sterile, pyrogenicity, general security and purity mark required by accurate FDA offices or the regulator of other regulation and control medicines It is accurate.

For intranasal administration or pass through inhalation, by using suitable propellant, chemical combination used according to the invention Thing can be delivered easily from pressurized package or sprayer in the form of aerosol spray presentation, for example, dicholorodifluoromethane, three Chlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide or other suitable gases.In the case of a pressurized aerosol, dosage unit It can be determined by the valve for the amount for providing to deliver metering.It can prepare for example for inhalator or the glue of the gelatin of insufflator Capsule and cartridge case (Cartridge), it includes compound and the mixture of powders of the appropriate powdered substrate of such as lactose or starch.

Compound can be prepared for being injected intravenously (BolusInjection) by injection, such as by single-bolus high-dose Or continuous infusion carries out parenteral.Preparation for injection can exist with unit dosage forms, for example, be present in add it is anti- In the ampoule of rotten agent or in multi-dose container.The composition can be taken outstanding in such form such as oiliness or aqueous vehicles Supernatant liquid, solution or lotion, and formulatory agents such as suspending agent, stabilizer and/or dispersant can be included.

Pharmaceutical preparation for parenteral includes the aqueous solution of the reactive compound of water-soluble form.It is in addition, active The suspension of reagent can be prepared as appropriate oily injection suspensions.Suitable lipophilic solvent or medium include fat oil example Such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglyceride, or liposome.Water injection suspension liquid can wrap Material such as sodium carboxymethylcellulose, sorbierite or the glucan of the suspension viscosity containing increase.Water injection suspension liquid can contain Increase the material of suspension viscosity, such as sodium carboxymethylcellulose, sorbierite, or glucan.Alternatively, suspension can also be included and closed Suitable stabilizer increases the stability of compound to allow the reagent for preparing highly enriched liquid.

Alternately, the active ingredient can exist with powder form, before use using appropriate medium for example Aseptic apirogen water is built.Compound can be also prepared in rectal compositions such as suppository or enema,retention (such as comprising normal Advise suppository base, such as cocoa butter or other glyceride) in.

In addition to above-mentioned preparation, compound can also be configured to durative action preparation (depot preparation).Pass through implantation (for example, subcutaneously or intramuscularly) or pass through intramuscular administration.This durative action preparation can by implantation (such as subcutaneously or intramuscularly) or Pass through intramuscular administration.Thus, for example, available appropriate polymer or hydrophobic substance (such as with the breast in acceptable oil Liquid form) or ion exchange resin, or the compound is for example prepared with sl. sol. salt form with sl. sol. derivative form.

The exemplary pharmaceutical carrier of hydrophobic compound is to include phenmethylol, apolar surfaces active agent, mixed with water Molten organic polymer and the co-solvent system of water phase.The co-solvent system can be VPD co-solvent systems.VPD is 3%w/ The solution of the Liquid Macrogol of the phenmethylol of v, 8%w/v non-polar surfactants polyoxyethylene sorbitan monoleate and 65%w/v, with anhydrous Ethanol supplies volume.VPD co-solvent systems (VPD：5W) include with 5% aqueous dextrose 1:1 diluted VPD.This is molten altogether Agent system dissolves hydrophobic compound well, and itself is low in toxicity caused by Formulations for systemic administration.Naturally, cosolvent system The ratio of system can be significantly changed without destroying its dissolubility and toxic characteristic.In addition, being also to become is determined to cosolvent component Change, for example, other low-toxicity nonpolar surfactants can be used to substitute polysorbate80；The ratio of polyethylene glycol How many example is also what can be changed；The polymer of other bio-compatibles can replace polyethylene glycol, such as polyvinylpyrrolidone；And And other sugar or polysaccharide can be used for substituting dextrose.

Alternatively, it is possible to using other delivery systems for hydrophobic drug composition.Liposome and emulsion are to use In the delivery vehicle of hydrophobic drug or the known example of carrier.The some organic molten of such as dimethyl sulfoxide can also be used Agent, although usually using the toxicity of bigger as cost.In addition, sustained release system can be used in the compound, as containing therapeutic agent The semipermeable matrices delivering of solid hydrophobic polymers.Various slow-release materials have been determined and have been that those skilled in the art is It is known.According to its chemical property, spansule can discharge compound several weeks to more than 100 days；In other alternatives In, according to therapeutic agent and preparation used, can be discharged in a few hours, a couple of days, several weeks or several months.According to different chemistry The biological stability of property and therapeutic agent, can use other strategies for protein stabilization.

Pharmaceutical composition can also include suitable solid phase or gel phase carriers or excipient.Such carrier or excipient Example include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivative, the polymer of gelatin and such as polyethylene glycol.

Pharmaceutical composition can be administered by a variety of methods known in the art.Method of administration and/or mode are desired by Result and it is different.According to method of administration, pharmacological activity reagent can be wrapped up with material to protect target composition or other Compound of the therapeutic agent from sour and other inactivation reagents.Can use routine medicinal practice for such pharmaceutical composition to The administration of subject provides suitable preparation or composition.Any suitable method of administration, can use, such as, but not limited to, Intravenously, parenteral, it is intraperitoneal, it is intravenously, percutaneously, subcutaneously, intramuscular, in urethra, or it is administered orally.According to different pernicious swollen The order of severity of knurl or other diseases to be treated, illness or the patient's condition and the other patient's condition for influencing object to be treated, the medicine The whole body or local delivery of compositions can use over the course for the treatment of.Can by pharmaceutical composition as described above with it is other Be used for treat the therapeutic agent of specific disease or illness and apply together, the specific disease or illness can be and the medicine Compositions are used for the identical disease or illness for the treatment of, can be relevant diseases or illness, or can even is that not Relevant disease or illness.

Pharmaceutical composition according to the present invention can be according to known and prepared in the method for this area conventional practice.Ginseng See such as Remington:The Science and Practice of Pharmacy, Mack Publishing Co.20th ed.2000；And Sustained and Controlled Release Drug Delivery Systems, J.Robinson Editor, Marcel Dekker, Inc., New York, 1978.Pharmaceutical composition preferably in GMP, (advise by quality control of pharmaceutical production Model) under the conditions of produce.Preparation for parenteral administration can for example contain excipient, sterile water, or brine, polyalkylene two Alcohol such as polyethylene glycol, the oil of plant origin, or hydrogenated naphthalene.Bio-compatible, biodegradable lactide polymer, lactide Or glycolide copolymer, or Pluronic F68 can be used for control compound release.For the present invention's The parenteral delivery systems of other potentially usefuls of molecule include vinyl-vinyl acetate copolymer particle, osmotic pumps and can plant The infusion system entered.Preparation for suction can contain excipient, for example, lactose, or can be containing for example, polyoxy second The aqueous solution of alkene -9- lauryl ethers, glycocholate and dexycholate, or can be oily solution or gel for administration.

Pharmaceutical composition according to the present invention is usually applied to subject in multiple occasions.Interval between single dose can To be weekly, monthly or every year.Also may be used by the time interval indicated by therapeutic response or other parameters as known in the art To be irregular.Alternatively, described pharmaceutical composition can be used as sustained release preparation, need not more frequently give in this case Medicine.Dosage and frequency change according to the half-life period in subject of the pharmacological activity reagent included in pharmaceutical composition. Applied dose and frequency can be preventative or curative change according to treatment.It is relatively low in prophylactic use Dosage with relatively infrequent interval for a long time in administration.Some subjects may continue to receive treatment in its remaining years. In treatment use, it is sometimes desirable to relatively high dosage is applied with relatively short interval, it is excellent until the progress mitigation or termination of disease Choosing is until subject shows the partially or completely improvement of disease symptoms.Hereafter, subject can apply prevention scheme.

For purposes of this application, can be related by the disease, illness or the patient's condition observing to receiving treatment One or more improved symptoms carry out monitoring treatment, or pass through observation with receiving the disease, illness or the disease for the treatment of The relevant improved one or more clinical parameters of condition carry out monitoring treatment.In the case of NSCLC, clinical parameter can include, But it is not limited to, reduces tumor load, reduce pain, improve lung function, improve Karnofsky behavior scores, and reduce tumour Diffusion or the generation of transfer.In the case of oophoroma, similar clinical parameter can be applied, for example, reducing tumor load, is reduced Pain, mitigate abdominal symptoms, mitigate urinary tract symptom, improve Karnofsky behavior scores, and reduce tumour diffusion or transfer Occur.As used herein, term " treatment ", " treatment " or equivalent terms are not intended to imply that treated disease, barrier Hinder or the permanent of illness is cured.Composition according to the present invention and method are not limited to human treatment, but it is also suitable for treatment society Or economically important animal, such as dog, cat, horse, ox, sheep, goat, pig and social or economically important other animal things Kind.The pharmacokinetics principle of the medicine delivery of control illustrates, for example, unless otherwise indicated, combination according to the present invention Thing and method are not limited to the treatment of the mankind.

Sustained release preparation or controlled release preparation are as known in the art.For example, sustained release or controlled release preparation can be a kind of (1) mouths Take substrate sustained release or controlled release preparation；(2) multilayer sustained release or Dospan preparation are taken orally；(3) it is a kind of to take orally more particle slow releases or control Release formulation；(4) oral osmotic sustained release or controlled release preparation；(5) chewable sustained release or controlled release preparation are taken orally；Or (6) corium sustained release or Control-released plaster.

The pharmacokinetics principles illustrated of the medicine delivery of control is in for example, B.M.Silber et al. “Pharmacokinetic/Pharmacodynamic Basis of Controlled Drug Delivery”inControlled Drug Delivery:Fundamentals and Applications(J.R.Robinson&V.H.L.Lee Editor, 2d ed., Marcel Dekker, New York, 1987), ch.5, pp.213-251, are incorporated herein by reference.

Quoting one skilled in the art can easily be prepared for by controlled release by improving above-mentioned pharmaceutical formulation The preparation put or be sustained, the preparation include active agent according to the present invention pharmacologically, such as according to by quoting simultaneously Enter " the Influence of Drug Properties and Routes of Drug of the V.H.K.Li of this paper et al. Administration on the Design of Sustained and Controlled Release Systems”inControlled DrugDelivery:Fundamentals and Applications(J.R.Robinson&V.H.L.Lee Editor, 2d ed., Marcel Dekker, New York, 1987), ch.1, pp.3-94, are incorporated herein by reference.This system Preparation Method usually considers the physicochemical properties of pharmacological activity reagent, such as water-soluble, distribution coefficient, molecular size, stability, Protein and other large biological molecules with non-specific binding.Pharmacological activity reagent is contemplated in this preparation process Biological factor, such as absorb, be distributed, metabolism, acting duration, side effect there may be and the margin of safety.Therefore, originally Preparation can be improved to the system with the above-described desired property specifically applied by one those of ordinary skill in field Agent.

The U.S. Patent number 6,573,292 for the Nardella being all incorporated herein by reference, the United States Patent (USP) of Nardella Numbers 6,921,722, the U.S. Patent number 7 of the U.S. Patent number 7,314,886 of Chao et al. and Chao et al., 446,122, it is public Open using various pharmacological activity reagents and many diseases and the patient's condition for including cancer of medicine composite for curing, and determined so Pharmacological activity reagent and pharmaceutical composition treatment validity method.

In view of reported in following embodiments as a result, another aspect of the present invention is a kind of method for treating NSCLC, including To the step of the substituted hexose 01 derivatives of a effective amount of such as two to the water wei ling alcohol of the patient therapeuticallv with malignant tumour Suddenly.

Usually, when the substituted hexose 01 derivatives are two to the water wei ling alcohol, the described of two to the water wei ling alcohol is controlled It is about 1mg/m to treat effective dose²To about 40mg/m².Preferably, the therapeutically effective amount of two to the water wei ling alcohol is about 5mg/m²Extremely About 25mg/m².Those of ordinary skill in the art can be by using the hexose 01 derivatives specifically substituted molecular weight and spy The activity of fixed substituted hexose 01 derivatives determines controlling for the substituted hexose 01 derivatives in addition to two to the water wei ling alcohol Live vol is treated, the active for example substituted hexose 01 derivatives of the hexose 01 derivatives specifically substituted are to standard cell lines system External activity.Being adjusted as described above such as dosage other conjunctions are described with description as described in administration time table and embodiment Suitable dosage.

Usually, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol pass through selected from by vein and oral structure Into group in approach administration time table.Preferably, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol pass through Intravenously administrable.

The method can also include the step of ionizing radiation using treatment effective dose.This method can be wrapped further The step of including other chemotherapeutants using treatment effective dose, other chemotherapeutants are selected to be made of following Group：Cis-platinum, carboplatin, oxaliplatin, bevacizumab, taxol, albumin paclitaxel braxane (make by white associated proteins taxol For delivery vehicle), docetaxel, Etoposide, gemcitabine, preparing vinorelbine tartrate, and pemetrexed.Using these The suitable method of reagent and suitable dosage are well known in the present art.

Usually, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol can substantially suppress cancer stem cell (CSC) growth.Usually, the growth inhibition ratio of cancer stem cell is at least 50%.Preferably, the growth suppression of cancer stem cell Rate processed is at least 99%.

Usually, for example, two to the water wei ling alcohol the substituted hexose 01 derivatives can effectively suppress have by O⁶- first The growth of base guanine-cancer cell of drug resistance caused by dnmt rna (MGMT).Usually, such as two remove water winged euonymus The substituted hexose 01 derivatives of alcohol can effectively suppress the growth of the cancer cell resistant to Temozolomide.

The method can further comprise the tyrosine kinase inhibitor using therapeutically effective amount as described above.

The method can further comprise the EGFR inhibitor using therapeutically effective amount as described above.As described above, The EGFR inhibitor influences wild type binding site or the binding site of mutation, including EGFR variations III.

In addition, in order to treat the brain metastes of NSCLC, the method can further comprise to patient therapeuticallv's effective dose Increase substitution the hexitol ability that passes through blood-brain barrier reagent.Alternatively, this method can further comprise applying to patient With the reagent for being used to resist bone marrow suppression of therapeutically effective amount.

In view of reported in following embodiments as a result, another aspect of the present invention is a kind of method for treating oophoroma, bag Include the substituted hexose 01 derivatives to a effective amount of such as two to the water wei ling alcohol of the patient therapeuticallv with malignant tumour Step.

Usually, when the substituted hexose 01 derivatives are two to the water wei ling alcohol, the described of two to the water wei ling alcohol is controlled It is about 1mg/m to treat effective dose²To about 40mg/m².Preferably, the therapeutically effective amount of two to the water wei ling alcohol is about 5mg/m²Extremely About 25mg/m².Those of ordinary skill in the art can be by using the hexose 01 derivatives specifically substituted molecular weight and spy The activity of fixed substituted hexose 01 derivatives determines controlling for the substituted hexose 01 derivatives in addition to two to the water wei ling alcohol Live vol is treated, the active for example substituted hexose 01 derivatives of the hexose 01 derivatives specifically substituted are to standard cell lines system External activity.Being adjusted as described above such as dosage other conjunctions are described with description as described in administration time table and embodiment Suitable dosage.

Usually, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol pass through selected from by vein and oral structure Into group in approach administration time table.Preferably, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol pass through Intravenously administrable.

The method can also include the step of ionizing radiation using treatment effective dose.This method can be wrapped further The step of including other chemotherapeutants using treatment effective dose, other chemotherapeutants are selected to be made of following Group：Cis-platinum, carboplatin, oxaliplatin, bevacizumab, taxol, albumin paclitaxel braxane (make by white associated proteins taxol For delivery vehicle), docetaxel, Etoposide, gemcitabine, preparing vinorelbine tartrate, and pemetrexed.Using these The suitable method of reagent and suitable dosage are well known in the present art.When treating oophoroma, confrontation ovum can be used Nest cancer is effective or may effective other therapeutic agent；These medicaments are discussed in further detail below.

Usually, such as the substituted hexose 01 derivatives of two to the water wei ling alcohol can substantially suppress cancer stem cell (CSC) growth.Usually, the growth inhibition ratio of cancer stem cell is at least 50%.Preferably, the growth suppression of cancer stem cell Rate processed is at least 99%.

Usually, for example, two to the water wei ling alcohol the substituted hexose 01 derivatives can effectively suppress have by O⁶- first The growth of base guanine-cancer cell of drug resistance caused by dnmt rna (MGMT).Usually, such as two remove water winged euonymus The substituted hexose 01 derivatives of alcohol can effectively suppress the growth of the cancer cell resistant to Temozolomide.

The method can further comprise the tyrosine kinase inhibitor using therapeutically effective amount as described above.

In general, the application effect of dianhydrogalactitol and the platiniferous medicament selected from the group being made of cis-platinum and oxaliplatin is at least It is addition.In some cases, the application effect of these medicaments is super addition.

As described above and as embodiment provided below, the substituted hexitol of such as two to the water wei ling alcohol can also be used In treatment oophoroma.

The risk of oophoroma increases with ovulation frequency and ovulation duration.Other risk factors swash including post menopausal Extract for treating, fertility drug and obesity.About 10% case is related with increased genetic risk；With gene mutation BRCA1 or The risk that the women of BRCA2 has ovarian cancer is up to 50%.Although the individual of what ethnic background in office can occur for such mutation, But they are occurred more frequently in the individual with some particular race backgrounds, such as Ashkenazy Jew (can chase after Their ancestors trace back to such as Germany, Austria, Poland, Hungary is Romanian, Czech Republic, Slovakia, Wu Ke The regional Jew of orchid, Byelorussia, Lithuania, Latvia or Russia).

Most common oophoroma including the case more than 95% is epithelial ovarian cancer (ovarian carcinoma).Have Five main epithelial ovarian cancer hypotypes, wherein high-level serosity (high-grade serous) is most common.These are swollen Knurl is considered starting from wrapping up in the cell of ovary, and some are then formed at fallopian tubal.It is thin that more uncommon type includes reproduction Born of the same parents' knurl and sex cords mesenchymoma.Since the symptom of oophoroma does not show usually in disease early stage, and if showing, lead to It is often universal and cannot be clearly attributed to oophoroma, so needs biopsy to confirm.

Current form of therapy includes some combinations of operation, radiotherapy and chemotherapy.However, in the U.S., entirety 5 years Survival rate only has 45% or so.Chemotherapy currently used for oophoroma includes taxol, Docetaxel, cis-platinum, carboplatin, Ji His shore, topotecan, Etoposide and adriamycin of west.Other such as oxaliplatins, satraplatin, picoplatin, Nedaplatin, three platinum and The platiniferous medicament of lipoplatin is also used.A kind of olaparib (Olaparib), PARP inhibitor, is also developed recently Into the chemotherapy for oophoroma.However, in most case, the paired platiniferous medicament of tumor development has drug resistance.Recurring Property malignant tumour in the case of, carboplatin can also be combined with gemcitabine or taxol.Using tamoxifen or it can also come bent Azoles, but their typically no effects.The beautiful medicament for Buddhist nun, mTOR inhibitors and PI3 kinase inhibitors of other such as department also by It is proposed.In addition, the deacetylase (histone deacetylase, HDAC) of such as Trichostatin A is also by as anti-ovary Cancer medicament and propose.

For most of oophoromas, by assessing antigen (the also referred to as mucoprotein for being referred to as CA-125 by MUC16 codings 16) level is monitored.The antigen is proteantigen, it is the film associated mucin for including single transmembrane domain.

Therefore, another aspect of the present invention is a kind of method for treating oophoroma, it is included to the patient with oophoroma Using therapeutically effective amount substituted hexose 01 derivatives the step of.The hexose 01 derivatives suitably substituted are as described above；It is special The hexitol not substituted preferably is two to the water wei ling alcohol.Usually, the therapeutically effective amount of two to the water wei ling alcohol goes water to defend for two The about 1mg/m of lance alcohol²To about 40mg/m²Dosage.Preferably, the therapeutically effective amount of two to the water wei ling alcohol is two to the water wei ling alcohol About 5mg/m²To about 25mg/m²Dosage.Usually, two to the water wei ling alcohol passes through in by vein and the oral group formed Approach administration.

In an alternative solution, the oophoroma is the wild type p53 cancer of cisplatin.

In the method according to the invention, the hexose 01 derivatives substituted as described above of therapeutically effective amount can be with one The anti-tumor agents of kind or a variety of therapeutically effective amounts are used together in the treatment of oophoroma.Usually, as described above, described take The hexitol in generation is two to the water wei ling alcohol.The suitable medicament of antitumor activity with anti ovary tumour includes but is not limited to： Taxol, Docetaxel (docetaxel), cis-platinum, carboplatin, topotecan, gemcitabine, bleomycin, Etoposide, Ah Mycin (can be with Pegylated Liposomal form use), tamoxifen, Letrozole, olaparib, U.S. of department replace Buddhist nun, mTOR suppressions Preparation, PI3 kinase inhibitors and Trichostatin A.

Usually, the substituted hexose 01 derivatives can substantially suppress the growth of cancer stem cell.Usually, it is described Substituted hexose 01 derivatives can effectively suppress to have by O⁶Drug resistance caused by-methyl guanine-dnmt rna (MGMT) The growth of the cancer cell of property.

In the scheme of another replacement, the method is further included applies the platiniferous chemotherapeutant of therapeutically effective amount The step of, and wherein described platiniferous chemotherapeutant is selected from by cis-platinum, carboplatin, iproplatin, oxaliplatin, four platinum, Satraplatin, pyrrole The group that platinum, Nedaplatin and three platinum are formed.

The other medicament of antitumor activity with ovarian cancer resistance is well known in the art.Medicine according to the present invention Combination includes these other medicaments of therapeutically effective amount and the hexose 01 derivatives substituted as described above of therapeutically effective amount. The one or more in these other medicaments can be used.These other medicaments can be as described above with one or more The medicament of ovarian cancer resistance activity is used together in drug regimen, the drug regimen includes such as two to the water wei ling alcohol or two The substituted hexose 01 derivatives of acetyl group two to the water wei ling alcohol.These medicaments are jointly referred to herein as " having anti-ovum The other assistant medicament of nest cancer activity ".These medicaments include following：The U.S. Patent number 8,981,131 of Bhedi et al. discloses The use of tricyclic compound, such as (5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -3- ((4- methylpiperazine-1-yls) methyl) - 3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans -2 (9bH) -one hydrochlorides；4- (((5aR, 9bS) -3a- hydroxyls - 5a, 9- dimethyl -2- oxos -2,3,3a, 4,5,5a, 6,7,8,9b- decahydro naphtho- [1,2-b] furans -3- bases) methyl) piperazine - 1- carboxylate hydrochlorides；(5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -3- ((4-o- tolyl piperazine -1- bases) methyl) - 3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans -2 (9bH) -one hydrochlorides；Or (5aR, 9bR) -3a- hydroxyls -3- ((((5aR, 9bS) -3a- hydroxyls -5a, 9- dimethyl -2- oxos -2,3,3a, 4,5,5a, 6,7,8,9b- decahydro naphtho-s [1,2- B] furans -3- bases) methylamino) methyl) -5a, 9- dimethyl -3,3a, 4,5,5a, 6,7,8- octahydro naphtho- [1,2-b] furans - 2 (9bH) -one hydrochlorides).The U.S. Patent number 8,981,094 of Bongartz et al. is disclosed as DGAT inhibitor especially The use of the piperidine/piperazine derivatives of DGAT1 inhibitor.The U.S. Patent number 8,981,085 of Le Huerou et al. discloses The use of the pyrrolopyrimidine of CHK1 or CHK2 inhibitor.The U.S. Patent number 8,981,084 of Balogu et al. discloses evil two The use of azoles hdac inhibitor.The U.S. Patent number 8,980,955 of Turchi et al. is disclosed to be derived as halogen ester isoborneol The use of the replication protein A inhibitor of thing.The U.S. Patent number 8,980,934 of Pauls et al. discloses the Yin of TTK protein kinases The use of azoles inhibitor.The U.S. Patent number 8,980,933 of Schobert et al. discloses Kang Purui fourths (combretastatin) use of analog.The U.S. Patent number 8,980,909 of Chen et al. discloses the happiness for suppressing HDAC Set the application of alkali derivant.The U.S. Patent number 8,980,902 of Brown et al. discloses piperazinyl phenyl formamide PARP inhibitor Use.The U.S. Patent number 8,980,879 of Liu et al. people discloses the use of BET bromine domain inhibitor, including 5- (rings third Ylmethyl) -2,4,5,11- tetrahydrochysene -1H-2 of -11- methyl -8- ((methyl sulphonyl) methyl), 5,11- tri- azepine dibenzo [cd, H] Azulene -1- ketone；5- (4- fluorophenyls) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- Three azepine dibenzo [cd, h] Azulene -1- ketone；5- (2,4- difluorophenyl) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4, 5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -1- ketone；5- (cyclopropane carbonyl) -11- methyl -8- ((methyl Sulfonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -1- ketone；5- (4- fluorophenyls)- 4- (2- methoxy ethyls) -11- methyl -8- ((methyl sulphonyl) methyl) -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepines Dibenzo [cd, h] Azulene -1- ketone；3- (5- (4- fluorophenyls) -11- methyl -8- ((methyl sulphonyl) methyl) -1- oxos -2,4, 5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -4- bases) methyl propionate；N- (5- (4- fluorophenyls) -11- first Base -1- oxos -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) ethyl sulfonamide；8- is fluoro- 5- (4- fluorophenyls) -11- methyl -2,4,5,11- tetrahydrochysene -1H-2,5,6,11- tetra- azepine dibenzo [cd, h] Azulene -1- ketone；N- (5- (4- fluorophenyls) -11- methyl isophthalic acids-oxo -2,4,5,11- tetrahydrochysene -1H-2,5,6,11- tetra- azepine dibenzo [cd, h] Azulene - 8- yls) -2- (1- methyl isophthalic acid H- pyrazoles -4- bases) acetamide；8- amino -5- (4- fluorophenyls) -11- methyl -2,4,5,11- tetra- Hydrogen -1H-2,5,11- tri- azepines-dibenzo [cd, h] Azulene -1- ketone；N- (5- (4- fluorophenyls) -11- methyl isophthalic acids-oxo -2,4,5, 11- tetrahydrochysenes -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) benzsulfamide；N- (4- (N- (5- (4- fluorophenyls)- 11- methyl isophthalic acids-oxo -2,4,5,11- tetrahydrochysene -1H-2,5,11- tri- azepine dibenzo [cd, h] Azulene -8- bases) sulfamic) benzene Base) acetamide.The U.S. Patent number 8,980,875 of Mailliet et al. discloses the use of platinum N- heterocyclic carbene derivatives. The U.S. Patent number 8,980,850 of Smith et al. disclose NEDD8 activation enzyme inhibitor use, such as ((1S, 2S, 4R)- 4- (4- ((1S) -2,3- dihydro -1H- indenes -1- bases amino) -7H- pyrrolo-es [2,3-d] pyrimidin-7-yl) -2- hydroxycyclopents base) Methylsulfamic acid ester or { (1S, 2S, 4R) -4- [(6- { [chloro- 2- methoxyl groups -2,3- dihydro -1H- indenes -1- of (1R, 2S) -5- Base] amino } pyrimidine-4-yl) epoxide] -2- hydroxycyclopents base } methylsulfamic acid ester.The U.S. Patent number 8 of Wang et al., 980,838 disclose the use of the cyclic peptidomimetic inhibitor of WDR5/MLL1 interactions.The U.S. Patent number of Lowy et al. 8,980,268 disclose the use of anti-Ang-2 antibody.The anti-TGFα antibody of U.S. Patent number 8,980,257 of Kaneda et al. Use.The U.S. Patent number 8,975,398 of Hansen et al. discloses the use of NAMPT inhibitor, such as N- { 4- [1- (2- first Base propiono) piperidin-4-yl] phenyl }) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2- chlorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- [4- ({ 1- [(2S) -2- methyl Bytyry] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (1,3-thiazoles -2- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- Base)-N- (4- { [1- (tetrahydrochysene -2H- pyrans -4- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；N- [4- ({ 1- [difluoro (phenyl) acetyl group] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides； N- [4- ({ 1- [(4,4- difiuorocyclohexyl) carbonyl] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine - 3- acid amides；N- (4- { [1- (2- methyl -2- phenylpropionyl) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azacyclo- Butane -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (1,3-thiazoles -4- bases carbonyl) piperidin-4-yl] epoxide } phenyl) nitrogen Azetidine -3- acid amides；N- [4- ({ 1- [(5- methylthiophene -2- bases) carbonyl] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine - 3- yls) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- 4- [(1- { [4- (trifluoromethyl) phenyl] acetyl group } piperidines - 4- yls) epoxide] phenyl } azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (tetrahydrofuran -2- bases carbonyl) piperazines Pyridine -4- bases] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- [4- ({ 1- [3- (trifluoromethyl) benzene first Acyl group] piperidin-4-yl } epoxide) phenyl] azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (thiene-3-yls Carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- [4- ({ 1- [3- (fluoroforms Epoxide) benzoyl] piperidin-4-yl } epoxide) phenyl] azetidine -3- acid amides；N- (4- { [1- (3- methylbutyryls) piperazines Pyridine -4- bases] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；1- (pyridazine -3- bases)-N- (4- { [1- (four Hydrogen furans -3- bases carbonyl) piperidin-4-yl] epoxide } phenyl) azetidine -3- acid amides；N- [4- ({ 1- [(3- fluorophenyls) second Acyl group] piperidin-4-yl } epoxide) phenyl] -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2- fluorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (2,4- difluorobenzene first Acyl group) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；N- (4- { [1- (4- fluorobenzoyls Base) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides；And N- (4- { [1- (3- fluorobenzene first Acyl group) piperidin-4-yl] epoxide } phenyl) -1- (pyridazine -3- bases) azetidine -3- acid amides.The United States Patent (USP) of Blein et al. Numbers 8,975,376 disclose anti-α₂The use of-integrin antibody.The U.S. Patent number 8,975,287 of Karp et al. discloses 1, The use of 2,4- oxadiazoles benzoic acid compounds.The U.S. Patent number 8,975,267 of Caldarelli et al. discloses tricyclic pyrrole Cough up the use of derivative, such as N- (2,6- diethyl phenyl) -9- (methoxy) -2- { [2- methoxyl groups -4- (4- methyl piperazines Piperazine -1- bases) phenyl] amino } -8- methyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, 2- [(the bromo- 2- of 4- Methoxyphenyl) amino]-N- (2,6- diethyl phenyl) -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinoline azoles Quinoline -7- acid amides, N- (2,6- diethyl phenyl) -2- ({ 2- methoxyl groups -4- [4- (pyrrolidin-1-yl) piperidin-1-yl] phenyl } ammonia Base) -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, N- (2,6- diethyl phenyl) -2- ({ 4- [4- (dimethylamino) piperidin-1-yl] -2-m- ethoxyl phenenyls } amino) -8,9- dimethyl -6,9- dihydro -5H- pyrroles Cough up simultaneously [3,2-h] quinazoline -7- acid amides, N- (2,6- diethyl phenyl) -2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) Phenyl] amino } -8,9- dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, N- (2,6- diethylbenzenes Base) -2- ({ 4- [4- (2- hydroxyethyls) piperazine -1- bases] -2- methoxyphenyls } amino) -8,9- dimethyl -6,9- dihydro - 5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, 2- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl] amino } -8,9- Dimethyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides, and 2- [(the bromo- 2- methoxyphenyls of 4-) ammonia Base]-N- (2,6- diethyl phenyl) -9- methyl -6,9- dihydro -5H- pyrrolo-es [3,2-h] quinazoline -7- acid amides.Bauer etc. The U.S. Patent number 8,974,781 of people discloses the use of anti-P- cadherin antibodies.The U.S. Patent number 8 of Abraham et al., 969,587 disclose the use of BRAF kinases (serine/threonine protein kitase) inhibitor, such as 1- (3- (6,7- dimethoxies Base quinazoline -4- bases epoxide) phenyl) -3- (5- (1,1,1- tri- fluoro- 2- methylpropanes -2- bases) isoxazole -3- bases) urea.Maier Et al. U.S. Patent number 8,969,401 disclose sulphonylpyrroles as HDAC (histon deacetylase (HDAC)) inhibitor Use.The U.S. Patent number 8,969,396 of Du et al. discloses the BRAF including Hsp90 (heat shock protein 90) inhibitor and suppresses The use of agent, such as 3- (2,4- dihydroxy -5- isopropyl-phenyls) -4- (1- Methvl-indole -5- bases) -5- hydroxyls-[1,2,4] Triazole.The U.S. Patent number 8,969,395 of Ribeiro Salvador et al. discloses the use of triterpene compound derivative. The U.S. Patent number 8,969,381 of Wilson et al. discloses the use of Chemokines CC XCR4 conditioning agents, such as N¹-(((S)- 1,2,3,4- tetrahydroisoquinoline -3- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-diamines；N¹- (((R) -1,2,3,4- tetrahydroisoquinoline -3- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-two Amine；N¹- (((S) -4- benzyl diethylenediamine -2- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-diamines； And N¹- (((R) -4- benzyl diethylenediamine -2- bases) methyl)-N¹- ((S) -5,6,7,8- tetrahydroquinoline -8- bases) butane-Isosorbide-5-Nitrae-two Amine.(3- chloro- 4- (cyclopropylaminocarbonyl) the aminobenzene oxygen of 4- disclosed in the U.S. Patent number 8,969,379 of Furitsu et al. Base) -7- methoxyl group -6- quinoline amides use.The U.S. Patent number 8,969,375 of Lai et al. discloses CDK9 kinase inhibitions The use of agent, such as 4- [1- (3- luorobenzyls) -2,3- dihydro -1H- indoles -6- bases] -2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridine；1- (3- luorobenzyls) -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- benzos Imidazoles；1- benzyls -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- indoles -3- nitriles；1- (3- fluorine Benzyl) -6- { 2- [1- (methyl sulphonyl) piperidin-4-yl] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1H- benzimidazoles； 6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1- (tetrahydrochysene -2H- pyrans -4- ylmethyls) -1H- benzos Imidazoles；6- { 2- [1- (methyl sulphonyl) piperidin-4-yl] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1- (tetrahydrochysene -2H- pyrroles Mutter -4- ylmethyls) -1H- benzimidazoles；5- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -3- (tetrahydrochysene - 2H- pyrans -4- ylmethyls) -3H- imidazos [4,5-b] pyridine；1- (3- luorobenzyls) -6- [2- (piperidin-4-yl) -1H- pyrroles And [2,3-b] pyridin-4-yl] -1H- indoles -3- nitriles；4- [the fluoro- 1- of 5- (3- luorobenzyls) -1H- indoles -6- bases] -2- (piperidines - 4- yls) -1H- pyrrolo-es [2,3-b] pyridine；6- { 2- [1- (2,3- dihydroxypropyl) piperidin-4-yl] -1H- pyrrolo-es [2,3- B] pyridin-4-yl } -1- (3- luorobenzyls) -1H- indoles -3- nitriles；1- (3- luorobenzyls) -6- 2- [1- (methyl sulphonyl) piperidines - 4- yls] -1H- pyrrolo-es [2,3-b] pyridin-4-yl } -1H- indoles -3- nitriles；And 1- [(5- fluorine pyridin-3-yl) methyl] -6- [2- (piperidin-4-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl] -1H- benzimidazoles.The U.S. of Marchionni et al. is special Profit number 8,969,366 discloses the use of substituted pyrimidine radicals pyrrolopyridinone derivatives.The U.S. of Charrier et al. is special Profit number 8,969,360 discloses the use of ATR kinase inhibitors.The U.S. Patent number 8,969,335 of Hoelzemann et al. is public The use of IKK ε and the TBK1 inhibitor including benzonitrile derivative is opened.The U.S. Patent number 8,969,313 of Yu discloses The use of DACT protein activators.The U.S. Patent number 8,962,855 of Chen et al. discloses the application of nitrogen mustard derivatives.Wang Et al. U.S. Patent number 8,962,679 disclose the uses of the daidzein derivatives including alkoxy benzopyran-4-one ketone. The U.S. Patent number 8,962,663 of Mahadevan et al. discloses pleckstrin (pleckstrin) homology structure The use of domain inhibitor.The U.S. Patent number 8,962,642 of Mortimore et al. discloses 5- cyano group -4- (pyrrolo-es [2,3- B] pyridin-3-yl) pyrimidine derivatives use.The U.S. Patent number 8,962,637 of McAllister et al. is disclosed as c- The use of the substituted aromatic bicyclic compound of SRC/JAK inhibitor.8,962,630 disclosure of U.S. Patent number of Brain et al. As CDK kinases inhibitors include 7- cyclopenta -2- (5- piperazines -1- bases-pyridine -2- bases amino) -7H- pyrrolo-es The use of the Pyrrolopyrimidine compounds of [2,3-d] pyrimidine -6- carboxylic acid dimethylamides.The U.S. Patent number 8 of Kuntz et al., 962,620 disclose the use of substituted 6,5- fused bicyclic aryl compounds.The U.S. Patent number 8,962 of Ashwell et al., 619 disclose the use of substituted imidazopyridyl-aminopyridine compounds.The U.S. Patent number of Christopher et al. 8,962,611 disclose the use of the substituted imidazopyridine as HDM2 inhibitor.The United States Patent (USP) of Brubaker et al. Numbers 8,962,608 disclose the use of the cycloalkyl nitrile pyrazole amide as janus kinase inhibitors.Schoeberl's et al. U.S. Patent number 8,961,966 discloses the use of anti-ERBB3 (receptor tyrosine protein kinase) antibody.Heaton's et al. U.S. Patent number 8,957,109 discloses the use of chroman derivatives.The U.S. Patent number 8 of Dannhardt et al., 957,103 disclose conjugation 3- (indyl)-and 3- (azaindolyl) -4- aryl maleimide compounds.Kim's et al. U.S. Patent number 8,957,102 discloses the use of c-Met inhibitor, including 1,5- dimethyl -3- oxo -2- phenyl -2,3- Dihydro-1 h-pyrazole -4- carboxylic acids [the fluoro- 4- of 3- (2- phenyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide)-phenyl]-acid amides； 2- (4- fluoro-phenyls) -1,5- dimethyl -3- oxo -2,3- dihydro-1 h-pyrazole -4- carboxylic acid [the fluoro- 4- of 3- (2- phenyl -1H- pyrroles Cough up simultaneously [2,3-b] pyridin-4-yl epoxide]-phenyl]-acid amides；2- (4- fluoro-phenyls) -1,5- dimethyl -3- oxos -2,3- bis- Hydrogen -1H- pyrazoles -4- carboxylic acids [the fluoro- 4- of 3- (3- phenyl -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide)-phenyl]-acid amides；N- (the fluoro- 4- of 3- (2- (thiophene -2- bases) -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide) phenyl) -2- (4- fluorophenyls) -1,5- Dimethyl -3- oxo -2,3- dihydro-1 h-pyrazole -4- acid amides；And N- (the fluoro- 4- of 3- (2- (thiene-3-yl) -1H- pyrrolo-es [2,3-b] pyridin-4-yl epoxide) phenyl) -2- (4- fluorophenyls) -1,5- dimethyl -3- oxo -2,3- dihydro-1 h-pyrazoles -4- Acid amides.The U.S. Patent number 8,957,078 of Brenchley et al. discloses the pyrazolopyrimidine as ATR kinase inhibitors Use.The U.S. Patent number 8,957,068 of Caferro et al. discloses 3- pyrimidine-4-yls-evil as mutation IDH inhibitor The use of oxazolidine -2- ketone.The U.S. Patent number 8,957,056 of Danishefsky et al. discloses Charles McGrath statin (Migrastatin) use of analog.The U.S. Patent number 8,956,613 of Wu et al. discloses making for gemcitabine prodrug With.The U.S. Patent number 8,952,163 of Blackburn et al. is disclosed as HDAC6 (histone deacetylase 6) inhibitor The use of substituted hydroxamic acid.The U.S. Patent number 8,952,161 of Beaton et al. discloses gonadotropin-releasing hormone (GRH) The use of receptor antagonist.The U.S. Patent number 8,952,157 of Ding et al. discloses making for anti-apoptotic Bcl-2 protein inhibitors With, such as 4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2,3- bis- Fluorophenoxy)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；2- (4- amino- 3- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；4- (4- [2- (4- chlorphenyls) -4, 4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2,5- dichlorophenoxy)-N- ({ 4- [(3- morpholine -4- bases Propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；N- (4- ((4- amino tetrahydrochysene -2H- pyrans -4- bases) methyl ammonia Base) -3- nitrophenylsulfonyls) -2- (3- chlorophenoxies) -4- (4- ((2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene Base) methyl) piperazine -1- bases) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases) -2- (3- fluorophenoxies)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzene Formamide；2- (2- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine - 1- yls)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；2- (the chloro- 4- fluorobenzene of 2- Epoxide) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } piperazine -1- bases)-N- ({ 4- [(3- Morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyl Hexamethylene -1- alkene -1- bases] methyl } piperazine -1- bases) -2- (2- fluorophenoxies)-N- (4- [(3- morpholine -4- bases propyl group) amino] - 3- nitrobenzophenones } sulfonyl) benzamide；4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases) -2- (2- fluorophenoxies)-N- ({ 4- [(2- morpholine -4- bases ethyl) amino] -3- nitrobenzophenones } sulfonyl) benzene Formamide；And 2- (3- chlorophenoxies) -4- (4- { [2- (4- chlorphenyls) -4,4- dimethyleyelohexane -1- alkene -1- bases] methyl } Piperazine -1- bases)-N- ({ 4- [(3- morpholine -4- bases propyl group) amino] -3- nitrobenzophenones } sulfonyl) benzamide.Kufe et al. U.S. Patent number 8,952,054 disclose MUC1 oligomerizations micromolecular inhibitor such as chromocor derivative use. The U.S. Patent number 8,952,043 of Blaquiere et al. discloses Ben Bing Evil heptan makes because of (benzoxepin) PI3K inhibitor With.The U.S. Patent number 8,951,987 of Hamilton et al. discloses the use of tetrahydrouridine derivative.U.S. of Combs et al. State's patent No. 8,951,536 discloses making for the N- hydroxyamidines heterocyclic compounds of the conditioning agent as indoleamine 2,3-dioxygenase With.The U.S. Patent number 8,946,445 of Wang et al. discloses the use of heterocycle apoptosis inhibitor, such as (Z) -5- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thienos [3,2-b] pyrroles (Z) the chloro- 5- of -2- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thiophenes Fen simultaneously [3,2-b] pyrroles；(Z) -5- (2- ((3,5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles - 5- yls) -2- methyl -4H- thienos [3,2-b] pyrroles；(Z) (((3,5- dimethyl -1H- pyrroles -2- bases) is sub- by 2- by the bromo- 5- of -2- Methyl) -3- methoxyl group -2H- pyrroles -5- bases) -4H- thienos [3,2-b] pyrroles；(Z) -5- (2- ((3,5- dimethyl -1H- pyrroles Cough up -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -6H- thienos [2,3-b] pyrroles；And (Z) -5- (2- ((3, 5- dimethyl -1H- pyrroles -2- bases) methylene) -3- methoxyl group -2H- pyrroles -5- bases) -2- methyl -6H- thienos [2,3-b] Pyrroles.The U.S. Patent number 8,946,413 of Hughes et al. discloses the 3- amino cyclopentyls as chemokine receptor anagonists The use of alkane formamide.The U.S. Patent number 8,946,409 of Becker et al. discloses the use of polycyclic beta-lactam derivatives. The U.S. Patent number 8,946,289 of Hong et al. discloses the Ma Nishating for blocking HIF (hypoxia inducible factor) path (Manassatin) use of compound.The U.S. Patent number 8,946,278 of Seefeld et al. discloses as AKT that (albumen swashs Enzyme B) inhibitor Heterocyclylcarboxamderivatives use, such as N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } second Base) the chloro- 4- of -5- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) Phenyl] methyl } ethyl) -4- (the bromo- 1- methyl isophthalic acids H- pyrazoles -5- bases of 4-) -5- methyl -2- thenoyl amines；N- ((1S) -2- ammonia Base -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -4- (the chloro- 1-- methyl isophthalic acids H- pyrazoles -5- bases of 4-) -5- methyl -2- thiophenes Fen formamide；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) chloro- 4- of -5- (the chloro- 1- methyl of 4- - 1H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -4- (the bromo- 1- methyl isophthalic acids H- pyrazoles -5- bases of 4-) chloro- 2- thenoyl amines of -5-；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) Phenyl] methyl } ethyl) -5- methyl -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) the chloro- 4- of -5- (1- ethyl -1H- pyrazoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) the chloro- 4- of -5- (Isosorbide-5-Nitraes-dimethyl -1H- pyrazoles -5- Base) -2- thenoyl amines；N- { (1S) -2- amino -1- [(3- fluorophenyls) methyl] ethyl } the chloro- 4- of -5- (1- methyl isophthalic acid H- pyrroles Azoles -5- bases) -2- thenoyl amines；N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] methyl } ethyl) -5- ethyls - 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -2- thenoyl amines；And N- ((1S) -2- amino -1- { [2- (trifluoromethyl) phenyl] Methyl } ethyl) -4- (Isosorbide-5-Nitrae-dimethyl -1H- pyrazoles -5- bases) -5- methyl -2- thenoyl amines.The United States Patent (USP) of Curd et al. Numbers 8,946,205 disclose the use of anoxic activation prodrug, including N, N '-bis- (2- bromoethyls) phosphatide amic acid (phosphorodamidic acid) (1- methyl -2- nitro -1H- imidazoles -5- bases) methyl esters.The United States Patent (USP) of Gangjee et al. Numbers 8,946,239 disclose substituted pyrrolo--, furans simultaneously-, and the use of cyclopenta pyrimidine dicyclic compound. The U.S. Patent number 8,946,235 of Butterworth et al., which discloses 2- (2,4,5- substituted 2-znilino) pyrimidine compound, to be made With.The U.S. Patent number 8,946,224 of Craighead et al. discloses making for substituted [1,2,4] triazol [4,3-a] pyrazine With.The U.S. Patent number 8,946,216 of Deng et al. discloses the use of the indazole derivative as ERK inhibitor, including N- [3- [6- (1- methyl ethoxies) -3- pyridine radicals] -1H- indazole -5- bases] -4- (phenyl methyl) -2- morpholine formamides；N-[3- [6- (1- methyl ethoxies) -3- pyridine radicals] -1H- indazole -5- bases] -2- morpholine formamides；N- [3- (4- pyridine radicals) -1H- Yin Azoles -5- bases] -4- (4- benzothiazolylmethyls) -2- morpholine formamides；N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -4- (3- thiophenes Fen ylmethyl) -2- morpholine formamides；4- [(2- fluorophenyls) methyl]-N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -2- Quinoline formamide；N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -4- (2- pyridylmethyls) -2- morpholine formamides；N-[3-(4- Pyridine radicals) -1H- indazole -5- bases] -4- (2- pyridylmethyls) -2- morpholine formamides；And 4- [(2- bromophenyls) methyl]-N- [3- (4- pyridine radicals) -1H- indazole -5- bases] -2- morpholine formamides.The U.S. Patent number 8,940,936 of Lee et al. discloses virtue The use of epoxide phenoxy group acyclic compound.The U.S. Patent number 8,940,760 of Page et al. is disclosed to be aoxidized as NADPH The use of the pyrazolo pyridine derivatives of enzyme inhibitor.The U.S. Patent number 8,940,756 of Flynn et al. is disclosed as c- The use of the dihydronaphthridine of Kit inhibitor.The U.S. Patent number 8,940,737 of Wang et al. discloses cell death inducer Use, such as 6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- (1- benzyls Base -1H- pyrazoles -4- bases) pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro isoquinolines Quinoline -2 (1H)-yl] -3- [1- (pyridin-4-yl methyl) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1,3- benzo thiophenes Azoles -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (pyridin-3-yl methyl) -1H- pyrazoles -4- Base] pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (4- hydroxybenzyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) - - 2 (1H)-yl of 3,4- dihydro-isoquinoline] -3-- [1- (1- phenylethyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；6- [8- (1, 3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- (1- { 4- [2- (dimethylamino) second Epoxide] benzyl } -1H- pyrazoles -4- bases) pyridine-2-carboxylic acids；{ [(5,6- bis- is fluoro- by 8- by -6- by 3- (1- benzyl -1H- pyrazoles -4- bases) 1,3- benzothiazole -2- bases) carbamoyl] -3,4- dihydro-isoquinolines -2 (1H)-yl } pyridine-2-carboxylic acids；6- [8- (1,3- Benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- { 1- [2- (4- fluorophenyls) ethyl] -1H- Pyrazoles -4- bases } pyridine-2-carboxylic acids；6- [8- (1,3- benzothiazole -2- bases carbamoyl) -3,4- dihydro-isoquinolines -2 (1H)-yl] -3- [1- (3- chlorobenzyls) -1H- pyrazoles -4- bases] pyridine-2-carboxylic acids；And 3- (1- benzyl -1H- pyrazoles -4- Base) -6- { 8- [(fluoro- 1, the 3- benzothiazoles -2- bases of 6-) carbamoyl] -3,4- dihydro-isoquinolines -2 (1H)-yl } pyridine -2- Carboxylic acid.The U.S. Patent number 8,940,733 of Howard et al. discloses making for asymmetric Pyrrolobenzodiazepines dimer Zhuo With.The U.S. Patent number 8,940,726 of Duncan et al. discloses the use of PRMT5 inhibitor.U.S. of Pellecchia et al. State's patent No. 8,937,193 discloses the use of ApoG2 (Apogossypolone) derivative.Burlison et al. U.S. Patent number 8,937,094 disclose the uses of Hsp90 conditioning agents, including 5- (4- ethyoxyl -2- hydroxy phenyls) -4- (4- (morpholinomethyl) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- methoxyphenyls) -4- (4- ( Quinoline is for methyl) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- propoxyphenyls) -4- (4- (morpholino first Base) phenyl) -4H-1,2,4- triazole -3- formamides；5- (2- hydroxyl -4- isopropyl phenyls) -4- (4- (morpholinomethyl) benzene Base) -4H-1,2,4- triazole -3- formamides；5- (2,4- Dimethoxyphenyl) -4- (4- (morpholinomethyl) phenyl) -4H-1, 2,4- triazole -3- formamides；5- (2- hydroxyl -4- isopropyl phenyls) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- first Acid amides；5- (2- hydroxy-4-methyls phenyl) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；5- (4- hydroxyls- 3- isopropyl phenyls) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；5- (3- tertiary butyl-4-hydroxy benzene Base) -4- (4- methoxyphenyls) -4H-1,2,4- triazole -3- formamides；And 5- (4- hydroxyl -3- propyl group phenyl) -4- (4- first Phenyl) -4H-1,2,4- triazole -3- formamides.The U.S. Patent number 8,937,068 of Seipelt et al. discloses pyrido The use of pyrazine compound.The U.S. Patent number 8,933,212 of Fayard et al. discloses to reduce the protease of transfer The use of nexin1 inhibitor.The U.S. Patent number 8,933,116 of Wu et al. discloses inhibitors of gamma-secretase.Ohki et al. U.S. Patent number 8,933,103 disclose Pyridione derivatives Axl inhibitor use, including N- { 4- [2- amino -5- (3,4- Dimethoxyphenyl) pyridin-3-yl] phenyl } -5- (4- fluorophenyls) -4- oxos -1- (2,2,2- trifluoroethyl)-Isosorbide-5-Nitrae - Dihydropyridine -3- carboxamide hydrochlorides.The U.S. Patent number 8,933,084 of Andrews et al. is disclosed as Trk inhibitor The use of macrocyclic compound, such as fluoro- 2,11,15,19,20,23- six azepine five rings [15.5.2.1 of (6R) -9-^7,11.0^{2, 6}.0^20,24] pentacosane -1 (23), 7,9,17 (24), 18,21- hexene -16,25- diketone.The U.S. Patent number of Singh et al. 8,933,080 disclose the use of the triazole of the bridging bicyclic heteroaryl substitution as Axl inhibitor.U.S. of McGuigan et al. State's patent No. 8,933,053 discloses the use of the Phosphoramidate derivatives of the fluoro- 2 '-BrdUs of 5-.Sasaki et al. U.S.s State's patent No. 8,927,718 discloses the use of the condensed heterocyclic derivates as Smo (transmembrane protein) inhibitor, including 3,6- Diethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1- methyl -4- oxos -5- (2- oxo -2- phenylethyls) -4,5- bis- Hydrogen -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide；3- vinyl -6- ethyls-N- [1- (hydroxyacetyl) piperidin-4-yl] - 1- methyl -4- oxos -5- (2- oxo -2- phenylethyls) -4,5- dihydro -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide；With And 6- ethyls -3- (ethylamino)-N- [1- (hydroxyacetyl) piperidin-4-yl] -1- methyl -4- oxos -5- (2- oxos -2- Phenylethyl) -4,5- dihydro -1H- pyrrolo-es [3,2-c] pyridine-2-carboxamide.Huang et al. U.S. Patent numbers 8,927,717 Disclose the use of thiochromene simultaneously [2,3-c] quinoline -12- ketone derivatives, including 3- ((4- chlorphenyls) is thio) -2- hydroxyl quinolines Quinoline -4- carboxylic acids, 6,9- bis- chloro- 12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- hydroxyls -12H- thiochromenes of 10- simultaneously [2, 3-c] quinoline -12- ketone, the chloro- 6- methoxyl groups -12H- thiochromenes of 10- simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- dimethylaminos of 10- Base -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- of 10- (piperazine -1- bases) -12H- thiochromenes simultaneously [2,3-c] quinoline - 12- ketone, the chloro- 6- of 10- (4- methylpiperazine-1-yls) -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, 10- chloro- 6- (4- ethyls Piperazine -1- bases) -12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, the chloro- 6- of 10- (4- (2- hydroxyethyls) piperazine -1- bases) - 12H- thiochromenes simultaneously [2,3-c] quinoline -12- ketone, and 6- (4- benzyl diethylenediamine -1- bases) chloro- 12H- thiochromenes of -10- simultaneously [2,3- C] quinoline -12- ketone.Abraham et al. U.S. Patent numbers 8,927,711 disclose the use of quinazoline JAK inhibitor, including (3- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinazoline -2- bases) ketone；(4- (1H- pyrazole-3-yls amino) Quinazoline -2- bases) (3- fluorophenyls) ketone；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinazoline -2- bases) Ketone；(4- (1H- pyrazole-3-yls amino) quinazoline -2- bases) (4- fluorophenyls) ketone；(4- (1H- pyrazole-3-yls amino) quinoline Oxazoline -2- bases) (2- methoxyphenyls) ketone；(4- (1H- pyrazole-3-yls amino) quinazoline -2- bases) (4- fluorophenyls) methanol； 2- (fluorine (4- fluorophenyls) methyl)-N- (1H- pyrazole-3-yls) quinazoline -4- amine；2- (difluoro (4- fluorophenyls) methyl)-N- (5- Methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine；2- (difluoro (4- fluorophenyls) methyl)-N- (1H- pyrazole-3-yls) quinazoline- 4- amine；N- (5- cyclopropyl -1H- pyrazole-3-yls) -2- (difluoro (4- fluorophenyls) methyl) quinazoline -4- amine；3- (2- (4- fluorobenzene Formoxyl) quinazoline -4- bases amino) -1H- pyrazoles -5- nitriles；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinoline Oxazoline -2- bases) methanol；2- ((4- fluorophenyls) (methoxyl group) methyl)-N- (5- methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine； 2- (amino (4- fluorophenyls) methyl)-N- (5- methyl isophthalic acid H- pyrazole-3-yls) quinazoline -4- amine；3- (2- ((4- fluorophenyls) (hydroxyls Base) methyl) quinazoline -4- bases amino) -1H- pyrazoles -5- nitriles；(the fluoro- 4- of 5- (5- methyl isophthalic acid H- pyrazole-3-yls amino) quinoline azoles Quinoline -2- bases) (4- fluorophenyls) methanol；(4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) -7- (trifluoromethyl) quinoline Oxazoline -2- bases) ketone；And (4- fluorophenyls) (4- (5- methyl isophthalic acid H- pyrazole-3-yls amino) -7- (trifluoromethyl) quinazoline - 2- yls) methanol.The U.S. Patent number 8,927,580 of Richardson et al. discloses such as two -2- pyridyl ketone 4- ethyls -4- The use of double pyridine radicals thiosemicarbazones of methyl -3- thiosemicarbazones.8,927,562 disclosure of U.S. Patent number of Meng et al. The use of mTOR fused tricyclic inhibitor.The U.S. Patent number 8,927,560 of Ahmed et al. discloses 4- azepines -2,3- bis- The use of dehydrogenation podophyllotoxin compounds.Ying et al. U.S. Patent numbers 8,927,548 disclose the triazole of Hsp90 inhibitor The use of compound.The U.S. Patent number 8,927,538 of Kamal et al. disclose using carbazole connect pyrrolo- [2,1-c] [1, 4] benzodiazepine heterocomplex as with DNA react with formed N2- guanine adducts reagent use, the N2- birds Purine adduct is located in the ditch of duplex DNA, and parent is incorporated at N10-C11 by acid amides unstable under acid condition Electronics imines.Giannini et al. U.S. Patent numbers 8,927,533 disclose lactams substitution contain sulfur derivatives.Flynn etc. People's U.S. Patent number 8,921,565 discloses the use of the pyridine keto-amide as c-Met kinase inhibitor, such as N- (4- ((2- acetylaminos pyridin-4-yl) epoxide) -2,5- difluorophenyls) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxos -1,2- bis- Pyridinium hydroxide -3- formamides；N- (2,5- bis- fluoro- 4- ((2- propionamidos pyridin-4-yl) epoxide) phenyl) -4- ethyoxyl -1- (4- Fluorophenyl) -2- oxo -1,2- dihydropyridine -3- formamides；N- (4- (2- (cyclopropanecarbonyl amino) pyridin-4-yl) epoxide)- 2,5- difluorophenyls) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides, (2,5- bis- is fluoro- by N- 4- ((2- trimethyl-acetyls pyridin-4-yl) epoxide) phenyl) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxos -1,2- bis- Pyridinium hydroxide -3- formamides, N- (2,5- bis- fluoro- 4- ((2- isobutyrimide yl pyridines -4- bases) epoxide) phenyl) -4- ethyoxyls -1- (4- fluorophenyls) -2- oxo -1,2- dihydropyridine -3- formamides.The U.S. Patent number 8,921,522 of Kamal et al. discloses The use of benzothiazole derivant, including the alkene being connected with 2- phenylbenzothiazols, chalcone, pyrazoline, pyrazoles, isoxazole Quinoline, and isoxazole.The U.S. Patent number 8,921,546 of Chao et al. discloses the use of Imidazothiazole, such as 7- (2- Quinoline -4- bases-ethyoxyl) -2- (4- nitro-phenyls) imidazo [2,1-b] [1,3] benzothiazole and 4- (7- (2- morpholino second Epoxide) benzo [d] imidazo [2,1-b] thiazol-2-yl) aniline.8,921,414 disclosure of U.S. Patent number of Reddell et al. The use of spiroketal.The U.S. Patent number 8,921,407 of Ying et al. discloses the pyrazoles chemical combination as Hsp90 conditioning agents The use of thing.The U.S. Patent number 8,921,367 of Friberg et al. discloses the AMG900 (N- as aurora kinase inhibitors (4- (3- (2- aminopyrimidine -4- bases) pyridine -2- bases epoxide) phenyl) -4- (4- methylthiophene -2- bases) phthalazines -1- amine) make With.The U.S. Patent number 8,920,799 of Graham et al. discloses the Axl ligand binding moieties of Axl tyrosine kinase receptors Use.The U.S. Patent number 8,778,340 of Dupont et al. discloses the use of the anti-angiogenic agent including antibody. The U.S. Patent number 8,748,470 of Lengyel et al. discloses the use of fatty acid binding protein inhibitor, including carbazole fourth Acid, aryl sulfonic acid amides, sulfonyl thiophene, 4- hydroxy pyrimidines, 2,3- dimethyl indoles, Benzoylbenzene, xenyl-alkanoic acid, 2- oxazoles-alkanoic acid, tetrahydro pyrimidine ketone, pyridone, pyrazinones, aryl carboxylic acid, tetrazolium, triazolopyrimidones, indoles, BMS480404 ((2S) -2- [2,3- double [(2- chlorphenyls) methoxyl group] phenyl] -2- hydroxyacetic acids), or BMS309403 (2- [[2 '-(5- ethyl -3,4- diphenyl -1H- pyrazol-1-yls) [1,1 '-xenyl] -3- bases] epoxide]-acetic acid]).Clozel etc. The U.S. Patent number 8,541,433 of people discloses the use of macitentan.The U.S. Patent number 8,362,072 of Jensen et al. is public The use of BRCA1 (mammary cancer 1 albumen) generation reinforcing agents is opened.The U.S. Patent number 8,268,889 of Kloog et al. discloses The use of farnesyl- thiosalicylic acid and the like.

The U.S. Patent number 7,968,514 of Coelingh Bennink et al. discloses the use of immunogenic peptide. The U.S. Patent number 7,323,164 of Chandrasekher et al. discloses the use of interleukin 24.Chandrasekher Et al. U.S. Patent number 7,074,575 disclose the use of interleukin 19.The U.S. Patent number 6 of Miller et al., 237,307 disclose the use of 2- phenyl -1- [4- (2- amino ethoxies)-benzyl]-indole derivatives.U.S. of Howell et al. State's patent No. 5,597,798 discloses the use with the combination of taxol and epidermal growth factor.The United States Patent (USP) of Frederick Application publication number 2014/0336150 discloses karenitecin (- 20 (S) camplotheca acuminatas of 7- [(2 '-trimethyl silyl) ethyl] Alkali) use.The U.S. Patent Application Publication No. 2014/0315959 of Moore et al. discloses making for benzylidenei benzo hydrazides With.The U.S. Patent Application Publication No. 2014/0309184 of Rocconi et al. disclose Smo inhibitor with it is other including platiniferous medicine The use of the drug regimen of the medicine of thing.The U.S. Patent Application Publication No. 2014/0302174 of Chan et al. discloses and Ji Xi His shore, cis-platinum or carboplatin and 5- [the 2- tert-butyl groups -5- (4- fluoro-phenyls) -1H- imidazol-4 yls] -3- (2,2- dimethyl-the third Base) -3H- imidazos [4,5-b] pyridine -2- base amine therapeutic alliance.The U.S. Patent Application Publication No. 2014/ of Moore et al. 0275174 discloses the use of 2- amino -4H- naphtho-s [1,2-b] pyrans -3- nitriles.The U.S. Patent application of Kuhnert et al. is public The number of opening 2014/0134169 discloses the use of Dll4 antagonists.The U.S. Patent Application Publication No. 2013/0231286 of Chen is public The use of prolactin receptor antagonist is opened.The U.S. Patent Application Publication No. 2013/0203861 of Liu et al. people discloses hexamethylene The use of ketene compound.The U.S. Patent Application Publication No. 2012/0269827 of Whiteman et al. discloses the knot with CD56 The use of compound.The U.S. Patent Application Publication No. 2012/0237502 of Darnowski discloses 17,20- lyase inhibitors The use of example, such as 3 β-acetoxyl group -17- (3- pyridine radicals) androstane -5,16- diene, 6- [(7S) -7- hydroxyls -6,7- dihydro - 5H- pyrrolo-es [1,2-c] imidazoles -7- bases]-N- methyl -2- naphthalenecarboxamides, 3 beta-hydroxyl-17s-(1H- benzimidazole -1- bases) hero Steroid -5,16- diene, or 6- [(7S) -7- hydroxyls -6,7- dihydro -5H- pyrrolo-es [1,2-c] imidazoles -7- bases]-N- methyl -2- naphthalenes Formamide.The U.S. Patent Application Publication No. 2012/0183546 of Weinreich discloses making for angiopoietin-2 inhibitor With.The U.S. Patent Application Publication No. 2010/0009330 of Sherman et al. is disclosed including 4- iodo -3- nitrobenzamides PARP inhibitor use.The U.S. Patent Application Publication No. 2009/0118271 of Umeda et al. discloses Water-soluble precursor The use of medicine, for example, (9S) -1- butyl -9- ethyl -9- hydroxyls -1H, 12H- pyrans simultaneously [3 ', 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2′:6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -9- ethyl -9- hydroxyls -1- [2- (4- morpholinoes) ethyl] -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2- De] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -1- [3- (dimethylamino) propyl group] -9- ethyl -9- hydroxyls - 1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketone；(9S) -9- ethyl -9- hydroxyl -1- phenethyls -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2′:6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -9- ethyl -9- hydroxyls -1- [2- (pyridine -2- bases) ethyl] -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2- De] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；(9S) -9- ethyl -1- heptyl -9- hydroxyls -1H, 12H- pyrans simultaneously [3 ", 4″:6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones；And (9S) -9- ethyl -9- hydroxyl -1- propyl group -1H, 12H- pyrans simultaneously [3 ", 4 ":6 ', 7 '] indolizine simultaneously [1 ', 2 ':6,5] pyrido [4,3,2-de] quinazoline -2,10,13 (3H, 9H, 15H)-triketones.The U.S. Patent Application Publication No. 2009/ of Ye et al. The use of ginkgolides disclosed in 0099102, including ginkalide A and ginkolide B.The U.S. Patent application of Zeldis is public The number of opening 2007/0299020 discloses 4- (amino) -2, and (2,6- dioxos (3- piperidyls)-isoindoline -1,3- diketone makes With.The use of anti-aramine (antialamin) disclosed in the U.S. Patent Application Publication No. 2006/0058217 of White et al.. The U.S. Patent Application No. 2005/0272766 of Koya et al. discloses 1- acetaldehyde amide indolizine (1-glyoxylamide Indolizine use).These patents and patent applicationss are disclosed to be integrally incorporated herein by quoting.

Another aspect of the present invention is that a kind for the treatment of is suffered from selected from by II phases non-small cell lung cancer (NSCLC), III phases The method of the patient of the malignant tumour of the group of NSCLC and IV phases NSCLC compositions, this method comprise the following steps：

(a) to a effective amount of two to the water wei ling alcohol of patient therapeuticallv to treat the malignant tumour；And

(b) to patient therapeuticallv it is a effective amount of based on the antitumor agent of platinum to treat the malignant tumour.

In the method, in a kind of alternative solution, two to the water wei ling alcohol is applied after surgery excision NSCLC and is based on The antitumor agent of platinum.In another alternative solution, two to the water wei ling alcohol is applied before surgery excision NSCLC and based on platinum Antitumor agent to make Tumor shrank before surgery.

Brain metastes may occur for patient.This method is especially effective to the NSCLC patient for having been acknowledged or suspecting brain metastes.

In a kind of alternative solution, the two to the water wei ling alcohol and it is described based on the antitumor agent of platinum single medicine combine Applied in thing, wherein described pharmaceutical composition includes：(i) two to the water wei ling alcohol；(ii) antitumor agent based on platinum；And (iii) at least one pharmaceutically acceptable carrier.In another alternative solution, the two to the water wei ling alcohol and described it is based on The antitumor agent of platinum is applied in two kinds of pharmaceutical compositions：(i) include two to the water wei ling alcohol and at least one is pharmaceutically acceptable Carrier the first pharmaceutical composition；And (ii) includes the antitumor agent based on platinum and at least one pharmaceutically acceptable load Second pharmaceutical composition of body.

Patient can have the genotype of wild type p53.In another alternative solution, patient can have mutation P53 genotype；As the example shows, the mutation in p53 causes the resistance of two to the water wei ling alcohol is less than to Temozolomide or contained The resistance of platinum antineoplastic medicine, therefore two to the water wei ling alcohol is particularly effective such patient.The work of p53 is further elucidated below With.

In another alternative solution, patient can have the genotype of Wild type EGFR.

In another alternative solution, patient is in target of the coding as at least one tyrosine kinase inhibitor (TKI) Protein gene in there is at least one mutation.In another alternative solution, patient is characterized in that thering is at least one A other gene in wild type or mutation status, the gene code are assigned to the therapeutic effect of at least one TKI The product of resistance.The coding in wild type or mutation status is assigned to the another of the resistance of at least one TKI therapeutic effects Outer gene is AHI-1.The mutation of AHI-1 can be caused by provirus is inserted into.

In another alternative solution, patient is characterized by having one of the BCR-ABL fusion proteins as TKI targets Mutation in partial ABL1 protein kinase domains.

In another alternative solution, patient is characterized by having assigning tyrosine kinase inhibitor (TKI) resistance Germline deletion polymorphism (germline deletion polymorphism).Usually, germline DNA deletion polymorphisms are positions In the germline DNA deletion polymorphisms of the 2903bp of BIM genes, germline DNA deletion polymorphisms cause spliced variants, the spliced variants Expression is caused to lack BH₃The isotype of the BIM albumen of domain, so as to suppress the induction of Apoptosis.

Usually, platiniferous antitumor agent is selected from by cis-platinum, carboplatin, oxaliplatin, satraplatin (satraplatin), pyrrole Platinum (picoplatin), Nedaplatin (nedaplatin), three platinum (triplatin), lobaplatin (lobaplatin), eptalatin (heptaplatin) and cisplatin liposome (lipoplatin) composition group.Preferably, platiniferous antitumor agent be selected from by cis-platinum, The group of carboplatin and oxaliplatin composition.Particularly preferred platiniferous antitumor agent is cis-platinum.

In another alternative solution, the dosage of two to the water wei ling alcohol and platiniferous antitumor agent cause two to the water wei ling alcohol and Platiniferous antitumor agent plays synergistic effect.

Another aspect of the present invention is pharmaceutical composition, including：

(1) two to the water wei ling alcohol of therapeutically effective amount；

(2) the platiniferous antitumor agent of therapeutically effective amount；And

(3) alternatively, at least one pharmaceutically acceptable carrier.

Described pharmaceutical composition can be prepared to be selected from by II phases non-small cell lung cancer (NSCLC), III phases for treatment The malignant tumour of the group of NSCLC and IV phases NSCLC compositions.Also described pharmaceutical composition can be prepared brain turn has occurred for treatment Malignant tumour move, selected from the group being made of II phases non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC.

In another alternative solution for being used for pharmaceutical composition, the dosage of two to the water wei ling alcohol and platiniferous antitumor agent makes Obtain two to the water wei ling alcohol and platiniferous antitumor agent plays synergistic effect.

It is usually described pharmaceutically acceptable when described pharmaceutical composition includes at least one pharmaceutically acceptable carrier Carrier be selected from by water-based and non-aqueous solvent, decentralized medium, coating, antibacterium and/or antifungal agent and isotonic and/or inhale Receive the group that delayed-action activator is formed.

Pharmaceutical composition can be formulated for parenteral administration, and other methods of administration are possible.

In another alternative, said composition can include at least one p53 analogies.It is set forth below and serves as The compound of p53 analogies.

Another aspect of the present invention be treatment suffer from be selected from by II phases non-small cell lung cancer (NSCLC), III phases NSCLC and The method of the patient of the malignant tumour of the group of IV phases NSCLC compositions, wherein the patient has the p53 genes of mutation, this method Comprise the following steps：

(1) propagation and/or evil of the presence of patient's body Mutation p53 gene, wherein Mutation p53 effect gene malignant tumour are determined Resistance of the property tumour at least one antitumor agent；

(2) to a effective amount of two to the water wei ling alcohol of patient therapeuticallv to treat malignant tumour, wherein the two to the water wei ling alcohol Therapeutically effective amount determined by the result of the cell line of the p53 genes with mutation；

(3) antitumor agent based on platinum a effective amount of to patient therapeuticallv to be to treat malignant tumour, wherein described based on platinum The therapeutically effective amount of antitumor agent is determined by the result of the cell line of the p53 genes with mutation；And

(4) alternatively, to a effective amount of p53 analogies of patient therapeuticallv to treat malignant tumour.

P53 genes for also referred to as TP53 in human gene prevent genome mutation and serve as tumor inhibitor. In the mankind, the mutation in p53 is generally related with the risk increase of cancer development.The gene serves as transcription factor activation agent.P53 eggs White structure includes：

(1) acidic amino acid end transcriptional activation domain, also referred to as activation structure domain 1 (AD1), its activating transcription factor (residue 1-42)；N- contains at end specificity and participates in adjusting several two complementary transcriptional activation domains for promoting apoptogene, main Domain is on residue 1-42 and secondary domain is on residue 55-75；(2) the activation structure domain 2 (residue important to apoptosis activity 43-63)；(3) domain (residue 64-92) of the Pro-rich important to p53 apoptosis activities exported by the core of MAPK； (4) the central DNA combinations Core domain (DBD) (residue 102-292) comprising a zinc atom and several arginine residues；Should Domain is responsible for corepressor (co-repressor) LMO3 with reference to p53；(5) nuclear localization signal domain (residue 316- 325)；(6) homooligomeric (homo-oligomerization) domain (OD) (residue 307-355)；Tetramerization is to internal P53's is active most important；And (7) participate in lowering the C-terminal region (residue 356-393) that the DNA of central domain is combined. The transcriptional activation domain (9aaTAD) of 9 amino acid tandems is identified in AD1 the and AD2 regions of transcription factor p53.p53 Many knockout mutationss be known.The structure and activity of p53 albumen are described in " the Crystal Structure of Y.Cho et al. of a p53 Tumor Suppressor-DNA Complex:Understanding Tumorigenic Mutations, "Science265:346-355 (1994), is incorporated herein by reference.Also have known splice variant (S.Surget's et al. “Uncovering the Role of p53Splice Variants in Human Malignancy:AClinical Perspective, "OncoTargets Ther.7：57-68 (2013), is incorporated herein by reference).A large amount of phases of known p53 Interaction；The protein is multi-functional.One special interaction is the interaction with test point kinases (" the Regulatory Interactions Between the Checkpoint Kinase of D.M.Goudelock et al. Chk1 and the Proteins of the DNA-Dependent Protein Kinase Complex ", J.Biol.Chem.278：29940-29947 (2003), is incorporated herein by reference).

Usually, the presence of patient's body Mutation p53 gene passes through selected from more by gene sequencing, Restriction Fragment Length Sample and determine whether the p53 in the cell sample from patient is combined the method for formed group to determine with pGL3 carriers. The use of pGL3 carriers is described in the PCT Patent Application publication number WO 01/96602 of the Yang being incorporated herein by reference et al.. It is other to be used to determine that the method for p53 states is disclosed in " the A New Method for Determining of A.L.Gartel et al. The Status of p53 in Tumor Cell Lines of Different Origin, "Oncol.Res.13：405- 408 (2003), are incorporated herein by reference.The U.S. Patent number 6 of Hermeking et al. is also disclosed in the measure of p53 functions, The U.S. Patent number 6 of 740,523 and Hermeking et al., 335,156, it is both incorporated herein by reference.

Substantial amounts of p53 analogies are known in the prior art, and are described in the U.S. Patent number 7,994 of Rabizadeh et al., The U.S. Patent Application Publication No. 2013/0210144 of 184 and Arora et al..

Many p53 analogies known in the art, include but not limited to following：

(i) N '-[2- [2- (4- methoxyphenyls) vinyl] -4- quinazolyls]-N, two hydrochloric acid of N- dimethyl -1,3- propane diamine Salt hydrate) (CP-31398)；

(ii) compound of formula (P-1)：

Wherein：

(A)R¹And R⁴It is each independently selected from the group consisted of：Amino, cyano group, nitro, carboxyl, halogen, hydroxyl, SO₂、 C₁-C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₈Alkoxy, C₁-C₁₁Alkoxyalkyl, C₁-C₆Alkyl amino and C₁-C₆Amino alkane Base；

(B)R²And R³It is each independently selected from the group being made of CH and N；

(C)R⁵It is CH or O；

(D)R⁶Selected from the group consisted of：Halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated, C₁- C₁₀Alkyl, have side chain or unbranched, C₁-C₁₀Alkoxy, have side chain or unbranched, C₁-C₁₀Acyl group, have side chain or Unbranched, C₁-C₁₀Acyloxy, have side chain or unbranched, C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, Aryloxy group, aryl sulfonyl, heterocyclic aryl and heterocycle aryloxy group；

(E)R⁷Selected from the group consisted of：Hydrogen, halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain Or unbranched C₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, Aryloxy group, aryl sulfonyl, heteroaryl and heteroaryloxy；

(F)R⁸Selected from the group being made of nitro, hydroxyl and carboxyl；And

(G)R⁹For methyl；Or its pharmaceutically acceptable ester or salt；

(iii) has the compound of stable, internal constraint secondary protein structure, wherein the compound has formula (P-2)：

Wherein：

(A) B is C (R¹)₂, O, S, or NR¹；

(B) each R¹Independently be hydrogen, amino acid side chain, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or Aryl alkyl；

(C)R²It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, acyl group, peptide, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkane independently of one another Base, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula The part of (P-2 (a))：

Wherein：

(1)R^2’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynes independently of one another Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m ' is zero or any numeral；

(3) b is each independently 1 or 2；And

(4) c is 1 or 2；

(D)R³Be hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, peptide, Targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl Alkyl, acyl group, peptide, targeting moiety or label), -- N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, ring independently of one another Alkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (b)) part：

Wherein：

(1)R^3’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, targeting Part or label) or-N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, virtue independently of one another Base, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m " is zero or any numeral；And

(3) d is respectively 1 or 2；

(E)R⁴For each independent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aryl alkyl；

(F) m, n ', be each independently 0,1,2,3 or 4, wherein m, n with n " ' and n's " and be 2 to 6；

(G) m " ' is 0 or 1；

(H) a is 1 or 2；

(I) o is each independently 1 or 2；And

(J) p is 1 or 2；

, wherein it is desired to meet at least one in condition：(i) m is that 1,2,3 or 4 and at least one o is 2；(ii) p is 2；(iii) m " ' is that 1 and a is 2；(iv)R²It is beta amino acids；(v)R²The part of formula (P-2 (a)), wherein m ' be at least 1 and At least one b is 2；(vi)R²It is the part of formula (P-2 (a)), wherein c is 2；(vii)R²It is the part of formula (P-2 (a)), wherein R²' it is beta amino acids；(viii)R³It is beta amino acids；(ix)R³It is the part of formula (P-2 (b)), wherein m " is at least 1 and at least One d is 2；And (x) R³It is the part of formula (P-2 (b)), wherein R³' it is beta amino acids.

Suitable platiniferous antitumor agent is as described above.In a kind of alternative solution, two to the water wei ling alcohol and containing platinum antineoplastic The dosage of agent causes two to the water wei ling alcohol and platiniferous antitumor agent to play synergistic effect.

It is illustrated by the following examples the present invention.These embodiments are included simply to illustrate that property purpose, not purport In the limitation present invention.

Embodiment 1

The interior curative effect of two to the water wei ling alcohol treatment non-small cell lung cancer is used in mice xenograft model

Background

The median overall survival of non-small cell lung cancer (NSCLC) IV phase patients is 4 months, 1 year and 5 annual survival rates difference Less than 16% and 2%.Usually first with operation followed by with tyrosine kinase inhibitor (TKI), (for example, Tarceva, Ji Fei is replaced Buddhist nun) treatment or therapeutic scheme (for example, cis-platinum) based on platinum either a program treatment NSCLC.TKI has caused EGFR to be mutated patient Very big improved result；However, TKI resistances become a notable unsatisfied medical demand, and using platinum class as base The long-term prognosis of the therapy of plinth is poor.In addition, the incidence of metastatic encephaloma is higher in NSCLC patient and prognosis is poor.

Two to the water wei ling alcohol is a kind of bifunctional alkylating agent of unique structure, its N in targeting guanine⁷When mediate It is crosslinked between DNA chain, so that different from the mechanism of action of TKI and cis-platinum.Two to the water wei ling alcohol further pass through blood brain barrier and Accumulated in tumor tissues.Two to the water wei ling alcohol shows the activity to non-small cell lung cancer in preclinical and clinical test, Combine either as single medicament and with other therapeutic schemes, it can be used for drug resistance all to illustrate two to the water wei ling alcohol NSCLC and with metastatic encephaloma NSCLC patient treatment option.

The purpose for the research reported in the present embodiment is assessed compared to the other medicines including cis-platinum, and two remove water winged euonymus Activity of the alcohol in the In vivo model of drug resistance NSCLC.Treated mouse is subject to TKI resistances (H1975) or TKI is sensitive (A549) the Rag2 mouse of the subcutaneous human lung adenocarcinoma xenograft tumours in source.

Cell line and animal

Two kinds of people's NSCLC cell lines, A549 (TKI is sensitive) and H1975 (TKI resistances), are used as female Rag2 mouse Xenograft Tumor Models.Mouse is 6 to 8 week old, weight 18 to 23g.Every group uses 10 mouse.What is be reported below is The result of A549 NSCLC cell lines.

Medicine

Cis-platinum is used in Normal Saline with the dosage of 5mg/kg.Intravenously administrable.

Two to the water wei ling alcohol is injected in 0.9% sodium chloride with the dosage of 1.5mg-6mg/kg.Intraperitoneal administration.

Research packet is shown in following table 1 (" VAL-083 " is two to the water wei ling alcohol).

Table 1

Research packet

※TA：Detectable substance；CA：Tester

Treatment originates in 100mm³To 150mm³Gross tumor volume.

Experimental design

Cell prepares and assembling cultureA549 human lung carcinoma cell lines are from American Type Culture Collecti (Cat.#CCL- 185) obtain.Cell starts from the freezing bottle of laboratory preservation, and the cell is freezed from ATCC original bottles, and is stored in liquid nitrogen In.The cell culture that using passage number be 3 to 10 generations and 80%-90% converges.Cell is being supplemented with 10% hyclone With grown in 1640 culture mediums of RPMI of the L-Glutamine of 2mL at 37 DEG C in the environment of 5%CO2.By cell according to 1:3- 1:The 8 weekly squamous subculture of amplification times.

It is with the hank's balanced salt solution of not calcic or magnesium that cell is simple for cell preparation and subcutaneous (s.c.) inoculation harvest Single flush is once.Fresh trypsin-EDTA solutions (0.25% trypsase and tetra- sodium of EDTA) are added, flask of water is kept flat Put, to ensure that cell is covered by trypsase-EDTA, and extra trypsase-EDTA is suctioned out.Make cell at 37 DEG C Stand a few minutes.Cell is observed under inverted microscope, until cellular layer disperses, fresh culture is added, takes out cell suspension 50L and with trypan blue (1：1) mix, and cytometer is carried out by using Cellometer Auto T4 full-automatic cells calculating instrument Number and cell survival rate assessment.Cell is centrifuged 7 minutes in 200 × g and suctions out supernatant.Cell is resuspended in growth medium In, to obtain 100 × 10⁶The concentration of cell/mL.For inoculation, 1 is injected at every mouse:In 1 Matrigel matrigels The volume injected of 50 μ L uses 5 × 10⁶Cell.

Tumour cellTransplant the 0th day, be implanted into tumour cell with the dimensions subcutaneous of the 50 μ L in matrigel with No. 28 syringe needles Mouse；Dorsal injection of the tumour cell in mouse.Mouse is randomized to either the group based on gross tumor volume.Before randomization The average value of the gross tumor volume of 1-5 groups is respectively 89.15mm³, 86.08mm³, 95.49mm³, 87.15mm³And 81.76mm³。

AdministrationTwo to the water wei ling alcohol (DAG) is provided as freeze-drying prods with the DAG of every bottle 40mg.For administration, add The 0.9% sodium chloride for injection brine (physiological saline) of USP levels of 5mL, to produce the DAG solution of 8mg/mL concentration.Stoste is in room Temperature stablize 4 it is small when or 4 DEG C stablize 24 it is small when.Further dilution with prepare 0.9mg/mL injection solution (0.2mL with 0.18mg/ mouse are administered；Recover liquid dilution from 8mg/mL)；The injection solution of 0.45mg/mL is (in 0.2mL with 0.09mg/ mouse Administration；1 to 2 dilution 0.9mg/mL solution)；(it is administered with the injection solution of 0.225mg/mL in 0.2mL with 0.045mg/ mouse；1 Than 2 dilution 0.45mg/mL solution).

Intravenous injectionMouse is injected required volume, to be based on individual mice weight to animal based on No. 28 syringe needles of use Predetermined close (mg/kg) is applied in injection.The volume injected of 20g mouse is 200 μ L.Mouse is subject to of short duration during intravenous injection (being less than 30 seconds) suppresses.By under thermolamp by animal kept for 1-2 minutes between a period of time realize the blood of intravenous injection Enlargement of pipe.

Intraperitoneal injectionMouse is individually weighed and (is shown in Table in intraperitoneal injection with specified injection concentration according to weight 1).The volume injected of 20g mouse is 200 μ L.Abdominal surface is cleaned with 70% isopropanol and cleans injection site.

Data acquisition

Tumor monitoringKind of calliper tumor size is begun through within first day in treatment, to monitor tumour growth.Weekly One, Wednesday and Friday obtain the measurement of the length and width of tumour.According to formula L × W²/ 2, wherein length (unit：Mm) determined Justice is the major axis of tumour, calculates gross tumor volume.Animal is weighed in measurement of tumor.Tumour is set to allow maximum growth to arrive before termination 800mm³。

Blood is carried out by cardiac puncture in the terminal with discrepant CBC (whole blood count) to all animals to adopt Collection.It is found that untreated control group and organizes the statistics of the hemoglobin (g/L) between 4 or 5 (two to the water wei ling alcohol treatment groups) Conspicuousness (p<0.05) analyzed for CBC.Carry out variance analysis；However, it should be noted that also have in control mice low white Cell (WBC) number (this is because the bacterial strain is immunologic inadequacy, this can influence WBC productions).For WBC, it was observed that leaching Statistical significance (the p of bar cell and eosinophil<0.05).For CBC/ difference analysis, compare not with bearing animals (mouse number # controls 1 and control 2) and (the 1st group of the untreated animal with tumour；Mouse number #1-10) between do not have Difference.

The observation of animal

Clinical observationAll animals are observed after administration and at least one time daily, if it is considered to being necessary, for falling ill The pretreatment of rate and the death rate and treatment phase, observation can be frequent.Especially, unsound sign is based on lean body mass, food It is intended to change, and as changed gait, drowsiness, the sign of the nervous behavior substantially showed.If it find that serious toxicity or swollen The sign of the relevant disease of knurl, animal receive excessive Isoflurane, and receive carbon dioxide asphyxia and terminate, and perform an autopsy on sb. to comment Estimate other signs of toxicity.Check following organ：Liver, courage, spleen, lung, kidney, heart, intestines, lymph node and bladder.Do not find to appoint What uncommon result.

University of British Columbia Institutional Animal protective committee (IACC) to this method carried out examine and Accreditation.The inhabitation and use of animal are all carried out according to Canadian Animal Protection Association's guide.

Summary for two to the water wei ling alcohol (" VAL-083 ") and the administration of cis-platinum is shown in following table 2-3：

Table 2

Two to the water wei ling alcohol is administered

Table 3

Cisplatin administration

And conclusion as a result

The results are shown in Fig. 1-2.

Fig. 1 is the figure for showing weight of the female Rag2 mouse after 5,000,000 A549 cells are subcutaneously injected.The knot of embodiment Fruit is shown as weight on the y axis, and days post inoculation is shown as in x-axis.In Fig. 1-2 of embodiment, ● it is untreated right According to；■ is cis-platinum control；▲ be 1.5mg/kg two to the water wei ling alcohol；▲ be 3.0mg/kg two to the water wei ling alcohol；And ◆ It is the two to the water wei ling alcohol of 6.0mg/kg.

According to Fig. 1's as a result, being controlled in the mouse (the 2nd group) with 5mg/kg plus cisplatin in treatment and with 6mg/kg two to the water wei ling alcohol Body weight loss is observed in the mouse for the treatment of for (the 5th group).Due to notable lean body mass, stop the 5th group for the treatment of after 3 dosage.Weight It is expressed as average value ± S.D..

Fig. 2 is the gross tumor volume (average value ± S.E.M. (standard error)) for the female Rag2 mouse for showing to have A549 tumours Figure, wherein embodiment result is days post inoculation in x-axis to be on the y axis gross tumor volume.The top of Fig. 2 is represented whole All mouse during research.The bottom representative survival of Fig. 2 is all small to the 70th day (last day of untreated control group) Mouse.

Summarize as a result, mouse is administered in the following way：Undressed control (the 1st group), Q7D × 3 (interval 7 days Medication 1 time, continuous 3 times) intravenous injection 5mg/kg cis-platinums (the 2nd group), on every Mondays, three, five medications, intraperitoneal injection for 3 weeks 1.5mg/kg two to the water wei ling alcohol (the 3rd group), 3mg/kg two to the water wei ling alcohol (the 4th group) and 6mg/kg two to the water wei ling alcohol (the 5th group), and gross tumor volume is measured weekly 3 times, and it is summarized in Fig. 2.Top sample group represents the gross tumor volume of all animals, Bottom sample group represents the result of the animal to survive 70 days.It is worth noting that, the 70th day research in remaining animal number Mesh is 2/10 (the 1st group), 6/10 (the 2nd group), 7/10 (the 3rd group), 6/10 (the 4th group) and 8/10 (the 5th group).For a group 1-5, 43rd day, 200mm is observed respectively within 49 days, 45 days, 42 days and 54 days³Mean tumour volume.For a group 1-4, at the 56th day, Respectively reach 400mm within 66 days, 67 days and 81 days³Mean tumour volume.The doubling time of group 1-4 is respectively 13,17,22 Hes 39.Compared to untreated control group, the tumour life of 26 days is observed in the animal for applying 3mg/kg two to the water wei ling alcohol Long delay.On the contrary, the positive control of the cis-platinum of 5mg/kg only has the tumor growth delay of 4 days.

In terms of the tolerance of the dosage, cause the notable weight loss and disease of mouse in the two to the water wei ling alcohol of 6mg/kg State, and only application of 3 in 9 predetermined closes.Since 1 mouse can not receive last dosage, the 5mg/kg's of cis-platinum Dosage can also be close to MTD (maximal tolerance dose).

In short, compared with the cis-platinum of 5mg/kg, dosage is that the administration of the two to the water wei ling alcohol of 3m/kg generates significant swell Knurl growth delay.

Embodiment 2

Therapeutic choice using dianhydrogalactitol as new anti-chemotherapy non-small cell lung cancer

World Health Organization predicts that, by 2025, the incidence of lung cancer may be more than annual 1000000, non-small cell lung cancer (NSCLC) the 90% of new diagnosed SARS case is accounted for.The median overall survival of the IV phase patients of NSCLC is to survive for 4 months, 1 year and 5 years Rate is respectively smaller than 16% and 2%.Usually with tyrosine kinase inhibitor (TKI) (for example, Tarceva, Gefitinib) treatment or The either a program of therapeutic scheme (for example, cis-platinum) based on platinum treats metastatic NSCLC.TKI has caused EGFR to be mutated patient Very big improved result；However, TKI resistances become a notable unsatisfied medical demand, and using platinum class as base The long-term prognosis of the therapy of plinth is poor.In addition, the incidence of metastatic encephaloma is higher in NSCLC patient and prognosis is poor.Especially It is that non-small cell lung cancer accounts for the 90% of the cases of lung cancer that China makes a definite diagnosis.

Two to the water wei ling alcohol is a kind of bifunctional alkylating agent of unique structure, its N in targeting guanine⁷When mediate It is crosslinked between DNA chain, so that different from the mechanism of action of TKI and cis-platinum.In China, two to the water wei ling alcohol is approved for treatment lung Cancer, it has also been recorded the work of anti-NSCLC in the clinical test that the historical National Cancer Institute (NCI) in the U.S. supports Property；However, with the effect of two to the water wei ling alcohol compared to cis-platinum and the effect of two to the water wei ling alcohol is in TKI resistances NSCLC Relevant particular problem is not resolved before this as far as we know.Further, two to the water wei ling alcohol passes through blood brain barrier simultaneously Accumulated in tumor tissues.Two to the water wei ling alcohol shows the work to non-small cell lung cancer in preclinical and clinical test Property, it can be the treatment option for drug resistance NSCLC and the NSCLC patient with metastatic encephaloma to illustrate two to the water wei ling alcohol. When the concurrent testing in standard Syngenic mice fibrosarcoma model (the RIF-1 cell lines in C3H mouse), two to the water wei ling alcohol The advantage to cis-platinum is shown in terms of tumor growth delay.For the intraperitoneal injection by two to the water wei ling alcohol single The mouse of (10mg/kg) processing, compared to control group, its tumour growth is delayed by 5.6 days, and passes through single dose cis-platinum (4mg/kg) processed tumour growth is delayed by 1.5 days.Two to the water wei ling alcohol and the Combined Treatment of cis-platinum are by tumour growth 8.7 days are delayed, generates the effect more than addition.

Show that the collaboration that two to the water wei ling alcohol previous clinical research active in NSCLC is combined together with cis-platinum is made New data so that two to the water wei ling alcohol promises to be replacing for NSCLC with brain metastes and chemotherapy tolerance NSCLC For scheme.

In vitro, the thin of two to the water wei ling alcohol and cisplatin combined medication is tested in NSCLC cell lines A549 and H1975 Cellular toxicity acts on.Two water of its results show go the addition in two cell line of dulcitol and cis-platinum or oxaliplatin and exceed The effect of addition.

In vivo, in two sseparated researchs, we have evaluated two to the water wei ling alcohol compared to cis-platinum in EGFR-TKI Activity in the In vivo model of resistance NSCLC.Treated mouse is subject to TKI sensitive (A549) or TKI resistances (H1975) are come The Rag2 mouse of the subcutaneous human lung adenocarcinoma xenograft tumours in source.Two to the water wei ling alcohol is given in a manner of 3 times/week of intraperitoneal injections Give 3 weeks, compared with cis-platinum (5mg/kg), assess the effect of two to the water wei ling alcohol is controlled in tumour growth in vivo.Physiological saline Used as control treatment.Progression of disease is assessed by gross tumor volume, clinical observation and measured body weight.Blood sample is carried out CBC/ variance analyses, to assess bone marrow suppression or the change of other blood chemistries.

For A549 cells, compared with control group, 26 are observed in the animal handled with 3mg/kg two to the water wei ling alcohol It tumor growth delay, and for the mouse with cisplatin treated, the generation delay of its tumour is 4 days.Compared with control group, use The animal of 3mg/kg two to the water wei ling alcohol processing significantly reduced (p=0.001) in the mean tumour volume of the 68th day.

For H1975 cells, in 4mg/kg groups after the two to the water wei ling alcohol of 6 dosage, due to significant weight Mitigate and stop treatment, mouse recovers rapidly afterwards.The life span middle position for the mouse treated with 4mg/kg two to the water wei ling alcohol Number is 41 days, and all other treatment group and control group are 31 days.Compared with control group, handled with 4mg/kg two to the water wei ling alcohol Animal significantly reduced (p=0.004) in the mean tumour volume of the 31st day.

Method

In vivo model

Using the volume injected inoculating cell number of every 50 μ L of mouse as 5 × 10⁶The A549 cells of a cell.With every mouse The volume injected inoculating cell number of 50 μ L is 2 × 10⁶The H1975 cells of a cell.

With 100-150mm³Mean tumour volume start to treat.

Table 4

For testing the therapeutic scheme of two to the water wei ling alcohol effect

The (the 5th in the mouse of 5mg/kg plus cisplatin in treatment (the 2nd group) and the mouse treated with 4mg/kg two to the water wei ling alcohol Group) observe body weight loss.In 4mg/kg groups after the two to the water wei ling alcohol of 6 dosage, due to significant weight loss And stopping treatment, subsequent mouse recovers rapidly.

External model

Two to the water wei ling alcohol and the external activity of cisplatin combined medication are tested in NSCLC cell lines A549 and H1975.With The IC10-30 concentration (10%-30% cell growth inhibitions concentration) of single medicament, uses two to the water wei ling alcohol and cis-platinum or difficult to understand husky Sharp platinum handles cell at the same time, and in the 5th day monitoring cytotoxicity of colorimetric MTT measure.(Student ' s t- are examined by T Test) analyze experiment value and calculate P values with handling the prediction addition value combined.

Tumor growth inhibition (TGI) is calculated according to equation (1)：

Tumor growth delay (TGD) is calculated according to equation (2)：

TGD=DT_tx-DT_Control (2)。

For these calculating, TV is gross tumor volume, and tx is treatment, and int is initial, and DT is the multiplication of mean tumour volume Time：It is from 200mm for A549³To 400mm³Or it is 300mm for H1975³To 600mm³.MTV is mean tumour volume (unit mm³), TCR is tumor control rate.

As a result

TKI resisting cells A549 the results are shown in table 5 and Fig. 3.As shown in fig. 3 and table 5, it was observed that being gone with the two of 3mg/kg The processing of water dulcitol has significant survival benefit.Fig. 3 is the internal of A549 in female Rag2 Mice Bodies (TKI- is sensitive) cell Model opens Pulan-Meyer (Kaplan-Meier) survivorship curve, the survivorship curve compared for 5mg/kg cis-platinums, 1.5mg/kg and The two to the water wei ling alcohol of 3.0mg/kg acts on the effect of A549 (TKI- is sensitive) NSCLC.Carry out log-rank statistical tests (Mantel-Cox), show that p value is 0.0446, show the significant difference between survival curve.Compared with untreated control group, see Observing the animal handled with 3mg/kg two to the water wei ling alcohol has the tumor growth delay of 26 days, and is used as positive controls 5mg/kg cisplatin treateds then cause the tumor growth delay of 4 days compared with untreated control group.Compared with untreated control group, The animal handled with 3mg/kg two to the water wei ling alcohol significantly reduced (p=0.001) in the mean tumour volume of the 68th day.These are seen Examine the result shows that, when cis-platinum cannot obtain statistically significant benefit, two to the water wei ling alcohol remain to maintain activity.

Table 5

The analytical parameters of 1-4 groups in A549 models

* is shown compared with untreated control, in the result that the unpaired t of the gross tumor volume of processing in the 68th day is examined.

TKI resisting cells H1975 the results are shown in table 6 and Fig. 4.As shown in Fig. 4 and table 6, it was observed that two with 4mg/kg Dianhydrogalactitol processing has significant survival benefit.Fig. 4 is the body of H1975 in female Rag2 Mice Bodies (TKI- is sensitive) cell Interior model opens Pulan-Meyer (Kaplan-Meier) survivorship curve, the survivorship curve compared for 5mg/kg cis-platinums, 2mg/kg, The two to the water wei ling alcohol of 3mg/kg and 4mg/kg acts on the effect of H1975 (TKI- is sensitive) NSCLC.Water is gone to defend with 4mg/kg bis- The life span median of the mouse of lance alcohol processing is 41 days, and every other treatment group and control group are 31 days.Carry out log- Rank statistical tests (Mantel-Cox), instruction p value is 0.0009, shows the significant difference between survival curve.With control group Compare, the animal handled with 4mg/kg two to the water wei ling alcohol significantly reduced (p=0.004) in the mean tumour volume of the 31st day. These observation indicate that, when cis-platinum cannot obtain statistically significant benefit, two to the water wei ling alcohol even in TKI resistances Activity is also maintained under setting.

Table 6

The analytical parameters of 1-5 groups in H1975 models

* is shown compared with untreated control, in the result that the unpaired t of the gross tumor volume of processing in the 31st day is examined.

In the active anticancer In vivo model of single standard, VAL-083 is better than cis-platinum in terms of tumor growth delay.It is small Mouse uses cis-platinum injections immediately by one intra-peritoneal injection cis-platinum or two to the water wei ling alcohol or after two to the water wei ling alcohol is injected Processing.It is interesting that working as in standard Syngenic mice fibrosarcoma model (the RIF-1 cell lines in C3H mouse), two remove water winged euonymus The Combined Treatment of alcohol and cis-platinum is to postpone 8.65 days effects generated more than addition.The results are shown in table 7.

Table 7

Other in vitro study is carried out to study single two to the water wei ling alcohol or two to the water wei ling alcohol and cis-platinum (A) or Austria The cytotoxic effect of husky profit platinum (B) combination.Fig. 5 A are to show two to the water wei ling alcohol (DAG) cis-platinum (CDDP) alone or in combination Interaction in vitro is in the design sketch of A549 (TKI- is sensitive) NSCLC cells.Data are shown as average value ± standard error, N=7.Fig. 5 B Be show two to the water wei ling alcohol (DAG) alone or in combination oxaliplatin interaction in vitro in A549 (TKI- sensitive) NSCLC cells Design sketch.Data are shown as average value ± standard error, N=7.Fig. 6 shows two to the water wei ling alcohol cis-platinum body alone or in combination The outer cytotoxic effect for acting on H1975NSCLC cells.Data are shown as average value ± standard error.

Two to the water wei ling alcohol is sensitive to NSCLC TKI resistances (H1975) and TKI- with the combination of cis-platinum or oxaliplatin (A549) cell is respectively provided with the cytotoxic effect more than addition.The result is similar with the result observed in vivo, supports two Dianhydrogalactitol and the potential synergistic benefits of the combination of the therapy based on platinum.

In conclusion these results show in the tumor model of TKI sensitivities and the tumor model of TKI resistances, two go Water dulcitol is better than cis-platinum, and the combination of two to the water wei ling alcohol and cis-platinum has synergistic effect, also show two to the water wei ling alcohol and exist There are clinical potentials in the NSCLC of TKI resistances.Especially, based on the scheme of platinum almost without effect in the case of, two remove water Dulcitol also keeps activity.In addition, in sensitive (A549) and TKI- resistances (H1975) cell lines of the TKI- of NSCLC in vitro, The combination of two to the water wei ling alcohol and cis-platinum or oxaliplatin has super addition effect.Also, in vivo, two to the water wei ling alcohol and suitable The combination of platinum is not worse than addition.

In conclusion these results support NSCLC of the two to the water wei ling alcohol as the Endodontic failure based on platinum and based on TKI The viable therapeutic selection of patient, and support the potential benefit as a part for the therapeutic alliance based on platinum in new diagnosis patient.

Embodiment 3

Other results in cell line

Background

The median overall survival of non-small cell lung cancer (NSCLC) IV phase patients is 4 months, 1 year and 5 annual survival rates difference Less than 16% and 2%.Usual first use is performed the operation followed by being treated with tyrosine kinase inhibitor (TKI) or the therapeutic scheme based on platinum The either a program treatment NSCLC of (for example, cis-platinum).TKI has caused the very big improved result of EGFR mutation patients；However, TKI Resistance becomes a notable unsatisfied medical demand, and the long-term prognosis of the therapy based on platinum class is poor.Two Dianhydrogalactitol is a kind of bifunctional alkylating agent of unique structure, its N in guanine⁷When mediated dna interchain linkage so that It is different from the mechanism of action of TKI and cis-platinum.Two to the water wei ling alcohol is shown to non-small cell in preclinical and clinical test The activity of lung cancer, it can be the treatment option for drug resistance NSCLC to illustrate two to the water wei ling alcohol.In China, two remove water winged euonymus Alcohol is approved for treatment lung cancer；But on two to the water wei ling alcohol relative to cis-platinum and with being gone the effect of cisplatin combination with two The particular problem for the effect of water dulcitol is in TKI resistances NSCLC has not been studied as far as we know.The purpose of the research is to grind Study carefully TKI- is sensitive and TKI- resistances NSCLC in two go activity of the water winged euonymus relative to cis-platinum and with cisplatin combination.

Method

Two to the water wei ling alcohol and the external activity of cisplatin combined medication are tested in the H460 cell lines of NSCLC.According to Compusyn constant ratio schemes, while the two to the water wei ling alcohol and cis-platinum that are used in certain cell concentration range carry out cell Processing, and in the 5th day monitoring cytotoxicity of colorimetric MTT measure.With TKI sensitive (A549) or TKI- resistances (H1975) the internal living of the two to the water wei ling alcohol compared with cis-platinum is tested in the Rag2 mouse of the xenograft tumours in source Property.

Two kinds of people's NSCLC cell lines A549 and H1975 are used for subcutaneous human lung adenocarcinoma tumour, with 3 times/week of intraperitoneal injections Mode gives two to the water wei ling alcohol 3 weeks.Progression of disease is assessed by gross tumor volume, clinical observation and measured body weight.

As a result

For H460, PRELIMINARY RESULTS shows that the combination of two to the water wei ling alcohol+cis-platinum is lived with the cytotoxicity more than addition Property (Combination index<0.7).

For A549, compared with untreated control group, the animal handled with 3mg/kg two to the water wei ling alcohol was at the 68th day Mean tumour volume significantly reduces (p=0.001).Compared to untreated control group, at 3mg/kg two to the water wei ling alcohol It observed the tumor growth delay of 26 days in the animal of reason.Compared to untreated control group, positive control 5mg/kg cis-platinums Cause tumor growth delay 4 days.

For H1975, compared with untreated control group, the animal handled with 4mg/kg two to the water wei ling alcohol was at the 31st day Mean tumour volume significantly reduces (p=0.004).The life span median of the mouse handled with 4mg/kg two to the water wei ling alcohol For 41 days, and 5mg/kg cis-platinums and the median of untreated control were 31 days.

Conclusion

Show in short, two to the water wei ling alcohol is highly effective and preliminary in vitro study in NSCLC xenogeneic models The combination of two to the water wei ling alcohol and cis-platinum has synergistic effect.

Embodiment 4

Two to the water wei ling alcohol has the cellular cytoxicity activity of ovarian cancer resistance system

Two to the water wei ling alcohol has the cellular cytoxicity activity of basic ovarian cancer resistance system.

Fig. 7 is to show dosage in the ovarian tumor cell system sample sets handled in vitro with two to the water wei ling alcohol-anti- Answer the figure of curve.Ovarian tumor cell system sample sets are following：● represent A2780；■ represents 2780-CP16；▲ represent OVCAR-10；▼ represents HEY；And ◆ represent OVCA-433.Using 5 days MTT colorimetric method for determining cell viabilities with draw dosage- Response curve.A2780 is shown with cisplatin-sensitive model, and other four kinds of cell lines then show cisplatin-resistance.Cis-platinum The cell line 2780-CP16 of resistance derives from A2780.The characteristic of some in these cell lines is described in G.S.Hagopian etc. " the Expression of p53 in Cisplatin-Resistant Ovarian Cell Lines of people:Modulation with the Novel Platinum Analog(1R,2R-Diaminocyclohexane)(trans-diacetato) (dichloro)-platinum(IV),”Clin.Cancer Res.5：655-663 (1999), and it is described in Z.H.Siddik Et al. " Independent Pathways of p53 Induction by Cisplatin and X-Rays in a Cisplatin-Resistant Cell Line,”Cancer Res.58：698-703 (1998), is incorporated by reference into this Text.

The data of Fig. 7 are with the IC of the two to the water wei ling alcohol in wild type p53 human ovarian tumor sample sets₅₀Form represents In table 8.

Table 8

The IC of two to the water wei ling alcohol in wild type p53 human ovarian tumor sample sets₅₀

Fig. 8 is to show that two to the water wei ling alcohol (" DAG "), cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali-Pt ") are out of office The figure of vitro cytotoxicity in raw type p53 human ovarian tumor's cell sample groups.Show two to the water wei ling alcohol, cis-platinum and Austria Relative activity (IC of the husky profit platinum to wild type p53 ovarian tumor cell₅₀)。

Fig. 9 is showing two to the water wei ling alcohol and platinum medicine cis-platinum and oxaliplatin, and wild type p53 human ovarian swells in vitro The figure of the resistant multiple of knurl sample sets；Resistant multiple is shown relative to A2780.Normalized relative to sensitive A2780 models The activity of two to the water wei ling alcohol and platinum medicine.The bright resistant tumor model of the chart has cis-platinum 10 to 30 times of resistance, to difficult to understand husky Sharp platinum has 2 to 5 times of resistance, and has 4 to 7 times of resistance to two to the water wei ling alcohol.Therefore, the wild type of resistance to cis-platinum P53 ovarian tumor models only show the partial intersection resistance to oxaliplatin and dianhydrogalactitol.

Therefore, the conclusion of the embodiment is that, even in being shown to cis-platinum in the ovarian neoplasm of basic resistance, two go water to defend Lance alcohol also show significant cytotoxic effect.

Embodiment 5

The Study of cytotoxicity of NSCLC tumor models

Table 9 shows two to the water wei ling alcohol (DAG) and platinum medicine cis-platinum and oxaliplatin wild type p53 human ovarian in vitro The cytotoxicity of tumor sample group.The cell line includes the cell line with wild type p53, has the cell line of Mutation p53 Wherein p53 is knocked the cell line of (" sky ", " null ").The feature of these cell lines is described in F.Bunz's et al. “Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage,” Science282:1497-1501 (1998), is incorporated herein by reference.

Table 9

Figure 10 is to show the external cytotoxicity of the cis-platinum in human body NSCLC tumor cells specimens groups and resist relatively The figure of property.Used cell line is H460, A549, H838 and H226 with wild type p53, has mutant p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.H460 is considered sensitive to cis-platinum；It is other Cell line in addition to H1975 is considered then resistant to cis-platinum.Some cell lines are more sensitive to oxaliplatin.

Figure 11 is the external cytotoxicity and phase for showing the oxaliplatin in human body NSCLC tumor cells specimens groups The figure of antagonism.Used cell line is H460, A549, H838 and H226 with wild type p53, has Mutation p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.

Figure 12 is to show the external cytotoxicity of the DAG in human body NSCLC tumor cells specimens groups and resist relatively The figure of property.Used cell line is H460, A549, H838 and H226 with wild type p53, has mutant p53 H1975, SkLU1, H2122 and H157, and the H1229 without p53.

Figure 13 is to show two to the water wei ling alcohol (" DAG ") and platinum medicine cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali- Pt ") for transformation HCT-116 models vitro cytotoxicity figure.In order to preferably explore the dependence of activity and p53 states Relation, employs the colorectum HCT-116 models of molecular modification.These are homogenic, and model passes through molecular modification to knock out p53 (p53^-/-) or p21 (p21^-/-)。P53^+/+Or p21^+/+Represent corresponding control.The p53^-/-Cell line is described in J.Boyer etc. " the Characterization of p53 Wild-Type and Null Isogenic Colorectal Cell of people Lines Resistant to 5-Fluorouracil,Oxaliplatin,and Irinotecan,”Clin.Cancer Res.10：2158-2167 (2004), is incorporated herein by reference.The p21^-/-Cell line is described in the " Role of Z.Han et al. of p21 in Apoptosis and Senescence of Human Colon Cancer Cells Treated with Camptothecin,”J.Biol.Chem.277：17154-17160 (2002), is incorporated herein by reference.Using these IC₅₀ Resistance of the value with definite knockout group relative to corresponding control.

Figure 14 is to show two to the water wei ling alcohol (" DAG ") and platinum medicine cis-platinum (" cis-Pt ") and oxaliplatin (" Oxali- Pt ") external resistant multiple in the HCT-116 models of transformation figure.It is anti-in the colorectum HCT-116 models of transformation Property multiple shows that the missing of p53 and p21 can cause twice or the stronger resistance to cis-platinum and oxaliplatin, but to DAG's Resistance can then decline (p53^-/-) or there is no resistance (p21^-/-)。

Figure 15 show two to the water wei ling alcohol (" DAG ") and cis-platinum or with oxaliplatin people's A549 NSCLC models body Combination index in external model.

Figure 16 is to show two to the water wei ling alcohol (DAG) combination with cisplatin or oxaliplatin interaction in vitro in the effect of A549 cells Fruit is schemed.Left part sample sets show the result of DAG combination with cisplatin；Right part sample sets show the result of DAG joint oxaliplatins.

Figure 17 is to show two to the water wei ling alcohol (DAG) combination with cisplatin or oxaliplatin interaction in vitro in the effect of H460 cells Fruit is schemed.Left part sample sets show the result of DAG combination with cisplatin；Right part sample sets show the result of DAG joint oxaliplatins. Under the H460 cell independent studies of N=3, the almost significant super additivity of drug combination of cis-platinum+DAG, and Ao Shali The drug combination of platinum+DAG then has super additivity.Data are shown as average value ± standard error.

Figure 18 shows two to the water wei ling alcohol (DAG) combination with cisplatin or oxaliplatin interaction in vitro in H1975 cells Design sketch.Left part sample sets show the result of DAG combination with cisplatin；Right part sample sets show the knot of DAG joint oxaliplatins Fruit.Under the H1975 cell independent studies of N=3, the drug combination of cis-platinum+DAG has an additivity, and oxaliplatin+DAG Drug combination reaches significant super additivity.Data are shown as average value ± standard error.

Figure 19 is to show two to the water wei ling alcohol (DAG) combination with cisplatin or oxaliplatin interaction in vitro in the effect of H157 cells Fruit is schemed.Top sample group shows the result of DAG combination with cisplatin；Bottom sample group shows the result of DAG joint oxaliplatins. Data are shown as average value ± standard error.In ED75, ED90 and ED95 display data.Compared to other cell lines, H157 is shown Go out the resistance of higher degree.

Make to increase the resistance of cis-platinum and oxaliplatin respectively researches show that the missing of p53 in HCT-116 models 3 times and 6 times, and the resistance of VAL-083 is then less than twice.As single medicament, two to the water wei ling alcohol, cis-platinum and Ao Sha Sharp platinum all shows good cytotoxicity to some extent in all NSCLC cell lines, and wherein H460 is most sensitive (IC₅₀<0.5μM).The IC of two to the water wei ling alcohol, cis-platinum and oxaliplatin₅₀Scope in other cell lines is 0.9- respectively 6.1 μM, 0.5-2.2 μM and 0.6-2.6 μM, and drug susceptibility is no obvious between wild type, saltant type and sky p53 groups Difference.This shows that wild type p53 is not activated and/or other hereditary changes reduce cellular cytoxicity activity.Two to the water wei ling alcohol and The combination of cis-platinum or oxaliplatin shows significant super additivity (p in the A549 models of NSCLC<0.05) make with collaboration With (CI<1).This forcefully supports nonoverlapping mode of action between platinum medicine and two to the water wei ling alcohol.

The embodiment the result shows that, two to the water wei ling alcohol is not only a series of including having Mutation p53 gene or missing It is effective cytotoxic agent in the NSCLC tumor model cell lines of p53 genes, it is also thin in the tumor model of missing p21 genes It is effective in born of the same parents system.In addition, two to the water wei ling alcohol is shared in terms of cytotoxicity in itself and cis-platinum and with oxaliplatin Significant addition effect is shown, it is shared with oxaliplatin, and being observed has super additivity.

Advantages of the present invention

The present invention provides improved resistant to chemotherapy by conventional means confirmation to treat using two to the water wei ling alcohol Non-small cell lung cancer (NSCLC) and oophoroma method and composition.

It is expected to be well tolerated to treat NSCLC or oophoroma using two to the water wei ling alcohol, and will not causes in addition Side effect.Two to the water wei ling alcohol can be used together with radiation or other chemotherapeutics.In addition, two to the water wei ling alcohol can be used for NSCLC or the brain metastes of oophoroma are treated, and can be used for therapeutic agent, tyrosine-kinase of the treatment to such as cis-platinum based on platinum Enzyme inhibitor (TKI) or the NSCLC or oophoroma of the resistant patient of Temozolomide.

The method of the present invention has the industrial feasibility for being used to prepare the medicine for treating NSCLC or oophoroma.This hair Bright composition has the industrial feasibility as pharmaceutical composition.

The claim to a method of the present invention is provided far more than the specific method step being normally applied substantially, and will Ask in addition to the concrete application substantially stated or implied in detail in the claims, the people of methods ＆＆ steps of implementation use except The step of in this area outside conventionally known method, therefore specifically should what the scope limitation of claims was enumerated wherein In.In certain scenarios, these claims are directed to use with the new method of existing medicine.

Illustrative description herein the present invention can suitably it is no it is any herein with no specific disclosure of element Or element, implement in the case of limitation or constraint.Thus, for example, term " containing ", " comprising ", "comprising" etc. should be extensive And unrestricted geographical solution.In addition, as used herein, in addition to special instruction, term " comprising " is intended to narration " substantially By ... form " and " forming ... " alternative solution.In addition, terms and expressions used herein are utilized as illustrating Rather than the term of limitation, and be not intended to exclude using such terms and expressions it is following show and describe it is any etc. Jljl or its any part, and will recognize, various modifications can be carried out in the range of the present invention for required protection. It will thus be appreciated that although specifically disclosing the present invention by preferred embodiment and optional feature, but those skilled in the art The improvement and modification of invention disclosed herein can be used, and these improvements and modifications are considered as in invention disclosed herein In the range of.The present invention is extensive herein and is usually described.Belong to each relatively narrow of general the open scope Species and time belong to combination also constitute these invention a part.This includes the general description each invented, and has from the category The collateral condition or negative limitation of any theme are removed, whether is especially resided therein but regardless of the excision material.

In addition, in the case where describing the feature or aspect of the present invention in the way of Ma Kushi group, art technology Personnel are it will be recognized that therefore the present invention is also described with regard to the subgroup of any individual member or member of Ma Kushi group.It should also manage Solution, foregoing description is intended to illustrative and not restrictive.By looking back above description, many embodiments are for this area Technical staff will be apparent.Therefore, the scope of the present invention reference should not be made to foregoing description to determine, and should refer to appended The four corner of the equivalent of claim and these claims determines.All articles including patent publications It is incorporated herein by reference with the disclosure of bibliography.

Claims (44)

1. one kind treatment is suffered from selected from the group being made of II phases non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC Malignant tumour patient method, this method comprises the following steps：(a) water winged euonymus is removed to patient therapeuticallv a effective amount of two Alcohol is to treat the malignant tumour；And (b) is a effective amount of pernicious to treat based on the antitumor agent of platinum to patient therapeuticallv Tumour.

2. according to the method described in claim 1, the two to the water wei ling alcohol and institute are applied wherein after surgery excision NSCLC State the antitumor agent based on platinum.

3. according to the method described in claim 1, the two to the water wei ling alcohol and institute are applied wherein before surgery excision NSCLC State based on the antitumor agent of platinum to make Tumor shrank before surgery.

4. according to the method described in claim 1, brain metastes occur for wherein described patient.

5. according to the method described in claim 1, wherein described two to the water wei ling alcohol and it is described based on the antitumor agent of platinum with list One pharmaceutical composition is applied, and wherein described pharmaceutical composition includes：(i) two to the water wei ling alcohol；(ii) antitumor agent based on platinum； And (iii) at least one pharmaceutically acceptable carrier.

6. according to the method described in claim 1, wherein described two to the water wei ling alcohol and it is described based on the antitumor agent of platinum with two Kind pharmaceutical composition is applied：(i) the first medicine group of two to the water wei ling alcohol and at least one pharmaceutically acceptable carrier is included Compound；And (ii) includes the second drug regimen of antitumor agent and at least one pharmaceutically acceptable carrier based on platinum Thing.

7. according to the method described in claim 1, wherein described patient has wild-type p 53 gene type.

8. according to the method described in claim 1, wherein described patient has the p53 genotype of mutation.

9. according to the method described in claim 1, wherein described patient has Wild type EGFR genotype.

10. according to the method described in claim 1, wherein described patient is used as at least one tyrosine kinase inhibitor in coding (TKI) there is at least one mutation in the gene of the protein of target.

11. according to the method described in claim 1, wherein described patient is characterized in that, there are at least one other to be in The gene of wild type or mutation status, the gene code assign the product to the resistance of at least one TKI therapeutic effects.

12. according to the method for claim 11, wherein the wild type or the coding in mutation status are assigned at least A kind of other gene of the resistance of TKI therapeutic effects is AHI-1.

13. according to the method for claim 12, wherein the AHI-1 genes are the results of provirus insertion.

14. according to the method described in claim 1, wherein described patient is characterized in that, have in the BCR- as TKI targets Mutation in the ABL1 protein kinase domains of a part for ABL fusion proteins.

15. according to the method described in claim 1, wherein described patient is characterized in that, has and assign tyrosine kinase suppression The germline deletion polymorphism of agent (TKI) resistance.

16. according to the method for claim 15, wherein the germline DNA deletion polymorphisms are positioned at BIM genes The germline DNA deletion polymorphisms of 2903bp.

17. according to the method for claim 16, wherein the germline DNA deletion polymorphisms cause spliced variants, the montage Variation causes the expression for lacking the isotype of the BIM albumen of BH3 domains, so as to suppress the induction of Apoptosis.

18. according to the method described in claim 1, wherein described platiniferous antitumor agent be selected from by cis-platinum, carboplatin, oxaliplatin, The group that satraplatin, picoplatin, Nedaplatin, three platinum, lobaplatin, eptalatin and cisplatin liposome form.

19. according to the method for claim 18, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin and oxaliplatin The group of composition.

20. according to the method for claim 19, wherein the platiniferous antitumor agent is cis-platinum.

21. according to the method described in claim 1, the dosage of wherein described two to the water wei ling alcohol and the platiniferous antitumor agent makes Obtain the two to the water wei ling alcohol and contained platinum antineoplastic agent plays synergistic effect.

22. according to the method for claim 21, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin and oxaliplatin The group of composition.

23. according to the method for claim 22, wherein the platiniferous antitumor agent is cis-platinum.

24. a kind of pharmaceutical composition, including：(a) two to the water wei ling alcohol of therapeutically effective amount；(b) platiniferous of therapeutically effective amount resists Tumour agent；And (c) is alternatively, at least one pharmaceutically acceptable carrier.

25. according to claim 24 described pharmaceutical composition, wherein described pharmaceutical composition is configured to be used to treat to be selected from by II The malignant tumour for the group that phase non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC are formed.

26. according to claim 24 described pharmaceutical composition, wherein described pharmaceutical composition is configured to be used to treat that brain has occurred Malignant tumour shift, selected from the group being made of II phases non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC.

27. pharmaceutical composition according to claim 24, wherein the two to the water wei ling alcohol and the platiniferous antitumor agent Dosage cause the two to the water wei ling alcohol and contained platinum antineoplastic agent to play synergistic effect.

28. pharmaceutical composition according to claim 24, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin, Austria The group that husky profit platinum, satraplatin, picoplatin, Nedaplatin, three platinum, lobaplatin, eptalatin and cisplatin liposome form.

29. pharmaceutical composition according to claim 28, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin and Austria The group of husky profit platinum composition.

30. according to the method for claim 29, wherein the platiniferous antitumor agent is cis-platinum.

31. pharmaceutical composition according to claim 24, wherein the composition is comprising at least one pharmaceutically acceptable Carrier, and wherein described pharmaceutically acceptable carrier is selected from by water-based and non-aqueous solvent, decentralized medium, coating, anti- The group that bacterium and/or antifungal agent and isotonic and/or absorption delaying agent are formed.

32. pharmaceutical composition according to claim 24, wherein described pharmaceutical composition are formulated for parenteral.

33. pharmaceutical composition according to claim 24, wherein described pharmaceutical composition further include at least one p53 simulations Thing.

34. pharmaceutical composition according to claim 33, wherein the p53 analogies are selected from the group consisted of：

(i)

N '-[2- [2- (4- methoxyphenyls) vinyl] -4- quinazolyls]-N, N- dimethyl -1,3- propane diamine dihydrochlorides Hydrate) (CP-31398)；

(ii) compound of formula (P-1)：

Wherein：

(A)R¹And R⁴It is each independently selected from the group consisted of：Amino, cyano group, nitro, carboxyl, halogen, hydroxyl, SO₂、C₁- C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₈Alkoxy, C₁-C₁₁Alkoxyalkyl, C₁-C₆Alkyl amino and C₁-C₆Aminoalkyl；

(B)R²And R³It is each independently selected from the group being made of CH and N；

(C)R⁵It is CH or O；

(D)R⁶Selected from the group consisted of：Halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀ Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain or without branch The C of chain₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, fragrant oxygen Base, aryl sulfonyl, heterocyclic aryl and heterocycle aryloxy group；

(E)R⁷Selected from the group consisted of：Hydrogen, halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain Or unbranched C₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, Aryloxy group, aryl sulfonyl, heteroaryl and heteroaryloxy；

(F)R⁸Selected from the group being made of nitro, hydroxyl and carboxyl；And

(G)R⁹For methyl；Or its pharmaceutically acceptable ester or salt；With

(iii) there is the compound of stable, internal constraint secondary protein structure, wherein the compound has formula (P- 2)：

Wherein：

(A) B is C (R¹)₂, O, S, or NR¹；

(B) each R¹Independently be hydrogen, amino acid side chain, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or Aryl alkyl；

(C)R²Be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, Peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Base alkyl, acyl group, peptide, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkene independently of one another Base, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (a)) part：

Wherein：

(1)R^2’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynes independently of one another Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m ' is zero or any numeral；

(3) b is each independently 1 or 2；And

(4) c is 1 or 2；

(D)R³It is hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, peptide, target To part, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkane Base, acyl group, peptide, targeting moiety or label), -- N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkanes independently of one another Base, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (b)) part：

Wherein：

(1)R^3’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label, -- OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, targeting Part or label) or-N (R⁵)₂(wherein R⁵Be independently of one another hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, Heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m " is zero or any numeral；And

(3) d is respectively 1 or 2；

(E)R⁴For each independent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aryl alkyl；

(F) m, n ', be each independently 0,1,2,3 or 4, wherein m, n with n " ' and n's " and be 2 to 6；

(G) m " ' is 0 or 1；

(H) a is 1 or 2；

(I) o is each independently 1 or 2；And

(J) p is 1 or 2；

, wherein it is desired to meet at least one in condition：(i) m is that 1,2,3 or 4 and at least one o is 2；(ii) p is 2；(iii) m " ' is that 1 and a is 2；(iv)R²It is beta amino acids；(v)R²The part of formula (P-2 (a)), wherein m ' be at least 1 and At least one b is 2；(vi)R²It is the part of formula (P-2 (a)), wherein c is 2；(vii)R²It is the part of formula (P-2 (a)), wherein R^2’It is beta amino acids；(viii)R³It is beta amino acids；(ix)R³It is the part of formula (P-2 (b)), wherein m " is at least 1 and at least One d is 2；And (x) R³It is the part of formula (P-2 (b)), wherein R^3’It is beta amino acids.

35. one kind treatment is suffered to be selected from and is made of II phases non-small cell lung cancer (NSCLC), III phase NSCLC and IV phase NSCLC The method of the patient of the malignant tumour of group, wherein the patient has the p53 genes of mutation, this method comprises the following steps：

(a) propagation and/or evil of the presence of patient's body Mutation p53 gene, wherein Mutation p53 effect gene malignant tumour are determined Resistance of the property tumour at least one antitumor agent；

(b) to a effective amount of two to the water wei ling alcohol of patient therapeuticallv to treat malignant tumour, wherein the two to the water wei ling alcohol Therapeutically effective amount determined by the result of the cell line of the p53 genes with mutation；

(c) antitumor agent based on platinum a effective amount of to patient therapeuticallv to be to treat malignant tumour, wherein described based on platinum The therapeutically effective amount of antitumor agent is determined by the result of the cell line of the p53 genes with mutation；And

(d) alternatively, to a effective amount of p53 analogies of patient therapeuticallv to treat malignant tumour.

36. according to the method for claim 35, wherein the presence of the patient's body Mutation p53 gene is by selecting free radical Whether the p53 because being sequenced, in Restriction Fragment Length diversity and the definite cell sample from patient is combined with pGL3 carriers The method of the group formed determines.

37. according to the method for claim 35, wherein the described method includes simulated to a effective amount of p53 of the patient therapeuticallv The step of thing is to treat the malignant tumour.

38. according to claim 37 the method, wherein the p53 analogies are selected from the group consisted of：

(i)

N '-[2- [2- (4- methoxyphenyls) vinyl] -4- quinazolinyls]-N, N- dimethyl -1,3- malonamide two Hydrochloride hydrate) (CP-31398)；

(ii) compound of formula (P-1)：

Wherein：

(A)R¹And R⁴It is each independently selected from the group consisted of：Amino, cyano group, nitro, carboxyl, halogen, hydroxyl, SO₂、C₁- C₆Alkyl, C₁-C₆Haloalkyl, C₁-C₈Alkoxy, C₁-C₁₁Alkoxyalkyl, C₁-C₆Alkyl amino and C₁-C₆Aminoalkyl；

(B)R²And R³It is each independently selected from the group being made of CH and N；

(C)R⁵It is CH or O；

(D)R⁶Selected from the group consisted of：Halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀ Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain or without branch The C of chain₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, fragrant oxygen Base, aryl sulfonyl, heterocyclic aryl and heterocycle aryloxy group；

(E)R⁷Selected from the group consisted of：Hydrogen, halogen, cyano group, nitro, have side chain or unbranched saturation or undersaturated C₁-C₁₀Alkyl, have side chain or unbranched C₁-C₁₀Alkoxy, have side chain or unbranched C₁-C₁₀Acyl group, have side chain Or unbranched C₁-C₁₀Acyloxy, have side chain or unbranched C₁-C₁₀Sulfanyl, amino-sulfonyl, aryl, aroyl, virtue Epoxide, aryl sulfonyl, heteroaryl and heteroaryloxy；

(F)R⁸Selected from the group being made of nitro, hydroxyl and carboxyl；And

(G)R⁹For methyl；Or its pharmaceutically acceptable ester or salt；With

(iii) there is the compound of stable, internal constraint secondary protein structure, wherein the compound has formula (P- 2)：

Wherein：

(A) B is C (R¹)₂, O, S, or NR¹；

(B) each R¹For each independent hydrogen, amino acid side chain, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base or aryl alkyl；

(C)R²Be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, Peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, virtue Base alkyl, acyl group, peptide, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkene independently of one another Base, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (a)) part：

Wherein：

(1)R^2’It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, β amino Acid, peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl Base, aryl alkyl, targeting moiety or label) ,-(CH₂)_0-1N(R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynes independently of one another Base, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m ' is zero or any numeral；

(3) b is each independently 1 or 2；And

(4) c is 1 or 2；

(D)R³It is hydrogen, alkyl, alkenyl, alkynyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, peptide, targeting Partly, label ,-OR⁵(wherein R⁵Be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aryl alkyl, Acyl group, peptide, targeting moiety or label) ,-N (R⁵)₂(wherein R⁵Be independently of one another hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Heterocyclic radical, aryl, heteroaryl, aryl alkyl, acyl group, peptide, targeting moiety or label) or formula (P-2 (b)) part：

Wherein：

(1)R³Be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl, alpha amino acid, beta amino acids, Peptide, targeting moiety, label ,-OR⁵(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, targeting moiety Or label) ,-N (R⁵)₂(wherein R⁵It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl independently of one another Base, aryl alkyl, acyl group, peptide, targeting moiety or label)；

(2) m " is zero or any numeral；And

(3) d is respectively 1 or 2；

(E)R⁴For each independent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aryl alkyl；

(F) m, n ', be each independently 0,1,2,3 or 4, wherein m, n with n " ' and n's " and be 2 to 6；

(G) m " ' is 0 or 1；

(H) a is 1 or 2；

(I) o is each independently 1 or 2；And

(J) p is 1 or 2；

, wherein it is desired to meet at least one in condition：(i) m is that 1,2,3 or 4 and at least one o is 2；(ii) p is 2；(iii) m " ' is that 1 and a is 2；(iv)R²It is beta amino acids；(v)R²The part of formula (P-2 (a)), wherein m ' be at least 1 and At least one b is 2；(vi)R²It is the part of formula (P-2 (a)), wherein c is 2；(vii)R²It is the part of formula (P-2 (a)), wherein R^2’It is beta amino acids；(viii)R³It is beta amino acids；(ix)R³It is the part of formula (P-2 (b)), wherein m " is at least 1 and at least One d is 2；And (x) R³It is the part of formula (P-2 (b)), wherein R^3’It is beta amino acids.

39. according to the method for claim 35, wherein the platiniferous antitumor agent be selected from by cis-platinum, carboplatin, oxaliplatin, The group that satraplatin, picoplatin, Nedaplatin, three platinum, lobaplatin, eptalatin and cisplatin liposome form.

40. according to the method for claim 39, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin and oxaliplatin The group of composition.

41. according to the method for claim 40, wherein the platiniferous antitumor agent is cis-platinum.

42. according to the method for claim 35, wherein the dosage of the two to the water wei ling alcohol and the platiniferous antitumor agent So that the two to the water wei ling alcohol and contained platinum antineoplastic agent play synergistic effect.

43. according to the method for claim 42, wherein the platiniferous antitumor agent is selected from by cis-platinum, carboplatin and oxaliplatin The group of composition.

44. according to the method for claim 43, wherein the platiniferous antitumor agent is cis-platinum.