MX2008008944A - Combination of mtor inhibitor and antipolate compound - Google Patents

Abstract

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

Description

COMBINATION OF MTOR INHIBITOR AND ANTIFOLATE COMPOUND Field of the Invention The present invention relates to a cancer combination treatment, for example, a combination of pharmaceutically active organic compounds, for example a combination of antifolate compounds and mTOR inhibitors.

An mTOR inhibitor as used in the present invention is a compound that directs intracellular mTOR ("mammalian rapamycin target"). mTOR is an element of the kinase family related to 3-kinase (P13-kinase) of phosphatidylinositol. The rapamycin compound and other mTOR inhibitors inhibit mTOR activity through a complex with its intracellular receptor FKBP12 (protein 12 that binds to FK506). mTOR modulates the translation of specific mRNAs through the regulation of the phosphorylation status of several different translation proteins, mainly 4E-PB1, P70S6K (kinase 1 p70S6) and eEF2. An mTOR inhibitor as used in the present invention includes rapamycin and rapamycin derivatives. Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus of the formula The rapamycin derivatives include for example rapamycin substituted at position 40 and / or 16 and / or 32. Examples of rapamycin derivatives include 40-O-alkyl-rapamycin derivatives, for example derivatives of 40-O-hydroxyalkyl-rapamycin, for example 40-O- (2-hydroxy) -ethyl-rapamycin (everolimus), also designated as "compound A" rapamizine derivatives, which are substituted at the 40 position by heterocyclyl, for example 40- epi- (tetrazolyl) -rapamycin (also known as ABT578), 32-deoxo-rapamycin derivatives and 32-hydroxy-rapamycin derivatives such as 32-deoxorapamycin, 16-O-substituted rapamycin derivatives such as 16-pent-2 -iniloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-rapamycin, or 16-pent-2-ynyloxy-32 (S or R) -dihydro-40-O- (2 -hydroxyethyl) -rapamycin, rapamycin, rapamycin derivatives which are acylated in the oxygen at position 40, for example 40- [3-hydroxy-2- (hydroxy-methyl) -2-methylpropanoate] -rapamycin (also known as CCI779 or temsirolimus), rapamycin derivatives (sometimes also referred to as rapporteurs) as described in WO9802441 or WO0114387, including for example AP23573, such as 40-O-dimethylphosphinyl-rapamycin, compounds described under the name of biolumis (biolimus A9), including 40-O- (2-ethoxy) ethyl- rapamycin, and compounds described under the name of TAFA-93, AP23464, AP23675 or AP23841; or rapamycin derivatives such as for example those described in the publications WO2004101583, WO9205179, WO9402136, WO9402385 and WO9613273. Preferred mTOR inhibitors include rapamycin and / or 40-O- (2-hydroxyethyl) -rapamycin, and / or 32-deoxorapamycin, and / or 16-pent-2-ynyloxy-32-deoxorapamycin, and / or 16-pent- 2-inyloxy-32 (S or R) -dihydro-rapamycin, and / or 16-pent-2-ynyloxy-32 (S or R) -dihydro-40-0- (2-hydroxyethyl) -rapamycin, and / or 40- [3-hydroxy-2- (hydroxy-methyl) -2-methylpropanoate] -rapamycin (also known as CCI779) and / or 40-epi- (tetrazolyl) -rapamycin (also known as ABT578), and / or the so-called rapporteurs, for example as described WO9802441, WO0114387 and WO0364383, AP23573, AP23464, AP23675 or AP23841, for example AP23573, and / or compounds described under the name of TAFA-93, and / or compounds described under the name of biolimus. More preferably, an mTOR inhibitor is selected from the group consisting of rapamycin, and / or 40-O- (2-hydroxyethyl) -rapamycin, and / or 32-deoxorapamycin, and / or 16-pent-2-ynyloxy-32- deoxorapamycin, and / or 16-pent-2-ynyloxy-32 (S or R) -dihydro-rapamycin, and / or 16-pent-2-ynyloxy-32 (S or R) -dihydro-40-0- (2 -hydroxyethyl) -rapamycin, and / or 40- [3-hydroxy-2- (hydroxy-methyl) -2-methylpropanoate] -rapamycin (also known as CCI779) and / or 40-epi- (tetrazolyl) -rapamycin (also known as ABT578), and / or AP23573, preferably 40-O- (2-hydroxyethyl) -rapamycin. The mTOR inhibitors, on the basis of the observed activity, have been found to be useful as pharmaceuticals, for example, as immunosuppressants, for example for the treatment of conditions after a transplant; as anti-inflammatory compounds, for example for the treatment of IBD, RA; as anti-allergic compounds, for example for the treatment of psoriasis and having additional potent antiproliferative properties which make them useful for cancer chemotherapy, such as for the treatment of solid tumors, especially of advanced solid tumors. Rapamycin and other rapamycin derivatives can be administered as appropriate, for example in doses which are known for rapamycin or rapamycin derivatives for example everolimus, they can be administered, for example orally, in doses of 0.1 mg to 25 mg, for example 1 mg to 15 mg, such as 0.1 mg to 10 mg, for example 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, preferably 1 mg to 10 mg, per example in the form of tablets (dispersible); for example a weekly dose of up to 70 mg, for example 30 mg to 70 mg, such as 30 mg to 50 mg; depending on the disease that is being treated. Other rapamycin derivatives can be administered in similar dosage ranges. The antifolate compounds are known and have an inhibitory effect on one or more enzymes that utilize folic acid, and in particular metabolic derivatives of folic acid, as a substrate. An antifolate compound as used in the present invention includes for example compound such as described in patent US5344932, which include for example a compound of the formula wherein R is -OH or -NH2; R3 is 1,4-phenylene or 1,3-phenylene substituted or unsubstituted with chloro, fluoro, methyl, methoxy or trifluoromethyl; bediyl or furanediyl substituted or unsubstituted with chloro, fluoro, methyl, methoxy or trifluoromethyl; cyclohexandiyl; or alcandíilo; R is hydrogen, methyl or hydroxymethyl; and R5 is hydrogen, alkyl of 1 to 6 carbon atoms, or amino; for example the configuration of the substituent on the carbon atom designated with * is S; for example in free form or in the form of a pharmaceutically acceptable salt; optionally in the form of a solvate; preferably the compound of the formula for example, in the form of a sodium salt, such as a disodium salt, for example in the form of a solvate such as a hydrate, for example a heptahydrate. A compound of the formula PERMETREXED is known under the name Permetrexed and is approved for injection in the form of a disodium salt heptahydrate under the trade name Alimta®. The antifolate compounds of the formula I appear to be particularly active as inhibitors of thymidylate synthetase, which catalyzes the methylation of deoxyuridyl acid to deoxythymidylic acid using N5, N10-methylhydro-trauhydrofolate as a coenzyme. The compounds can be used in this way to inhibit the growth of such neoplasms that otherwise depend on the inhibited enzyme. The compounds of US Pat. No. 5,349,432 are described to inhibit the growth of neoplasms including choriocarcinoma, leukemia, female breast adenocarcinoma, epidermal head and neck cancers, small cell lung squamous cell cancer and various lymphosarcomas. The compounds of US5344932 are also described to be useful for the treatment of mycosis fungoides, skin cancer type; and psoriasis. Specifically Alimta® is recommended for the treatment of mesothelioma (malignant), which is a cancer of mesothelial cells, for example where cancer can be developed in the pleura (pleural mesothelioma), abdomen, for example mesothelioma of the tissues that line the abdominal cavity (peritoneal mesothelioma) and the lining of the lungs, or in the lining of the reproductive organs (benign mesothelioma), lung cancer Recurrent non-small cell (NSCLC), gestational trophoblastic tumor. The recommended dose of ALIMTA® is 500 mg / m2 administered as an intravenous infusion for 10 minutes on day 1 of each 21-day cycle, for example for the treatment of non-small cell lung cancer, for example or in combination with cisplatin for the treatment of mesothelioma, for example malignant pleural mesothelioma (the recommended dose of cisplatin is 75 mg / m 2 infused over 2 hours starting approximately 30 minutes after the end of ALIMTA administration). One limitation of the development of antifolate compounds is that the cytotoxic activity and the subsequent effectiveness of antifolates may be associated with substantial toxicity for some patients. Antifolates, moreover in the form of a class, are associated with severe sporadic myelosuppression with gastrointestinal toxicity which, although not frequent, carries a great risk of mortality. The inability to control these toxicities leads to the abandonment of the clinical development of some antifolates and has complicated the clinical development of others.

It has now been discovered that a combination of an mTOR inhibitor and an antifolate, for example a compound of the formula Ius5344932 > shows surprising results in the treatment of conditions for which mTOR inhibitors and / or a compound of the formula IUS5344932 are useful, for example for the treatment of inflammatory or (auto) immune disorders, such as for example psoriasis and for the treatment of cancer, for example for the treatment of tumors. Surprisingly, certain toxic effects caused by antifolates of the formula Ius5344932 > through the presence of an mTOR inhibitor, without adversely affecting the therapeutic efficacy. Surprisingly, a combination treatment with a compound of the formula IUS5344932 and an mTOR inhibitor can synergistically reduce the amount of each single drug, if administered in combination, compared to a simple treatment to achieve similar effects. Surprisingly, the combination of an mTOR inhibitor and a compound of the formula Iuss 344932 can reduce the toxic events associated with the administration of antifolate drugs of the formula Iuss 344932 > for example in a synergistic way. In various aspects the present invention provides 1.1 A combination comprising an mTOR inhibitor and an antifolate compound A combination provided by the present invention includes a pharmaceutical combination. In another aspect the present invention provides 1.2 A pharmaceutical combination comprising an mTOR inhibitor and an antifolate compound A (pharmaceutical) combination provided by the present invention includes -fixed combinations, in which two or more pharmaceutically active agents are in the same formulation. , for example an mTOR inhibitor and an antifolate compound. - units in which two or more pharmaceutically active agents are sold in the same package, for example an mTOR inhibitor and an antifolate compound in separate formulations, for example with instructions for co-administration; and - free combinations in which combinations are separately packaged in which two or more pharmaceutically active agents, for example an mTOR inhibitor and an antifolate compound, although instructions are provided for simultaneous or sequential administration. In another aspect the present invention provides 1.3 A pharmaceutical composition comprising an mTOR inhibitor and an antifolate compound in combination, in addition to a pharmaceutically acceptable excipient. 1.4 A pharmaceutical package comprising an inhibitor mTOR and an antifolate compound in addition to instructions for combined administration. 1.5 A pharmaceutical pack comprising an mTOR inhibitor in addition to instructions for administration in combination with an antifolate compound. 1.6 A pharmaceutical package comprising an antifolate compound in addition to instructions for administration in combination with an mTOR inhibitor. A combination provided by the present invention includes a pharmaceutical combination, a pharmaceutical composition and a pharmaceutical pack according to the present invention, and is also referred to as "a combination of (according to) the present invention." A combination in the present invention is useful for the treatment of disorders that are transmitted by mTOR and / or thymidylate synthetase, for example disorders that are transmitted by mTOR and thymidylate synthetase, such as disorders for which mTOR inhibitors and / or antifolate compounds, for example disorders for which mTOR inhibitors and antifolate compounds are useful, for example for the treatment of inflammatory, immune disorders, for example autoimmune disorders, such as psoriasis and for the treatment of disorders associated with cancer , for example disorders associated with cell overproliferation, such as disorders associated with cancer, solid tumors, endocrine tumors, the growth of neoplasms, mesothelioma. The disorders associated with cancer, for example disorders associated with cell overproliferation, as used in the present invention, are understood to include for example premalignant conditions, hyperproliferative disorders, cancer either primary or metastatic, cervical cancer, cancer originating from uncontrolled cell proliferation, solid tumors, disorders associated with tumor growth, lymphoma, B-cell or T-cell lymphoma, benign tumors, benign disproliferative disorders, renal carcinoma, esophageal cancer, stomach cancer, bladder cancer, cancer breast, colon cancer, lung cancer, melanoma, nasopharyngeal cancer, osteocarcinoma, ovarian cancer, uterine cancer; prostate cancer, skin cancer, mycosis fungoides, leukemia, tumor neovascularization, angiomas, myelodysplastic disorders, lack of response to signals that induce normal death (immortalization), motility and cellular invasiveness increases, genetic instability, dysregulated gene expression neuroendocrinologist cancer (carcinoids), blood cancer, lymphocytic leukemia, neuroblastoma (neuroblastoma is a disease in which malignant cells (cancer) form a nervous tissue of the adrenal gland, neck, chest or spinal cord), cancer of soft tissue, metastasis. Disorders associated with cancer as used in the present invention means that they include solid tumors and / or tumor metastases (wherever they are located, for example, brain tumors and other tumors of the central nervous system (eg, meningeal tumors, brain, spinal cord, cranial nerves and other parts of the central nervous system, for example glioblastomas or marrow blastomas), cancer of the head and / or neck, breast tumors, tumors of the circulatory system (eg heart, separation membrane and pleura) , and other intrathoracic organs, vascular tumors and vascular tissue associated with tumor), tumors of the excretory system (for example kidney, renal pelvis, urethra, bladder and other urinary organs not specified), tumors of the gastrointestinal tract (for example esophagus, stomach , small bowel, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal), tumors that involve the liver and intrahepatic bile ducts icos, gallbladder and other unspecified parts of the biliary tract, pancreas and other digestive organs); head and neck; oral cavity (lips, tongue, gum, floor of the mouth, palate and other parts of the mouth, parathyroid gland and other parts of the salivary glands, oropharyngeal or pharyngeal tonsils, piriform sinus, hypopharynx and other sites on the lips, oral cavity and pharynx); reproductive system tumors (eg, vulva, vagina, cervix, uterus Corpus, uterus, ovary, and other sites associated with female genital organs, placenta, penis, prostate, testes, and other sites associated with male genital organs); respiratory tract tumors (e.g., nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchi, and lung, e.g., lung and small cell cancer or non-small cell lung cancer); tumors of the skeletal system (for example, bones and articular cartilages of the extremities, articular cartilages of bones and other sites); skin tumors (eg skin malignomelanoma, non-melanoma skin cancer, basal cell skin carcinoma, squamous cell skin carcinoma, mesothelioma, Kaposi's sarcoma, mycosis fungoides); and tumors involving other tissues including peripheral nerves and autonomic nervous system, soft connective tissue, retroperitoneum and peritoneum, eyes and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and non-specific malignant neoplasm of lymph nodes, malignant neoplasm secondary respiratory and digestive system and secondary malignant neoplasm from other sites. The term "cancer-associated disorders" as used in the present invention means that they include disorders by endocrine tumors transmitted by endocrine tumors, including neuroendocrine tumors, such as pancreatic neuroendocrine tumors. Carcinoid tumors are neuroendocrine tumors and include carcinoid tumors arising from the upper part of the digestive tract, for example bronchial or gastric carcinoid, middle part of the digestive tract, eg intestine carcinoid tumors of the small intestine or appendix; or back part of the digestive tract for example rectal carcinoid tumors; such as carcinoids of the Gl tract. Symptoms of carcinoid cancer include, for example, a carcinoid syndrome. The disorders associated with cancer as used in the present invention are understood to include disorders associated with the growth of neoplasms, for example including choriocarcinoma, leukemia, female breast adenocarcinoma, head and neck epidermal cancers, squamous cell lung cancer small, and various lymphomacomas.

The disorders associated with cancer as used in the present invention are understood to include mesothelioma (malignant), which is a cancer of mesothelial cells, for example where the cancer can develop in the pleura (pleural mesothelioma), abdomen, mesothelioma example of tissues that line the abdominal cavity (peritoneal mesothelioma) and the lining of the lungs, or in the lining of the reproductive organs (mesothelioma) benign), recurrent non-small cell lung cancer (NSCLC), gestational trophoblastic tumor. When a tumor, a tumor disease, a carcinoma or a cancer has been mentioned heretofore or is mentioned subsequently, metastasis in the original organ or tissue and / or in any other location is also alternatively or additionally involved. , wherever the location of the tumor and / or metastasis is. The disorders as used in the present invention include diseases. In another aspect the present invention provides 2.1 A method for the treatment of disorders that are transmitted by mTOR and / or thymidylate synthetase. such as inflammatory, (auto) immune, allergic or cancer-associated disorders, for example disorders associated with cell overproliferation; preferably autoimmune disorders and disorders associated with cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, for example either in sequences or simultaneously. 2.2 A method for the treatment of cancer, for example wherein the cancer is transmitted by mTOR and / or thymidylate synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, for example either in sequences or simultaneously. 2.3 A method for inhibiting cancer growth, for example wherein the cancer is transmitted by mTOR and / or thymidylate synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, for example, either in sequences or simultaneously. 2.4 A method for inhibiting or controlling cancer, for example wherein the cancer is transmitted by thymidylate mTOR synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with a compound of antifolate, for example in sequences or simultaneously. 2.5 A method for inducing regression of cancer, for example where the cancer is transmitted by mTOR and / or thymidylate synthetase, for example by inducing the reduction of the cancer mass, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, for example either in sequences or simultaneously. 2.6 A method for treating invasiveness of cancer or symptoms associated with said cancer growth, for example wherein the cancer is transmitted by mTOR and / or thymidylate synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically amount effective of an mTOR inhibitor in combination with an antifolate compound, for example either in sequences or simultaneously. 2.7 A method for preventing metastatic dispersion of cancer cells, for example wherein the cancer is transmitted by mTOR and / or thymidylate synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor. in combination with an antifolate compound, for example either in sequences or simultaneously. Said treatment can be carried out through the use of any combination as established in paragraphs 1.1 to 1.6 above. In another aspect the present invention provides 3.1 The use of any combination as set forth in items 1.1 to 1.6 above, for any method as set forth in paragraphs 2.1 to 2.7 above. 3.2 Any combination as set forth in paragraphs 1.1 to 1.6 above for any method such as established in paragraphs 2.1 to 2.7 above. In another aspect, the present invention provides 4.1 The use of a combination of an mTOR inhibitor to an antifolate compound according to the present invention in a pharmaceutical form, for example, for use in any method as set forth in paragraphs 2.1 to 2.7 above. 4.2 A combination of an mTOR inhibitor with an antifolate compound according to the present invention in a pharmaceutical form, for example, for use in any method as set out in paragraphs 2.1 to 2.7 above. 4.3 In another aspect, the present invention provides 5.1 The use of a combination of an mTOR inhibitor with an antifolate compound according to the present invention for the manufacture of a medicament, for example for use in any method as set forth in paragraphs 2.1 to 2.7 above. 5.2 A combination of an mTOR inhibitor with an antifolate compound according to the present invention for use in the preparation of a medicament, for example for use in any method as described in paragraphs 2.1 to 2.7 above. 5.3 A method for the preparation of a medicament for use in any method as defined in paragraphs 2.1 to 2.7 above, wherein the method further comprises a) combining, for example mixing, an mTOR inhibitor and an antifolate compound with a pharmaceutically acceptable excipient, or b) combining, eg mixing, an mTOR inhibitor with a pharmaceutically acceptable excipient to obtain a pharmaceutical composition COMP1, and to combine for example, mixing, an antifolate compound with a pharmaceutically acceptable excipient to obtain a pharmaceutical composition COMP2, and either (i) combining the pharmaceutical composition COMP1 and the pharmaceutical composition COMP2 in a single package , or (ii) packing the pharmaceutical composition COMP1 separately and packaging the pharmaceutical composition COMP2 separately, while adding to each package instructions for the combined administration of the pharmaceutical composition COMP2 and the pharmaceutical composition COMP2. The combined treatment of disorders that are transmitted by mTOR and / or thymidylate synthetase according to the present invention, can provide improvements compared to the simple treatment, for example, the toxicity of the antifolate compounds can be decreased, it can be increased the activity of an mTOR inhibitor or the activity of an antifolate compound compared to a treatment simple, for example, the combined treatment may result in synergistic effects or may overcome the resistance against an mTOR inhibitor or an antifolate compound, for example when used in any method as defined in paragraphs 2.1 to 2.7 above. In another aspect the present invention provides 6.1 A combination according to the present invention, characterized in that it comprises an amount of an mTOR inhibitor and an amount of an antifolate compound, wherein the amounts are suitable to produce a synergistic therapeutic effect. 6.2 A method for improving the therapeutic utility of an antifolate compound, characterized in that it comprises administering together, for example, concomitantly or in sequences, a therapeutically effective amount of an mTOR inhibitor and an antifolate compound. 6.3 A method for improving the therapeutic utility of an mTOR inhibitor, characterized in that it comprises administering together, for example, concomitantly or in sequences, a therapeutically effective amount of an mTOR inhibitor and an antifolate compound. 6.4 A method for reducing the toxicity associated with the administration of an antifolate compound, characterized in that it comprises administering to the subject an effective amount of an antifolate compound in combination with an amount effective of an mTOR inhibitor. for example to be used in any method as defined in paragraphs 2.1 to 2.7 above. The treatment as used in the present invention includes treatment and prevention, preferably treatment.

A combination according to the present invention, for example, for use in any method provided according to the present invention, may further comprise another drug substance. Another drug substance, as used in the present invention, includes any drug in addition to an mTOR inhibitor or an antifolate compound which may have beneficial effects in a use or a method provided by the present invention. Such drugs include for example anti-inflammatory drugs and / or immunomodulators anticancer drugs anesthetic drugs antidiarrheal drugs In another aspect the present invention provides 7.1 A combination according to the present invention, a method or use provided by the present invention further comprising a combination of an mTOR inhibitor with an antifolate compound and at least one other drug substance, for example wherein the other drug substance is selected from an anti-inflammatory drug or an immunomodulatory drug, an anti-cancer drug, an anesthetic drug and / or an antidiarrheal drug. In another aspect the present invention provides the use of an mTOR inhibitor in combination with an antifolate compound in any method provided by the present invention. In another aspect the present invention provides the use of an mTOR inhibitor in combination with an antifolate compound in any combination or pharmaceutical composition, or the pharmaceutical packet provided by the present invention. Anti-inflammatory and / or immunomodulatory drugs which will be useful in combination, for example, in combination therapy with a combination of the present invention include for example - transmitters, for example calcineurin inhibitors, for example cyclosporin A, FK 506; - Ascomycins having immunosuppressive properties, for example ABT-281, ASM981; corticosteroids; cyclophosphamide; azathioprene, leflunomide, mizorbine; - mycophenolic acid or salt; for example sodium, mycophenolate mofetil; - 15-deoxyspergualin or a homologue, analog or derivative immunosuppressant thereof; - transmitters, for example inhibitors of tyrosine kinase activity bcr-abl; - transmitters, for example inhibitors of tyrosine kinase activity of c-kit receptor; - transmitters, for example inhibitors of tyrosine kinase activity of PDGF receptor, for example Gleevec (imatinib); transmitters, for example inhibitors of p38 MAP kinase activity, transmitters, for example inhibitors of tyrosine kinase activity of VEGF receptor, transmitters, for example inhibitors of PKC activity, for example as described in publication WO0238561 or WO0382859, for example the compound of example 56 or 57-transmitters, for example inhibitors of the kinase activity JAK3, for example a-cyano- (3,4-dihydroxy) -] N-benzylcinnamamide N-benzyl-3, 4-dihydroxy-benzylidene-cyanoacetamide (Tirfostin AG 490), prodigiosin 25-C (PNU 156804), [4- (4, -hydroxyphenyl) -amino-6,7-dimethoxyquinazoline] (WHI-P131), [4- ( 3 '-bro mo-4' -hydroxy If enyl) -amino-6,7-dimethoxyquinazoline] (WHI-P154), [4- (3 ', 5'-dibromo-4'-hydroxylphenyl) -amino-6, 7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-. { (3R, 4R) -4-methyl-3- [methyl- (7H-pyrrol [2,3-d] pyrimidin-4-yl) - amino] -piperidin-1 -yl} -3-oxo-propionitrile, in free form or in a pharmaceutically acceptable salt form for example, mono-citrate (also referred to as CP-690,550), or a compound as described in WO2004052359 or WO2005066156; - transmitters, for example agonists or modulators of S1P receptor activity, for example optionally phosphorylated FTY720 or an analogue thereof, for example 2-amino-2- [4- (3-benzyloxy-phenylthio) -2-chlorophenyl] ethyl-1 , Optionally phosphorylated 3-propanediol or 1 - acid. { 4- [1 - (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino) -ethyl] -2-ethyl-benzyl} -zetidine-3-carboxylic acid or its pharmaceutically acceptable salts; immunosuppressive monoclonal antibodies, for example, monoclonal antibodies to leukocyte receptors, for example Blys / BAFF receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD28, CD40, CD45, CD45, CD52, CD48, CD86, IL-12, IL-17 receptor, IL-23 receptor or its ligands; - other immunomodulatory compounds, for example a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, for example in at least an extracellular portion of CTLA4 or a mutant thereof linked to a protein sequence CTLA4, for example CTLA4lg (for the example designated ATCC 68629) or a mutant thereof, for example LEA29Y; transmitters, for example inhibitors of activities of adhesion molecule, for example LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists, - transmitters, for example inhibitors of MIF activity, 5-aminosalicylate (5-ASA) agents, such as sulfasalazine, Azulfidine®, Asacol®, Dipentum®, Pentasa®, Rowasa®, Canasa®, Colazal®, for example drugs containing mesalamine; for example, mesalazine in combination with heparin; - transmitters, for example inhibitors of TNF-alpha activity, for example including antibodies binding to TNF-alpha, for example infliximab (Remicade®), thalidomide, lenalidomide, - non-steroidal anti-inflammatory drugs for nitric oxide release (NSAIDs), for example including drugs without donation that inhibit COX (CINOD); - phosphodiesterase, for example transmitters such as inhibitors of PDE4B activity, - transmitters, for example caspase activity inhibitors, - transmitters, for example agonists of the GPBAR1 G protein-coupled receptor protein, - transmitters, for example inhibitors of the activity of ceramide kinase, - "multifunctional anti-inflammatory drugs" (MFAIDs), for example inhibitors of cytosolic phospholipase A2 (cPLA2), such as inhibitors of phospholipase A2 anchored with membrane bound to glycosaminoglycans; - antibiotics such as penicillin, cephalosporins, erythromycins, tetracyclines, sulfonamides such as sulfadiazine, sulfisoxazole; sulfones, such as dapsone; pleuromutilins, fluoroquinolones, for example, metronidazole, quinolones such as ciprofloxacin; levofloxacin; probiotics and edible bacteria, for example Lactobacillus, Lactobacillus reuteri; - antiviral drugs, such as ribvirvir, vidarabine, acyclovir, ganciclovir, zanamivir, oseltamivir phosphate, famciclovir, atazanavir, amantadine, didanosine, efavirenz, foscamet, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valaciclovir, valganciclovir, zidovudine. Antiinflammatory drugs that are useful in combination, for example, in combination therapy, with a combination of the present invention, include nonsteroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen , fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, thiaprofenic acid and thioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanaco, diclofenac, fenclofenac, fencloric acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, acid mefenamic and niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and pyrazolones (apazone, bezpiperilon, feprazone, mofebutazone, oxifenbutazone) , phenylbutazone); cyclooxygenase-2 (COX-2) inhibitors such as celecoxib; inhibitors of phosphodiesterase type IV (PDE-IV); chemokine receptor antagonists, especially CCR1, CCR2 and CCR3; cholesterol lowering agents such as reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; anticholinergic agents such as muscarinic antagonists (ipratropium bromide); other compounds such as theophylline, sulfasalazine and aminosalicylates, for example 5-aminosalicylic acid and prodrugs thereof, antirheumatics. Anticancer drugs which will be useful as a combination part, for example in combination therapy, with a combination of the present invention, they include for example i. a steroid; for example prednisone. ii. a kinase inhibitor and an adenosine; which directs, decreases or inhibits metabolisms of nucleobase, nucleoside, nucleotide and nucleic acid, such as 5-iodotubercidin, which is also known as 7H-pyrrolo [2,3-d] pyrimidin-4-amine, 5-iodo-7 -β-D-ribofuranosyl. iii. an adjuvant; which increases the 5-FU-TS bond as well as a compound that directs, decreases or inhibits, alkaline phosphatase, such as leucovorin, levamisole. iv. an adrenal cortex antagonist; which directs, decreases or inhibits the activity of the drenal cortex and changes the peripheral metabolism of corticosteroids, resulting in a decrease in 17-hydroxycorticosteroids, such as mitotane. v. an inhibitor of the AKT path; such as a compound that directs, decreases or inhibits Akt, also known as protein B kinase (PKB), such as deguelin, which is also known as 3H-bis [1] benzopyran [3,4-b: 6 ', 5'-e] pyran-7 (7aH) -one, 13,13a-dihydro-9, 10-dimethoxy-3,3-dimethyl-, (7aS, 13aS); and triciribine, which is also known as 1,4,5,6,8-pentaazaacenaphthylene-3-amine, 1,5-dihydro-5-methyl-1-β-D-ribofuranosyl. saw. an alkylating agent; which originates the alkylation of the DNA and results in the breaking up of the DNA molecules, as well as cross-linking of the double strands, thereby interfering with DNA replication and RNA transcription, such as nitrogen mustards, for example chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, estramustine (Emcyt®); nitrosueras, such as carmustine, fotemustine, lomustine, streptozocin (streptozotocin, STZ, Zanosar®), BCNU; Gliadel; dacarbazine, mechlorethamine, for example in the form of a hydrochloride, procarbazine, for example in the form of a hydrochloride, thiotepa, temozolomide (TEMODAR®), mitomycin, altretamine, busulfan, estramustine, uramustine. Cyclophosphamide can be administered, for example in the form as it is marketed, under the trade name CYCLOSTIN®; and ifosfamide, such as HOLOXAN®. vii. an angiogenesis inhibitor; which directs, decreases or inhibits the production of new blood vessels, for example, it directs methionine aminopeptidase-2 (MetAP-2), macrophage inflammatory protein-1 (MIP-1 alpha), CCL5, TGF-beta, lipoxygenase, cyclooxygenase and topoisomerase, or indirectly targeting p21, p53, CDK2 and collagen synthesis, for example, including fumagillin, which is known as 2,4,6,8-decatetraenedioic acid, mono ester [(3R, 4S, 5S, 6R) -5-methoxy-4 - [(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxiranyl] -1-oxaspiro [2.5] oct-6-yl], (2E, 4E, 6E, 8E) - (9CI); shikonin, which is also known as 1, 4-naphthalenedione, 5,8-dihydroxy-2- [(1 R) -1-hydroxy-4-methyl-3-pentenyl] - (9CI); tranilast, which is also known as benzoic acid, 2 - [[3- (3,4-dimethoxyphenyl) -1-oxo-2-propenyl] amino]; Ursolic acid; suramin; bengamide or a derivative thereof, thalidomide, TNP-470. viii. an anti-androgen; which blocks the action of androgens of adrenal and testicular origin that stimulates the growth of normal and malignant prostatic tissue, such as nilutamide; bicalutamide (CASODEX®), which can be formulated, for example, as described in patent US4636505. ix. an antiestrogen, which antagonizes the effect of estrogens at the estrogen receptor level, for example, including an aromatase inhibitor that inhibits estrogen production, ie the conversion of androtendione and testosterone substrates to estrone and estradiol, respectively, ** for example including atamestane, exemesta.no, formestane, aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, letrozole, toremifene; bicalutamide; Flutamide; tamoxifen, tamoxifen citrate; tamoxifen; fulvestrant; raloxifene, raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is marketed, for example NOLVADEX®; and raloxifene hydrochloride is marketed as EVISTA®. Fulvestrant can be formulated as described in patent US4659516 and is commercialized as FASLODEX®. x. an anti-hypercalcemia agent; which is used to treat hypercalcemia, such as gallium nitrate hydrate (III); and disodium pamidronate. xi. an antimetabolite; which inhibits or interrupts DNA synthesis that results in cell death, such as folic acids, for example, methotrexate, permetrexed, raltitrexed; purines, for example 6-mercaptopurine, cladribine, clofarabine; fludarabine, thioguanine (thioguanine), 6-thioguanine, pentostatin (deoxicoformicin); cytarabine; flexuridine; fluorouracil; 5-fluorouracil (5-FU), floxuridine (5-FUdR), capecitabine; gemcitabine; gemcitabine hydrochloride; hydroxyurea (for example Hydrea®); DNA demethylation agents such as 5-azacytidine and decitabine; edatrexate; Capecitabine and gemcitabine can be administered, for example, in the marketed form such as XELODA® and GEMZAR®. xii. an inducer of apoptosis; which induces the series of normal events in a cell that leads to its death, for example by selectively inducing the X-linked protein apoptosis-inhibited mammalian inhibitor XIAP, or for example by deactivating BCL-xL; such as ethanol, 2 - [[3- (2,3-dichlorophenoxy) propyl] amino]; gambogic acid; embelin, also known as 2,5-cyclohexadiene-1,4-dione, 2,5-dihydroxy-3-undecyl- (9CI); arsenic trioxide. xiii. an aurora kinase inhibitor; which directs, diminishes or inhibits the late stages of the cell cycle from the G2 / M checkpoint all the time through mitotic checkpoint and late mitosis; such as binuclein 2, which is also known as methanimidamide, N '- [1- (3-chloro-4-fluorophenyl) -4-cyano-1 H -pyrazol-5-yl] -N, N-dimethyl- ( 9CI). xiv. a Bruton tyrosine kinase inhibitor (BTK); which directs, decreases or inhibits the development of human and murine B cells; such as terreic acid. xv. a calcineurin inhibitor; which directs, decreases or inhibits the T cell activation path, such as cypermethrin, which is also known as cyclopropanecarboxylic acid, 3- (2,2-dichloroethenyl) -2,2-dimethyl-, cyano (3-) ester phenoxyphenyl) methyl; deltamethrin, which is also known as cyclopropanecarboxylic acid, 3- (2,2-dibromoethenyl) -2,2-dimethyl- (S) -cyano (3-phenoxyphenyl) methyl ester, (1R.3R); fenvalerate, which is also known as benzeneacetic acid, 4-chloro-α- (1-methylethyl) -, cyano (3-phenoxyphenyl) methyl ester; and Tirfostin 8; although excluding ciclosporin or FK506. xvi. a CaM II kinase inhibitor; which directs, decreases or inhibits the CaM kinase; constitutes a family of structurally related enzymes including phosphorylase kinase, myosin light chain kinase, and CaM I-IV kinases; such as 5-isoquinolinesulfonic acid, ester 4 - [(2S) -2 - [(5-isoquinolinylsulfonyl) methylamino] -3-oxo-3- (4-phenyl-1-) piperazinyl) propyl] phenyl (9CI); benzenesulfonamide, N- [2 - [[[3- (4-chlorphenyl) -2-propenyl] methyl] amino] methyl] phenyl] -N- (2-hydroxyethyl) -4-methoxy. xvii. a CD45 tyrosine phosphatase inhibitor; which directs, decreases or inhibits the dephosphorylation of regulatory pTyr residues or protein-tyrosine kinases of the Src family, which aid in the treatment of a variety of inflammatory or immune disorders; such as phosphonic acid, [[2- (4-bromophenoxy) -5-nitrophenyl] hydroxymethyl]. xviii. a CDC25 phosphatase inhibitor; which directs, decreases or inhibits dephosphorylate cyclin dependent kinases overexpressed in tumors; such as 1,4-naphthalenedione, 2,3-bis [(2-hydroxyethyl) thio]. xix. a CHK kinase inhibitor; which directs, decreases or inhibits the overexpression of the antiapoptotic protein Bcl-2; such as debromohimenialdisina. The targets of a CHK kinase inhibitor are CHK1 and / or CHK2. xx. a control agent for regulating genestein, olomoucine and / or tyrphostins; such as daidzein, which is also known as 4H-1-benzopyran-4-one, 7-hydroxy-3- (4-hydroxyphenyl); Iso-Olomoucin and Tirfostin 1. xxi. a cyclooxygenase inhibitor; for example, including Cox-2 inhibitors; that direct, decrease or inhibit the enzyme Cox-2 (cyclooxygenase-2); such as 1 H-indole-3-acetamide, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-N- (2-phenylethyl); 2- acid arylaminophenylacetic substituted with 5-alkyl and derivatives, for example celecoxib (CELEBREX®), rofecoxib (VIOXX®), etoricoxib, valdecoxib; or a 5-alkyl-2-arylaminophenylacetic acid, for example 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenyl acetic acid, lumiracoxib; and celecoxib. xxii. a cRAF kinase inhibitor which directs, decreases or inhibits the activation of E-selectin and vascular adhesion molecule-1 induced by TNF; such as 3- (3,5-dibromo-4-hydroxybenzylidene) -5-iodo-1,3-dihydroindol-2-one; and benzamide, 3- (dimethylamino) -N- [3 - [(4-hydroxybenzoyl) amino] -4-methylphenyl].

Raf kinases play an important role as extracellular signal regulation kinases in cell differentiation, proliferation and apoptosis. An objective of the cRAF kinase inhibitor includes but is not limited to RAF1. xxiii. a cyclin-dependent kinase inhibitor; which directs, decreases or inhibits the cyclin-dependent kinase that plays an important role in the regulation of the mammalian cell cycle; such as N9-isopropyl-olomoucine; olomoucina; purvalanol B, which is also known as benzoic acid, 2-chloro-4 - [[2 - [[(1R) -1 - (hydroxy methyl) -2-methyl propi Ijam i no] -9- (1-methylethyl) ) -9H-purin-6-M] amino] - (9CI); roascovitine; indirubin, which is also known as 2H-indol-2-one, 3- (1, 3-dihydro-3-oxo-2H-indol-2-ylidene) -1, 3-dihydro- (9CI); kenpaulone, which is also known as indole [3,2-d] [1] benzazepin-6 (5H) -one, 9-bromo-7,12-dihydro- (9CI); purvalanol A, which is also known as 1-Butanol, 2 - [[6 - [(3-chlorophenyl) amino] -9- (1-methyl-ethyl) -9H-purin-2-yl] amino] -3-methyl-, (2R) - ( 9CI); indirubin-3'-monooxime The progress of the cell cycle is regulated through a series of sequential events that include the activation and subsequent deactivation of cyclin-dependent kinases (Cdks) and cyclins. Cdks are a group of serine / threonine kinases that form active heterodimeric complexes by binding their regulatory units, cyclins. Exemplary targets of a cyclin-dependent kinase inhibitor include, but are not limited to, CDK, AHR, CDK1, CDK2, CDK5, CDK4 / 6, GSK3beta and ERK. xxiv. a cyclin protease inhibitor; which directs, diminishes or inhibits the cysteine protease that plays an important role in the cellular change and apoptosis of mammals; such as 4-morpholinecarboxamide, N - [(1 S) -3-fluoro-2-oxo-1- (2-phenylethyl) propyl] amino] -2-oxo-1- (phenylmethyl) ethyl]. xxv. a DNA intercalator, which binds to DNA and inhibits DNA, RNA and protein synthesis; such as plicamicin, dactinomycin. xxvi. a DNA strand switch, which causes the strand of DNA to be cut and results in the inhibition of DNA synthesis, RNA inhibition and protein synthesis; such as bleomycin. xxvii. an E3 ligase inhibitor; which directs, diminishes or inhibits the E3 ligase that inhibits the transfer of chains of ubiquitin to proteins, marking them for degradation in the proteasome; such as N - ((3,3,3-trifluoro-2-trifluoromethyl) propionyl) sulfanilamide. xxviii. an endocrine hormone; which acting mainly in the pituitary gland causes the suppression of hormones in men, the net effect being a reduction of testosterone to levels of castration; in women, the synthesis of both ovarian and androgen estrogen is inhibited; such as leuprolide; megestrol, megestrol acetate. xxix. compounds that direct, diminish or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo or heterodimers) such as compounds, proteins or antibodies that inhibit the members of the tyrosine kinase family of EGF receptor, ErbB1, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligadnes and are in particular the compounds, proteins or monoclonal antibodies described in generic and specific form in WO 9702266, for example the compound of Example 39, EP0564409, WO9903854, EP0520722, EP0566226, EP0787722, EP0837063, US5747498, WO9810767, WO9730034, WO9749688, WO9738983 and especially WO9630347, for example a compound known as CP 358774, WO9633980, for example a compound known as ZD 1839; and the WO 9503283, for example a compound known as ZM105180, for example including the double-acting tyrosine kinase inhibitor (ErbB1 and ErbB2) lapatinib (GSK572016), for example lapatinib ditosylate; panituzumab, trastuzumab (HERCEPTIN®), cetuximab, iressa, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2. 11, E6.3 or E7.6.3, derivatives of 7H-pyrrolo- [2,3-d] pyrimidine which are described, for example, in WO03013541, erlotinib, gefitinib. Erlotinib can be administered in the form as it is marketed, for example, TARCEVA® and gefitinib as IRESSA®, human monoclonal antibodies against the epidermal growth factor receptor including ABX-EGFR. xxx an EGFR, tyrosine kinase inhibitor PDGFR; such as EGFR kinase inhibitors including tirfostin 23, tirfostin 25, tirfostin 47, tirfostin 51 and tirfostin AG 825; 2-propenamide, 2-cyano-3- (3,4-dihydroxyphenyl) -N-phenyl- (2E); tirfostin Ag 1478; lavendustin A; 3-pyridineacetonitrile, a - [(3,5-dichlorophenyl) methylene] -, (aZ); an example of an EGFR, an example of a tyrosine kinase inhibitor PDGFR including for example tirfostin 46. The tyrosine kinase inhibitor PDGFR includes tirfosin 46. The targets of an EGFR kinase inhibitor include guanidyl cyclase (GC-C) HER2, EGFR, PTK and tubulin. xxxi. a farnesyltransferase inhibitor; who drives, decreases or inhibits the protein; such as hydroxypharnesylphosphonic acid; butanoic acid, ester 2 - [[(2S) -2 - [[(2S, 3S) -2 - [[(2R) -2-amino-3-mercaptopropyl] amino] -3-methylpentyl] oxy] -1 - oxo-3-f-enyl propyl] amino] -4- (methylsulfonyl) -, 1 -methylethyl, (2S); manumicin A; L-744,832 or DK8G557, tipifarnib (R115777), SCH66336 (lonafamib), BMS-214662, xxxii. a Flk-1 kinase inhibitor; which directs, decreases or inhibits the activity of tyrosine kinase Flk-1; such as 2-propenamide, 2-cyano-3- [4-hydroxy-3,5-bis (1-methylethyl) phenyl] -N- (3-phenylpropyl) - (2E). A target of a Flk-1 kinase inhibitor includes but is not limited to, KDR. xxxiii. a glycogen synthase kinase-2 inhibitor (GSK3); which directs, decreases or inhibits glycogen synthase kinase-2 (GSK3); such as ndirubin-3'-monooxime. Glycogen synthase kinase-3 (GSK; tau protein kinase I), a ubiquitously expressed, highly conserved histidine / threonine protein kinase, is involved in the signal transduction cascades of multiple cellular processes, which is a kinase of protein that has been shown to be involved in the regulation of a diverse formation of cellular functions, including protein synthesis, cell proliferation, cell differentiation, microtubule assembly / disassembly and apoptosis. xxxiv. a histone deacetylase inhibitor (HDAC); which inhibits histone deacetylase and which possesses activity antiproliferative; such as the compounds described in WO0222577, especially N-hydroxy-3- [4 - [[(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E -2-propenamide; N-hydroxy-3- [4 - [([2- (2-methyl-1 H -indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propenamide and pharmaceutically acceptable salts of the same, suberoylanilide hydroxamic acid (SAHA), [4- (2-amino-phenylcarbamoyl) -benzylcarbamic acid pyridine-3-ylmethyl ester and derivatives thereof, butyric acid, pyroxamide, Trichostatin A, oxamflatin, apicidin, depsipeptide; depopulation; trapoxin, HC toxin, which is known as the cycle [L-alanyl-D-alanyl- (DS, 2S) -D-amino-D-oxooxy-pentanoyl-D-prolyl] (9CI), sodium phenylbutyrate, suberoyl bis-hydroxamic acid, Trichostatin A, BMS-27275, pyroxamide, FR-901228, valproic acid, xxxv, an HSP inhibitor, which directs, decreases or inhibits the intrinsic ATPase activity of HSP90, degrades, directs, decreases or inhibits the HSP90 client protein through the ubiquitin proteosome pathway The compounds direct, decrease or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90 for example 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other compounds related to geldanamycin; radicicol inhibitors and HADC. Other examples of an HSP90 inhibitor include geldanamycin, 17-demethoxy-17- (2-propenylamino). Potential indirect targets of an HSP90 inhibitor include FLT3, BCR-ABL, CHK1, CYP3A5 * 3 and / or NQ01 * 2. Nilotinib is an example of an inhibitor of tyrosine kinase BCR-ABL. xxxvi. an inhibitor of ß-alpha l-kappa kinase (IKK); which directs, decreases or inhibits NF-kappaB, such as 2-propenenitrile, 3 - [(4-methylphenyl) sulfonyl] - (2E). xxxvii an insulin receptor tyrosine kinase inhibitor that modulates the activities of phosphatidylinositol 3-kinase, microtubule-associated protein and S6 kinases; such as hydroxyl-2-naphthalenylmethylphosphonic acid, LY294002. xxxviii. an N-terminal kinase inhibitor (JNK) that directs, decreases or inhibits the N-terminal kinase; such as pyrazoleantrone and / or epigallocatechin gallate. The N-terminal kinase (JNK), a serine-directed protein kinase, is involved in the phosphorylation and activation of c-Jun and ATF2 and plays an important role in metabolism, growth, cell differentiation and apoptosis. A target for a JNK kinase inhibitor is included but not limited to DNMT. xxxix a microtubule binding agent; which acts by interrupting the microtubule network that is essential for mitotic and interphase cellular function; such as vinca alkaloids, for example, vinblastine, vinblastine sulfate; vincristine, vincristine sulfate; vindesine; vinorelbine; taxanes, such as taxanes, for example docetaxel; paclitaxel; discodermolidas; cokycin, epothilones and derivatives thereof, for example epothilone B or a derivative thereof. Paclitaxel is marketed as TAXOL®; Docetaxel is marketed as TAXOTERE®; vinblastine sulfate such as VINBLASTIN R.P®; and vincristine sulfate such as FARMISTIN®. Also included are the generic forms of paclitaxel, as well as various forms of paclitaxel dosage. Generic forms of paclitaxel include but are not limited to betaxolol hydrochloride. Various dosage forms of paclitaxel are included but not limited to albumin nanoparticle paclitaxel marketed as ABRAXANE®; ONXOL®, CYTOTAX®. Discodermolide can be obtained, for example, as described in patent US5010099. Also included are Epotholin derivatives which are described in patent publications US6194181, WO98 / 0121, WO9825929, WO9808849, WO9943653, WO9822461 and WO0031247. Especially preferred are Epotholin A and / or B. xl. a protein kinase inhibitor activated with mitogen (MAP); which directs, decreases or inhibits the Mitogen-activated protein, such as benzenesulfonamide, and N- [2 - [[[3- (4-chlorophenyl) -2-propenyl] methyl] amino] methyl] phenyl] -N- (2 -hydroxyethyl) -4-methoxy. The mitogen-activated protein (MAP) kinases are a group of protein serine / threonine kinases that are activated in response to a variety of extracellular stimuli and transmit signal transduction from the cell surface to the nucleus. They regulate several physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion and metastasis. xli. an MDM2 inhibitor that directs, decreases or inhibits the interaction of MDM2 and the p53 tumor suppressor; such as trans-4-iodine, 4'-boranyl-chalcone. xlii. a MEK inhibitor; which directs, decreases or inhibits the kinase activity of the MAP kinase MEK; t as sorafenib, for example Nexavar® (sorafenib tosylate), butanedinitrile, bis [amino [2-aminophenyl) thio] methylene]. An objective of a MEK inhibitor includes but is not limited to ERK. an indirect target of a MEK inhibitor includes but is not limited to cyclin D1. xliii: a matrix metalloproteinase inhibitor (MMP), which directs, decreases or inhibits a class of protease enzyme that selectively catalyzes the hydrolysis of polypeptide bonds including enzymes MMP-2 and MMP-9 that are involved in the promotion of the loss of tissue structure around tumors and facilitates the growth of tumor, angiogenesis and metastasis such as actinonin, which is also known as butandiamide, N-4-hydroxy-N1 - [(1S) -1 - [[(2S ) -2- (hydroxymethyl) -1-pyrrolidinyl] carbonyl] -2-methylpropyl] -2-pentyl-, (2R) - (9CI); epigallocatechin gallate; inhibitors peptidomimetics and non-peptidomimetics of collagen; tetracycline derivatives, for example, batimastat of peptidomimetic hydroxamate inhibitor; and its orally bioavailable analogue marimastat, prinomastat, metastat, neovastat, tanomastat, TAA211, BMS-279251, BAY 12-9566, MMI270B or AAJ996. An objective of an MMP inhibitor includes but is not limited to polypeptide deformylase. xliv. an inhibitor of tyrosine kinase NGFR; which directs, decreases or inhibits the tyrosine phosphorylation p? Oc ', rk dependent on nerve growth factor; such as tirfostin AG 879. Targets of a tyrosine kinase inhibitor NGFR include but are not limited to HER2, FLK1, FAK, TrkA and / or TrkC. An indirect target inhibits the expression of RAF1. xlv. a p38 MAP kinase inhibitor that includes SAPK2 / p38 kinase inhibitor; which directs, decreases or inhibits p38-MAPK, which is a member of the MAPK family, such as 4- [4- (4-fluorophenyl) -5- (4-pyridinyl) -1 H -imidazol-2-yl] . An example of a SAPK2 / p38 kinase inhibitor includes but is not limited to benzamide, 3- (dimethylamino) -N- [3 - [(4-hydroxybenzoyl) amino] -4-methylphenylj. A member of the MAPK family is a serine / threonine kinase activated by tyrosine phosphorylation and threonine residues. This kinase is phosphorylated and activated through many cell tensions and inflammatory stimuli, although it will be involved in the regulation of important cellular responses such as apoptosis and inflammatory reactions. xlvi. a p56 tyrosine kinase inhibitor which directs, decreases or inhibits tyrosine kinase p56 which is an enzyme that is a tyrosine kinase of the lymphoid specific src family critical for the development and activation of t-cell; such as damnacanthal, also known as 2-anthracencarboxaldehyde, 9,10-dihydro-3-hydroxy-1-methoxy-9,10-dioxo, Tirfostin 46. an objective of the tyrosine kinase inhibitor p56 includes but is not limited to Lck. Lck is associated with the cytoplasmic domains of CD4, CD8 and the beta chain of the IL-2 receptor, and is considered to be involved in the early steps of T-cell activation transmitted by TCR. xlvii. a tyrosine kinase inhibitor PDGFR; which directs, decreases or inhibits the activity of the receptor-C-kit tyrosine kinases (part of the PDGFR family) such as direction, decrease or inhibition of the tyrosine kinase family activity of the c-kit receptor which especially inhibits the c-Kit receiver. Exemplary targets of a tyrosine kinase inhibitor PDGFR include but are not limited to PDGFR, FLT3 and / or c-KIT; such as tirfostin AG 1296; tirfostin 9; 1,3-butadiene-1,1,3-tricarbonitrile, 2-amino-4- (1H-indol-5-yl); N-phenyl-2-pyrimidine-amine derivative, for example IRESSA®. PDGF plays a central role in the regulation of chymalotaxis and proliferation cell survival in normal cells, as well as various disease states such as cancer, atherosclerosis and fibrotic disease. The PDGF family is composed of dimeric isoforms (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD), which exert their cellular effects by differentially binding to the tyrosine kinases of two receptors. PDGFR-a and PDGFR-β have molecular masses of 170 and 180 kDa, respectively. xlviii. a phosphatidylinositol 3-kinase inhibitor; which directs, decreases or inhibits Pl-3-kinase; such as wortmannin, also known as 3H-Furo [4,3,2-de] indene [4,5-h] -2-benzopyran-3,6,9-trione, 11 - (acetyl oxy) - 1, 6b , 7, 8, 9a, 10, 11,11 b-octahydro-1- (methoxymethyl) -9a, 11b-dimethyl-, (1S, 6bR, 9aS, 11R5,11bR) - (9CI); 8-phenyl-2- (morpholin-4-yl) -chromen-4-one; quercetin, quercetin dihydrate. The activity of 3-kinase Pl has been shown to increase in response to a number of hormonal stimuli and growth factor including insulin, platelet-derived growth factor, insulin-derived growth factor, epidermal growth factor, colony stimulation factor. and hepatocyte growth factor, and has been implicated in processes related to cell growth and transformation. An example of a phosphatidylinositol 3-kinase inhibitor target includes, but is not limited to, Pi3K. xlix. a phosphatase inhibitor; which directs, diminishes or inhibits phosphatase; such as channtidic acid; cantharidin; and L-leucinamide, N- [4- (2-carboxylethenyl) benzoyl] glycyl-L-α-glutamyl- (E). Fostases remove the phosphoryl group and restore the protein to its original dephosphorylated state. Therefore, the phosphorylation-dephosphorylation cycle can be considered as a "on-off" molecular switch. I. Platinum agent; which contains platinum and inhibits the synthesis of DNA by forming interheads and inter-strand cross-linking of DNA molecules; such as carboplatin; cisplatin; oxaliplatin; cisplatin; Satraplatinum and platinum agents such as ZD0473, BBR3464. Carboplatin can also be administered, for example, in the form as it is marketed, for example CARBOPLAT®; and oxaliplatin as ELOXATIN®. li. a protein phosphatase inhibitor, including a PP1 and PP2 inhibitor and a tyrosine phosphatase inhibitor; which directs, decreases or inhibits protein phosphatase. Examples of a PP1 and PP2A inhibitor include cantharidic acid and / or cantharidin. Examples of tyrosine phosphatase inhibitor include, but are not limited to, L-P-bromotetramisol oxalate; 2 (5H) -furanone, 4-hydroxy-5- (hydroxymethyl) -3- (1-oxohexadecyl) -, (5R); and benzylphosphonic acid. The term "PP1 or PP2 inhibitor" as used in the present invention, refers to a compound that directs, decreases or inhibits Ser / Thr protein phosphatases. Type I phosphatases that include PP1 can be inhibited by two heat-stable proteins known as inhibitor-1 (1-1) and inhibitor-2 (I-2). They preferentially dephosphorylate a subunit of phosphorylase kinase. Type II phosphatases are subdivided into spontaneously active (PP2A), classes of phosphatases dependent on CA2 + (PP2B) and Mg2 + (PP2C). The term "tyrosine phosphatase inhibitor" as used in the present invention refers to compounds that direct, diminish or inhibit tyrosine phosphatase. Protein tyrosine phosphatases (PTPs) are relatively recent additions to the phosphatase family. They eliminate the phosphate groups of phosphorylated tyrosine protein residues. PTPs display diverse structural characteristics and play important roles in the regulation of the proliferation of cell differentiation, cell adhesion and motility, and cytoskeletal function. Exemplary targets of a tyrosine phosphatase inhibitor include but are not limited to alkaline phosphatase (ALP), heparanase, PTPase, and / or prostatic acid phosphatase. lii a PKC inhibitor and a delta kinase PKC inhibitor: The term "PKC inhibitor" as used in the present invention, refers to a compound that directs, decreases or inhibits protein kinase C as well as its isozymes. Protein C kinase (PKC), a ubiquitous phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, differentiation and apoptosis. The Examples of a PKC inhibitor target include but are not limited to, MPK and / or NF-kappaB. Examples of a PKC inhibitor include, but are not limited to, 1-H-pyrrolo-2,5-dione, 3- [1- [3- (dimethylamino) propyl] -1H-indol-3-ll] -4- (1H-indol-3-ll); bisindolylmaleimide IX; sphingosine, which is known as 4-octadecen-1, 3-diol, 2-amino-, (2S, 3R, 4E) - (9CI); staurosporine, known as 9,13-Epox-1 H, -9H-diindole [1, 2,3-gh: 3 ', 2', 1 '-lm] pyrrolo [3,4-j] [1,7] benzodiazonin-1-one, staurosporine derivatives such as those described in EP0296110, for example midostaurin; 2.3, 10.11, 12.13-hexahydro-10-methoxy-9-methyl-11- (methylamino) -, (9S, 1 OR, 11R, 13R) - (9CI); tirfostin 51; and hypericin, known as phenanthrum [1, 10,9,8-opqra] perylene-7, 14-dione, 1, 3,4,6,8,13-hexahydroxy-10, 11-dimethyl-, stereoisomer (6CI, 7CI, 8CI, 9CI), UCN-01, safingol, BAY 43-9006, briostatin 1, perifosine; Ilmofosin; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196. The term "delta kinase inhibitor", as used in the present invention, refers to a compound that directs, decreases or inhibits the delta isozymes of PKC. The isozyme delta is a conventional PKC isozyme and is dependent on Ca2 +. An example of delta kinase inhibitor PKC is included but not limited to Rottlerin, also known as 2-Propen-1-one, 1- [6 - [(3-acetyl-2,4,6-trihydroxy-5-methylphenyl ) methyl] -5,7-dihydroxy-2, 2-dimethyl-2 H-1-benzopy n-8-ylj-3-phenyl-, (2E) - (9CI). liii. a polyamine synthesis inhibitor; who drives, decreases or inhibits polyamine spermidine; such as DMFO also known as (-) - 2-difluoromethylornitin; N1, N12-diethylpermine 4HCl. The spermidine of polyamines and spermine are of vital importance for cell proliferation, although its precise mechanism of action is not yet clear. Tumor cells have an altered polyamine homoestasis reflected by increased activity of biosynthetic enzymes and elevated polyamine assemblies. liv. a proteosome inhibitor, which directs, diminishes or inhibits the proteasome, such as aclacinomycin A; gliotoxin; PS-341; MLN 341; bortezomib; Velcade Examples of proteasome inhibitor targets include but are not limited to NADPH oxidase that generates O (2) (-) -, NK-kappaB and / or farnesyltransferase, geranyltransferase I. Iv. a PTP1B inhibitor which directs, decreases or inhibits PTP1B, a protein tyrosine kinase inhibitor; such as L-leucinamide, N- [4- (2-carboxylethenyl) benzoyl] glycyl-L-α-glutamyl->. (AND). Ivi. a protein tyrosine kinase inhibitor which includes an inhibitor of tirbsin kinase of the SRC family; an inhibitor of Syk tyrosine kinase; and a tyrosine kinase inhibitor JAK-2 and / or JAK-3; the term "protein tyrosine kinase inhibitor" as used in the present invention, refers to a compound that directs, decreases or inhibits protein tyrosine kinases. The kinases of protein tyrosine (PTKs) plays an important role in the regulation of cell proliferation, differentiation, metabolism, migration and survival. They are classified as receiving PTKs and non-receiving PTKs. The receptor PTKs contain a single polypeptide chain with a transmembrane segment. The extracellular end of this segment contains a high affinity ligand binding domain, while the cytoplasmic end comprises the catalytic center and the regulatory sequences. The extracellular end of this segment contains a high affinity ligand binding domain, while the cytoplasmic end comprises the catalytic center and the regulatory sequences. Exemplary targets of a tyrosine kinase inhibitor include but are not limited to ERK1, ERK2, Bruton tyrosine kinase (Btk), JAK2, ERK 1/2) PDGFR and / or FLT3. Examples of indirect targets include but are not limited to TNFalpha, NO, PGE2, IRAK, NOS, ICAM-1 and / or E-selectin. Examples of tyrosine kinase inhibitor include but are not limited to tirfostin AG 126; tirfostin Ag 1288; tirfostin Ag 1295; geldanamycin; and genistein. Tyrosine receptor kinases include elements of the Src, Tec, JAK, Fes, Abl, FAK, Csk and Syk families. They are located in the cytoplasm, as well as in the nucleus. They exhibit different kinase regulation, substrate phosphorylation and function. The deregulation of these kinases also They are linked to various human diseases. The term "SRC family tyrosine kinase inhibitor", as used in the present invention, refers to a compound which directs, decreases or inhibits SRC. Examples of a tyrosine kinase inhibitor of the SRC family include but are not limited to PP1, which is also known as 1H-pyrazolo [3,4-d] pyrimidin-4-amine, 1- (1,1- dimethyl ethyl) -3- (1-naphthalenyl) (9CI); and PP2, which is also known as 1H-Pyrazolo [3,4-d] -pyrimidin-4-amine, 3- (4-chlorophenyl) -1- (1,1-dimethylethyl) - (9CI). The term "tyrosine kinase inhibitor Syk" as used in the present invention refers to a compound that directs, decreases or inhibits Syk. Exemplary targets of a tyrosine kinase inhibitor Syk include but are not limited to Syk, STAT3 and / or STAT5. An example of a tyrosine kinase inhibitor Syk includes but is not limited to, piceatanol, which is also known as 1,2-benzenediol, 4 - [(1 E) -2- (3,5-dihydroxyphenyl) ethenyl] - (9CI). The term "tyrosine kinase inhibitor Janus (JAK-2 and / or JAK-3)" as used in the present invention, refers to a compound that directs, decreases or inhibits the tyrosine janus kinase. The tyrosine kinase inhibitor Janus shows antileukemic agents with antithrombotic, antiallergic and immunosuppressive properties. The targets of the tyrosine kinase inhibitor JAK-2 and / or JAK-3 include but are not limited to JAK2, JAK3, STAT3. An indirect target of a tyrosine kinase inhibitor JAK-2 and / or JAK-3 includes but is not limited to CDK2. Examples of a tyrosine kinase inhibitor JAK-2 and / or JAK-3 include but are not limited to Tirfostin AG 490; and 2-naphthyl vinyl ketone. Compounds that direct, decrease or inhibit the activity of members of the c-Abl family and their gene fusion products include, for example, PD180970; AG957; or NSC 680410. Ivii. a retinoid; which directs, decreases or inhibits the retinoid-dependent receptors such as isotretinoin, tretinoin, alitretinoin, bexarotene. Iviii an RNA II polymerase elongation inhibitor that directs, decreases or inhibits the nuclear and cytosolic p70S6 kinase stimulated by insulin in CHO cells; directs, decreases or inhibits transcription of RNA II polymerase, which may depend on casein kinase II; directs, decreases or inhibits the breakdown of germinal vesicles in bovine oocytes; such as 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Ivix a serine / threonine kinase inhibitor that inhibits serine / threonine kinases; such as 2-aminopurine. An example of a serine / threonine kinase inhibitor target includes but is not limited to dsRNA-dependent protein kinase (PKR). Examples of indirect targets of a serine / threonine kinase inhibitor include but are not limited to, MCP-1, NF-kappaB, elF2alpha, COX2, RANTES, IL8.CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, erythropoietin, and / or CYP1A1. Ix. an inhibitor of sterol biosynthesis; which inhibits the biosynthesis of sterols such as cholesterol; such as terbinadine. Exemplary targets of a sterol biosynthesis inhibitor include but are not limited to squalene epoxidase and CYP2D6. Ixi. a topoisomerase inhibitor; including topoisomerase inhibitor and topoisomerase II inhibitor. Examples of topoisomerase I inhibitor include but are not limited to topotecan, gimatecan, irinotecan, camptotecan and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO9917804); 10-hydroxycamptothecin for example acetate salt; idarubicin, for example the hydrochloride; irinotecan, for example the hydrochloride; etoposide; teniposide; topotecan, topotecan hydrochloride; doxorubicin; epirubicin, epirubicin hydrochloride; mitoxantrone, mjtoxantrone, for example hydrochloride; daunorubicin, daunorubicin hydrochloride, valrubicin, dasatinib (BMS-354825). Irinotecan can be administered, for example, in the form as it is marketed, for example under the trade name of CAMPTOSAR®. Topotecan can be administered as sold, for example under the trademark of HYCAMTIN®. The term "inhibitor of Topoisomerase II "as used in the present invention includes but is not limited to anthracyclines such as doxorubicin, including liposome formulation, for example CAELYX®, daunorubicin, including liposomal formulation for example DAUNOSOME®, epirubicin, idarubicin and nemorubicin; anthraquinones; , mitoxantrone and losoxantrone, etoposide and teniposide of podophyllotoxins Etoposide is marketed as ETOPOPHOS®, teniposide as VM 26-BRISTOL®, doxorubicin as ADRIBLASTIN® or ADRIAMYCIN®, epirubicin as FARMORUBICIN® idarubicin as ZAVEDOS®, and mitoxantrone as NOVANTRON®. Ixii tyrosine kinase inhibitor VEGFR that directs, decreases or inhibits known angiogenic growth factors and cytokines involved in the modulation of normal angiogenesis and pathology.The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF- D) and its corresponding receptor tyrosine kinase [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR) and VEGFR-3 (Flt-4)] play a role important and indispensable factor in the regulation of multiple facets of the angiogenic and lymphangiogenic processes. An example of a tyrosine kinase inhibitor VEGFR includes 3- (4-dimethylaminobenzylidenyl) -2-indolinone. The compounds that direct, decrease or inhibit the activity of VEGF are especially compounds, proteins or antibodies that inhibit the tyrosine kinase of VEGF receptor, inhibit a VEGFR receptor or bind to VEGF and particularly the compounds, proteins and monoclonal antibodies described in generic and specific form in WO9835958, for example 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or a pharmaceutically acceptable salt thereof, for example succinate, or in publications WO0009495, WO0027820, WO0059509, WO9811223, WO0027819 and EP0769947; for example, those described by M. Prewett and associates in Cancer Research 59 (1999) 5209-5218, by F. Yuan and associates in Proc. Nati Acad. Sci. USA, vol. 93, pp. 14765-14770, December 1996, by Z. Zhu and associates in Cancer Res. 58.1998.3209-3214, and by J. Mordenti and associates in Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999; in publications WO0037502 and WO9410202; Angiostatin, described by M. S. O'Reilly and associates, Cell 79,1994,315-328; Endostatin described by M. S. O'Reilly et al., Cell 88, 1997, 777-285; anthranilic acid amides; ZD4190; ZD6474 (vandetanib); SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies for example RhuMab (bevacizumab). By the term "antibody" is meant intact monoclonal antibodies, monoclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments provided they exhibit the desired biological activity, an example of a VEGF-R2 inhibitor includes axitinib, Ixiii. an agonist gonadorelin, such as abarelix, goserelin, goserelin acetate, Ixiv. a compound that induces the cell differentiation process such as retinoic acid, alpha-, gamma or 8-tocopherol or alpha-, gamma- or 8-tocotrienol. Ixv. a bisphosphonate, which includes, for example, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Ixvi. a heparanase inhibitor that prevents the degradation of heparan sulfate, for example PI-88, Ixvii. a biological response modifier preferably to lymphokine or interferons, for example interferon alpha, Ixviii. a telomerase inhibitor, for example telomestatin, Ixix. transmitters such as catechol-O-methyltransferase inhibitors, for example entacapone, Ixx: ispinesib, sunitinib (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y), Ixxi somatostatin or a somatostatin analog such as octreotide (Sandostatin® or Sandostatin LAR ®). Ixxii. growth hormone receptor agonists such as pegvisomant, filgrastim or pegfilgrastim or interferon alpha: Ixxiii. monoclonal antibodies for example useful for the treatment of leukemia (AML), such as alemtuzumab (Campath®), rituximab / Rituxan®), gemtuzumab, (ozogamicin, Mylotarg®), epratuzumab. Ixxiv. altretamine, amsacrine, asparaginase (Elspar®), denileukin diftitox, masoprocol, pegaspargasa. Ixxv. a phosphodiesterase inhibitor, for example anagrelide (Agrylin®, Xagrid®). Ixxvi. a cancer vaccine, such as MDX-1379. Ixxvii. a methylmalonic acid decreasing agent (see, for example, WO2002002093). Cancer treatment with a combination of the present invention, optionally in combination with another drug substance may be associated with radiotherapy. The treatment of cancer with a combination of the present invention, optionally in combination with another drug substance may be a second line treatment, for example after treatment with another anticancer drug or other cancer therapy. Anesthetics which may be useful as a combination part, for example in combination therapy with a combination of the present invention include for example ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl hydrochloride, xylocaine, and phenazopyridine. Anesthetics which may be useful as a combination part, for example in combination therapy with a combination of the present invention include for example diphenoxylate, loperamide, codeine. Antidiarrheal drug substances which may be useful as a combination part for example in combination therapy with a combination of the present invention include for example diphenoxylate, loperamide, codeine. For example, a combination according to the present invention can be used in combination with a methylmalonic acid-lowering agent (see, for example, publication WO2002002093). For example, a combination according to the present invention can be used in combination with a platinum compound, for example cisplatin. Other drug substances can be used in free form, in the form of a salt, for example a pharmaceutically acceptable salt form, optionally in the form of a solvate, optionally in the form of a pharmaceutically acceptable prodrug, including for example carboxylic acid derivatives of carboxylic acid containing drug substances such as pharmaceutically acceptable carboxylic acid esters. Said other drug substance can be in the form of isomers or any isomeric mixture where isomers may exist. If a combination of the present invention is administered in combination with other drug substances, the dosages of the other drug substance administered as a whole may vary, depending of course on the type of co-drug employed, on the specific drug employed, on the condition being treated. In general, doses similar to those provided by the supplier of the other drug substance may be suitable. The appropriate dosage of another drug substance can be carried out as appropriate, for example, according to, for example, analogously, as indicated as a specific drug in the literature or on the internet. As used in the present invention, the term "Toxicity" refers to a toxic event associated with administration in an antifolate, see for example the Publication of "Antifolate Drugs in Cancer Therapy", Humana Press, see e.g. "Book review - Antifolate Drugs in Cancer Therapy by Ann L. Jackman Author: Nair M.G.1 Source: Drug Discovery Today, Volume 4, Number 11, 1999." Methods To evaluate the effect of an mTOR inhibitor on the antitumor efficacy of a compound or a human tumor silaneus model, female unprotected mice can be treated. contain human breast carcinomas MX-1 with an antifolate compound for example, a compound of the formula I11S5344932 alone or in combination with an mTOR inhibitor. Animals can be maintained with standard laboratory porridge sterilized with ad libitum and sterilized water ad libitum. Human MX-1 tumor cells (5 * 10 <6>) obtained from donor tumors can be implanted subcutaneously in a thigh of female deprotected mice at 8 to 10 weeks of age. Starting on day 7 after the tumor cell implant, the animals can be treated with a compound of the formula Ius5344932 (100 mg / kg or 150 mg / kg) once a day on days 7 to 11 and 14 at 18 by peritoneal injection alone or together with an mTOR inhibitor (oral treatment, 1 to 30 mg / kg). The tumor response can be monitored by measurements of tumor volume twice a week during the course of the experiment. Toxicity can be monitored by body weight measurements made at the same time as measurements of tumor volume. Tumor growth retardation is understood as the difference in days between treated and control tumors so that they reach 1000 mm. The MX-1 human breast carcinoma skeleton responds to treatment with a compound of the formula Ius5344932 with doses of 100 mg / kg and 150 mg / kg that cause tumor growth delays of 17 and 21 days, respectively. An mTOR inhibitor administered to animals only in two doses of 5 mg / kg and 20 mg / kg in the same program as a compound of the formula Ius5344932 can cause tumor growth delays by several days. The combinations of a compound of the formula Ius5344932 may be administered together with an mTOR inhibitor as simultaneous combination regimens, or an mTOR inhibitor may be administered prior to the administration of a compound of the formula I11S534 932. or a compound of the formula I11S5344932 may be administered prior to the administration of a mTOR inhibitor. The administration of a compound of the formula IUS534 932 in combination with a mTOR inhibitor can reduce the tumor growth delay. Body weight can be used as a general measure of toxicity for each of the treatment regimens. The pattern of weight loss may reflect treatment regimens with weight loss during the treatment times of 7 to 11 and 14 to 18 with some weight recovery during the two-day intervention. The weight loss due to a compound of the formula IUS5344932 may be dose dependent although generally lower. Animals treated with a compound of the formula I11S5344932 and a mTOR inhibitor can gain weight during the course of the experiment.

The administration schedule of a compound of the formula IUS5344932 and a mTOR inhibitor can be varied. Clinical Trials We investigated an open-label, multiple-phase, Phase I study investigating the combination of Compound A with the standard permetrexed treatment regimen in patients with advanced NSCLC (not surgically or metastatically removable) previously treated with a line of chemotherapy. A maximum of 120 patients were enrolled. Objectives of the study Confirm feasible dose levels / regimens of RAD001 combined with the standard permetrexed regimen in patients with a chemotherapy regimen based on the safety evaluation and ability to deliver the required dose intensity of permetrexed. Confirm the PK of RAD001 in NSCLC patients treated with the combination of RAD001 and permetrexed and estimate the PK interaction between RAD001 and permetrexed. Confirm the clinical efficacy of combined administration of different levels / regimens of dose RAD001 with a standard permetrexed treatment based on the evaluation of general tumor response according to RECIST. The study was designed as a Bayesian sequential dose scale scheme based on: a time-of-event model of the emergence of DLTs which estimates the likelihood that patients will experience a DLT within their first treatment cycle ("DLT End of Cycle-1 range"). The study was designed as a Bayesian sequential dose escalation scheme based on: a time-of-event model of DLT emergence that estimates the likelihood that patients will experience a DLT within their first treatment cycle ("DLT range of End of Cycle ") and a model that estimates the probability that the Permetrexed Relative Dose Intensity (RDI) is optimal versus sub-optimal. The successive dose levels are initially investigated in 2 separate treatment arms, each corresponding to a different dosing schedule for Compound A: Arm 1: continuous daily dosing of Compound A in combination with the treatment cycle standard of 21 days of permetrexed. Arm 2: continuous weekly dosing of Compound A (Days 1, 8, 15) in combination with the standard 21-day treatment cycle of permetrexed. At the end of the evaluation of the continuous daily regime of Compound A in arm 1, an additional Compound A regimen may be initiated as follows: Daily interrupted dosage of Compound A without Administration of Compound A between Days 15 and 21 of each therapy cycle. Patients are randomized and assigned centrally to any arm and are enrolled in the normal dose level / regimen. Dose escalation can occur in parallel, but independently, in each arm. RDI is evaluated when the first 15 patients in each arm have been followed for at least 2 cycles and this point of time will be considered an interim analysis view. If the RDI assessment contradicts the dose escalation decision based on safety signals, then a second interim search will be planned. The RDI is evaluated as well as the end of the test. The study investigates two different dosing schedules of Compound A (daily and weekly) in combination with the standard 21-day permetrexed cyclic administration. Within each dosing program of Compound A, two different regimens are investigated, continuous dosing interrupted, and up to three individual dose levels RAD001 per regimen are explored. The doses of Compound A (C-A) within the two arms are as indicated below: ARM 1 DOSAGE3 C-A DAILY ARM 2 DOSAGE 3 C-A WEEKLY 1ER. REGIME - CONTINUOUS DAILY (QD) 1ER. REGIME - WEEKLY CONTINUOUS (QW) Dosage C-A Days 1-21 of each cycle "Dosage C-A Days 1, 8 and 15 of each cycle6 QD5C C-A 5 mg / day QW30C C-A 30 mg / week QD10 C-A 10 mg / day QW50 C-A 50 mg / week QD2.5 RAD0012.5mg / day QW20 CA2020mg / week The dosage of Compound A started on Day 2 of Cycle 1 in both arms, just before the infusion of permetrexed. The decision to escalate the dose of Compound A will depend on the DLT range of the end of the estimated cycle 1 and the RDI of the chemotherapy part of Compound A. Patients will continue to receive Compound A until the progress of the disease or unacceptable toxicity.

Compound A Permetrexed Dose All patients receive their respective doses of Compound A along with the standard 21-day permetrexed cycle, applying standard pre-medications, and dose-adjustment discontinuation (see appendix). Permetrexed is administered on Day 1 in a dose of 500 mg / m2 as an intravenous infusion of 10 minutes. Patients can receive up to 6 cycles of permetrexed. Endpoints: dose-limiting toxicities occur at any time, relative dose intensity of chemotherapy. The study aims to provide patients with six cycles of permetrexed chemotherapy. A cycle is defined by an interval between two consecutive administrations of chemotherapy regimens (with a default of 21 days) and Day 1 of each cycle is defined as the day of the initiation of chemotherapy. During each cycle, patients have regular safety laboratory tests on a weekly basis (Days 8 and 15). On Day 1 they undergo a total safety evaluation before additional chemotherapy is started. Only in the treatment of the Cycle with RAD001, is delayed until Day 2 to allow a serial blood sampling for the evaluation of PK profiles of baseline of permetrexed on Day 1. PK blood sampling is continued on Day 8 of Cycle 1 (the PK profile of baseline RAD001), and on Day 1 of Cycle 2 (combination PK profiles for both study drugs are administered together) . Computed tomography (CT) scans are performed routinely for tumor measurements every six weeks (after every 2 cycles of permetrexed) while the patient is receiving chemotherapy. Upon termination or cessation of chemotherapy, all patients may continue to receive RAD001 on a continuous daily or weekly basis (regardless of the RAD001 regimen while on chemotherapy) until the progression of the disease or unacceptable toxicity occurs. In these cases, CT scans are performed every 6 weeks. Efficacy was evaluated using the following endpoints: General response range (ORR) according to RECIST (optionally modified RESIST), early progress range (EPR) according to RECIST (optionally modified RESIST). The evaluation of the tumor is carried out through a CT scan throughout the study, the drug-drug interaction is evaluated from the comparison of study levels when administered alone or in combination. In clinical trials COMPOUND A in combination with permetrexed showed adequate efficacy with respect to the tumor growth. The combination of COMPOUND A with permetrexed shows synergistic effects in several aspects.

Claims (14)

1. CLAIMS 1. A combination comprising an mTOR inhibitor and an antifolate compound.
2. 2. A pharmaceutical composition comprising an mTOR inhibitor and an antifolate compound in combination in addition to a pharmaceutically acceptable excipient.
3. 3. A pharmaceutical package comprising an mTOR inhibitor and an antifolate compound in addition to instructions for combined administration.
4. 4. A pharmaceutical package comprising a mTOR inhibitor plus instructions for combined administration.
5. 5. A pharmaceutical package comprising an antifolate compound in addition to instructions for administration in combination with the mTOR inhibitor.
6. 6. A method for the treatment of disorders that are transmitted by mTOR and / or thymidylate synthetase, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an mTOR inhibitor in combination with an antifolate compound, either in sequences or simultaneously.
7. 7. The use of a combination, pharmaceutical combination, pharmaceutical composition or pharmaceutical pack as described in any one of claims 1 to 5, for the manufacture of a medicament for use in a method as described in claim 6.
8. 8. A method for the preparation of a medicament for use in a method as described in claim 6, characterized in that it comprises any of: a) combining, eg, mixing, an mTOR inhibitor and an antifolate compound with a pharmaceutically acceptable excipient, or b) combining, for example, mixing a mTOR inhibitor with a pharmaceutically acceptable excipient, to obtain a pharmaceutical composition COMP1, and combining, for example, mixing, an antifolate compound, with a pharmaceutically acceptable excipient to obtain a pharmaceutical composition COMP2, and either (i) combining the pharmaceutical composition COMP1 and the pharmaceutical composition COMP2 in a single package, or (ii) packaging the pharmaceutical composition COMP1 separately and packaging the pharmaceutical composition COMP2 separately, although adding to each package instructions for the combined administration of the pharmaceutical composition COMP1 and the pharmaceutical composition COMP2.
9. 9. A combination as described in the present invention, a method or use provided by the present invention further comprising a combination of an mTOR inhibitor with an antifolate compound, at least one other drug substance.
10. 10. A combination, pharmaceutical combination, pharmaceutical composition, pack, pharmaceutical, method or use according to any of claims 1 to 9, characterized in that an mTOR inhibitor is rapamycin, 40-O- (2-hydroxyethyl) -rapamicin, 32-deoxorapamicin, 16-pent-2-ynyloxy-32-deoxorapamicin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-rapamycin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-40-0- (2-h id roxieti I) - rapamycin, 40- [3-hydroxy-2- (hydroxy-methyl) -2-methylpropanoateto-rapamycin (also known as CCI779), 40-epi - (tetrazolyl) -rapamicin (also known as ABT578), a so-called rapalog, for example, AP23573, a compound described under the name TAFA-93, or a compound described under the name of biolimus.
11. 11. A combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical pack, method or use as described in claim 10, characterized in that the mTOR inhibitor is 40-O- (2-hydroxyethyl) -rapamicin.
12. 12. A combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical pack, method or use as described in any one of claims 1 to 11, characterized in that an antifolate compound is a compound of the formula R is -OH or -NH2; R3 is 1,4-phenylene or 1,3-phenylene substituted or unsubstituted with chloro, fluoro, methyl, methoxy, or trifluoromethyl, thienodiyl or furanediyl substituted or unsubstituted with chloro, fluoro, methyl, methoxy, or trifluoromethyl, cyclohexanediyl, or alkenediyl; R 4 is hydrogen, methyl, or hydroxymethyl; and R5 is hydrogen, alkyl of 1 to 6 carbon atoms, or amino; in free form or in the form of a pharmaceutically acceptable salt; optionally in the form of a solvate.
13. 13. A combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical pack, method or use as described in claim 12 characterized in that the antifolate compound is permetrexed of the formula
14. 14. A combination, pharmaceutical combination, pharmaceutical composition, pharmaceutical package, a method or use as described in claim 13, characterized in that permetrexed is in the form of a disodium salt or in the form of a heptahydrate.