CN101374524A

CN101374524A - Combination of mTOR inhibitor and antipolate compound

Info

Publication number: CN101374524A
Application number: CNA2007800031116A
Authority: CN
Inventors: H·莱恩; T·奥赖利
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-01-12
Filing date: 2007-01-12
Publication date: 2009-02-25
Also published as: GB0600618D0

Abstract

Use of a combination of an mTOR inhibitor and an antifolate compound.

Description

MTOR inhibitor and antifol combination of compounds form

The present invention relates to the cancer therapeutic alliance, for example the combining form of pharmaceutical active organic compound, for example combining form of antifol chemical compound and mTOR inhibitor.

MTOR inhibitor used herein is the chemical compound of targeting mTOR (" the mammal target spot of rapamycin ") in cell.MTOR is the member of phosphatidyl-inositol 3-kinase (P13-kinases) associated kinase family.Chemical compound rapamycin and other mTOR inhibitor suppress the mTOR activity by forming complex with its intracellular receptor FKBP12 (FK506-conjugated protein 12).MTOR regulates the translation of specific mRNA by regulating the proteic phosphorylation state of some different translations, and described translation albumen mainly is 4E-PB1, P70S6K (p70S6 kinases 1) and eEF2.

MTOR inhibitor used herein comprises rapamycin and rapamycin derivative.

Rapamycin is the known macrolide antibiotic by the following formula of streptomyces hygroscopicus generation

Rapamycin derivative comprises for example at the 40th and/or 16 and/or 32 substituted rapamycin.

The example of rapamycin derivative comprises 40-O-alkyl-rapamycin derivative, 40-O-hydroxy alkyl-rapamycin derivative for example, and for example 40-O-(2-hydroxyl)-ethyl-rapamycin (everolimus) is also referred to as " compd A " here,

The rapamycin derivative that on 40, is replaced by heterocyclic radical, 40-table-(tetrazole radical)-rapamycin (being also referred to as ABT578) for example,

32-deoxidation-rapamycin derivative and 32-hydroxyl-rapamycin derivative, as 32-deoxidation rapamycin,

Rapamycin derivative such as 16-penta-2-alkynyloxy group-32-deoxidation-rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin or 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin that 16-O-replaces,

On 40 oxygen by the rapamycin derivative of acidylate, 40-[3-hydroxyl-2-(hydroxyl-methyl)-2 Methylpropionic acid ester for example]-rapamycin (being also referred to as CCI779 or Te Luomosi (temsirolimus)),

As disclosed rapamycin derivative among WO9802441 or the WO0114387 (being also sometimes referred to as forms of rapamycin analogs (rapalogs)), for example comprise AP23573, as 40-O-dimethyl oxygen phosphino--rapamycin,

With the disclosed chemical compound of title of hundred Li Mosi (biolimus) (hundred profits are not taken charge of A9), comprise 40-O-(2-ethyoxyl) ethyl-rapamycin and with the disclosed chemical compound of the title of TAFA-93, AP23464, AP23675 or AP23841; Or

Disclosed rapamycin derivative in WO2004101583, WO9205179, WO9402136, WO9402385 and WO9613273 for example.

Preferred mTOR inhibitor comprises

Rapamycin, and/or

40-O-(2-hydroxyethyl)-rapamycin, and/or

32-deoxidation rapamycin, and/or

16-penta-2-alkynyloxy group-32-deoxidation rapamycin, and/or

16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, and/or

16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-0-(2-hydroxyethyl)-rapamycin, and/or

40-[3-hydroxyl-2-(hydroxyl-methyl)-2 Methylpropionic acid ester]-rapamycin (being also referred to as CCI779) and/or

40-table-(tetrazole radical)-rapamycin (being also referred to as ABT578), and/or

So-called forms of rapamycin analogs, for example disclosed chemical compound, AP23573, AP23464, AP23675 or AP23841 in WO9802441, WO0114387 and WO0364383, AP23573 for example, and/or

With the disclosed chemical compound of the title of TAFA-93, and/or

With the disclosed chemical compound of the title of hundred Li Mosi.

The mTOR inhibitor more preferably is selected from

Rapamycin, and/or

40-O-(2-hydroxyethyl)-rapamycin, and/or

32-deoxidation rapamycin, and/or

16-penta-2-alkynyloxy group-32-deoxidation rapamycin, and/or

16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, and/or

AP23573，

Preferred 40-O-(2-hydroxyethyl)-rapamycin.

According to viewed activity, find for example useful as drug of mTOR inhibitor, useful as immunosuppressants for example for example is used for the treatment of the situation after the transplanting; As anti-inflammatory compound, for example be used for the treatment of IBD, RA; As the antiallergic action chemical compound, for example be used for the treatment of psoriasis, and have and make it can be used for cancer chemotherapy for example to be used for the treatment of solid tumor, especially the effective antiproliferative activity of advanced solid tumor.

Rapamycin and other rapamycin derivative for example can be taken the circumstances into consideration administration with rapamycin or the known dosage of rapamycin derivative, for example everolimus can be paramount to 25mg with 0.1mg, paramount as 0.1mg to 15mg such as 0.1mg to 10mg for example 0.1mg, 0.25mg, 0.5mg, 0.75mg, 1mg, 2.5mg, 5mg or 10mg, the oral dose administration of preferred 1mg to 10mg for example can be with (can disperse) tablet form administration; For example weekly dose can comprise highly to 70mg, and 30mg to 70mg for example is as 30mg to 50mg; It depends on the disease of being treated.Other rapamycin derivative can be with similar dosage range administration.

The antifol chemical compound is known and one or more is had inhibitory action with the metabolic derivative of folic acid and particularly folic acid as the enzyme of substrate.

Antifol chemical compound used herein for example comprises the chemical compound described in the US5344932, for example comprises the chemical compound of following formula

Wherein

R ₁Be-OH or-NH ₂

R ₃Be be not substituted or by chlorine, fluorine, methyl, methoxyl group or trifluoromethyl replace 1,4-phenylene or 1,3-phenylene; The inferior thienyl or the furylidene that are not substituted or are replaced by chlorine, fluorine, methyl, methoxyl group or trifluoromethyl; Cyclohexylidene; Or inferior alkenyl group;

R ₄Be hydrogen, methyl or hydroxymethyl; And

R ₅Be the alkyl or the amino of hydrogen, 1 to 6 carbon atom;

For example be denoted as ^*Carbon atom on substituent configuration be S;

For example free form or pharmaceutical acceptable salt; It randomly is solvate forms;

The chemical compound of preferred following formula

For example being sodium salt such as disodium salt form, for example is for example heptahydrate form of solvate such as hydrate.

The chemical compound of formula PERMETREXED with the title of training beautiful Qu De known and with

Trade name be approved for injection with the form of disodium salt heptahydrate.

As if the antifol chemical compound of formula I particularly has the activity as thymidylate synthetase inhibitor, and this enzyme utilizes N ⁵, N ¹⁰-methylene tetrahydrofolate salt turns to deoxythymidylic acid as coenzyme catalytic deoxidation uridylic acid methyl.Therefore, can depend on these growth of tumor of the inhibition of this enzyme with this chemical compound inhibition.

The chemical compound of US5344932 it is said the growth of tumor of epiderm-like (epidermid) cancer, squamous or small cell lung cancer and various lymphosarcomas of adenocarcinoma, head and the neck that can suppress to comprise choriocarcinoma, leukemia, female breast.The chemical compound of US5344932 it is said and also can be used for treating mycosis fungoides---a kind of skin carcinoma; And psoriasis.

Specifically, Recommended being used for the treatment of (pernicious) mesothelioma, it is a kind of mesothelial cell's a cancer, and such cancer can be formed at nonsmall-cell lung cancer (NSCLC), the gestational trophoblastic neoplasms of pleura (mesothelioma of pleura), abdominal part (for example serving as a contrast the mesothelioma (optimum mesothelioma) of the mesothelioma of lining of the mesothelioma (peritoneal mesothelioma) of the tissue in the abdominal cavity and lung or genitals's lining), recurrence.

Recommended dose be 500mg/m ²Carried out administration the 1st day of each administration cycle with the intravenous input form in 10 minutes, the administration cycle is 21 days, for example is used for the treatment of nonsmall-cell lung cancer, for example or with the cisplatin combined mesothelioma that is used for the treatment of, for example (recommended dose of cisplatin is 75mg/m to malignant pleural mesothelioma ², finish back beginning in about 30 minutes, input in 2 hours in the ALIMTA administration).

A limiting factor of antifol chemical compound development is that the cytotoxicity of antifol may be relevant with the sizable toxicity of some patients with effectiveness subsequently.In addition, antifol one class is with the accidental enterotoxication material of serious bone marrow depression stomach function regulating, though such effect is rare, but the mortality risk height.Can not control these toxicity makes and to have abandoned the research and development of some antifols clinically and to have made the clinical development of other antifols complicated.

Find that now mTOR inhibitor and antifol be formula I for example _US5344932Combination of compounds is at mTOR inhibitor and/or formula I _US5344932Show astonishing result in the useful treatment of conditions of chemical compound, for example can be used for treating inflammation or (self) immune disorders, for example psoriasis and be used for the treatment of cancer, for example tumor.

Be surprisingly, can be by there being the mTOR-inhibitor at the situation decline low-head I that can not have a negative impact to therapeutic efficiency _US5344932Some toxic actions of causing of antifol.If administering drug combinations is compared with the single therapy that obtains similar action, use formula I _US5344932Chemical compound and the mTOR inhibitor therapeutic alliance synergistically quantity that reduced each single medicine surprisingly.Be mTOR inhibitor and formula I surprisingly _US5344932Combination of compounds can reduce and giving construction I _US5344932The relevant toxicity incident of antifolic, for example with the cooperative mode onset.

Some different aspect, the invention provides

1.1 one kind comprises mTOR inhibitor and antifol combination of compounds form.

Combining form provided by the invention comprises pharmaceutical combination.

On the other hand, the invention provides

1.2 pharmaceutical combination that comprises mTOR inhibitor and antifol chemical compound.

(medicine) provided by the invention combining form comprises

-fixed combining form, wherein two or more forms of pharmacologically active agents for example mTOR inhibitor and antifol chemical compound be arranged in same preparation,

-medicine box, two or more forms of pharmacologically active agents that wherein are arranged in independent preparation for example mTOR inhibitor are sold in identical packing with the antifol chemical compound, for example have the explanation that is used for co-administered; With

-independent assortment form, wherein two or more forms of pharmacologically active agents for example mTOR inhibitor and antifol chemical compound by independent packaging, but be provided for the explanation of administration simultaneously or sequentially.

On the other hand, the invention provides

1.3 a pharmaceutical composition, except that pharmaceutically useful excipient, it is united and comprises mTOR inhibitor and antifol chemical compound.

1.4 a drug packages, the explanation that it comprises mTOR inhibitor and antifol chemical compound and is used for administering drug combinations.

1.5 a drug packages, it comprises the mTOR inhibitor and is used for explanation with antifol chemical compound administering drug combinations.

1.6 a drug packages, it comprises the antifol chemical compound and is used for explanation with mTOR inhibitor administering drug combinations.

According to the present invention, combining form provided by the invention comprises pharmaceutical combination, pharmaceutical composition and drug packages and is also referred to as " combining form of the present invention " in this article.

Combining form of the present invention can be used for treating the disease by mTOR and/or thymidylate synthetase mediation, for example by the disease of mTOR and thymidylate synthetase mediation, as mTOR inhibitor and/or antifol chemical compound to its useful disease, for example mTOR inhibitor and antifol chemical compound are to its useful disease, for example can be used for treating inflammation, immune disorders, autoimmune disorder for example, as psoriasis be used for the treatment of disease with related to cancer, for example relevant disease with cell hyperproliferation, as with

-cancer,

-solid tumor,

-endocrine tumors,

-tumor growth,

The disease that-mesothelioma is relevant.

The disease of used herein and related to cancer, for example relevant with cell hyperproliferation disease comprise for example premalignant situation, hyper-proliferative disease, former or cancer, the cervical cancer that shifts, the cancer that rises to be derived from not controlled cell proliferation, solid tumor, disease, lymphoma, B-cell or T-cell lymphoma, benign tumor, optimum proliferative disorders disease, renal carcinoma, the esophageal carcinoma, gastric cancer, bladder cancer, breast carcinoma, colon cancer, pulmonary carcinoma, melanoma, nasopharyngeal carcinoma, osteocarcinoma, ovarian cancer, the uterus carcinoma relevant with tumor growth; Carcinoma of prostate, skin carcinoma, mycosis fungoides, leukemia, the tumor neovascularization, hemangioma, spinal cord abnormal development disease, can not respond (immortalization) to normal dead inducement signal, cell mobility and aggressive increase, genetic instability, the gene expression imbalance, (nerve) endocrine cancer (carcinoid tumor), leukemia, Lymphocytic leukemia, (neuroblastoma is a kind of wherein the adrenal gland to neuroblastoma, neck, form the disease of pernicious (cancer) cell in the nervous tissue of breast or spinal cord), the soft tissue cancer, shift.

Used herein and disease related to cancer comprise solid tumor and/or neoplasm metastasis (no matter its position how), for example brain and other central nerve neuroma (for example tumor of meninges, brain, spinal cord, cranial nerve and central nervous system's other parts, for example glioblastoma or spinal cord blastoma); Head and/or neck cancer; Mammary neoplasms; Blood circulation tumor (for example organ, vascular tumor and the vascular tissue relevant in heart, mediastinum and pleura and other thorax) with tumor; Excretory system tumor (for example kidney, renal pelvis, ureter, bladder, other and the urinary organs do not mentioned especially); Gastroenteric tumor (for example esophagus, stomach, small intestinal, colon, colorectum, rectosigmoid junction, rectum, anus and anal canal), relate to liver and stones in intrahepatic bile duct, gallbladder, other and the bile duct part do not mentioned especially, pancreas, other and Alimentary tumor); Head and neck; Oral cavity (other position of other parts, tonsil, oropharynx, nasopharynx, piriform recess, hypogloeeis and lip, oral cavity and the pharynx of other parts, the parotid gland and the salivary gland in lip, tongue, gingiva, mouthful end, palate, oral cavity); Genital system tumor (for example pudendum, vagina, cervix uteri, body of uterus, uterus, ovary and other position relevant, Placenta Hominis, penis, prostate, testis and with the genital orgnas,male relevant other position) with female sex organ; Respiratory tract neoplasms (for example nasal cavity and middle ear, paranasal sinus, larynx, trachea, bronchus and lung, for example small cell lung cancer or nonsmall-cell lung cancer); Skeletal system tumor (for example articular cartilage of bone and extremity, bone articular cartilage and other position); Cutaneous tumor (for example malignant melanoma of skin, non--the melanoma skin cancer, the basal cell carcinoma of skin, the squamous cell cancer of skin, mesothelioma, kaposi's sarcoma, mycosis fungoides); With the tumor that relates to some other tissue, described other tissue comprises peripheral nervous and autonomic nervous system, connective tissue and soft tissue, retroperitoneum and peritoneum, eyes and adnexa, thyroid, adrenal gland and other endocrine gland and dependency structure; The second malignant neoplasm of the second malignant neoplasm of not mentioning especially, breathing and the digestive system of lymph node and the second malignant neoplasm at other position.

Used herein and disease related to cancer comprises by the endocrine tumors disease of endocrine tumors mediation, comprises neuroendocrine tumor, as the pancreas neuroendocrine tumor.Carcinoid tumor is neuroendocrine tumor and comprises the carcinoid tumor that is derived from anterior intestine, for example bronchus or carcinoid of stomach tumor; Be derived from the carcinoid tumor of midgut, for example, small intestinal or carcinoid of appendix tumor; Or be derived from the carcinoid tumor of hindgut, for example rectal carcinoid tumor; Carcinoid tumor as the GI road.

The symptom of carcinoid tumor cancer comprises for example carcinoid syndrome.

Used hereinly comprise the disease relevant, for example comprise epidermal carcinoma, squamous or small cell lung cancer and the various lymphosarcoma of adenocarcinoma, head and the neck of choriocarcinoma, leukemia, female breast with growth of tumor with the disease of related to cancer.

Used herein and disease related to cancer comprises (pernicious) mesothelioma, it is mesothelial cell's a cancer, and for example such cancer can be formed at nonsmall-cell lung cancer (NSCLC), the gestational trophoblastic neoplasms of pleura (mesothelioma of pleura), abdominal part (for example serving as a contrast the mesothelioma (optimum mesothelioma) of the mesothelioma of lining of the mesothelioma (peritoneal mesothelioma) of the tissue in the abdominal cavity and lung or genitals's lining), recurrence.

In addition, no matter when tumor, tumor disease, cancer or cancer how, are mentioned in the position of tumor and/or transfer in context, also comprise the metastatic tumor in initial organ or tissue and/or any other position.

Disease used herein comprises disease.

On the other hand, the invention provides

2.1 a treatment is by the method for the disease of mTOR and/or thymidylate synthetase mediation, described disease such as inflammation, (self) immunity, allergy disease or with the disease of related to cancer, for example relevant disease with cell hyperproliferation;

Preferred autoimmune disorder and with the disease of related to cancer,

This method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.2 a treatment method for cancer, for example this cancer is by the mediation of mTOR and/or thymidylate synthetase, and this method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.3 method that suppresses growth of cancers, for example this cancer is by mTOR and/or thymidylate synthetase mediation, this method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.4 one kind is suppressed or the control method for cancer, for example this cancer is by mTOR and/or thymidylate synthetase mediation, this method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.5 method of inducing cancer to disappear, for example this cancer is by mTOR and/or thymidylate synthetase mediation, for example induce the cancer quality to reduce, it comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.6 method for the treatment of invasive cancer or the symptom relevant with such growth of cancers, for example this cancer is by mTOR and/or thymidylate synthetase mediation, this method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

2.7 method of preventing the cancer cell metastasis diffusion, for example this cancer is by mTOR and/or thymidylate synthetase mediation, this method comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, for example uses in turn or simultaneously.

Such treatment can be finished by using top 1.1 to 1.6 times described any combining forms.On the other hand, the invention provides

The purposes of 2.1 to 2.7 times described any methods above 3.1 top 1.1 to 1.6 times described any combining forms are used for.

3.2 be used for top 2.1 to 2.7 times described any methods above 1.1 to 1.6 times described any combining forms.

On the other hand, the invention provides

4.1 mTOR inhibitor of the present invention and antifol combination of compounds form for example are used for the purposes of the medicine of top 2.1 to 2.7 times described any methods as medicine.

4.2 for example be used for the mTOR inhibitor of the present invention and the antifol combination of compounds form of the medicine of top 2.1 to 2.7 times described any methods as medicine.

On the other hand, the invention provides

5.1 mTOR inhibitor of the present invention and antifol combination of compounds form are used to prepare medicine, for example are used for the purposes of the medicine of top 2.1 to 2.7 times described any methods.

5.2 be used to prepare medicine, for example be used for the mTOR inhibitor of the present invention and the antifol combination of compounds form of the medicine of top 2.1 to 2.7 times described any methods.

5.3 a method for preparing the medicine that is used for top 2.1 to 2.7 times described any methods, it comprises

A) mTOR inhibitor and antifol chemical compound are combined with pharmaceutically useful excipient for example admixed together, perhaps

B) the mTOR inhibitor is combined with pharmaceutically useful excipient for example admixed together, thereby obtain pharmaceutical composition COMP1, and the antifol chemical compound is combined with pharmaceutically useful excipient for example admixed together, thereby acquisition pharmaceutical composition COMP2, and

(i) pharmaceutical composition COMP1 and pharmaceutical composition COMP2 are combined in the unitary package, perhaps

(ii), still in each packing, put into the explanation that is used for pharmaceutical composition COMP1 and pharmaceutical composition COMP2 administering drug combinations with pharmaceutical composition COMP1 independent packaging and with pharmaceutical composition COMP2 independent packaging.

According to the present invention, compare with the use single therapy, therapeutic alliance by the disease of mTOR and/or thymidylate synthetase mediation has obtained improvement, for example can reduce the toxicity of antifol chemical compound, compare with single therapy, can increase the activity of mTOR inhibitor or the activity of antifol chemical compound, for example therapeutic alliance can produce synergism or can overcome Drug resistance to mTOR inhibitor or antifol chemical compound, for example above being used for during 2.1 to 2.7 times described any methods.

On the other hand, the invention provides

6.1 comprise the combining form of the present invention of some mTOR inhibitor and some antifols chemical compound, the suitable synergistic therapeutic action that produces of wherein said quantity.

6.2 a method of improving the treatment effectiveness of antifol chemical compound, it comprises mTOR inhibitor and the antifol chemical compound that for example gives jointly together or treat effective dose in turn.

6.3 a method of improving the treatment effectiveness of mTOR inhibitor, it comprises jointly and giving, for example together or treat the mTOR inhibitor and the antifol chemical compound of effective dose in turn.

6.4 the toxic method that reduction is relevant with the administration of antifol chemical compound, it comprises to the antifol chemical compound of the co-administered effective dose of described individuality and the mTOR inhibitor of effective dose, for example is used for top 2.1 to 2.7 times described any methods.

Treatment used herein comprises treatment and prevention, preferred therapeutic.

Combining form of the present invention, the combining form that for example is used for any method provided by the present invention can further comprise another kind of medicine.

Another kind of medicine used herein comprises any medicine that has beneficial effect in purposes provided by the present invention or method except that mTOR inhibitor or antifol chemical compound.Such medicine for example comprises

-antiinflammatory and/or immunomodulator,

-anticarcinogen

-anesthetis

-diarrhea.

On the other hand, the invention provides

7.1 combination of the present invention, method provided by the present invention or purposes wherein, also comprise at least a other medicines except that mTOR inhibitor and antifol combination of compounds,

For example wherein said other medicines be selected from anti-inflammatory agent, immunomodulator, anticarcinogen, anesthetis and/

Or diarrhea.

On the other hand, the invention provides mTOR inhibitor and antifol chemical compound and unite purposes in any method provided by the present invention.

On the other hand, the invention provides mTOR inhibitor and antifol chemical compound and unite application in any in combining form provided by the present invention or pharmaceutical composition or drug packages.

Tend to and combining form coupling of the present invention, the antiinflammatory and/or the immunomodulator that for example are used for therapeutic alliance for example comprise

-regulator, for example inhibitor of neurocalcin, for example cyclosporin A, FK506;

-have the ascosin class of immunosuppressant character, for example ABT-281, an ASM981;

-cortical steroid; Cyclophosphamide; Imuran; Leflunomide; Imidazoles stands the shore;

-Mycophenolic Acid or salt; Mycophenolic Acid sodium for example;

-15-deoxidation spergualin (spergualine) or its immunosuppressant homologue, analog or derivant;

-regulator, for example inhibitor of bcr-abl tyrosine kinase activity;

-regulator, for example inhibitor of c-kit receptor tyrosine kinase activity;

-regulator, for example inhibitor of pdgf receptor tyrosine kinase activity, for example Gleevec (imatinib);

-regulator, the inhibitor of p38MAP kinase activity for example,

-regulator, the active inhibitor of vegf receptor tyrosine kinase for example,

-regulator, the active inhibitor of PKC for example, disclosed chemical compound among WO0238561 or the WO0382859 for example, for example embodiment 56 or 70 chemical compound;

-regulator, the inhibitor of JAK3 kinase activity for example, N-benzyl-3 for example, 4-dihydroxy-benzal-cyanoacetamide alpha-cyano-(3, the 4-dihydroxy)-] N-benzyl cinnamamide (tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P131), [4-(3 '-bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] (WHI-P154), [4-(3 ', 5 '-two bromo-4 '-hydroxy phenyl)-amino-6, the 7-dimethoxyquinazoline] WHI-P97, KRX-211,3-{ (3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-amino]-piperidines-1-yl }-3-oxo-propionitrile, free form or pharmaceutical acceptable salt, for example single citrate (being also referred to as CP-690,550), or as disclosed chemical compound among WO2004052359 or the WO2005066156;

-regulator, the for example agonist of S1P receptor active or regulator, for example randomly by the FTY720 of phosphorylation or its analog, for example randomly by the 2-amino-2-[4-of phosphorylation (3-benzyloxy thiophenyl)-2-chlorphenyl] ethyl-1, ammediol or 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxy imino group)-ethyl]-2-ethyl-benzyl }-azetidine-3-formic acid or its pharmaceutically useful salt;

-immunosuppressant monoclonal antibody, for example, the leukocyte receptors monoclonal antibody of Blys/BAFF receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86, IL-12 receptor, IL-17 receptor, IL-23 receptor or its part for example;

-other immunomodulatory compounds, the zone, extracellular that for example has at least a portion CTLA4 or its mutant is the part of extracellular at least of CTLA4 or its mutant that links to each other with non-CTLA4 protein sequence at least for example, for example the reorganization binding molecule of CTLA4Ig (for example being called as ATCC68629) or its mutant, for example LEA29Y;

-regulator, the active inhibitor of adhesion molecule for example, for example LFA-1 antagonist, ICAM-1 or-3 antagonisies, VCAM-4 antagonist or VLA-4 antagonist,

-regulator, the active inhibitor of MIF for example,

-5-aminosalicylate (5-ASA) activating agent, as sulfasalazine,

The medicine that for example comprises mesalazine; For example with the mesalazine of combination with heparin;

-regulator, for example the inhibitor of TNF-alpha active for example comprises the antibody in conjunction with TNF-α, for example infliximab

Thalidomide, Li Nadu amine (lenalidomide),

-discharge the NSAID (non-steroidal anti-inflammatory drug) (NSAID) of nitrogen oxide, for example comprise that the COX-inhibition is for NO medicine (CINOD);

-phosphodiesterase (phospordiesterase), regulator for example, as the active inhibitor of PDE4B,

-regulator, the active inhibitor of caspase for example,

-regulator, the agonist of G protein-coupled receptor GPBAR1 for example,

-regulator, the active inhibitor of ceramide kinase for example,

-' multi-functional antiinflammatory ' medicine (MFAID), cytosol phospholipase A2 (cPLA2) inhibitor for example is as the PLA 2 inhibitors of film-grappling of linking to each other with glycosaminoglycan;

-antibiotics is as penicillins, cephalosporins, erythromycin series, Tetracyclines, sulfonamides, as sulfadiazine, sulfafurazole; The sulfone class is as dapsone; Pleuromulins, fluoroquinolones be metronidazole, quinolones such as ciprofloxacin for example; Levofloxacin; Probiotic bacteria (probiotics) and symbiotic antibacterial be Lactobacillus, Lactobacillusreuteri for example;

-antiviral agents is as ribavirin (ribivirin), vidarabine, acyclovir, ganciclovir, zanamivir, oseltamivir phosphate, famciclovir, atazanavir (atazanavir), amantadine, Didanosine, efavirenz, phosphine formic acid, indinavir, lamivudine, nelfinavir, ritonavir, Saquinavir, stavudine, valaciclovir, valganciclovir, zidovudine.

The anti-inflammatory agent that tends to for example be used for therapeutic alliance with combining form coupling of the present invention comprises that for example NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is as propanoic derivatives (alminoprofen, Benoxaprofen, the bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, uncle Luo Fen, tiaprofenic acid and tioxaprofen), acetogenin (indometacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, Isoxepac, Oxpinac, sulindac, Tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivative (flufenamic acid, meclofenamic acid, that acid of cresol, niflumic acid and tolfenamic acid), biphenyl acid derivant (diflunisal and flufenisal), former times health class (isoxicam, piroxicam, sudoxicam and Tenoxicam), salicylic acid esters (aspirin, sulfasalazine) and pyrazolone (azapropazone, Bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, Phenylbutazone); Cyclo-oxygenase-2 (COX-2) inhibitor such as celecoxib; IV type phosphodiesterase inhibitor (PDE-IV); The antagonist of chemokine receptors, especially CCR-1, CCR-2 and CCR-3; The material of cholesterol reducing such as HMG-CoA reductase inhibitor (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other Statins), chelating agen class (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivant (Ji Feibeite, chlorine Bei Te (clofibrat), fenofibrate and bezafibrate) and probucol; Anticholinergic such as muscarine antagonist (ipratropium bromide); Other chemical compound such as theophylline, sulfasalazine and aminosallcylic acid esters, for example 5-aminosalicylic acid with and prodrug, rheumatism.

Tend to for example comprise as the anticarcinogen that combined partner capable and combining form coupling of the present invention for example are used for therapeutic alliance

I. steroid; Prednisone for example.

Ii. adenosine-kinases-inhibitor; Its targeting, reduction or inhibition base (nucleobase), nucleoside, nucleotide and nucleic acid metabolism, as 5-iodine tubercidin, it is also referred to as 7H-pyrrolo-[2,3-d] pyrimidine-4-amine, 5-iodo-7-β-D-ribofuranosyl.

Iii. strengthen the auxiliary agent of 5-FU-TS key and the chemical compound of targeting, reduction or inhibition alkali phosphatase, as folinic acid, levamisole.

Iv. adrenal cortex antagonist; The periphery metabolism of its targeting, reduction or inhibition adrenal cortex activity and change corticosteroid, thus cause 17-hydroxyl corticosteroid to reduce, as mitotane.

The v.AKT approach restrainer; As targeting, reduction or suppress the chemical compound of Akt (being also referred to as protein kinase B (PKB)), as deguelin, its be also referred to as 3H-two [1] .alpha.-5:6-benzopyrans also [3,4-b:6 ', 5 '-e] pyrans-7 (7aH)-ketone), 13,13a-dihydro-9,10-dimethoxy-3, the 3-dimethyl-, (7aS, 13aS); And triciribine, it is also referred to as 1,4,5,6,8-pentaaza acenaphthylene-3-amine, 1,5-dihydro-5-methyl isophthalic acid-β-D-ribofuranosyl.

Vi. alkylating agent; It causes the DNA alkylation and causes dna molecular and bifilar crosslinked breaking, thereby has disturbed dna replication dna and rna transcription, as nitrogen mustards, and for example chlorambucil, embichin, cyclophosphamide, ifosfamide, melphalan, estramustine

Nitrosoureas (nitrosueras), as carmustine, fotemustine, Luo Mositing, streptozocin (streptozocin, STZ,

BCNU; Gliadel; Reaching click crust piperazine, chlormethine, for example is hydrochloride form, procarbazine, for example is hydrochloride form, thio-tepa, temozolomide

Mitomycin, hexamethyl melamine, busulfan, estramustine, uracil mustard.Cyclophosphamide for example can be with commercial form, for example with trade mark

Commercially available form is carried out administration; With ifosfamide can with

Form is carried out administration.

Vii. angiogenesis inhibitor; Its targeting, reduce or suppress cardiovascular generation, its targeting methionine amino peptidase-2 (MetAP-2) for example, macrophage inflammatory protein-1 (MIP-1 α), CCL5, TGF-β, lipoxidase, cyclo-oxygenase and topoisomerase, perhaps its direct targeting p21, p53, CDK2 and collagen are synthetic, for example comprise Amebacilin, it is also referred to as 2,4, and 6,8-ten carbon tetraene diacid, single [(3R, 4S, 5S, 6R)-5-methoxyl group-4-[(2R, 3R)-2-methyl-3-(3-methyl-2-butene base) Oxyranyle]-1-oxa-volution [2.5] suffering-6-yl] ester, (2E, 4E, 6E, 8E)-(9CI); Shikonin, it is also referred to as 1, the 4-naphthalenedione, 5, the 8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-(9CI); Tranilast, it is also referred to as benzoic acid, 2-[[3-(3, the 4-Dimethoxyphenyl)-1-oxo-2-acrylic] amino]-(9Cl); Ursolic acid; Suramin; Bengamide or derivatives thereof, Thalidomide, TNP-470.

Viii. antiandrogen; It has been blocked stimulates normal and the adrenal gland of malignant prostate tissue growth and the androgenic effect in testis source, as nilutamide; Bicalutamide

It for example can be prepared as disclosed among the US4636505.

Ix. antiestrogen; It for example comprises aromatase inhibitor in the estrogenic effect of the horizontal antagonism of estrogen receptor, its suppress estrogen production be substrate ANDROSTENEDIONE and testosterone respectively to the conversion of estrone and estradiol,

For example comprise atamestane, exemestane, formestane, amino glutethimide, Raleigh Mi Te (roglethimide), (.+-.)-Pyridoglutethimide, trilostane, testolactone, ketoconazole (ketokonazole), vorozole, fadrozole, Anastrozole, letrozole, toremifene; Bicalutamide; Flutamide; Tamoxifen, Tamoxifen Citrate; Tamoxifen; Fulvestrant; Raloxifene, RALOXIFENE HCL.Tamoxifen for example can be with its commercial form for example

Form carry out administration; With RALOXIFENE HCL with Form commercially available.Fulvestrant can as disclosed among the US4659516, prepare and with

Form commercially available.

X. hypercalcemia disease medicine; It is used to treat hypercalcemia, as Ganite (Fujisawa). (III) hydrate; And Pamidronate Disodium.

Xi. antimetabolite; Its inhibition or to destroy DNA synthetic, thus cause cell death, as the folic acid class, for example methotrexate, train beautiful Qu De, Raltitrexed; Purine class, for example Ismipur; Cladribine, clofarabine (clofarabine); Fludarabine, thioguanine, 6-thioguanine, spray Si Tating (deoxycoformycin); Cytosine arabinoside; Flexuridine; Fluorouracil; 5-fluorouracil (5-FU), floxuridine (5-FUdR), capecitabine; Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea (for example

The agent of DNA demethylation is as 5-azacytidine and decitabine; Edatrexate.Capecitabine and gemcitabine for example can be with commercial form, as

With

Form carry out administration.

Xii. cell death inducer; It has induced a series of normal cell incidents that cause cell death, for example selective induction X (X-linked) mammal inhibitor of apoptosis protein XIAP, perhaps for example reduce BCL-xL; As ethanol, 2-[[3-(2, the 3-dichlorophenoxy) propyl group] amino]; Gamlogic acid; Embelin, it is also referred to as 2,5-cyclohexadiene-1, the 4-diketone, 2,5-dihydroxy-3-undecyl-(9CI); Arsenic trioxide.

Xiii. aurora (aurora) inhibitors of kinases; Its targeting, reduction or inhibition are from the later stage (leading to mitotic all paths of mitosis checkpoint and latter stage) of the cell cycle of G2/M checkpoint; As Binucleine2, it is also referred to as carbonamidine, N '-[1-(3-chloro-4-fluorophenyl)-4-cyano group-1H-pyrazoles-5-yl]-N, and the N-dimethyl-(9CI).

Xiv.Bruton ' s tyrosine kinase (BTK) inhibitor; Its targeting, reduction or inhibition people and murine B cell development; As terreic acid.

Xv. neurocalcin inhibitor; Its targeting, reduction or suppressor T cell activated channel, as cypermethrin, it is also referred to as cyclopropane-carboxylic acid, 3-(2, the 2-dichloroethylene)-2, the 2-dimethyl-, cyano group (3-Phenoxyphenyl) methyl ester; Decis, it is also referred to as cyclopropane-carboxylic acid 3-(2, the 2-dibromo vinyl)-2, the 2-dimethyl-(S)-cyano group (3-Phenoxyphenyl) methyl ester, (1R, 3R); Kill the chrysanthemum ester, it is also referred to as phenylacetic acid, 4-chloro-α-(1-Methylethyl)-and, cyano group (3-Phenoxyphenyl) methyl ester; And tyrphostin (Tyrphostin) 8; But do not comprise cyclosporin or FK506.

The xvi.CaM kinase ii inhibitors; Its targeting, reduction or inhibition CaM kinases; Form the enzyme of gang's structurally associated, this enzyme comprises phosphorylase kinase, myosin light chain kinase and CaM kinases I-IV; As 5-isoquinolin sulfonic acid, 4-[(2S)-2-[(5-isoquinolyl sulfonyl) methylamino]-3-oxo-3-(4-phenyl-peiperazinyl) propyl group] phenylester (9CI); Benzsulfamide, N-[2-[[[3-(4-chlorphenyl)-2-acrylic] methyl] amino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxyl group.

The xvii.CD45 tyrosine phosphatase inhibitors; The pTyr residue that dephosphorylation is regulated on its targeting, reduction or the inhibition Src-family albumen-tyrosine kinase, it can help to treat many inflammatories and immune disorders; As phosphonic acids, [[2-(4-bromine phenoxy group)-5-nitrobenzophenone] hydroxymethyl].

The xviii.CDC25 inhibitors of phosphatases; Cross the dephosphorylation cell cycle protein dependent kinase of expressing in its targeting, reduction or the inhibition tumor; As 1,4-naphthalenedione, 2,3-two [(2-hydroxyethyl) sulfenyl].

The xix.CHK inhibitors of kinases; Its targeting, reduction or crossing of inhibition anti-apoptotic protein B cl-2 are expressed; As debrominate Hymenialdisine.CHK inhibitors of kinases target is CHK1 and/or CHK2.

Xx. be used to regulate the controlling agent of genistein, olomoucine and/or tyrphostin class; As daizeol, it is also referred to as 4H-1-.alpha.-5:6-benzopyran-4-ketone, 7-hydroxyl-3-(4-hydroxy phenyl); Different-olomoucine and tyrphostin 1.

Xxi. cyclooxygenase-2 inhibitor; For example comprise the Cox-2 inhibitor; Its targeting, reduction or inhibitory enzyme cox-2 (cyclo-oxygenase-2); As the 1H-indole-3-acetamide, 1-(4-chlorobenzene formacyl)-5-methoxyl group-2-methyl-N-(2-phenylethyl)-(9Cl); 2-arylamino phenylacetic acid and derivant that the 5-alkyl replaces, for example celecoxib

Rofecoxib

Etoricoxib, valdecoxib; Or 5-alkyl-2-arylamino phenylacetic acid, for example, 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid, Prexige (lumiracoxib); And celecoxib.

The xxii.cRAF inhibitors of kinases; Its targeting, reduction or the inductive E-of inhibition TNF select the rise of albumen and blood vessel adhesion molecule-1; As 3-(3,5-two bromo-4-hydroxyl benzals)-5-iodo-1,3-Indolin-2-one; And Benzoylamide, 3-(dimethylamino)-N-[3-[(4-hydroxy benzoyl) amino]-the 4-aminomethyl phenyl].The Raf kinases is regulated kinases as the extracellular signal transduction and is played an important role in cell differentiation, propagation and apoptosis.The target spot of cRAF inhibitors of kinases comprises RAF1 without limitation.

Xxiii. cell cycle protein dependent kinase inhibitor; Its targeting, reduction or inhibition cell cycle protein dependent kinase work in the adjusting in mammalian cell cycle; As N9-isopropyl-olomoucine; Olomoucine; Purvalanol B, it is also referred to as benzoic acid, 2-chloro-4-[[2-[[(1R)-1-(hydroxymethyl)-2-methyl-propyl] amino]-9-(1-Methylethyl)-9H-purine-6-yl] amino]-(9CI); Roascovitine; Indirubin, it is also referred to as the 2H-indol-2-one, 3-(1,3-dihydro-3-oxo-2H-indole-2-subunit)-1, the 3-dihydro-(9CI); Kenpaullone, it is also referred to as also [3,2-d] [1] benzazepine-6 (5H)-ketone of indole, 9-bromo-7, the 12-dihydro-(9CI); Purvalanol A, it is also referred to as the 1-butanols, the 2-[[6-[(3-chlorphenyl) amino]-9-(1-Methylethyl)-9H-purine-2-yl] amino]-the 3-methyl-, (2R)-(9CI); Indirubin-3 '-monoxime.Cell cycle progression is by a series of continuous event conditioning, and this incident comprises the activation of cell cycle protein dependent kinase (Cdks) and cyclin and deactivation subsequently.Cdks be by with its adjusting subunit, cyclin is in conjunction with the one group of serine/threonine kinase that forms active heterodimer complex.The example of cell cycle protein dependent kinase inhibitor target spot comprises CDK, AHR, CDK1, CDK2, CDK5, CDK4/6, GSK3 β and ERK without limitation.

Xxiv. cystatin; Its targeting, reduce or be suppressed at the cysteine proteinase that plays an important role in mammalian cell upset and the apoptosis; As 4-morpholine Methanamide, N-[(1S)-3-fluoro-2-oxo-1-(2-phenylethyl) propyl group] amino]-2-oxo-1-(phenyl methyl) ethyl].

The xxv.DNA intercalate agent; It combines with DNA and to suppress DNA, RNA and albumen synthetic; As plicamycin, dactinomycin.

Xxvi.DNA chain interruption agent; It causes the DNA chain splitting and causes DNA synthetic to suppress, suppressed RNA and albumen is synthetic; As bleomycin.

Xxvii.E3 ligase inhibitor; Its targeting, reduction or inhibition E3 ligase, this enzyme suppresses ubiquitin chain to proteic transfer, thereby it is degraded in proteasome; As N-((3,3,3-three fluoro-2-trifluoromethyls) propiono) sulfonamide.

Xxviii. endocrine hormone; It causes the males internal hormone to suppress by mainly acting on pituitary gland, clean effect is that testosterone is reduced to the castrating level; For the women, ovarioestrogen and androgen are synthetic all to be suppressed; As leuprorelin acetate; Megestrol, megestrol acetate.

Xxix. targeting, reduce or suppress epidermal growth factor subfamily receptor tyrosine kinase (all or the EGFR of heterodimer form, ErbB2, ErbB3, ErbB4) active chemical compound, as suppress the EGF receptor tyrosine kinase member of family, EGF receptor for example, ErbB1, ErbB2, ErbB3 and ErbB4 or with EGF or the bonded chemical compound of EGF-associated ligands, albumen or antibody, and particularly at WO 9702266 (for example chemical compound of embodiment 39), EP0564409, WO9903854, EP0520722, EP0566226, EP0787722, EP0837063, US5747498, WO9810767, WO9730034, WO9749688, WO9738983 and especially WO9630347 (chemical compound that for example is called as CP 358774), WO9633980 (chemical compound that for example is called as ZD1839); With general among the WO 9503283 (chemical compound that for example is called as ZM105180) and concrete disclosed these chemical compounds, albumen or monoclonal antibody, tyrosine kinase inhibitor (ErbB1 and the ErbB2) Lapatinib (GSK572016) that for example comprises biphasic effect, for example Lapatinib xylenesulfonate; The appropriate monoclonal antibody of Pan (panituzumab), trastuzumab (

), Cetuximab, Iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3,7H-pyrrolo--[2,3-d] pyrimidine derivatives, it for example is disclosed in WO03013541, Erlotinib, Gefitinib.Erlotinib can be with its commercial form for example

Form is by administration, Gefitinib can with

Form administration, the human monoclonal antibodies that acts on EGF-R ELISA comprises ABX-EGFR.

Xxx.EGFR, PDGFR tyrosine kinase inhibitor; Comprise tyrphostin 23, tyrphostin 25, tyrphostin 47, tyrphostin 51 and tyrphostin AG 825 as the EGFR inhibitors of kinases; The 2-acrylamide, 2-cyano group-3-(3, the 4-dihydroxy phenyl)-N-phenyl-(2E); Tyrphostin Ag 1478; Lavendustin A; 3-pyridine acetonitrile, α-[(3, the 5-Dichlorobenzene base) methylene]-, (α Z); The example of EGFR, PDGFR tyrosine kinase inhibitor for example comprises tyrphostin 46.The PDGFR tyrosine kinase inhibitor comprises tyrphostin 46.The target of EGFR inhibitors of kinases comprises guanylate cyclase (GC-C) HER2, EGFR, PTK and tubulin.

Xxxi. farnesyl transferase inhibitor; Its targeting, reduction or inhibition Ras albumen; As a-hydroxyl farnesyl phosphonic acids; Butanoic acid, 2-[[(2S)-2-[[(2S, 3S)-2-[[(2R)-2-amino-3-sulfydryl propyl group] amino]-the 3-methyl amyl] the oxygen base]-1-oxo-3-phenyl propyl] amino]-4-(methyl sulphonyl)-, 1-Methylethyl ester, (2S); Manumycin A; L-744,832 or DK8G557, Tipifarnib (R115777), SCH66336 (Lonafarnib), BMS-214662,

The xxxii.Flk-1 inhibitors of kinases; Its targeting, reduction or inhibition Flk-1 tyrosine kinase activity; As the 2-acrylamide, 2-cyano group-3-[4-hydroxyl-3,5-two (1-Methylethyl) phenyl]-N-(3-phenyl propyl)-(2E).The target of Flk-1 inhibitors of kinases comprises KDR without limitation.

Xxxiii. glycogen synthase kinase-3 (GSK3) inhibitor; Its targeting, reduction or inhibition glycogen synthase kinase-3 (GSK3); As indirubin-3 '-monoxime.In the signal transduction cascade of many cell processes, all relate to glycogen synthase kinase-3 (GSK-3; Low-light related protein kinase I)---a kind of high serine/threonine protein kitase conservative, that generally express, it is a kind of having shown participate in to have regulated not the protein kinase of cell function on the same group, and said cell function comprises that albumen is synthetic, cell proliferation, cell differentiation, microtubule assembling/decomposition and apoptosis.

Xxxiv. histone deacetylase (HDAC) inhibitor; Its inhibition of histone deacetylase also has anti-proliferative activity; As disclosed chemical compound in WO0222577, N-hydroxyl-3-[4-[[(2-hydroxyethyl especially) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-the 2E-2-acrylamide with and pharmaceutically useful salt; Octanedioyl aniline (suberoylanilide) hydroxamic acid (SAHA); [4-(2-amino-phenyl amino formoxyl)-benzyl]-anginin-3-ylmethyl ester with and derivant; Butanoic acid, Pyroxamide, trichostatin A, Oxamflatin, Apicidin, depsipeptide; Depudecin; Trapoxin, the HC toxin, it is also referred to as ring [L-alanyl-D-alanyl-(S, 2S)--amino--oxo oxirane caprylyl-D-prolyl] (9CI); Phenylbutyrate sodium, octanedioyl two-hydroxamic acid; Trichostatin A, BMS-27275, Pyroxamide, FR-901228, valproic acid.

The xxxv.HSP90 inhibitor; Its targeting, reduction or the intrinsic atpase activity of inhibition HSP90; By the degraded of ubiquitin protein body approach, targeting, reduction or inhibition HSP90 client albumen.The chemical compound of targeting, reduction or the inherent atpase activity of inhibition HSP90 especially suppresses chemical compound, albumen or the antibody of the atpase activity of HSP90, for example, and 17-allyl amino, 17-de-methoxy geldanamycin (17AAG), geldanamycin derivant; Other geldanamycin related compound; Radicicol and hdac inhibitor.Other example of HSP90 inhibitor comprises geldanamycin, 17-de-methoxy-17-(2-acrylic amino)-(9Cl).The potential indirect target of HSP90 inhibitor comprises FLT3, BCR-ABL, CHK1, CYP3A5*3 and/or NQ01*2.Nilotinib is an example of BCR-ABL tyrosine kinase inhibitor.

Xxxvi.I-κ B-alpha kinase inhibitor (IKK); Its targeting, reduction or inhibition NF-κ B, as the 2-acrylonitrile, the 3-[(4-aminomethyl phenyl) sulfonyl]-(2E).

Xxxvii. insulin receptor tyrosine kinase inhibitor; It regulates phosphatidyl-inositol 3-kinase, microtubule-associated protein and the kinase whose activity of S6; As hydroxyl-2-naphthyl methyl phosphonic acids, LY294002.

Terminal kinases (JNK) inhibitors of kinases of xxxviii.c-Jun N-; Its targeting, reduction or the terminal kinases of inhibition JunN-; As pyrazole anthrone and/or EGCG salt.The terminal kinases (JNK) of Jun N----protein kinase participation c-Jun that a kind of serine points to and phosphorylation and the activation of ATF2 also play an important role in metabolism, growth, cell differentiation and apoptosis.The target of JNK inhibitors of kinases comprises DNMT without limitation.

Xxxix. microtubule bonding agent; It works for mitosis and the very important microtubule network of karyostasis cell function by destroying; As vinca alkaloids, for example vinblastine, vinblastine sulfate; Vincristine, vincristine sulfate; Vindesine; Vinorelbine; Taxanes is as Docetaxel; Paclitaxel; Discodermolide class (discodermolides); Colchicine, epothilones with and derivant, for example epothilone B or derivatives thereof.Paclitaxel with

Form is sold; Docetaxel with

Form is sold; Vinblastine sulfate is with VINBLASTIN

Form is sold; With vincristine sulfate with

Form is sold.Also comprise the genus class form of paclitaxel and the various dosage forms of paclitaxel.The genus class form of paclitaxel comprises betaxolol hydrochloride without limitation.The various dosage forms of paclitaxel comprise without limitation with

The albumin nanoparticle type paclitaxel sold of form.Discodermolide for example can obtain as disclosed among the US5010099.Also be included in disclosed epothilone derivate among US6194181, WO98/0121, WO9825929, WO9808849, WO9943653, WO9822461 and the WO0031247.Especially preferred is Epothilones A and/or B.

Xl. mitogen activator protein (MAP) kinases-inhibitor; Its targeting, reduction or inhibition mitogen activator protein, as benzsulfamide, N-[2-[[[3-(4-chlorphenyl)-2-acrylic] methyl] amino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxyl group.Mitogen activator protein (MAP) kinases is an albumen serine/threonine kinase group, and it responds many extracellular stimulus and activates and mediate from cell surface to nuclear signal transduction.It regulates some physiologys and pathology cell phenomenon, comprises inflammation, apoptosis cell death, carcinogenecity conversion, tumor cell invasion and transfer.

The xli.MDM2 inhibitor; The interaction of its targeting, reduction or inhibition MDM2 and p53 tumor inhibitor; As trans-4-iodine, 4 '-boryl-chalcone derivative.

The xlii.MEK inhibitor; The kinase activity of its targeting, reduction or inhibition map kinase MEK; As Sorafenib, for example

(Sorafenib toluene fulfonate), succinonitrile, two [amino [the 2-aminophenyl) sulfenyl] methylene].The target of mek inhibitor comprises ERK without limitation.The indirect target of mek inhibitor comprises cyclin D1 without limitation.

Xliii. matrix metallo-proteinase inhibitor (MMP) inhibitor; The protease of its targeting, reduction or the hydrolysis of inhibition selectivity catalytic polypeptide key, comprise and participate in promoting the forfeiture of tumor structures surrounding and promote enzyme MMP-2 and the MMP-9 that tumor growth, blood vessel take place and shift, as actinonin, it is also referred to as succinamide, N-4-hydroxy-n 1-[(1S)-1-[[(2S)-and 2-(hydroxymethyl)-1-pyrrolidinyl] carbonyl]-the 2-methyl-propyl]-the 2-amyl group-, (2R)-(9CI); EGCG salt; Collagen is intended peptide (peptidomimetic) and non-plan inhibitor peptides; Tetracycline derivant, for example, hydroxamate is intended the inhibitor peptides batimastat; With and can be biological can be oral analog Marimastat, prinomastat, Mei Tasita (metastat), suffering cut down department he, tanomastat, TAA211, BMS-279251, BAY12-9566, MMI270B or AAJ996.The target of MMP inhibitor comprises the polypeptide deformylase without limitation.

Xliv.NGFR tyrosine-kinases-inhibitor; Its targeting, reduction or inhibition nerve growth factor dependency p140 ^C-trkTyrosine phosphorylation; As tyrphostin AG 879.The target of NGFR tyrosine-kinases-inhibitor comprises HER2, FLK1, FAK, TrkA and/or TrkC without limitation.A kind of indirect target suppresses the expression of RAF1.

The xlv.p38 map kinase inhibitor comprises the SAPK2/p38 inhibitors of kinases; Its targeting, reduction or inhibition p38-MAPK (it is the member of MAPK family), as phenol, 4-[4-(4-fluorophenyl)-5-(4-pyridine radicals)-1H-imidazoles-2-yl].The example of SAPK2/p38 inhibitors of kinases comprises Benzoylamide without limitation, 3-(dimethylamino)-N-[3-[(4-hydroxy benzoyl) amino]-the 4-aminomethyl phenyl].The member of MAPK family is by the activatory serine/threonine kinase of the phosphorylation of tyrosine and threonine residues.This kinases is thought that by many cellular stress and inflammatory stimulus phosphorylation and activation it participates in regulating important cellular response such as apoptosis and inflammatory reaction.

The xlvi.p56 tyrosine kinase inhibitor; Its targeting, reduction or inhibition p56 tyrosine kinase (it is a kind of to T-cell development and the very crucial lymph tissue specificity src family tyrosine kinase of activation); As damnacanthal, it is also referred to as the 2-anthraldehyde, and 9,10-dihydro-3-hydroxyl-1 methoxyl group-9,10-dioxo, tyrphostin 46.The target of p56 tyrosine kinase inhibitor comprises Lck without limitation.The kytoplasm zone of Lck and CD4, CD is relevant with the beta chain of IL-2 receptor, and thinks that it participates in the early stage step of the T-cell activation of TCR-mediation.

The xlvii.PDGFR tyrosine kinase inhibitor; The activity of its targeting, reduction or inhibition C-kit receptor tyrosine kinase (part of PDGFR family), the activity as targeting, reduction or inhibition c-Kit receptor tyrosine kinase family especially suppresses the c-Kit receptor.The object instance of PDGFR tyrosine kinase inhibitor comprises PDGFR, FLT3 and/or c-KIT without limitation; As tyrphostin AG1296; Tyrphostin 9; 1,3-butadiene-1,1,3-three nitriles, 2-amino-4-(1H-indole-5-yl); The N-phenyl-2-pyrimidine-amine derivatives, for example imatinib (imatinib),

Play an important role in the adjusting of PDGF cell proliferation, chemotaxis and survival in normal cell and various disease states such as cancer, atherosclerosis and fibrotic conditions.PDGF family is made up of dimerization hypotype (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD), and it brings into play its cytosis by differentially combining with two kinds of receptor tyrosine kinases.PDGFR-α and PDGFR-β have respectively～and 170 and the molecular weight of 180kDa.

Xlviii. phosphatidyl-inositol 3-kinase inhibitor; Its targeting, reduction or inhibition PI3-kinases; As wortmannin, it is also referred to as 3H-furo (Furo) [4,3,2-de] indeno [4,5-h]-2-.alpha.-5:6-benzopyran-3,6,9-triketone, 11-(acetoxyl group)-1,6b, 7,8,9a, 10,11,11b-octahydro-1-(methoxy)-9a, the 11b-dimethyl-, (1S, 6bR, 9aS, 11R, 11bR)-(9CI); 8-phenyl-2-(morpholine-4-yl)-chromene-4-ketone; Quercetin, Quercetin dihydrate.Shown as response many hormones and somatomedin (comprising insulin, platelet derived growth factor, insulin like growth factor, epidermal growth factor, colony stimulating factor and hepatocyte growth factor) stimulation, the PI3-kinase activity increases, and participation is grown with cell and transformed relevant process.The object instance of phosphatidyl-inositol 3-kinase inhibitor comprises Pi3K without limitation.

Xlix. inhibitors of phosphatases; Its targeting, reduction or inhibition phosphatase; As Cantharidic acid.; Cantharidin; With L-leucyl amine (leucinamide), N-[4-(2-carboxy vinyl) benzoyl] glycyl-L-α-Gu Anxianji-(E).Phosphatase is removed phosphoryl and albumen is reverted to its initial dephosphorylation state.Therefore, this phosphorylation-dephosphorylation circulation can be counted as molecule " switch ".

L. platinum agent; It comprises platinum and by between the thigh that forms dna molecular and strand in the crosslinked DNA of inhibition synthetic; As carboplatin; Cisplatin (cisplatin); Oxaliplatin; Cisplatin (cisplatinum); Husky platinum and platinum agent such as ZD0473, BBR3464.Carboplatin for example can be with its commercial form, for example

Form administration; With oxaliplatin can with

Form administration.

Li. protein phosphatase inhibitor comprises PP1 and PP2 inhibitor and tyrosine phosphatase inhibitors; Its targeting, reduction or Profilin phosphatase.The example of PP1 and PP2A inhibitor comprises Cantharidic acid. and/or cantharidin.The example of tyrosine phosphatase inhibitors comprises L-P-bromine tetramisole oxalates without limitation; 2 (5H)-furanones (furanone), 4-hydroxyl-5-(hydroxymethyl)-3-(1-oxo cetyl)-, (5R); And benzylphosphonic acid.

Term used herein " PP1 or PP2 inhibitor " is meant targeting, reduction or suppresses the chemical compound of Ser/Thr phosphoprotein phosphatase.I type phosphatase (it comprises PP1) can be suppressed by two kinds of heat-staple albumen that are called as inhibitor-1 (I-1) and inhibitor-2 (I-2).It is preferentially to a subunit dephosphorylation of phosphorylase kinase.II type phosphatase is subdivided into spontaneous onset (PP2A), CA ²⁺-dependency (PP2B) and Mg ²⁺-dependency (PP2C) phosphatase.

Term used herein " tyrosine phosphatase inhibitors " is meant targeting, reduction or suppresses the chemical compound of tyrosine phosphatase.Protein-tyrosine-phosphatase (PTPs) is included into phosphatase family recently.It is removed bound phosphate groups from albumen by the tyrosine residue of phosphorylation.PTPs shows different architectural characteristics and plays an important role in the adjusting of cell proliferation, differentiation, cell adhesion and mobility and cytoskeleton function.The object instance of tyrosine phosphatase inhibitors comprises alkali phosphatase (ALP), heparanase, PTPase and/or prostate acid phosphatase without limitation.

Lii.PKC inhibitor and PKC δ inhibitors of kinases: term used herein " pkc inhibitor " be meant targeting, reduction or Profilin kinase c with and the chemical compound of isozyme.Protein kinase C (PKC) (a kind of ubiquitous phospholipid dependent enzyme) participation and cell proliferation, differentiation and apoptosis-related signal transduction.The object instance of pkc inhibitor comprises MAPK and/or NF-κ B without limitation.The example of pkc inhibitor comprises 1-H-pyrrolo--2 without limitation, 5-diketone, 3-[1-[3-(dimethylamino) propyl group]-the 1H-indol-3-yl]-4-(1H-indol-3-yl); Bisindolylmaleimidesfor IX; Sphingol, it is also referred to as 4-vaccenic acid-1, the 3-glycol, 2-amino-, (2S, 3R, 4E)-(9Cl); Staurosporine, it is also referred to as 9, and 13-epoxy-1H, 9H-two indole also [1,2,3-gh:3 ', 2 ', 1 '-lm] pyrrolo-[3,4-j] [1,7] benzo two azonines (benzodiazonin)-1-ketone, staurosporine derivant are as disclosed material, for example midostaurin in EP0296110; 2,3,10,11,12,13-six hydrogen-10-methoxyl group-9-methyl isophthalic acid 1-(methylamino)-, (9S, 10R, 11R, 13R)-(9CI); Tyrphostin 51; And hypericin, its be also referred to as phenanthro-[1,10,9,8-opqra] perylene-7,14-diketone, 1,3,4,6,8,13-hexahydroxy-10, the 11-dimethyl-, and stereoisomer (6CI, 7CI, 8CI, 9CI), UCN-01, Safingol, BAY43-9006, bryostatin 1, perifosine; Llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196.Term used herein " PKC δ inhibitors of kinases " is meant targeting, reduction or suppresses the chemical compound of the δ isozyme of PKC.The PKC isozyme that this δ isozyme is a kind of routine and be Ca ²⁺-dependent.The example of PKC δ inhibitors of kinases comprises kamalin without limitation, and it is also referred to as 2-propylene-1-ketone, 1-[6-[(3-acetyl group-2; 4,6-trihydroxy-5-aminomethyl phenyl) methyl]-5,7-dihydroxy-2; 2-dimethyl-2H-1-.alpha.-5:6-benzopyran-8-yl]-the 3-phenyl-, (2E)-(9CI).

Liii. polyamine synthetic inhibitor; Its targeting, reduction or inhibition polyamine class spermidine; As DMFO, it is also referred to as (-)-2-Er Fujiajiniaoansuan; N1, N12-diethyl spermine 4HCl.This polyamine class spermidine and spermine are very important for cell proliferation, but still not clear its accurate mechanism of action.Tumor cell has the polyamine homeostasis of change, and this point can be compiled the level rising by biosynthetic enzyme activity increase and polyamine and reflect.

Liv. albuminous body inhibitor; Its targeting, reduction or Profilin enzyme body are as Aclacnomycin A; Gliocladin; PS-341; MLN341; Bortezomib; Velcade.The object instance of albuminous body inhibitor comprises O (2) (-)-product nadph oxidase, NF-κ B and/or farnesyl transferase, farnesyl transferase I without limitation.

The lv.PTP1B inhibitor; Its targeting, reduction or inhibition PTP1B---a kind of protein tyrosine kinase inhibitor; As the L-leucyl amine, N-[4-(2-carboxy vinyl) benzoyl] glycyl-L-α-Gu Anxianji-, (E).

Lvi. protein tyrosine kinase inhibitor comprises SRC family tyrosine kinase inhibitor; The Syk tyrosine kinase inhibitor; With JAK-2 and/or JAK-3 tyrosine kinase inhibitor;

Term used herein " protein tyrosine kinase inhibitor " is meant the chemical compound of targeting, reduction or Profilin tyrosine kinase.Protein tyrosine kinase (PTKs) plays an important role in the adjusting of cell proliferation, differentiation, metabolism, migration and survival.It is divided into receptor PTKs and non--receptor PTKs.Receptor PTKs comprises the single polypeptide chain with the membrane portions of striding.The extracellular end of this part comprises the high affinity ligand binding region, and its kytoplasm end comprises catalysis nuclear and regulates sequence.The object instance of tyrosine kinase inhibitor comprises ERK1, ERK2 without limitation, Bruton ' s tyrosine kinase (Btk), JAK2, ERK 1/2, DGFR and/or FLT3.The indirect target example comprises that without limitation TNF α, NO, PGE2, IRAK, iNOS, ICAM-1 and/or E-select albumen.The example of tyrosine kinase inhibitor comprises tyrphostin AG 126 without limitation; Tyrphostin Ag 1288; Tyrphostin Ag 1295; Geldanamycin; And genistein.

Non--receptor tyrosine kinase comprises Src, Tec, JAK, Fes, Abl, FAK, Csk and the member of Syk family.It is arranged in endochylema and nucleus.It shows different kinases adjusting, substrate phosphorylation effect and function.These kinase whose imbalances are also relevant with some human diseasess.

Term used herein " SRC family tyrosine kinase inhibitor " is meant targeting, reduction or suppresses the chemical compound of SRC.The example of SRC family tyrosine kinase inhibitor comprises PP1 without limitation, and it is also referred to as 1H-pyrazolo [3,4-d] pyrimidine-4-amine, 1-(1, the 1-dimethyl ethyl)-3-(1-naphthyl)-(9Cl); And PP2, it is also referred to as 1H-pyrazolo [3,4-d] pyrimidine-4-amine, 3-(4-chlorphenyl)-1-(1, the 1-dimethyl ethyl)-(9Cl).

Term used herein " Syk tyrosine kinase inhibitor " is meant targeting, reduction or suppresses the chemical compound of Syk.The object instance of Syk tyrosine kinase inhibitor comprises Syk, STAT3 and/or STAT5 without limitation.The example of Syk tyrosine kinase inhibitor comprises Piceatannol without limitation, and it is also referred to as 1, the 2-Benzenediol, 4-[(1E)-2-(3, the 5-dihydroxy phenyl) vinyl]-(9Cl).

Term used herein " Janus (JAK-2 and/or JAK-3) tyrosine kinase inhibitor " is meant targeting, reduction or suppresses the chemical compound of janus tyrosine kinase.Show that the Janus tyrosine kinase inhibitor is the antileukemia with antithrombotic formation, antiallergic and inhibitive ability of immunity.The target of JAK-2 and/or JAK-3 tyrosine kinase inhibitor comprises JAK2, JAK3, STAT3 without limitation.The indirect target of JAK-2 and/or JAK-3 tyrosine kinase inhibitor comprises CDK2 without limitation.The example of JAK-2 and/or JAK-3 tyrosine kinase inhibitor comprises tyrphostin AG 490 without limitation; With 2-naphthyl vinyl ketone.

The chemical compound of targeting, reduction or the inhibition c-Abl member of family or its gene fusion its lytic activity for example comprises PD180970; AG957; Or NSC 680410.

Lvii. retinoid; Its targeting, reduction or inhibition retinoid dependency receptor; As Accutane, retinoic acid, alitretinoin, bexarotene.

The lviii.RNA polymerase II prolongs inhibitor; The nuclear and the kytoplasm p70S6 kinases of insulin-stimulation in its targeting, reduction or the inhibition Chinese hamster ovary celI; Targeting, reduction or inhibition rna plymerase ii are transcribed (it may depend on casein kinase i I); With the germinal vesicle breakdown in targeting, reduction or the inhibition bovine oocyte; As 5,6-two chloro-1-β-D-ribofuranosyl benzimidazole.

Lvix. serine/threonine kinase inhibitor; It suppresses serine/threonine kinase; As 2-aminopurine.The object instance of serine/threonine kinase inhibitor comprises dsRNA-deopendent protein kinase (PKR) without limitation.The indirect target example of serine/threonine kinase inhibitor comprises MCP-1, NF-κ B, elF2 α, COX2, RANTES, IL8, CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, erythropoietin and/or CYP1A1 without limitation.

Lx. sterol biosynthesis inhibitor; It suppresses the biosynthesis of sterols such as cholesterol; As Terbinadine.The object instance of sterol biosynthesis inhibitor comprises squalene epoxidase and CYP2D6 without limitation.

Lxi. topoisomerase enzyme inhibitor; Comprise topoisomerase I inhibitor and topoisomerase II inhibitor.The example of topoisomerase I inhibitor comprise without limitation hycamtin, gefitinib (gimatecan), Irinotecan, bank holder for health (camptothecan) with and analog, 9-nitrocamptothecin and macromole camptothecine conjugates PNU-166148 (compd A 1 among the WO9917804); 10-hydroxycamptothecine, for example its acetate; Idarubicin, for example its hydrochlorate; Irinotecan, for example its hydrochlorate; Etoposide; Teniposide; Hycamtin, hydrochloric acid hycamtin; Doxorubicin; Epirubicin, epirubicin hydrochloride; Mitoxantrone, mitoxantrone hydrochloride; Daunorubicin, daunorubicin hydrochloride, valrubicin, Dasatinib (dasatinib) are (BMS-354825).Irinotecan for example can be with its commercial form, for example, and with trade mark

Commercially available form is carried out administration.Hycamtin for example can be with its commercial form, for example, and with trade mark Commercially available form is carried out administration.Term used herein " topoisomerase II inhibitor " comprises anthracycline antibiotics without limitation, as doxorubicin, comprises Liposomal formulation, for example,

Daunorubicin comprises Liposomal formulation, for example,

Epirubicin, idarubicin and Nemorubicin; Anthraquinone class mitoxantrone and losoxantrone; With etoposide class (podophillotoxines) etoposide and teniposide.Etoposide with

Form is commercially available; Teniposide is with VM Form is commercially available; Doxorubicin with

Or

Form is commercially available; Epirubicin with

Form is commercially available; Idarubicin with

Form is commercially available; Mitoxantrone with

Form is commercially available.

The lxii.VEGFR tyrosine kinase inhibitor; Its targeting, reduction and/or suppress the blood vessel originality somatomedin and the cytokine of the normal and adjusting that pathologic vessels takes place of known participation.VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) with and corresponding receptor tyrosine kinase [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR) and VEGFR-3 (Flt-4)] play most important and indispensable effect in aspect regulating angiogenesis and lymphatic vessel generation (lymphangiogenic) process many.The example of VEGFR tyrosine kinase inhibitor comprises 3-(4-dimethylamino benzal)-2-dihydroindolone.Targeting, reduction or suppress the active chemical compound of VEGFR especially suppress vegf receptor tyrosine kinase, suppress vegf receptor or with the bonded chemical compound of VEGF, albumen or antibody, and particularly these general and concrete disclosed these chemical compounds, albumen or monoclonal antibody: WO9835958 in data below, 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its pharmaceutically useful salt, for example its succinate for example; WO0009495, WO0027820, WO0059509, WO9811223, WO0027819 and EP0769947; For example people such as M.Prewett is in Cancer Research 59 (1999) 5209-5218.People such as F.Yuan are at Proc.Natl.Acad.Sci.USA, the 93rd volume, the 14765-14770 page or leaf, in 1996 12 months, people such as Z.Zhu is at Cancer Res.58,1998, among the 3209-3214 and people such as J.Mordenti at ToxicologicPathology, the 27th volume, the 1st phase, 14-21 page or leaf, these materials described in 1999; WO0037502 and WO9410202; People such as M.S.O ' Reilly, Cell 79,1994, his spit of fland of the described blood vessel of 315-328; People such as M.S.O ' Reilly, Cell 88,1997, his spit of fland of the described endothelium of 277-285; The ortho-aminobenzoic acid amide-type; ZD4190; ZD6474; SU5416; SU6668; Or anti-VEGF antibodies or anti-VEGF receptor antibody, for example RhuMab (bevacizumab).Multi-specificity antibody and antibody fragment (as long as it shows required biologic activity) that antibody is meant complete monoclonal antibody, polyclonal antibody, is formed by at least 2 complete second antibody.The example of VEGF-R2 inhibitor for example comprises that Ah former times is for Buddhist nun (axitinib).

Lxiii. GuRH-A, as 1: PN: WO02056903 PAGE: 25 claimed protein, goserelin, goserelin acetate,

Lxiv. the chemical compound of inducing cell atomization, as tretinoin, α-, γ-or 8-tocopherol or α-, γ-or 8-tocotrienol.

Lxv. diphosphate for example comprises etidronic acid (etridonic), clodronic acid, tiludronic acid, pamidronic acid, alendronic Acid, ibandronic acid, risedronic acid and zoledronic acid.

Lxvi. prevent the heparanase inhibitors of heparitin sulfate degraded, PI-88 for example,

Lxvii. biological response modifier, preferred Alymphokine or interferons, interferon-ALPHA for example,

Lxviii. telomerase inhibitor, Te Luotating (telomestatin) for example,

Lxix. regulator, as the inhibitor of catechol O-methyltransferase, entacapone for example,

Lxx:Ispinesib, Sunitinib (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y),

Lxxi somatostatin or somatostatin analogue are as octreotide

Or Sandostatin

Lxxii. growth hormone receptor antagonist is as the non-department of pegvisomant, filgrastim or pyrrole booth (pegfilgrastim) or interferon-ALPHA.

Lxxiii. monoclonal antibody for example is used for leukemia (AML) treatment, as alemtuzumab

Rituximab Gemtuzumab, (ozogamicin, Epratuzumab.

Lxxiv. hexamethyl melamine, amsacrine, asparaginase

Denileukin diftitox (denileukin diftitox), masoprocol, pegaspargase.

Lxxv. phosphodiesterase inhibitor, for example anagrelide

Lxxvi. Theratope is as MDX-1379.

Lxxvii. reduce the material (seeing for example WO2002002093) of Isosuccinic acid.

Use is randomly carried out treatment of cancer with the present invention's combination of another kind of drug combination and can be carried out together with radiotherapy.Use may be a second line treatment with the treatment of cancer that the present invention's combination of another kind of drug combination is carried out randomly, for example carries out after treating with other anticarcinogen or other treatment of cancer.

Tend to as combined partner capable, for example be used for for example comprising ethanol with the anesthetis of combinatorial association treatment of the present invention, bupivacaine, chloroprocaine, chirocaine, lignocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, Sevoflurane, codeine, fentanyl, hydromorphone, marcaine (marcaine), Pethidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, cinchocaine, ethyl chloride, lignocaine and phenazopyridine.

Tend to as combined partner capable, for example be used for for example comprising diphenoxylate, loperamide, codeine with the diarrhea of combinatorial association treatment of the present invention.

Combination for example of the present invention can with material (the seeing for example WO2002002093) coupling that reduces Isosuccinic acid.Combination for example of the present invention can with for example cisplatin coupling of platinum compounds.

Other medicines can with free form, salt form for example pharmaceutical acceptable salt use, randomly be solvate forms, randomly be the form of pharmaceutically acceptable prodrug, for example comprise the carboxylic acid derivates that contains carboxylic acid drug, as pharmaceutically useful carboxylate.Can or wherein may there be the form of any isomer mixture of multiple isomer in such other medicines for pure isomer.

If combination of the present invention and another kind of medication combined administration, then the dosage of the other medicines of this co-administered will change according to the drug type of used co-administered, used certain drug, the situation of being treated certainly.Except that the dosage that the supplier of described other medicines provides, similar dosage may suit usually.For example can be according to the suitable administration of for example carrying out other medicines on document or the Internet shown in the concrete medicine similarly with it.

Term used herein " toxicity " is meant the toxicity incident relevant with the administration of antifol, see for example " antifolic in the treatment of cancer (Antifolate Drugs in Cancer Therapy) ", Humana Press, see for example " books summary---the antifolic (Bookreview-Antifolate Drugs in Cancer Therapy) in the treatment of cancer; Ann L.Jackman. author: Nair M.G.1. source: drug discovery today (Drug Discovery Today); the 4th volume; o. 11th, 1999 ".

Method

For the mTOR inhibitor is assessed the influence of the antitumor efficacy of a kind of chemical compound in people's tumor xenogeneic graft model, only use for example formula I of antifol chemical compound _US5344932Chemical compound or unite with itself and mTOR inhibitor the female nude mice of lotus people MX-1 breast carcinoma handled.

Animal is maintained in the aseptic standard laboratory, make its ad lib and sterilized water.The people MX-1 tumor cell (5*10 of donor tumor will be derived from ⁶) in the subcutaneous thigh that is implanted to big female nude mice of 8 to 10 weeks.Beginning in the 7th day behind tumor cell transplantation is by the peritoneal injection formula I once a day only the 7th to 11 day and the 14th to 18 day _US5344932Chemical compound (100mg/kg or 150mg/kg) or unite and give mTOR inhibitor (oral medication, 1 to 30mg/kg) and come animal is handled.

In experimentation, can come tumor response to monitor by measuring gross tumor volume weekly for twice.Can monitor toxicity by in the monitoring gross tumor volume, measuring body weight.Tumor growth delay is meant that treatment and control tumor reach the difference between the required natural law of 1000mm.

People MX-breast carcinoma xenograft is the formula I of 100mg/kg and 150mg/kg to dosage _US5344932The treatment of chemical compound has response, and it has produced the tumor growth delay of 17 days and 21 days respectively.With two dosage of 5mg/kg and 20mg/kg, use and formula I _US5344932The mTOR inhibitor that the administration time list that chemical compound is identical solely delivers medicine to animal can produce the tumor growth delay of a couple of days.

Formula I _US5344932Combination of compounds can be with the form of while scheme for combining with the administration of mTOR inhibitor, perhaps can be at giving construction I _US5344932Chemical compound before give mTOR inhibitor, perhaps can be before giving the mTOR inhibitor giving construction I _US5344932Chemical compound.Formula I _US5344932Chemical compound and the delay that can reduce tumor growth of mTOR inhibitor administering drug combinations.

Can measure as the toxicity of each therapeutic scheme with body weight.Body weight reduction pattern has reflected that the therapeutic scheme that reduces with body weight had the recovery of some body weight in middle 2 days in 7 to 11 and 14 to 18 days treatment time.Formula I _US5344932It may be dose dependent that the body weight that chemical compound causes reduces, but it is generally speaking very little.Use formula I _US5344932Chemical compound and the body weight of animal in experimentation handled of mTOR inhibitor may increase.

Can change giving construction I _US5344932The time of chemical compound and mTOR inhibitor.

Clinical trial

Carry out a kind of multicenter I phase of open-label and study, compd A and training are studied uniting of U.S. bent moral standard care scheme with the patient who suffers from (unresectable or transfer) NSCLC in late period who has carried out treating with the chemotherapy of a line before.Recruit maximum 120 patients.

Research purpose

According to safety evaluation with transmit the ability that required dosage intensity is trained beautiful Qu De, determine for suffering from NSCLC, carried out for the patient of treatment with a kind of chemotherapy regimen before, train feasible dosage level/scheme of the RAD001 that beautiful Qu Defang case unites with standard

Determine that RAD001 is interacting with the intravital PK of NSCLC patient of RAD001 and the bent moral therapeutic alliance of Pei Mei and the PK between estimation RAD001 and the Pei Mei Qu De.

Be evaluated as the basis with the comprehensive tumor response of carrying out according to RECIST, determine that different RAD001 dosage level/schemes and standard train the clinical efficacy of beautiful Qu Dezhi treatment administering drug combinations.

Based on:

● estimate that the patient experience time-event model (" DLT during the 1st end cycle leads ") of DLT generation of the probability of DLT in its first treatment cycle,

This research is designed to Bayesian successive doses-proliferation time table.

Based on:

● estimate that the patient experience time-event model (" DLT during the 1st end cycle leads ") of DLT generation of the probability of DLT in its first treatment cycle

With

● the relative dosage intensity (RDI) of estimating the beautiful Qu De of training is the model of the best to the probability of suboptimum, and this research is designed to Bayesian successive doses-proliferation time table.

At first study the successive doses level in 2 independent treatment groups, each organizes the different dosing timetable corresponding to compd A:

● group 1: the standard treatment cycle associating in 21 days with the beautiful Qu De of training gives compd A every day continuously.

● group 2: with the standard treatment cycle associating in 21 days of the beautiful Qu De of training, (the 1st, 8,15 day) gives compd A continuously weekly

After the 1st group of compd A continuous dosing regimens every day assessment finishes, can followingly begin another compd A dosage regimen like that again:

● intermittently give compd A every day, do not give compd A the 15th to 21 day of each treatment cycle)

With the patient the center be assigned randomly to each the group in and under current dosage level/scheme, recruit.Can be parallel and in each group, carry out the dosage amplification independently.

When preceding 15 patients have carried out at least 2 cycles in each group, carry out the RDI assessment, think it at this moment is the interim analysis prospect.If RDI assessment determines to contradict with dosage amplification based on safety signal, then plan during this research, to carry out second metaphase and look forward to.When off-test, also RDI is assessed.

This research is to studying with two kinds of different dosing timetables (every day and administration weekly) of the compd A of training U.S. bent moral standard circulation administration in 21 days associating.In each compd A administration time table, to two kinds of different schemes---continuously and intermittently administration study and each project study maximum three RAD001 dosage levels independently.

Compd A in two groups (C-A) dosage is as follows:

^aIn 6 treatment cycle, all patients unite and accept C-A and Pei Mei Qu Dehua and treat

^bIn the 1st cycle, began to carry out the C-A administration at the 2nd day

^cThe starting dose level

In two groups,, just before the U.S. bent moral input of training, begin to carry out the compd A administration the 2nd day of the 1st cycle.The DLT that will be estimated when the decision of making the dosage that progressively increases compd A will be depended on the 1st end cycle leads and the chemotherapy companion's of compd A RDI.The patient will continue to accept compd A until disease progression or unacceptable toxicity occurs.

Compd A

Train U.S. bent moral dosage

All patients accept its compd A dosage separately with 21 day cycle of standard of the beautiful Qu De of training, and application standard premedication (pre-medication), medication are interrupted and adjustment (seeing appendix).

● train beautiful Qu De at the 1st day with 500mg/m ²Dosage vein input administration in 10 minutes.

The patient can accept high to maximum 6 U.S. bent moral cycles of training.

Terminal point: the toxicity of restriction administration takes place at any time, the relative dosage intensity of chemotherapy.

The target of this research is to treat the cycle for the patient provides six beautiful Qu Dehua of training.One-period is defined as the interval between the chemotherapy regimen (giving tacit consent to 21 days) of two successive administrations, and that day that was defined as beginning chemotherapy on the 1st day in each cycle.In each cycle, patient (the 8th and 15 day) weekly carries out conventional laboratory safety inspection.At the 1st day, before the further chemotherapy of beginning, it also carried out the comprehensive security assessment.

Only in the periodicity treatment of using RAD001, be delayed to the 2nd day and allow to carry out sequence and get blood so that the basic PK that trained beautiful Qu De on the 1st day is assessed.Continue to get PK blood sample (the basic PK of RAD001) the 8th day of the 1st cycle and continue to get PK blood sample (the associating PK of two of administration kinds of research medicines together) the 1st day of the 2nd cycle.

When the patient accepted chemotherapy, routine carried out computed tomography (CT) to carry out measurement of tumor every six weeks (at the beautiful Qu De of training every 2 all after dates).End of chemotherapy or in have no progeny, all patients all according to every day or weekly successive administration continue to accept RAD001 (no matter RAD001 scheme how, carry out chemotherapy simultaneously), until disease progression or unacceptable toxicity take place.In such situation, every carrying out CT scan six weeks one time.

Assess effect with following terminal point: the early stage progression rates (EPR) of the overall response rate (ORR) of RECIST (the optional RESIST that revises), RECIST (the optional RESIST that revises).In whole research process, carry out tumor assessment with CT scan, when independent or administering drug combinations, by research level relatively come drug-drug interactions is assessed.

In clinical trial, the compd A of uniting with the U.S. bent moral of training is showing suitable effect aspect the tumor growth.Compd A shows synergism in many aspects with the combination of the beautiful Qu De of training.

Claims

1. one kind comprises mTOR inhibitor and antifol combination of compounds form.

2. pharmaceutical composition, it comprises mTOR inhibitor and antifol chemical compound and pharmaceutically useful excipient.

3. drug packages, the explanation that it comprises mTOR inhibitor and antifol chemical compound and is used for administering drug combinations.

4. drug packages, it comprises the mTOR inhibitor and is used for explanation with itself and antifol chemical compound administering drug combinations.

5. drug packages, it comprises the antifol chemical compound and is used for explanation with itself and mTOR inhibitor administering drug combinations.

6. a treatment is by the method for the disease of mTOR and/or thymidylate synthetase mediation, and it comprises to its mTOR inhibitor and the antifol chemical compound of individual co-administered treatment effective dose of needs, in turn or administration simultaneously.

7. any described combining form, pharmaceutical combination, pharmaceutical composition or a drug packages are used for preparing the purposes of the medicine of the method that is used for claim 6 in the claim 1 to 5.

8. method for preparing the medicine of the method that is used for claim 6, it comprises

B) the mTOR inhibitor is combined with pharmaceutically useful excipient for example admixed together, thereby obtain pharmaceutical composition COMP1 and the antifol chemical compound is combined with pharmaceutically useful excipient for example admixed together, thereby acquisition pharmaceutical composition COMP2 and

(ii) pharmaceutical composition COMP1 is packed separately and pharmaceutical composition COMP2 is packed separately, but in each packing, put into explanation pharmaceutical composition COMP1 and pharmaceutical composition COMP2 administering drug combinations.

9. combining form of the present invention, method provided by the invention or purposes, it also comprises at least a other medicines except mTOR inhibitor and antifol combination of compounds.

10. any described combining form in the claim 1 to 9, pharmaceutical combination, pharmaceutical composition, drug packages, method or purposes, wherein the mTOR inhibitor is a rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32-deoxidation rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-rapamycin, 16-penta-2-alkynyloxy group-32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxyl-2-(hydroxyl-methyl)-2 Methylpropionic acid ester]-rapamycin (being also referred to as CCI779), 40-table-(tetrazole radical)-rapamycin (being also referred to as ABT578), so-called forms of rapamycin analogs, for example AP23573, with the disclosed chemical compound of the title of TAFA-93 or with the disclosed chemical compound of the title of hundred Li Mosi.

11. the described combining form of claim 10, pharmaceutical combination, pharmaceutical composition, drug packages, method or purposes, wherein the mTOR inhibitor is 40-O-(2-hydroxyethyl)-rapamycin.

12. any described combining form, pharmaceutical combination, pharmaceutical composition, drug packages, method or a purposes in the claim 1 to 11, wherein the antifol chemical compound is a formula

Chemical compound, wherein

R ₁Be-OH or-NH ₂

R ₄Be hydrogen, methyl or hydroxymethyl; And

R ₅Be the alkyl or the amino of hydrogen, 1 to 6 carbon atom;

It is free form or pharmaceutical acceptable salt; It randomly is solvate forms.

13. the described combining form of claim 12, pharmaceutical combination, pharmaceutical composition, drug packages, method or purposes, the beautiful Qu De of the training that wherein said antifol chemical compound is a following formula

14. the described combining form of claim 13, pharmaceutical combination, pharmaceutical composition, drug packages, method or purposes, the disodium salt form of the beautiful Qu Dewei heptahydrate of training wherein form.