MXPA06011278A

MXPA06011278A - Combinations of signal transduction inhibitors

Info

Publication number: MXPA06011278A
Application number: MXPA/A/2006/011278A
Authority: MX
Inventors: Stephen Louis Eck; David William Fry; Judith Ann Salsbery Leopold
Original assignee: Pfizer Inc
Priority date: 2004-03-30
Filing date: 2006-09-29
Publication date: 2007-04-20

Abstract

The present invention relates to methods for treating cancer comprising utilizing a combination of signal transduction inhibitors. More specifically, the present invention relates to combinations of so called cell cycle inhibitors with mitogen stimulated kinase signal transduction inhibitors, more specifically combinations of CDK inhibitors with mitogen stimulated kinase signal transduction inhibitors, more preferably MEK inhibitors. Other embodiments of the invention relate to additional combinations of the aforesaid combinations with standard anti-cancer agents such as cytotoxic agents, palliatives and antiangiogenics.Most specifically this invention relates to combinations of 6-acetyl-8 -cyclopentyl-5 -methyl-2-(5-piperazin -1-yl-pyridin-2 -ylamino)-8H- pyrido[2, 3-d]pyrimidin-7 -one including salt forms, which is a selective cyclin-dependent kinase 4 (CDK4) inhibitor, in combination with one or more MEK inhibitors, most preferably N-[(R)-2, 3-dihydroxy -propoxy]-3, 4-difluoro-2-(2-fluoro -4-iodo-phenylamino) -benzamide. The aforementioned combinations are useful for treating inflammation and cell proliferative diseases such as cancer and restenosis.

Description

COMBINATIONS OF SIGNAL TRANSDUCTION INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to methods for treating cancer, comprising the use of a combination of signal transduction inhibitors. More specifically, the present invention relates to combinations of so-called cell cycle inhibitors with inhibitors of signal transduction pathways through mitogen-stimulated kinases, more specifically combinations of CDK inhibitors with inhibitors of signal transduction via kinases. stimulated by mitogens, more preferably MEK inhibitors. Other embodiments of the invention relate to additional combinations of the above combinations with usual anticancer agents such as cytotoxic, palliative and anti-angiogenic agents. Very specifically, this invention relates to combinations of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 - / - pyrido [2,3-d] pyrimidin-7-one, which is a selective inhibitor of cyclin-dependent kinase 4 (CDK4), in combination with MEK inhibitors, most preferably N - [(R) -2.3- dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. The present invention includes all the salts, metabolites, prodrugs, isomers and polymorphs of each of the aforementioned active agents. The above-mentioned combinations are useful for treating inflammation and cell proliferation diseases such as cancer and restenosis. Cell cycle inhibitors are key gatekeepers of signal transduction kinases that control the progression of the cell cycle. Cell cycle inhibitors include inhibitors of cyclin dependent kinases (CDK), Aurora kinase inhibitors, PLK inhibitors and CHK1 inhibitors. Preferred cell cycle inhibitors in the present invention are inhibitors of cyclin-dependent kinases. Cyclin dependent kinases, and related serine / threonine protein kinases, are important cellular enzymes that perform essential functions in the regulation of cell division and cell proliferation. The catalytic units of the cyclin-dependent kinases are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (D.G. Johnson and C.L. Walker, Annu., Rev. Pharmacol., Toxicol. (1999) 39: 295-312). Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and probably other heterodimers, including CDK3 and CDK7, are important regulators of cell progression. cellular cycle. Additional functions of the cyclin / CDK heterodimers include transcription regulation, DNA repair, differentiation and apoptosis (DO Morgan, Annu, Rev. Cell, Dev. Biol. (1997) 13261-13291. has shown that inhibitors of cyclin-dependent pinases are useful in the treatment of cancer.It has been shown that the increased activity or temporarily abnormal activation of cyclin-dependent kinases results in the development of human tumors (CJ Sherr, Science (1996) 274: 1672-1677), M. Malumbres, Nature Rev. Cancer, 2001, 1, 222-231 and CJ Sherr, Cancer Cell, 2002, 2, 103-112 In fact, the development of human tumors it is commonly associated with alterations in the same CDK proteins, or in their regulators (C. Cordón-Cardo, Am. J. Pathol. (1995) 147: 545-560; JE Karp and S. Broder, Nat. Med. (1995). ) 1: 309-320; M. Hall et al., Adv. Cancer Res. (1996) 68: 67-108). CDKs of natural origin, such as p16 and p27, cause in vitro growth inhibition in lung cancer cell lines (A. Kamb, Curr. Top. Microbiol. Immunol. (1998) 227: 139-148). It has also been shown that some CDK inhibitors are useful as chemoprotective agents due to their ability to inhibit cell cycle progression in normal non-transformed cells (Chen et al., J. Nati. Cancer Institute (2000) 92: 1999-2008) . A number of CDK inhibitors are currently being evaluated by pharmaceutical companies, but none have been approved for commercial use to date (P.M. Fischer, Curr Opin, Drug Discovery (2001) 4: 623-634; D.W. Fry and M.D. Garrett, Curr. Opin. Oncologic, Endocrine & Metabolic Invest. (2000) 2: 40-59; K.R. Webster and D. Kimball, Emerging Drugs (2000) 5: 45-59; T.M. Sielecki et al., J. Med. Chem. (2000) 43: 1-18; P. Fisher, Curr. Opin. Drug Disc. & Development 2001, 4, 623-634; K. Webster, Emerging Drugs 2000, 5, 45-59; and D. Fry, Curr. Opin. Oncologic, Endocrine & Metabolic Invest.Drugs. 2000, 2, 40-59. Selective inhibitors of CDK4 / 6 have been described in the commonly assigned international patent application PCT / 1B03 / 00059, filed on January 10, 2003 (application O59), the entire contents of which are incorporated by reference in this point, to all purposes The '059 application describes a particularly potent and selective inhibitor of CDK4 / 6, 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one: 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylam) -8-pyrid [2,3-c] ] pyrimidin-7-one is preferably administered as the isethionate salt. A preferred isethionate salt comprises a mono-isethionate salt of form A. Another preferred salt of sephionate is the salt with polymorphic form B. Another preferred isethionate salt is the polymorphic salt with form D. In usual enzymatic assays, the compound of formula 1 has Cl50 concentrations for the inhibition of CDK4 and CDK2 (at 25 ° C) of 0.011 μM and of > 5 μM, respectively. A discussion of standardized tests of CDK4 and CDK2 for determinations of CI5o can be found in D.W. Fry et al., J. Biol. Chem. (2001) 16617-16623.

The present invention is directed primarily to combinations of cell cycle inhibitors with other signal transduction inhibitors (ST1). The abbreviations STI, as used herein, refer to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell. These inhibitors include small molecules, antibodies, and antisense molecules. Examples of said signal transduction inhibitors include tyrosine kinase inhibitors and serine / threonine kinase inhibitors. Such inhibitors include MEK inhibitors, bcr-abl tyrosine kinase inhibitors, PDGFR inhibitors, c-Kit inhibitors, erbB inhibitors, VEGF-R inhibitors, Hsp 90 inhibitors, FLT-3 inhibitors, K inhibitors. -Rases, PI3 kinase inhibitor, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, and multi-targeted kinase inhibitors (see "Signal Transduction", Gomperts,, Kramer and Tatham, Academic Press, Elsevier Science, 2002. It is believed that in tumors, the Ras-Raf-MEK-ERK pathway is the single most important route for the signal transduction of mitogenic signals from the plasma membrane to the nucleus.Activated Raf activates by phosphorylation signaling kinases MEK1 and MEK2 (MEK 1/2) These are kinases with double specificity, which activate clhanas of the ERK family, ERK1 and ERK2, by phosphorylation of both threonine and tyrosine, and activation of ERK causes phosphorylation and activation of the kinase ri S9, and of transcription factors such as c-Fos, c-Jun and c-Myc, which results in the switching and activation of various genes involved in proliferation. Different growth factors, such as the erbB family, PDGF, FGF and VEGF, transmit signals through the Ras-Raf-MEK-ERK route. In addition, mutations in ras proto-oncogenes can result in constitutive activation of this pathway. Ras genes are mutated in approximately 30% of all human cancers, and the frequencies of ras mutations are particularly high in colon and pancreatic cancers (50% and 90%, respectively). Due to being located after diverse mitogenic factors, MEK 1 and 2 play a crucial role in the transmission of proliferative signals from the plasma membrane to the nucleus. This makes these proteins an important target in cancer therapy, since their inhibition would interrupt several signaling pathways. Thus, an MEK inhibitor can be active against a wide range of cancers comprising, but not limited to, breast, colon, lung, prostate, ovarian and pancreatic cancers. 2- (2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide, also referred to as CI-1040, is a potent and highly selective inhibitor of the two isoforms of MEK, MEK1 and MEK 2. The inhibition of MEK activity by CI-1040 causes a significant decrease in the levels of phosphorylated ERK1 and ERK2. This decrease produces a blockage of G1, and hinders the growth of tumor cells, both in culture and in mice. CI-1040 has been shown to possess anticancer activity against a broad spectrum of tumor types, including those of the colon and those of pancreatic origin (Sebolt-Leopold J. et al., "Blockade of the MAP kinase pathway suppresses growth of colon tumors in alive ", Nature Med. 1999; 5: 810-16; and Sebolt-Leopold JS, "Summary of the preclinical pharmacology of CI-1040". RR 700-00156. June 27, 2000). CI-1040 is described in PCT publication number WO 99/01426, the content of which is incorporated herein by reference to its teachings on how to prepare CI-1040, how to formulate it in pharmaceutical forms, and how to use it for chronic treatment by Oral route of solid tumors, such as cancers of the breast, colon, prostate, skin and pancreas. CI-1040 is also described in U.S. Pat. No. 6,251, 943 for use in the treatment or prevention of septic shock. N ~ [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is a potent and highly selective inhibitor of MEK1 / 2, which significantly inhibits the phosphorylation of ERK1 and ERK2. N - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide is described in PCT publication number WO 02 / 06213, whose content is incorporated in this point as reference to its teachings on how to prepare it, how to formulate it in pharmaceutical forms, and how to use it for the chronic oral treatment of solid tumors, such as cancers of the breast, colon, prostate , skin and pancreas. It is more potent and more metabolically stable than its predecessor, CI-1040.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a method for treating abnormal cell growth, preferably cancer, in a patient, preferably a human being, in need of such treatment, said method comprising administering to the patient a combination of an amount of a cell cycle inhibitor and an amount of one or more signal transduction inhibitors (preferably one to three, more preferably one or two, most preferably one), wherein the amounts of the cell cycle inhibitor and the inhibitor or signal transduction inhibitors, taken in together, they are therapeutically effective to treat said abnormal cell growth, preferably cancer. Cell cycle inhibitors include inhibitors of CDK, Aurora kinase inhibitors, PLK inhibitors, or CHK1 inhibitors. Preferably, said cell cycle inhibitors are selective inhibitors of CDK, more preferably a selective inhibitor of CDK-4/6. Most preferably, said selective inhibitor of CDK-4/6 is 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamine) -8H-pyrido [2,3-d] pyrimid-7-one. The term "inhibitors of cyclin-dependent kinases", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the activity of any of the known cyclin-dependent kinases, most preferably CDK4 / 6. Preferred CDK4 / 6 inhibitors are described in the international publication WO 03/062236, published on July 31, 2003, and in U.S. patent applications. Nos. 60 / 486,351, filed July 11, 2003, and 60 / 440,805, filed January 17, 2003. Examples of such inhibitors include: 8-cyclopentyl-2- (pyridin-2 -lamino ) -8H-pyrido [2,3-d] pyrimidn-7-one, 6-bromo-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-hydrochloride; lamino) -8H-pyrido [2,3-d] pyrimidin-7-one, 8-cyclopentyl-6-etl-2- (5-piperazin-1-l-pyridin-2-ylamino) hydrochloride) -8H-pyrido [2,3-d] pyridin-7-one, 8-cyclopenti-7-oxo-2- (5-piperazin-1-lp) ethyl ester hydrochloride Ridn-2-ylammon) -7,8-dihydro-pyrido [2,3-d] pyrimidine-6-carboxylic acid, 6-amino-8-cyclopentyl-2- (5-hydrochloride -piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one, 6-bromo-8-cyclopentyl-2-hydrochloride [5 - ((R) -1-methyl-pyrrolidin-2-yl) -pyridin-2-ylamino] -8H-pyrido [2,3-d] pyrimidin-7-one, 6-bromo-8-cyclohex l-2- (pyridin-2-yl-amino) -8H-pyrido [2,3-d] pyrimidin-7-one, 6-bromo-8-cyclopentyl-2-methyl- 8H-pyrido [2,3-d] pyrimidin-7-one, 6-b romo-8-cyclopentyl-5-methyl-2- (5-piperizin-1-yl-pyridin-2-ylamino) -8 - / - pyrid [2,3-ori-pyrimidine] -7-one, 8-cyclopentyl-6-fluoro-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimide hydrochloride Din-7-one, 8-cyclopentyl-6-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyridyl hydrochloride [2, 3-d] pyrimidin-7-one, 8-cyclopentyl-6-isobutoxy-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyridyl hydrochloride [ 2,3-d] pyrimidin-7-one, 6-benzyl-8-cyclopentyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido hydrochloride [2, 3-d] pyrimidin-7-one, 8-cyclopentyl-6-hydroxyethyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido hydrochloride [2, 3- d] pyrimidin-7-one, 2- [5- (4-tert-butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino] -8-cyclopentyl-5-ethyl acid ethyl ester methyl-7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidine-6-carboxylic acid, 6-acetyl-8-cyclopentyl-2- (5-piperazine) -1-yl-pyridin-2-ylammon) -8H-pyrido [2,3-d] pyrimidin-7-one, 6-acetyl-8-cyclopentyl-5-methyl-2- (5 -piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-af] pyrimidin-7-one, 6-bromo-8-cyclopentyl-5-methyl-2 - (pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidn-7-one, 6-bromo-8-cyclopentyl-2- (pyridin-2- ilamno) -8H-pyrido [2,3-d] p'irimidn-7-one, 4-cyclopentylamino-2- (5-piperazin-1-pyridin -2-ylamino) -pyridiam-d-carbonyl, N4-cyclopentyl-5-nitro-N2- (5-piperazin-1-yl-pyridin-2-yl) -p Rmidmid-2, 4-diamine, 4-cyclopentylamino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-5-carbaldehyde, ethyl ester of 4-cyclopentyl-amine -2- (5-piperazin-1-ylpyridin-2-ylamino) -pyrimidine-5-carboxylic acid methyl ester of 4-cyclopentylamino-2- (5-piperazin-1-) L-pyridin-2-ylamino) -pyrimidin-5-carboxylic acid, [4-cyclopentylamino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidine] -5-yl] -methanol, 1- [4-chloropentylamino-2- (5-piperazin-1-y! -pyridin-2-ylamino) -pyrimidin-5-yl] -ethanone, ethyl ester of acid 3- [4-cyclopentylamino-2- (5-piperazin-1-yl-pyridin-2-ylamine) -pyrimidin-5-yl] -but- 2-enoic, 4-amino-2- (5-piperazin-1-l-pyridin-2-ylamino) -pyrimidine-5-carbonitrile, 5-nitro-N2- (5-pyr) perazin-1-yl-pyridin-2-yl) -pyridin-2,4-diamine, 4-amino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidine -5-carbaldehyde, 4-amino-2- (5-piperazin-1-yl-pyridin-2-ylammon) -pyridyl-5-carboxylic acid ethyl ester, Methyl ester of 4-amino-2 acid - (5-piperazin-1-yl-pyridin-2-ylammon) -pyrimidine-5-carboxylic acid, [4-amino-2- (5-piperazin-1-yl) -pyridin-2-ylamino) -pyrimidin-5-yl] -methanol, 1 - [4-amino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin- 5-yl] - ethanone, 3- [4-amino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-5-yl] ethyl ester - but-2-enoic, 4-cyclopentylamino-2- (5-pyrrolidin-1-yl-pyridin-2-ylammon) -pyrimidin-5-carbonitrile, N2- [ 5- (3-amino-pyrrolidin-1-yl) -pyridin-2-yl] -N-cyclopentyl-5-nitro-pyrimidine-2,4-diamine, 4-cyclopentyl-2-amino - (5-morpholin-4-yl-pyridin-2-ylamino) -pyrimidine-5-carbaldehyde, 4-cyclopentylamino-2- (3,4,5,6-tetrahydro-2H- [1] ethyl ester , 3 '] bipyridinyl-6'-ylamino) -pyridin-5-carboxylic acid methyl ester of 4-cyclopentylamino-6-methyl-2- (5-piperazin-1) -yl-pyridin-2-ylamino) -pyrimidine-5-carboxylic acid,. { 2- [5- (bis-methoxymethyl-amino) -pyridin-2-ylamino] -4-cyclopentylamino-pyrimidin-5-yl} -methanol, 1- [4-benzylamino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-5-yl] -ethanone, 4- [4-cyclopentylamino-2- (5-piperaz N-1-yl-pyridin-2-ylamino) -pyrimidin-5-yl] -pent-3-en-2-one, 4-amino-2- (pyridin-2-ylamino ) -pyridin-5-carbonyl ether, 5-nitr-N2-pyridn-2-yl-pyrimidin-2,4-diamine, 4- amino-2- (pyridin-2-ylamino) -pyridin-5-carbald), ethyl ester of 4-amino-2- (pyridin-2-ylamino) -pyrimid N-5-carboxylic acid, 5-bromo-N2- (5-piperazin-1-yl-pyridin-2-yl) -pyrimide-2,4-diamine, [4-amino- 2- (5-morpholin-4-yl-pyridin-2-ylamino) -pyrimidin-5-yl] -methanol, 1- [4-amino-2- (5-morpholin-4-yl-pyridin- 2-amino) -pyrimmi-d-n-5-yl] -ethanone, [6- (5-acetyl-4-amino-pyrimidin-2-ylamino) -pyridine- 3-yloxy] -acetic acid, 4-cyclopentylamino-2- (4-hydroxymethyl-5-pyrrolidin-1-yl-pyridin-2-ylamino) -pyrimidin-5-carbonitrile, N2- [5- (3-Amino-pyrrolidin-1-yl) -6-chloro-pyridin-2-yl] -N4-cyclopentyl-5-n-pyrimidin-2,4-di amine, 2- (5-bromo-pyridin-2-ylammon) -4- cyclopentylammon-pyrimidine-5-carbaldehyde, ethyl ester of 4-cyclopentylamino-2- (1H-pyrrolo [3,2-b] pyridin-5-ylammon) -pyrimidin -5-carboxylic acid, methyl ester of 4-cyclopentylamino-2- (4,6-dichloro-5-piperazin-1-ylpyridin-2-ylamino) -6-methyl-pyrimidn-5- carboxylic, 2- (2-. { 5- [bis- (2-methoxy-ethyl) -amino] -pyridin-2-ylamino} 4-cyclopentylamino-pyrimidin-5-yl) -2-methyl-propan-1-ol, 1- [4-phenylamino-2- (5-piperazin-1-yl-pyridin-2- Lamino) -pyrimidin-5-yl] -ethanone, 4- [4- (3-hydroxy-cyclopentylamino) -2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-5-yl ] -pent-3-en-2-one, 4- [5-cyano-2- (pyridin-2-ylamino) -pyridin-4-ylamino] -cyclohexanecarboxylic acid, 2- (4-) acid amino-5-nitro-pyrimidin-2-ylamino) -isonicotinic acid, 4-amino-6-methyl-2- (pyridin-2-ylamino) -pyridn-5- carbaldehyde, 5-iodo-N2-pyridin-2-yl-pyrimidine-2,4-diamine, N- [5-bromo-2- (5-piperazin-1-pyridine -2-ylamino) -pyrimidin-4-yl] -acrylamide, N2- (5-piperazin-1-yl-pyridin-2-yl) -5-prop-1-ynyl-pyrimidine-2,4 -diamine, 5- [2- (4-fluoro-phenol) -ethyl] -N2- (5-p-piperazin-1-yl-pyrid-2-yl) -pyrimid N-2,4-diamine, [6- (4-amino-5-propenyl-pyrimidin-2-ylamino) -pyridin-3-yloxy] -acetic acid, 5- Bromo-N4-cyclopentyl-N2- (5-pyrrolidin-1-yl-pyridin-2-yl) -pyrimidine-2,4-diamine, N2- [5- (3-Amino-pyrrolidin-1-yl) -6-chloro-pyridin-2-yl] -5-bromo-N4-cyclopentyl-pyrimidine-2,4-diamine, -bromo-N4-cyclopentyl-N2- (5-piperazin-1-lyridin-2-yl) -pyrimidine-2,4-diamine, 5-bromo-N4-cyclopentyl-N2- (1H -pyrrolo [3,2-b] pyridin-5-yl) -pyrimidin-2,4-diamamine, 5-bromo-N 4 -cyclopentyl-N 2 - (4,6- dichloro-5-p-piperazin-1-yl-pyridin-2-yl) -6-methylene-pyridin-2,4-diamamine, N2-. { 5- [bis- (2-methoxy-ethyl) -amino] -pyrid-2-yl} -5-bromo-N4-cyclopentyl-pyrimid-2,4-diamine, 5-bromo-N4-phenyl-N2- (5-piperazin-1-pyridyl) -2-yl) -pyridine-2,4-diamine, 3- [5-bromo-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-4-ylamino] -cyclopentanol, N4-cyclopentyl-5-iodo-N2- (5-pyrrolidin-1-yl-pyridin-2-yl) -pyridi-2,4-diamine, N2- [ 5- (3-Amino-pyrrolidin-1-yl) -6-chloro-pyridin-2-yl] -N-4-cydopentyl-5-iodo-pyrimidin-2,4-d-amines, N-4-cyclopentyl -5-Iodo-N2- (5-p-piperazin-1-yl-pyridin-2-yl) -pyridin-2,4-d-amines, N4-cyclopentyl-5-iodo-N2- ( 1 H -pyrrolo [3,2-b] pyridin-5-yl) -pyrimidin-2,4-diamine, 4- [6- (5-bromo-4-cyclopenthyl) tert-butyl ester no-pyrimidin-2-ylamino) -pyridin-3-yl] -piperazin-1-carboxylic acid, tert-butyl ester of 4- [6- (4-cyclopentyllamide) 5-formyl-pyrimidin-2-ylamino) -pyridin-3-yl] -piperazine-1-carboxylic acid, tert-butyl ester of 4- [6- (5-acetyl-4-chloropylamino-) pyrimidin-2-ylamino) -pyridin-3-yl] -piperazine-1-carboxylic acid ethyl ester 2- [ 5- (4-tert-butoxycarbonyl-piperazin-1-yl) -pyridin-2-ylamino] -4-cyclopentylamino-pyrimidine-5-carboxylic acid, N-cyclopentyl-N '- (5-piperazin-1-yl- pyridin-2-yl) -pyridin-4,6-diamine, N-isopropyl-N '- (5-piperazin-1-yl-pyridin-2-yl) -pyrimidin-4 , 6-diamnan, 4- [6- (6-cyclopentylamino-pyridin-4-ylamino) -pyridin-3-yl] -piperazin-1-f-butyl ester carboxylic acid, N- [5- (3-amino-pyrrolidn-1-yl) -pyridin-2-yl] -N'-cyclopentyl-pyrimidin-4,6-diamine, ester 4-acid butyl alcohol. { 6- [4-Cyclopentylamino-5- (1-methyl-3-oxo-but-1-enyl) -pyrimidin-2-ylamino] -pyridin-3-yl} -piperazin-1-carboxylic acid, N-cyclopentyl-N '- (5-piperazin-1-yl-pyridin-2-yl) - [1, 3,5] triazin-2,4-d-amines, 1 - [ 4-cyclopentylamino-2- (5-piperazin-1-yl-pyridin-2-ylamino) -pyrimidin-5-yl] -ethanone, 5-bromo-N4-cyclopentyl-N2- (5-piperazine) 1-yl-pyridn-2-yl) -pyridin-2,4-d-amines, 4-cyclopentylamino-6- (5-piperazin-1-yl-pyr) din-2-ylamino) -nicotinonitrile, N4-cyclopentyl-5-nitro-N2- (5-pyridin-1-yl-pyridin-2-yl) -pyridin-2,4-diamine, 4-cyclopentyl-amino-6 - (5-piperazin-1-yl-pyridn-2-ylamino) -pyridin-3-carbaldehyde, ethyl ester of 4-cyclopentylamino-6- (5-piperazin-1-yl- pyridin-2-ylamino) -nicotinic acid, 4-cyclopentylamino-6- (5-piperazin-1-yl-pyridin-2-ylamino) -nicotinic acid methyl ester, [4-cyclopentylamino-6- ( 5-Piperazin-1-l-pyridin-2-ylamino) -pyridin-3-yl] -methanol, 1 - [4-cyclopentylamino-6- (5-piperazin-1-yl-pyridin-2) -lamino) -pyridin-3-yl] -ethanone, 3- [4-cyclopentylamino-6- (5-piperazin-1-yl-pyridin-2-ylamine) -pyridin-3-ethyl acid ethyl ester - il] -but-2-enoic, (5-cyclopentyl-5,6-dihydro-pyrido [2,3-e] [1, 2,4] triazin-3-yl) - (5-p¡perazin -1-l-pyridin-2-yl) -amine, (8-cyclopentyl-7-methoxy-quinazolin-2-yl) - (5-piperazin-1-yl-pyridin-2-yl) -amine, ( 8-cyclopentyl-7-methoxy-pyridyl [3,2-d] pyrimidin-2-yl) - (5-piperazin-1-yl-pyridin-2-yl) -amine, 6-acetyl -8-Cyclopentyl-2- (5-p-piperazin-1-yl-pyridin-2-ylamino) -8H-pteridin-7-one, 3-acetyl-1-cyclopentyl-7- (5-piperazin-1 - il-pyridin-2-ylamino) -1 H -pyrido [3,4-b] pyrazin-2-one, 1-cyclopentyl-3-ethyl-4-methyl-7- (5-piperazin-1-yl-pyridine -2-ylamino) -3,4-dihydro-1 H -pyrimido [4,5-d] pyrimidin-2-one, 1-cyclopentyl-3-ethyl-4-methyl-7- (5-piperazin- 1-pyridin-2-ylamine) -3,4-dihydro-1 H -pyrido [4,3-d] pyrimidin-2-one, 3-acetyl-1-cyclopentyl-4-methyl-7 (5-piperazin-1-yl-pyridin-2-ylamino) -1 H- [1,6] naphthyridin-2-one, (9-isopropyl-6-methyl-9H-purin-2-yl) - (5 -piperazin-1-yl-pyridin-2-yl) -amine, 2- [9-isopropyl-6- (5-piperazin-1-yl-pyridin-2-ylamino) -9H-purin-2-ylammon ] -ethanol, N2- (4-amino-cyclohexyl) -9-ci Clopentyl-N6- (5-piperazin-1-yl-pyridin-2-yl) -9H-purin-2,6-d-amines, 2- [9-isopropyl-6- (5-piperazin-1-yl- pyridin-2-ylamino) -9H-purin-2-ylamino] -3-methyl-butan-1-ol(1-isopropyl-4-methyl-1 H -pyrazolo- [3,4-d] pyrimidin-6-yl) - (5-piperazin-1-yl-pyridin-2-yl) -amine, 2- [ 1-isopropyl-4- (5-piperazin-1-yl-pyridin-2-ylamino) -1 H -pyrazolo [3,4-d] pyrimidin-6-ylamino] -ethanol, N6- (4-amino- cyclohexyl) -1-cyclopentyl-N4- (5-piperazin-1-yl-pyridin-2-yl) -1H-pyrazoloP ^ -djpyrimidine ^^ -diamine, 2- [1-isopropyl-4- (5-piperazine -1-yl-pyridin-2-ylamino) -1 H-pyrazolo [3,4-d] pyrimidin-6-ylammon] -3-methy1-butan-1-ol, -cyclopentyl-7- (1-hydroxy-ethyl) -8-methyl-3- (5-piperazin-1-yl-pyridin-2-ylamino) -5H-pyridono [3,2-c] pyridazine-6 -one, 5-cyclopentyl-8-methyl-3- (5-piperazin-1-yl-pyridin-2-ylamino) -5H-pyrido [3,2-c] pyridazin-6-one, 7 -benzyl-5-cyclopentyl-3- (5-piperazin-1-yl-pyridin-2-ylamino) -5H-pyridono [3,2-c] pyridazin-6-one, [ 5- (1, 1-dioxo-1 (6-thiomorpholin-4-yl) -pyridin-2-yl] - (4-isopropyl-3-methoxy-2-methyl- [1,7] naphthyridin-6-) il) -amine, (2-ethyl-4-isopropyl-3-methoxy- [1, 73-naphthyridin-6-yl) -pyridin-2-yl-amine, (2,4-diisopropyl-3-methoxy- [1, 7] naphthyridin-6-yl) - (5-isopropenyl-pir) D and n-2-yl) -amine, [4- (2-ylamino-pyridin-4-yl) -pyrimidin-2-yl] - (5-piperazin-1-yl-pyridin-2) -yl) -amine, [4- (5-ethyl-2-methylamino-pyridin-4-yl) -pyrimidin-2-yl] - (5-morpholin-4-yl-pyridin-2-) il) -amine, [5-methoxy-4- (2-methylamino-pyridin-4-yl) -pyrimidin-2-yl] - (5-morpholin-4-yl-pyridin-2-) il) -amine, and 5-fluoro-N 4 -isopropyl-N 2 - (5-piperazin-1-yl-pyridin-2-yl) -pyrimidine-2,4-diamine. Other interesting CDK inhibitors include AG-24322, R-roscovitine, CYC202 (a selective inhibitor of CDK2), flavopiridol (NSC 649890, HMR 1275) (a non-selective CDK inhibitor), NU6102 (a selective CDK1 / 2 inhibitor). ), alsterpaulone (a CDK1 / B inhibitor), indirubin-3'-monooxime (an inhibitor of CDK1 / B / 5), BMS 387032 (a CDK inhibitor (1 / B) (2 / E) (4 / D) )) and 7-hydroxystaurosporine (UCN-01, NSC 638850). In EP1250353, WO 02/96888, WO 03/076437, WO 03/76436, WO 03/76434, WO 01/64368; in the provisional US application No. 60/491, 474 and in the US provisional application. No. 60/491, 474 other specific CDK inhibitors are described. One skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have discovered that it is surprisingly effective to complement the deletion of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a CDK protein. Supra-regulation includes: overexpression of CDK4 / 6 or cyclin D, hypo-expression of p16 or mutation of CDK4 / 6 (see D. Fry, Curr Opin. Oncologic, Endocrine &Metabolic Invest. Drugs. , 2, 40-59 The expression "signal transduction inhibitors" (STIs), as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that promote growth, The proliferation and survival of a cell A person skilled in the art will appreciate that the STIs so defined include inhibitors of growth factors and inhibitors of the signal transduction pathway through mitogen-stimulated kinases.These inhibitors also include small molecules. Antibodies, Antibodies, and Antisense Molecules The inhibitors of signal transduction, as described herein, comprise inhibitors of tyrosine kinases, serine / threonine inhibitors. kinases, dual specificity kinase inhibitors, lipid kinase inhibitors, histone deacetylase inhibitors, Bc12 inhibitors, p53 inhibitors, MDMZ inhibitors, Ras inhibitors and Hsp 90 inhibitors. One embodiment of the invention is directed to combinations of an amount of a cell cycle inhibitor with an amount of a double specificity kinase inhibitor, such as an MEK inhibitor, wherein the amounts of the cell cycle inhibitor and the double specificity kinase inhibitor, taken together , are therapeutically effective to treat such abnormal cell growth, preferably cancer. The expression "dual specificity kinase inhibitors" refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell by inhibiting the activity of multiple tyrosine-cinases and serine / threonine -kinases, such as MEK1 or MEK2. Examples of such highly preferred MEK inhibitors include 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide and N - [(R) -2, 3-D-Hydroxy-propoxy] -3,4-d? -fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. 2- (2-Chloro-4-iodo-phenylamino) -? - cyclopropylmethoxy-3,4-difluoro-benzamide and N - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro- 2- (2-fluoro-4-iodo-phenylamino) -benzamide are selective inhibitors of MEK 1 and MEK 2. Selective inhibitors of MEK 1 or MEK 2 are those compounds that inhibit the MEK 1 or MEK 2 enzymes, without substantially inhibiting them other enzymes such as MKK3, ERK, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src.

A most preferred embodiment of the invention is directed to a combination of the CDK inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamine) -8H -pyrid [2,3-d] pyrimidin-7-one and a MEK inhibitor, wherein the amounts of the cell cycle inhibitor and the MEK inhibitor, taken together, are therapeutically effective to treat said growth abnormal cell, preferably cancer. Examples of MEK inhibitors according to the present invention include, but are not limited to, the MEK inhibitors described in the following PCT publications: WO 99/01426, WO 99/01421, WO 00/42002, WO 00 / 42022, WO 00/41994, WO 00/42029, WO 00/41505, WO 00/42003, WO 01/68619, and WO 02/06213. Another embodiment of MEK inhibitor of the invention includes the compound 1,4-diamino-2,3-dicyano-1,4-bis [2-aminophenylthio] butadiene (U-0126). One skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have found that it is surprisingly effective to complement the deletion of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates an MEK protein. In another preferred embodiment of the present invention, certain combinations of small inhibitory molecules of CDK and inhibitors of MEK can be combined additionally with STI antibodies such as Herceptin (trastuzumab), Erbitux (C225), and small molecules STIs such as Iressa (gefitinib) and Tarceva (erlotinib). Another embodiment of the invention is directed to those combinations of an amount of a cell cycle inhibitor (preferably a selective CDK inhibitor, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5-methyl -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimi-din-7-one), with an amount of one or more inhibitors of serine / threonine kinase (preferably an inhibitor), wherein the amounts of the cell cycle inhibitor and inhibitor or serine / threonine kinase inhibitors, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. More preferably, said serine / threonine kinase inhibitors include inhibitors of Raf kinase, Akt inhibitors and mTOR inhibitors. Another embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective CDK inhibitor, more preferably a selective inhibitor of CDK4 / 6 (most preferably 6-acetyl-8-cyclopentyl). -5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimid-7-one-one) and a ratio of a Raf kinase inhibitor, wherein the amounts of the cell cycle inhibitor and the kinase inhibitor Raf, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. Raf ", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the Raf protein. A preferred example of such inhibitors is BAY 43-9006. Raf kinase include those described in WO 03/68223, published on August 21, 2003, WO 03/82272, published October 9, 2003, WO 03/22840, published March 20, 2003, WO 03/22838, published March 20, 2003, WO 03 / 22837, published March 20, 2003, WO 03/22836, published March 20, 2003, and WO 03/22833, published March 20, 2003. A person skilled in the art will appreciate that historically anticancer agents have been employed against specific tumors, for example brain, breast, lung, for example non-microcystic lung, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have discovered that it is surprisingly effective to complement the deletion of a way with the suppression of other kinase ways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a Raf protein. In a particular embodiment, the expression level of Raf is +2 or +3 on a scale of four values comprising from 0 (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to a combination of a cell cycle inhibitor (preferably a selective CDK inhibitor, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5-methyl). l-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidin-7-one) and an Akt inhibitor, wherein the amounts of the cell cycle inhibitor and Akt inhibitor or inhibitors, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "Akt inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling ways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the protein Akt. Examples of such Akt inhibitors include the compounds described in European nt application EP 1379251, and in international publications WO 03/86403, WO 03/86394 and WO03 / 86279, published all on October 23, 2003. A specialist in the art it will be appreciated that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia. , and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the authors of the present invention have found that it is surprisingly effective to complement the suppression of a way with the suppression of other kinase ways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates an Akt protein. In a particular embodiment, the expression level of Akt is +2 or +3 on a scale of four values comprising 0 (normal) to +1, a +2, and a +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to a combination of a cell cycle inhibitor (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5- methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8-pyrido [2,3-d] pyrimidin-7-one) and a mTOR inhibitor, wherein the amounts of the cell cycle inhibitor and mTOR inhibitor or inhibitors, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "mTOR inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the mTOR protein. Examples of such inhibitors include rapamycins, preferably rapamycin, CCI 779, Rad001 and Arry 142886. One skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are aimed at the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the authors of the present invention have found that it is surprisingly effective to complement the suppression of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a m-TOR protein. In a particular embodiment, the expression level of m-TOR is +2 or +3 on a scale of four values comprising from 0 (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to those combinations of a type of a cell cycle inhibitor (preferably a selective CDK inhibitor, more preferably a selective CDK4 / 6 inhibitor, most preferably 6-acetyl-8-dclopentyl-5-methyl -2- (5-pperazin-1-yl-pyridin-2-ylamino) -8 - / - pyrid [2,3-d] pyrimid-7-one), with an amount of one or more tyrosine kinase inhibitors (preferably an inhibitor), wherein the amounts of the cell cycle inhibitor and the tyrosine kinase inhibitor or inhibitors, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer . More preferably, said tyrosine kinase inhibitors include inhibitors of bcr-abl tyrosine kinase, PDGFR inhibitors, c-Kit inhibitors, erbB inhibitors, VEGF-R inhibitors, FGFR inhibitors, TGFβR inhibitors, inhibitors of Src, and IGF1-R inhibitors. One embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective CDK inhibitor, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-c). clopentyl-5-methyl-2- (5-plperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one) , and an amount of a bcr-abl tyrosine kinase inhibitor, wherein the amounts of the cell cycle inhibitor and the tyrosine kinase inhibitor bcr-abl, taken together, are therapeutically effective to treat such abnormal cell growth, preferably Cancer. The term "firsin-kinase inhibitors bcr-abl", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the bcr-abl protein. Examples of such inhibitors include Gleevec. One skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain clnases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the authors of the present invention have found that it is surprisingly effective to complement the suppression of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a bcr-abl protein. In a particular embodiment, the level of expression of bcr-abl is +2 or +3 on a scale of four values comprising from 0 (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl). -methyl-2- (5-p-piperazin-1-yl-pyridin-2-ylammon) -8H-pyrid [2,3-d] pyrimidin-7-one) and an amount of a PDGFR inhibitor, wherein the amounts of the cell cycle inhibitor and PDGFR inhibitor, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "inhibitors of PDGFR", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the PDGFR protein. Examples of such inhibitors include CP-868, 596, ST-1571, PTK-787 and PKC-412. PDGFR inhibitors include the compounds described and claimed in US patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed on February 9, 2000); 09/539930 (filed on March 31, 2000); 09/202796 (filed on May 22, 1997); 09/384339 (filed on August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds described and claimed in the following provisional US patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed on November 30, 1999), 60/200834 (filed on May 1, 2000), 60/406524 (filed on August 28, 2002) and 60/417074 (filed on October 8, 2002) ). PDGFR inhibitors are also described and claimed in the international patent publication WO2001 / 40217, published on June 7, 2001. A person skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic lung, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have discovered that it is surprisingly effective to complement the deletion of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a PDGFR receptor. In a particular embodiment, the expression level of PDGFR is +2 or +3 on a scale of four values comprising from 0 (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to a combination of an amount of a CDK inhibitor (preferably 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) - 8 / - / - pyrido [2,3-d] pyrimidin-7-one) and an amount of a c-Kit inhibitor, wherein the amounts of the CDK inhibitor and the c-Kit inhibitor, taken together, they are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "c-Kit inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the c-Kit protein. Examples of such inhibitors include the compounds described in international patent publications WO 03/028711, published April 10, 2003, and WO 03/002114, published January 9, 2003. A person skilled in the art will appreciate that Historically, anticancer agents have been used against specific tumors, for example brain, breast, lung, for example non-microcystic, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have discovered that it is surprisingly effective to complement the deletion of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates a c-Kit protein. In a particular embodiment, the level of expression of c-Kit is +2 or +3 on a scale of four values comprising from O (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Another embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5 -metl-2- (5-p-piperazin-1-yl-pyridin-2-ylam) -8H-pyrido [2,3-d] pyrim-din-7 -one) and an amount of an erbB inhibitor, which includes an erbB-1 inhibitor, an erbB-2 inhibitor, or an erbB1 / erbB2 inhibitor, wherein the amounts of the cell cycle inhibitor and the erbB inhibitor , taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "erbB inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of erbB proteins. Examples of such erbB, erbB2 or erbB1 / erbB2 inhibitors include Herceptin (trastuzumab), Erbitux, Iressa (gefitinib), Tarceva (erlotinib), EKB-569, PKI-166, GW-572016, E-2-methoxy- N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -alyl) -acetamide and CI -1033, preferably E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl); l.}. -alyl) -acetamide and CI-1033, more preferably E-2-methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-lox) !) -phenylamino] -quinazolin-6-yl.} - allyl) -acetamide. The erbB2 receptor inhibitors include compounds such as E-2-methoxy-N- (3. {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6 -il.}. -alyl) -acetamide, GW-282974 (Glaxo Wellcome foot), and monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc., of The Woodlands, Texas, USA) and 2B-1 (Chiron). These erbB2 inhibitors include those described in WO 03/50108 (published June 19, 2003), WO 01/98277 (published December 27, 2001), WO 00/44728 (published August 3, 2000). ), WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published on January 22, 199.8), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), U.S. Pat. 5,587,458 (issued December 24, 1996), U.S. Pat. 5,877,305 (issued March 2, 1999), and U.S. Pat. 6,284,764 (granted on September 4, 2001), each of which is hereby incorporated in its entirety as a reference. Also disclosed are erbB2 receptor inhibitors useful in the present invention in U.S. Provisional Application No. 60 / 117,341, filed January 27, 1999, and in U.S. Provisional Application No. 60 / 117,346, filed on April 27, 1999. January 1999, both of which are incorporated herein by reference in their entirety. Other erbB2 receptor inhibitors include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome). Pan-erBB inhibitors (active against erbB1 and erB2) have been described in U.S. Pat. 5,464,861, issued November 17, 1995; 5,654,307, issued August 5, 1997; 6,344,459, granted on February 5, 2002; 6,127,374, granted October 3, 2000; 6,153,617, granted on November 28, 2000; 6,344,455, granted on February 5, 2002; 6,664,390, issued Dec. 16, 2003, and the international publication WO 02/00630, published January 3, 2002. A person skilled in the art will appreciate that historically anticancer agents have been used against specific tumors, for example, brain, breast, lung, for example non-microcystic lung, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. The combinations of the present invention are directed to the new understanding of the molecular basis of cancer, which in some cases includes the overexpression of certain kinases. Although it is possible that in a cancerous state a single kinase is supra-regulated or hyperexpressed, the present inventors have discovered that it is surprisingly effective to complement the deletion of a pathway with the suppression of other kinase pathways. Thus, in another aspect of the present invention, the method of the invention comprises the treatment of a cancer that supra-regulates an erbB2 protein. In a particular embodiment, the expression level of erbB2 is +2 or +3 on a scale of four values comprising from 0 (normal) to +1, to +2, and to +3. A value of +3 is associated with very aggressive tumors. Preferred erbB2 compounds specific to the combinations of the present invention include those which include one or more of the following compounds: (+) - [3-Met.l-4- (p.r¡d¡n- 3-xloxy) -phenyl] - (6-pyrimidin-3-yltrinyl-quinazolin-4-yl) -amine; 2-Methoxy-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2 inyl) -acetamide; (+) - [3-Methyl-4- (6-methy1-pyridin-3-yloxy) -phenyl] - (6-piperidin-3-eneletyl-quinazolin-4-yl) -amine; [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenyl] - (6-pyrimidin-4-ylenyl-quinazolin-4-yl) - Amy 2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} .prop-2-lnl) -acetamide; 2-Fluoro-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-lnil) -acetamida; E-2-Methoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridn-3-yloxy) -phenylamino] -quinazolin-6} -yl.}. -ali) -acetamide; [3-Met.l-4- (pyridin-3-yloxy) -phenyl] - (6-p.perd.din-4-ylethynyl-quinazolin-4-yl) -amine; 2-Methoxy-N- (1- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-ylethynyl} - cyclopropyl) -acetamide; EN- (3- { 4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -alyl) -2- methoxy acetamide; N- (3- {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -cynazolin-6-yl}. 2-inyl) -acetamide; N- (3-. {4- [3-Methyl-4- (6-methyl-pyridn-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop -2-inyl) -acetamide; EN- (3-. {4- [3-Chloro-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -ali) -acetamide; E-2-Ethoxy-N- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -alyl) - acetamide; 1-Ethyl-3- (3- {4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. 2-inyl) -urea; (3- { 4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. -prop-2-ynyl) - piperazin-1-carboxylic acid amide; (3- {4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. 2-inyl) -amide of (+) - 2-hydroxymethyl-pyrrolidin-1-carboxylic acid; 2-Dimethylamino-N- (3- {4- [3-methyl-4- (pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl} -prop-2-ynyl ) -acetamide; EN- (3-. {4- [3-Met.l-4- (6-methyl-pyridin-3-ylox) -phenylamino] -quinazolin-6-yl.} - allyl) - methanesulfonamide; (3- { 4- [3-Methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -cynazoln-6-yl}. -prop-2- Nyl) -isoxazole-5-carboxylic acid amide; 1- (1, 1-Dimethyl-3- { 4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl}. prop-2-ynyl) -3-etl-urea; and the pharmaceutically acceptable salts, prodrugs and solvates of the preceding compounds. In another preferred embodiment of the present invention, certain combinations of small molecules of CDK inhibitors and erbB inhibitors can be further combined with STIs antibodies such as Herceptin (trastuzumab), Erbitux, and small molecules STIs such as Iressa (gefitinib) and Tarceva (erlotinib). Another embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5-met. L-2- (5-piperazin-1-yl-tridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one) and an amount of an inhibitor of VEGF-R, wherein the amounts of the cell cycle inhibitor and the VEGF-R inhibitor, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "inhibitors of VEGF-R", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the VEGF-R protein. Examples of such inhibitors include CP-547,632 (3- (4-bromo-2,6-difluoro-benzyloxy) -5- [3- (4-pyrrolidin-1-yl-butyl) -amide hydrochloride. l) -ureido] -sothiazole-4-carboxylic acid), PTK 787, ZD 6474, AG-13736, AG-28262 and PKC 412. Preferred VEGF inhibitors include, for example, SU-5416 and SU-6668 (formerly Sugen Inc., of South San Francisco, California, USA, currently Pfizer Inc.) and CP-547,632. VEGF inhibitors are described, for example, in WO 99/24440 (published May 20, 1999), PCT International Application PCT / IB99 / 00797 (filed May 3, 1999), WO 95 / 21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), U.S. Pat. 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), U.S. Pat. 5,883,113 (issued March 16, 1999), U.S. Pat. 5,886,020 (issued March 23, 1999), U.S. Pat. 5,792,783 (issued August 11, 1998), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published on May 26, 1999). June 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98 / 02437 (published January 22, 1998), all of which are hereby incorporated in their entirety by reference, document WO 01/02369 (published January 11, 2001); the provisional US application number 60/491, 771 (filed July 31, 2003); the provisional US application number 60 / 460,695 (filed on April 3, 2003); and WO 03/106462A1 (published December 24, 2003). In the international patent publications WO 99/62890, published on December 9, 1999; WO 01/95353, published December 13, 2001; and WO 02/44158, published June 6, 2002, other examples of VEGF inhibitors are described. Other examples of some specific VEGF inhibitors are IM862 (Cytran Inc., of Kirkland, Washington, USA); avastin, an anti-VEGF monoclonal antibody from Genentech, Inc., of South San Francisco, California; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California). Another embodiment of the invention is directed to a combination of an amount of a cell cycle inhibitor (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl). -metl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrid [2,3-d] pyrimidin-7-one) with an amount of inhibitor of growth factor signaling, wherein the amounts of the cell cycle inhibitor and the inhibitor of growth factor, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. Examples of inhibitors of growth factor signaling include small molecules and monoclonal antibodies. These antibodies can bind to both the receptor and the growth factor. Avastin is an example of a monoclonal antibody that binds to the growth factor, and prevents it from binding to the receptor. Another embodiment of the invention is directed to combinations of cell cycle inhibitors (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5-methyl-2- ( 5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one), with an inhibitor selected from the group consisting of inhibitors of lipid kinases, histone deacetylase inhibitors , Bc12 inhibitors, p53 inhibitors, MDMZ inhibitors, Ras inhibitors and Hsp 90 inhibitors, wherein the amounts of the cell cycle inhibitor and inhibitor selected from inhibitors of lipid kinases, histone deacetylase inhibitors, Bc12 inhibitors , p53 inhibitors, MDMZ inhibitors, Ras inhibitors and Hsp 90 inhibitors, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. More preferably, the other inhibitors of kinases mentioned include Hsp 90 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, HDAC inhibitors, Bcl2 inhibitors, TGFbeta-R inhibitors, Chk1 inhibitors, Wee1 inhibitors, inhibitors of PLK, Src inhibitors, PDK inhibitors, PKC inhibitors, and p70S6K inhibitors. Another embodiment of the invention is directed to a combination of an amount of a CDK inhibitor (preferably 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazine-1-1-pyridine). 2-lamino) -8 - / - pyrido [2,3-d] pyrimidin-7-one) and an amount of a Hsp 90 inhibitor, wherein the amounts of the inhibitor of CDK and the inhibitor of Hsp 90, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "Hsp 90 inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the Hsp 90 protein. Examples of these inhibitors include the compounds described in international publications WO 03/089006; WO 03/041643; and WO 02/036171.

Another embodiment of the invention is directed to a combination of an amount of a CDK inhibitor (preferably 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyr). D-n-2-ylamino) -8H-pyrid [2> 3-d] pyrimidin-7-one) and an amount of a K-Ras inhibitor, wherein the amounts of the CDK inhibitor and the K-Ras Inhibitor, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "K-Ras inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the Function of K-Ras protein. Examples of these inhibitors include those described in U.S. Pat. 6,436,700; and in U.S. Patent Publication. 20030153521. Another embodiment of the invention is directed to a combination of an amount of a CDK inhibitor (preferably 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2). -allamine) -8 / - -pyrid [2,3-d] pyrimidin-7-one) and an amount of a PI3 kinase inhibitor, wherein the amounts of the cell cycle inhibitor and the inhibitor of PI3 kinase, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. The term "PI3 kinase inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the PI3 protein. Examples of these inhibitors include those described in WO 01/81346; WO 01/53266; and WO 01/83456, U.S. number 10 / 730,680 (filed on December 8, 2003); U.S. patent application number 10 / 743,852 (filed on December 22, 2003); the US provisional patent application number 60 / 475,970 (filed on June 5, 2003); the US provisional patent application number 60 / 475,992 (filed on June 5, 2003); the US provisional patent application number 60 / 476,073 (filed on June 5, 2003); the US provisional patent application number 60 / 476,251 (filed on June 5, 2003); the US provisional patent application number 60 / 475,971 (filed on June 5, 2003); and the US provisional patent application. number 60 / 476,057 (filed on June 5, 2003). Another embodiment of the invention is directed to those combinations of a number of cell cycle inhibitors (preferably a selective inhibitor of CDK, more preferably a selective inhibitor of CDK4 / 6, most preferably 6-acetyl-8-cyclopentyl-5- methyl-2- (5-piperazin-1-yl-pyridn-2-ylamino) -8 / - / - pyrid [2,3-d] pyrimidin-7- ona), with an amount of a multidirected kinase inhibitor, wherein the amounts of the cell cycle inhibitor and the multidirected kinase inhibitor, taken together, are therapeutically effective to treat such abnormal cell growth, preferably cancer. More preferably, said inhibitors of multidirected kinases include inhibitors with multiple activities against any of the aforementioned kinase pathways. Another embodiment of these inhibitors of multidirected kinases are the agents that have activity against PDGFR, VEGFR and FGFR (for example SU11248). Another modality of these inhibitors of multidirected kinases are the agents that have activity against PDGFR, c-Kit and brc-abl (for example Gleevec). Another embodiment of the invention is directed to a combination of a certainty of a CDK inhibitor, (preferably 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-) il-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyridin-7-one) and an amount of an Aurora inhibitor, wherein the amounts of the inhibitor of the cell cycle and the inhibitor of Aurora, taken together, are therapeutically effective to treat said cancer. The term "Aurora kinase inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the function of the Aurora protein. Examples of these inhibitors include those described in international patent publications WO 03/106417; WO 03/105855; WO 03/99211; WO 03/79973; and WO 03/31606. Each of the patents, patent applications, patent publications, and prior provisional patent applications is hereby incorporated in its entirety as a reference, including all preferences, modalities, species and subgenres described therein. The present invention is also directed to certain new combinations of MEK inhibitors with other STI's, specifically Aurora kinase inhibitors, PLK inhibitors, CHK1 inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, tyrosine kinase inhibitors. bcr-abl, PDGFR inhibitors, c-Kit inhibitors, erbB inhibitors, VEGF-R inhibitors, FGFR inhibitors, and IGF1-R inhibitors. The present invention of combination (ie, a combination of a cell cycle inhibitor with other STI's and MEK inhibitors with STI's) further comprises administering one or more additional anti-cancer therapeutic agents, selected from the group consisting of alkylating agents, anti-metabolites, antibiotics, hormonal agents, antitumor agents obtained from plants, topoisomerase I / II inhibitors (for example camptothecin derivatives), antibodies, immunological agents (for example interferons), and / or biological response modifiers. Alkylating agents include, but are not limited to: AMD-473, altretamine, AP-5280, apaziquone, brostalicin, bendamustine, busulfan, carboquone, carmustine, cyclophosphamide, estramustine, fotemaphine, glufosfamide, phosphamide, KW-2170, mafosfamide , melphalan, mitobronitol, mitolactol, nimustine, N-oxides of nitrogenous mustards, temozolomide, thiotepa and ranimustine. Alkylating compounds coordinated with platinum include, but are not limited to: cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, or satraplatin; Antimetabolites include, but are not limited to: 5-azacytidine, capecitabine, carmofur, cladribine, clofarabine, cytarabine, decitabine, doxifluridine, eflomitin, enocythabin, ethinylcytidine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, leucovorin, cytosine arabinoside, hydroxyurea, fludarabine, TS-1, gemcitabine, methotrexate, melphalan, 6-mercaptopurine, mercaptopurine, nelarabine, nolatrexed, ocphosphate, premetrexed disodium, pentostatin, pelltrexol, raltitrexed, riboside, tegafur, triapine, trimetrexate, UFT , vidarabine, vincristine, vinorelbine; or for example, one of the preferred antimetabolites described in European Patent Application No. 239362 such as N- (5- [N- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)) -N-methylamino] -2-tenoyl) ~ L-glutamic; Antibiotics include, but are not limited to: aclarubicin, actinomycin D, amrubicin, anamicin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, darrubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pyrarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin; The invention also contemplates the use of the combination of the present invention with hormonal therapy agents, for example exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate ( Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (^ -cyano-S - ^ - fiuorophenylsulfoni ^ -hydroxy ^ -methyl) -S '- (trifluoromethyl) propionanilide), and their combinations.

Antitumor substances obtained from plants include, for example, those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel. The cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCl (Camptosar), edecaline, epirubicin (Ellence), etoposide , exatecán, gimatecán, lurtotecán, mitoxantrona, pirarubicin, pixantrona, rubitecán, sobuzoxane, SN-38, taflupósido, and topotecán, and their combinations. Immunological compounds include interferons and many other immunity enhancing agents. Interferons include interferon alpha, interferon alfa-2a, interferon alfa-2b, interferon beta, interferon gamma-1a, or interferon gamma-n1. Other agents include filgrastim, lentinan, sizophilane, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileucine, gemtuzumab, ozogamycin, britumomab, miquimod, lenograstim, lentinan, melanoma vaccine ( Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleucine, thimalasin, tositumomab, Virullzin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, Provenge. Biological response modifiers are agents that modify the defense mechanisms of living organisms or biological responses, such as the survival, growth or differentiation of tissue cells, to direct them to have antitumor activity. Such agents include Krestin, lentinan, sizofirano, picibanil, or ubenimex. Other anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib, bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotene, TLK-286 or Tretinoin Non-kinase antiangiogenesis agents are other important active agents that can be combined with the non-kinase combination of the present invention. Antiangiogenesis agents, which include inhibitors of matrix metalloproteinases such as MMP-2 (matrix metalloproteinase 2), inhibitors of MMP-9 (matrix metalloproteinase 9), and COX-II (cyclooxygenase II) inhibitors, they can be used together with the combinations of SDIs mentioned above, in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREXR (celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), and Arcoxia (etoricoxib). In WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European patent application number 97304971.1 (filed July 8, 1997), patent application European number 99308617.2 (filed October 29, 1999), WO 98/07697 (published February 26, 1998), WO 98/03516 (published January 29, 1998), WO 98/34918 (published on 13). August 1998), WO 98/34915 (published August 13, 1998), WO 98/33768 (published August 6, 1998), WO 98/30566 (published July 16, 1998), publication of European Patent 606,046 (published July 13, 1994), European Patent Publication 931,788 (published July 28, 1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published on October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT international application number PCT / IB98 / 01113 ( filed July 21, 1998), European patent application number 99302232.1 (filed March 25, 1999), British patent application number 9912961.1 (filed June 3, 1999), US provisional application. number 60 / 148,464 (filed on August 12, 1999), U.S. Pat. 5,863,949 (issued January 26, 1999), U.S. Pat. 5,861, 510 (issued January 19, 1999) and European Patent Publication 780,386 (published June 25, 1997), all incorporated herein by reference in their entirety, are examples of matrix metalloproteinase inhibitors. tools. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 with respect to the other matrix metalloproteinases (ie, MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13). Some specific examples of useful MMP inhibitors combined with the compounds of the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds listed in the following list: 3 - [[4- (4- fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclopentyl) -amino] -propionic acid; 3-Exo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; (2R, 3R) 1- [4- (2-Chloro-4-fluoro-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidin-2-carboxylic acid hydroxyamide; 4- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3 - [[4- (4-Fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-cyclobutyl) -amino] -proponic acid; 4- [4- (4-Chloro-phenoxy) -benzenesulfonylamino] -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 3- [4- (4-Chloro-phenoxy) -benzenesulfonyl] -tetrahydro-pyran-3-carboxylic acid hydroxyamide; hydroxylamide of (2R, 3R) -1- [4- (4-fluoro-2-methyl-benzyloxy) -benzenesulfonyl] -3-hydroxy-3-methyl-piperidin-2-carboxylic acid; 3 - [[4- (4-fluoro-phenoxy) -benzenesulfonyl] - (1-hydroxycarbamoyl-1-methyl-ethyl) -amino] -proponic acid; 3 - [[4- (4-fIuoro-phenoxy) -benzenesulfonyl] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino] -propionic acid; 3-exo-3- [4- (4-chloro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; 3-endo-3- [4- (4-fluoro-phenoxy) -benzenesulfonylamino] -8-oxa-bicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide; and 3- [4- (4-Fluoro-phenoxy) -benzenesulfonylamino] -tetrahydro-furan-3-carboxylic acid hydroxyamide; and salts, solvates and prodrugs of said pharmaceutically acceptable compounds. Other anti-angiogenesis compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, reblmastat, removab, Revlimid, squalamine, ukraine and Vitaxin. A combination of the present invention may also be used with other agents useful in the treatment of abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as anti-cancer antibodies. CTLA4 (antigen 4 associated with cytotoxic lymphocytes), and other agents capable of blocking CTLA4; and antiproliferative agents such as other protein famesyl transferase inhibitors, for example, the protein famesyl transferase inhibitors described in the references cited in the above "Background" section. Antibodies specific for CTLA4 that can be used in the present invention include those described in U.S. Pat. 6,682,736, granted on January 27, 2004, which is incorporated herein in its entirety as a reference. In addition, the invention provides a combination of the present invention together with one or more supportive care products, for example a product selected from the group consisting of Aloxy, amifostine, ancestim, anethole, aprepitant, BAM-002, CyPat, darbepoetin, dazlizumab, denileucine, dexrazoxane, Emend, etanercept, erythropoietin, Filgrastim (Neupogen), Fragmin, lenograstim, GM-CSF, molgramostim, oprelvekine, ondansetron (Zofran), Procrit, sargramostim, vesnarinone, or combinations thereof. Said co-treatment can be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. In one embodiment, the additional therapeutic agent is selected from the group consisting of a camptothecin, irinotecan HCl, edecaline, epirubicin, docetaxel, paclitaxel, e'xemestane, Lupron, anastrozole, tamoxifen, Trelstar, Fllgrastim, ondansetron, Fragmin, Procrit, Aloxi , Emend, and their combinations. In a particular embodiment, the additional therapeutic agent is selected from the group consisting of paclitaxel, exemestane, tamoxifen, and combinations thereof. In a particular embodiment, the invention provides a combination for treating breast cancer, comprising a combination of a CDK inhibitor and an MEK inhibitor with a monoclonal antibody (preferably Herceptin), and one or more agents selected from paclitaxel , exemestane, tamoxifen, and their combinations.

In a particular embodiment, the invention provides a combination comprising a combination of a CDK inhibitor and an MEK inhibitor (optionally with a monoclonal antibody (preferably Herceptin)), and one or more hormonal agents selected from paclitaxel, exemestane, tamoxifen, and combinations thereof, and one or more cytotoxic agents selected from 5-FU, oxaliplatin and leucovorin (or combinations thereof as prescribed for FOLFOX). . The method of the invention also relates to a method of treating abnormal cell growth in a mammal, including the human being, which comprises administering to said mammal an amount of a combination of two or more STIs, as defined above. , or one of its pharmaceutically acceptable salts, solvates or prodrugs, which is effective in treating abnormal cell growth. In one embodiment of this method, abnormal cell growth is cancer, which includes, without limitation, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, cancer of the uterus, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, carcinoma of the vagina , carcinoma of the vulva, Hodgki's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra , cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma , neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumors of the spinal axis, brain stem glioma, pituitary adenoma, or a combination of one or more of the cancers mentioned. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prosthetic hypertrophy or restenosis. In another aspect, the method of the invention is directed to the method of administering the combination. More particularly, the active agents of the combination therapy are administered sequentially, in any order, or simultaneously. When the active agents are administered simultaneously, one skilled in the art will understand that the second agent can be administered some time after the first agent. The particular period of delay depends on the particular pharmacokinetic parameters and formulation of the active ingredient. Another aspect of the invention is the minimization of the combination dose. It frequently happens that individual dosing regimens for the active agents can lead to unwanted side effects, which can potentially lead to interruption of the medication. A particular preferred embodiment of the invention is to reduce the dosage to the minimum dose necessary to treat the cancer. Thus, a preferred embodiment is the administration of a combination in which the amounts of both active agents are less than the effective dose of either agent alone. Another embodiment of the invention consists in the administration of a combination having activity superior to the activity of any of the agents alone. Preferred combinations are those in which the combination is synergistic compared to either agent alone. Preferably, the combination is superadditive. This invention also relates to a device for treating abnormal cell growth, comprising a combination as defined above, and written instructions for the administration of all components. In a particular aspectIn the written instructions, the specific CDK inhibitor and its method of administration are described. In another particular aspect of the invention equipment, the written instructions specify the MEK inhibitor and describe its method of administration. In one embodiment of this equipment, said abnormal cell growth is cancer, which includes, without limitation, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or infra-ocular melanoma, cancer of the uterus, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, carcinoma of the vagina , carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra , cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumors of the spinal axis, brain stem glioma, pituitary adenoma, or a combination of one or more of the above-mentioned cancers. In another embodiment of this equipment, said abnormal cell growth is a benign proliferative disease, which includes psoriasis, benign prosthetic hypertrophy or restenosis, but is not limited thereto. The term "pharmaceutically acceptable salt or salts", as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the present invention. The compounds of the present invention which are basic in nature are capable of forming a wide variety of salts with different inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of these basic compounds are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide salts, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonlcotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1 '-methylene-bis- (2-hydroxy-3-naphthoate)]. The compounds of the present invention which include a basic radical, such as an amino group, can form pharmaceutically acceptable salts with different amino acids, in addition to the aforementioned acids. The active compounds of the present combination which are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and particularly calcium, magnesium, sodium and potassium salts of the compounds of the present invention. Some functional groups contained within the active compounds of the present combination can be replaced by bioisostomeric groups, that is to say, groups having special or electronic requirements similar to the original group, but which have improved physicochemical or other properties. Suitable examples are well known to those skilled in the art, including, but not limited to, the moieties described in the article by Patini et al., Chem. Rev, 1996, 96, 3147-3176, and in the references there cited. The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment employing or containing them. The compounds of the combinations of the present invention can also exist as tautomers. This invention relates to the use of all these tautomers and their mixtures. The subject of the invention also includes isotopically-labeled compounds, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which are identical to those mentioned for the active compounds described herein, except for the fact that one or more atoms they have been replaced by an atom that has an atomic mass or atomic number different from the atomic mass or the atomic number that is usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180 , 170, 35S, 1dF, and 36CI, respectively. The compounds of the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or of said prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those to which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and tissue substrate distribution assays. Particularly preferred are tritiated isotopes, ie 3H, and carbon 14, ie 14C, for their ease of preparation and their detectability. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, can provide certain therapeutic advantages resulting from increased metabolic stability, for example the increase of half-life in vivo or the reduction of dose requirements, and therefore may be preferred in some circumstances. By methods well known to those skilled in the art, it is generally possible to prepare isotopically-labeled active compounds of the combinations of this invention, and prodrugs thereof. This invention also comprises pharmaceutical compositions containing prodrugs of the active compounds of the present combination invention, and methods for treating cancer by administering prodrugs of the active compounds of the present combination invention. Active compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues, are covalently linked through an amide or ester bond to an amino-free group , hydroxy or carboxylic acid of the active compounds. Amino acid residues include, without limitation, the 20 natural amino acids commonly designated by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosin, isodesmosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline , Homocysteine, Homoserine, Ornithine and Methionisulfone. Other types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups can be derivatized using groups which include, but are not limited to: hemisuccinates, phosphate esters, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as indicated in Advanced Drug Delivery Reviews, 1996, 19, 115. carbamate prodrugs of hydroxyl and amino groups, as well as the prodrugs of carbonate, of sulfonate esters and of sulfate esters of hydroxy groups. Also included is the derivatization of hydroxyl groups such as (acyloxy) methyl and (ad'loxy) ethyl ethers, in which the acyl group can be an alkyl ester, optionally substituted with groups including, without limitation, ether, amine and carboxylic acid functions, or wherein the acyl group is an amino acid ester as described above above. In J. Med. Chem. 1996, 39, 10 prodrugs of this type are described. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All residues of these prodrugs can incorporate groups including, without limitation, ether, amine and carboxylic acid functions. The terms "synergistic" and "synergistic" mean that the activity of the combination of two or more effectors or active agents is at least greater than the activity of either agent alone, and preferably its effect is at least additive. More preferably, the synergy is more than additive. Most preferably, the synergy is superadditive. The term "additive" is used to mean that the result of the combination of the two or more effectors or agents is greater than the sum of each of the effectors or agents together, and preferably it is at least 10 percent greater than the effect. additive of the combination. The term "over-additive" is used to indicate that the result of the combination of two or more effectors is at least 25 percent greater than the additive effect of the combination.

DETAILED DESCRIPTION OF THE INVENTION Definitions and abbreviations Unless otherwise indicated, the description uses the definitions provided below. The term "cancer" includes, but is not limited to, the following cancers: cancer of the breast, ovary, cervix, prostate, testicle, esophagus, stomach, skin, bone, colon, pancreas, of thyroid, bile ducts, oral cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, squamous cell carcinoma, macrocystic carcinoma, adenocarcinoma, adenocarcinoma, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, kidney carcinoma , myeloid disorders, lymphoid disorders, Hodgkin's disease, tricholeukemia, and leukemia. The term "pharmaceutically acceptable" refers to substances that, within the scope of reasonable medical judgment, are suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic and the like responses, according to a benefit relationship reasonable risk, and effective for its intended use. The term "ligand" is used, in particular, to describe a small molecule that binds to a receptor. An important class of ligands in the present invention is constituted by the antibodies described above that bind to receptors of the family of epidermal growth factors. Ligands can be inhibitors of receptor function, and can be antagonists of the action of activators. Certain abbreviations common in the art are freely employed, and will be understood in the context. These include: pharmacokinetics (PK), pharmacodynamics (PD), fetal bovine serum (FBS), penicillin / streptomycin (pen / strep), Roswell Park Memorial Institute (RPMI), orally (per os, PO), once a day (QD), intraperitoneally (IP), subcutaneously (SC), enzyme-linked immunosorbent assay (ELISA), the maximum concentration of an analyte in a PK analysis (Cma?), and the concentration average of an analyte in a PK analysis (Cave). The term "treat" refers to reversing, alleviating, inhibiting the progress of, or preventing, a disorder or ailment to which that term applies, or preventing one or more symptoms of said disorder or ailment. The term "treatment" refers to the act of "treating", as it has just been defined. The term "abnormal cell growth", as used herein, and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by the expression of a mutated tyrosine kinase, or by the overexpression of the tyrosine kinase of a receptor; (2) benign and malignant cells of other proliferative diseases in which an aberrant firosin-kinase activation occurs; (4) any tumors that proliferate through receptor tyrosine kinases; (5) any tumors that proliferate by the aberrant activation of serine / threonine kinases; and (6) benign and malignant cells of other proliferative diseases in which aberrant serine / threonine kinase activation occurs. The expression "taken together is therapeutically effective" refers to the total dose of the agents in combination that produces the therapeutic effect. One skilled in the art will appreciate that the present invention provides for the temporary programming of the administration of the number of individual agents simultaneously, sequentially or through a separate dosing plan. Thus, the doctor will look for a therapeutic effect, for example the reduction of the size of a tumor, based on the collective quantities of the components, independently of the order of the sequence or the lapse of time between administrations.

Table A lists the abbreviations used through the specification TABLE A Abbreviations Abbreviation Description Aq Aqueous ACN Acetonitrile BOC-butoxycarbonyl • DCM Dichloromethane DSC differential scanning calorimetry Et3N Triethylamine EtOH ethyl alcohol h, min, s hour, minute, second IPA isopropyl alcohol MeOH methanol PXRD powder X-ray diffraction RH relative humidity RT temperature environment, ie 20 ° C-25 ° C THF tetrahydrofuran mgA / mL milligrams of active substance per milliliter of solution The term "inhibitors of cyclin-dependent kinases", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the activity of any of the known kinase-dependent kinases, most preferably CDK4 / 6. CDK inhibitors can be prepared by methods well known to those skilled in the art. Preferred CDK4 / 6 inhibitors can be prepared by the methods described in the international publication WO 03/062236, published on July 31, 2003, and US patent applications. Nos. 60 / 486,351, filed July 11, 2003, and 60 / 440,805, filed January 17, 2003. In EP1250353, WO 02/96888, WO 03/076437, WO 03/76436, WO 03/76434 and WO 01/64368, in the provisional application of US Pat. No. 60/491, 474, and in the provisional US application. No. 60/491, 474, other specific methods for preparing CDKs are described. The term "signal transduction inhibitors" (STIs), as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor growth, proliferation and survival of a cell. One skilled in the art will appreciate that the STIs thus defined include the inhibitors of growth factors and the inhibitors of signal transduction pathways through mitogen-stimulated kinases. These inhibitors also include small molecules, antibodies, and antisense molecules. Examples of said signal transduction inhibitors include tyrosine kinase inhibitors, serine / threonine kinase inhibitors, dual specificity kinase inhibitors, lipid kinase inhibitors, histone deacetylase inhibitors, inhibitors of Bc12, inhibitors of p53, MDMZ inhibitors, Ras inhibitors and Hsp 90 inhibitors. Methods for preparing such agents are well known in the literature, and to those skilled in the art. Inhibitors of double-specific kinases include MEK inhibitors. The term "MEK inhibitors", as used herein, refers to inhibitors that produce a direct effect on the signaling pathways that favor the growth, proliferation and survival of a cell, by inhibiting the activity of MEK1 or MEK2. Examples of such highly preferred MEK inhibitors include 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide and N - [(R) -2,3-dihydroxy-propoxy) ] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. 2- (2-Chloro-4-iodo-phenylamino) -? - cyclopropylmethyl-3,4-difluoro-benzamide and N - [(R) -2,3-d-hydroxy-propoxy] -3,4- difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide are selective inhibitors of MEK 1 and MEK 2. Selective inhibitors of MEK 1 or MEK 2 are those compounds that inhibit the enzymes MEK 1 or MEK 2, without substantially inhibit other enzymes such as MKK3, ERK, PKC, Cdk2A, phosphorylase-clrase, EGF and PDGF receptor kinases, and C-src. In general, a selective inhibitor of MEK 1 or MEK 2 has an IC 50 for MEK 1 or for MEK 2 which is at least one-fiftieth part (1/50) of its Cl 50 for any of the other enzymes mentioned above. A selective inhibitor can have an Cl50 that is at least 1/100, 1/500, or even 1/1000, 1/5000 or less of its Cl50 for one or more of the aforementioned enzymes. It can be determined if a compound is an MEK inhibitor using an assay, known to one skilled in the art, which measures the inhibition of MEK. For example, inhibition of MEK can be determined using the assays entitled "Enzyme Assays" of U.S. Pat. No. 5,525,625, column 6, beginning at line 35. In this section, the entire specification of US Pat. No. 5,525,625. Specifically, a compound is an MEK inhibitor if said compound shows activity in the assay entitled "Cascade Assay for Inhibitors of the MAP Kinase Pathway," from column 6, line 36, to column 7, line 4, of the USA No. 5,525,625 and / or shows activity in the assay entitled "In Vitro MEK Assay" in column 7, lines 4 to 27 of the aforementioned patent. Alternatively, the inhibition of MEK can be measured in the assay described in WO 02/06213 A1, the disclosure of which is incorporated herein by reference in its entirety. Examples of methods for preparing MEK inhibitors according to the present invention include, but are not limited to, the methods described in the following PCT publications: WO 99/01426, WO 99/01421, WO 00/42002, WO 00/42022, WO 00/41994, WO 00/42029, WO 00/41505, WO 00/42003, WO 01/68619, and WO 02/06213. Another embodiment of MEK inhibitor of the invention includes the compound 1,4-diamino-2,3-dicyano-1,4-bis [2-aminophenylthio] butadiene (U-0126), which can be prepared by well-known methods for those skilled in the art. Serine / threonine kinase inhibitors include Raf kinase inhibitors, Akt inhibitors, and mTOR inhibitors. Raf kinase inhibitors can be prepared by the methods described in WO 03/68223, published on August 21, 2003, WO 03/82272, published October 9, 2003, WO 03/22840, published March 20, 2003, WO 03/22838, published March 20, 2003, WO 03/22837, published March 20, 2003, WO 03/22836, published March 20 of 2003, and WO 03/22833, published on March 20, 2003. Akt inhibitors can be prepared according to the methods described in the European patent application EP 1379251, and in international publications WO 03/86403, WO 03/86394 and WO03 / 86279, all published on October 23, 2003. Inhibitors of mTOR can be prepared according to the methods described in European patent 648,494, international patent publications WO 03/64383, WO 96/41865 , WO 99/36533, WO 01/14387; and U.S. Pat. 5,525,610, 5,310,903, 5,362,718 and ,527,907. Examples of such inhibitors include rapamycins, preferably rapamycin, CCI 779, Rad001 and Arry 142886. STI tyrosine kinase inhibitors include, but are not limited to, tyrosine kinase inhibitors bcr-abl, inhibitors of PDGFR, inhibitors of c-Kit, erbB inhibitors, VEGF-R inhibitors, FGFR inhibitors and IGF1-R inhibitors. Tyrosine kinase bcr-abl inhibitors can be prepared by methods well known to those skilled in the art. Specific methods are described in European Patent Publication 564,409, issued January 19, 2000. Examples of such inhibitors include Gleevec PDGFR inhibitors can be prepared by methods well known to those skilled in the art. Specific methods are described in US patent applications: 09/221946 (filed on December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed on February 9, 2000); 09/539930 (filed on March 31, 2000); 09/202796 (filed on May 22, 1997); 09/384339 (filed on August 26, 1999); and 09/383755 (filed on August 26, 1999). Other methods are described in the US provisional patent applications: 60/168207 (filed on November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed on January 21, 2000); 60/168217 (filed on November 30, 1999), and 60/200834 (filed on May 1, 2000). C-Kit inhibitors can be prepared by methods well known to those skilled in the art. Specific methods are described in international patent publications WO 03/028711, published on April 10, 2003 and WO 03/002114, published on January 9, 2003. The erbB inhibitors include erbB1 and / or erbB2 inhibitors. Many of these compounds are currently in clinical trials, and their methods of preparation are well known to those skilled in the art. EGFR inhibitors (Erbbl) and their methods of preparation have been described in, for example, WO 95/19970 (published July 27, 1995), WO 98/14451 (published April 9, 1998), WO 98/02434 (published January 22, 1998), and U.S. Pat. 5,747,498 (granted May 5, 1998). EGFR inhibiting agents include, but are not limited to, monoclonal antibodies C225 and 22Mab anti-EGFR (ImClone Systems Incorporated of New York, New York, USA), compounds ZD-1839 (AstraZeneca), BIBX1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, New Jersey, USA), and OLX-103 (Merck &Co. of Whitehouse Station, New Jersey, USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Massachusetts). ErbB2 inhibitors can be prepared by the methods described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published on May 15, 1999). July 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), the patent of USA 5,587,458 (issued December 24, 1996), and U.S. Pat. 5,877,305 (granted on March 2, 1999), each of which is hereby incorporated in its entirety as a reference. Inhibitors of the ErbB2 receptor and methods to prepare them in the provisional EE application are also described. UU number 60 / 117,341, filed on January 27, 1999, and in the provisional application of EE. UU number 60 / 117,346, filed on January 27, 1999, both of which are incorporated herein by reference in their entirety. Other inhibitors of the erbb2 receptor include TAK-165 (Takeda) and GW-572016 (Glaxo-Wellcome). Pan-erBB inhibitors (active against erbB1 and erB2) and methods for preparing them have been described in US Pat. 5,464,861, issued November 17, 1995; 5,654,307, issued August 5, 1997; 6,344,459, granted on February 5, 2002; 6,127,374, granted October 3, 2000; 6,153,617, granted on November 28, 2000; 6,344,455, granted on February 5, 2002; 6,664,390, issued Dec. 16, 2003, and international publication WO 02/00630, published January 3, 2002. ErbB2 receptor inhibitors include GW-282974 (Glaxo Wellcome foot), monoclonal antibodies AR-209 ( Aronex Pharmaceuticals Inc. of The Woodlands, Texas, USA) and 2B-1 (Chiron), Herceptin, 2C4, and pertuzumab. In WO 01/98277, the description of which is incorporated herein in its entirety, some additional erbB2 inhibitors useful in the treatment of cancer are described. It has also been shown that other compounds, for example styrene derivatives, have inhibitory properties of tyrosine kinases. More recently, five publications of European patents, namely the European patent EP 0 566 226 A1 (published on October 20, 1993), the European patent EP 0 602 851 A1 (published on June 22, 1994), the European patent EP 0 635 507 A1 (published January 25, 1995), European Patent EP 0 635 498 A1 (published January 25, 1995), and European Patent EP 0 520 722 A1 (published December 30, 1992), refer to methods for preparing certain bicyclic derivatives, in particular quinazoline derivatives. In addition, international patent application WO 92/20642 (published November 26, 1992), relates to methods for preparing certain bis-mono and bicyclic aryl and heteroaryl compounds that inhibit tyrosine kinases, and states that they are useful for inhibit abnormal cell proliferation. International patent applications WO 96/16960 (published June 6, 1996), WO 96/09294 (published March 6, 1996), WO 97/30034 (published August 21, 1997), WO 98 / 02434 (published January 22, 1998), WO 98/02437 (published January 22, 1998), and WO 98/02438 (published January 22, 1998), also refer to bicyclic substituted heteroaromatic derivatives as inhibitors. of tyrosine-kinases that are useful for the same purpose. Other patent applications that refer to anticancer compounds are U.S. patent applications. numbers 09 / 488,350 (filed on January 20, '2000) and 09 / 488,378 (filed on January 20, 2000), both of which are incorporated herein in their entirety, as a reference. In U.S. Pat. 5,747,498 (issued May 5, 1998), U.S. patent application Ser. of serial number 08/953078 (filed October 17, 1997), and WO 98/02434 (published January 22, 1998), WO 98/02438 (published January 22, 1998), WO 96 / 40142 (published December 19, 1996), WO 96/09294 (published March 6, 1996), WO 97/03069 (published January 30, 1997), WO 95/19774 (published on Mar. 27, 1997). July 1995) and WO 97/13771 (published April 17, 1997), general synthetic methods are offered that can be used to prepare the erbB2 compounds of the present invention. Additional procedures are offered in U.S. patent applications. numbers 09 / 488,350 '(filed on January 20, 2000) and 09 / 488,378 (filed on January 20, 2000). The above patents and patent applications are hereby incorporated by reference in their entirety. Some starting materials may be prepared according to methods known to those skilled in the art, and certain synthetic modifications may be made according to methods known to those skilled in the art. A general procedure for preparing 6-iodoquinazolinone is offered in the article by Stevenson, T.M., Kazmierczak, F., and Leonard, N.J., J. Org. Chem. 1986, 51, 5, page 616. Couplings of boronic acid catalyzed by palladium are described in the article by Miyaura, N., Yanagi, T., and Suzuki, A., Syn. Comm. 1981, 11, 7, page 513. Heck copulations catalysed by palladium are described in the work by Heck et al., Organic Reactions, 1982, 27, 345 or by Cabri et al. In Acc. Chem. Res. 1995, 28 , 2. To find examples of palladium-catalyzed coupling of terminal alkynes to aryl halides, see the articles by Castro et al., J. Org. Chem. 1963, 28, 3136, or Sonogashira et al., Synthesis, 1977, 777. Terminal alkynes can be synthesized using suitably substituted / protected aldehydes, as described in the following articles: Colvin, EWJ et al., Chem. Soc. Perkin Trans. I, 1977, 869; Gilbert, J. C. et al., J. Org. Chem., 47, 10, 1982; Hauske, J. R. and others, Tet. Lett., 33, 26, 1992, 3715; Ohira, S. et al., J. Chem. Soc. Chem. Commun., 9, 1992, 721; Trost, B. M. J. Amer. Chem. Soc, 119, 4, 1997, 698; or Marshall, J.A. and others, J. Org. Chem., 62, 13, 1997, 4313. Alternatively, terminal alkynes can be prepared by a two-step procedure. The first is the addition of the anion of TMS (trimethylsilyl) -acetylene with lithium, to an appropriately substituted / protected aldehyde, as described in Nakatani, K. et al., Tetrahedron, 49, 9, 1993, 1901. Subsequent deprotection by bases can then be employed to isolate the terminal alkyne intermediate, as described in the article by Malacria, M.; Tetrahedron, 33, 1977, 2813; or in White, J. D. et al., Tet. Lett., 31, 1, 1990, 59. Starting materials whose synthesis has not been specifically described above, either are commercially available, or can be prepared by methods well known to those skilled in the art. Antibodies to erbB2 are known, and have therapeutic utility. U.S. Pat. No. 5,725,856 refers, in part, to a treatment by administration of an antibody that binds to the extracellular domain of the erbB2 receptor (HER2). U.S. Pat. No. 5,677,171 refers to a monoclonal antibody that binds the HER2 receptor. U.S. Pat. No. 5,720,954 refers to a treatment using a cytotoxic factor and an antibody against the HER2 receptor. U.S. Pat. No. 5,770,195 refers to the inhibition of the growth of tumor cells. U.S. Pat. No. 6,165,464 refers to an isolated human antibody that binds the HER2 receptor. U.S. Pat. No. 6,387,371 refers to a method of treating a cancer by administering an antibody and a factor that suppresses the growth of cancer cells. The erbB gene can be erbB1, erbB2, erbB3, erbB4, or combinations of these. In one aspect, the gene is erbBL. In another aspect, the gene is erbB2. In another aspect, the gene is erbB3. In still another aspect, the gene is erbB4.

In one aspect of the invention, the antibody can recognize the extracellular domain of the protein. VEGF inhibitors can be prepared by the methods described, for example, in WO 99/24440 (published May 20, 1999), PCT international application number PCT / IB99 / 00797 (filed May 3, 1999) , WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), U.S. Pat. 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), U.S. Pat. 5,883,113 (issued March 16, 1999), U.S. Pat. 5,886,020 (issued March 23, 1999), U.S. Pat. 5,792,783 (issued August 11, 1998), and WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997). June 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are hereby incorporated by reference in their entirety, WO 01/02369 (published January 11, 2001); the provisional US application number 60/491, 771 (filed July 31, 2003); the provisional US application number 60 / 460,695 (filed on April 3, 2003); and WO 03/106462A1 (published December 24, 2003). In the international patent publications WO 99/62890, published on December 9, 1999; WO 01/95353, published December 13, 2001; and WO 02/44158, published June 6, 2002, other examples of methods for preparing VEGF inhibitors are described. Methods for preparing other examples of some specific VEGF inhibitors (including IM862 (Cytran Inc. of Kirkiand, Washington, USA): avastin, an anti-VEGF monoclonal antibody from Genentech, Inc. of South San Francisco, California and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California)) are well known to those skilled in the art. The signal transduction inhibitors comprise a large number of inhibitors. The majority of these inhibitors are counted among the tyrosine kinase inhibitors or among the serine / threonine kinase inhibitors. However, there is a small number of STIs that are not inhibitors of tyrosine kinases or inhibitors of serine / threonine kinases. Examples of these inhibitors include inhibitors of double specificity kinases, inhibitors of lipid kinases, histone deacetylase inhibitors, inhibitors of Bc12, inhibitors of p53, inhibitors of MDMZ, inhibitors of Ras, inhibitors of Hsp 90, inhibitors of K-Ras , and inhibitors of TGFbeta-R. These inhibitors can be prepared by methods well known to those skilled in the art. PI3 kinase inhibitors can be prepared by methods well known to those skilled in the art. Specific methods are described in WO 01/81346; WO 01/53266 and WO 01/83456; U.S. patent application number 10 / 730,680 (filed on December 8, 2003); U.S. patent application number 10 / 743,852 (filed on December 22, 2003); the US provisional patent application number 60 / 475,970 (filed on June 5, 2003); the US provisional patent application No. 60 / 475,992 (filed June 5, 2003); the US provisional patent application number 60 / 476,073 (filed on June 5, 2003); the US provisional patent application number 60 / 476,251 (filed on June 5, 2003); the US provisional patent application number 60 / 475,971 (filed on June 5, 2003); and the US provisional patent application. number 60 / 476,057 (filed on June 5, 2003). The method of the invention comprises treating a mammal suffering from cancer, and comprises: administering to said mammal in need of such treatment, sequentially in any order, simultaneously, or both, (i) a therapeutically effective amount of a first STI compound, as defined above, and (ii) a therapeutically effective amount of a second STI compound, as defined above. In a preferred embodiment, the method of the invention comprises treating a person suffering from a cancer, and comprises: administering to said person in need of such treatment, sequentially in any order, simultaneously, or both, (i) ) a therapeutically effective amount of a first STI compound, as defined above, and (ii) a therapeutically effective amount of a second STI compound, as defined above. Cancer can be a solid cancer. In a particular aspect, the cancer is not a solid tumor, which includes, for example, a leukemia or a lymphoma. The volume of solid cancer may decrease after application of the method of the invention. When the STI is an antibody, it can be either a polyclonal antibody or a monoclonal antibody. In a particular aspect, the antibody is a monoclonal antibody. Thus, the antibody can be selected from the group consisting of Herceptin, 2C4, and pertuzumab. In one embodiment, the antibody is pertuzumab. In another embodiment, the antibody is 2C4. In yet another embodiment, the antibody is Herceptin. The amount of Herceptin administered may be less than about 2 mg / kg / week. In one aspect, the amount of Herceptin administered is less than about 0.6 mg / kg / week. The antibody can be administered at least about once a week. In another aspect, the antibody can be administered about once every two weeks. The method of the invention can be useful with a cancer characterized by the multiplication of a specific STI gene, by the overexpression of the STI protein, or by both. In one aspect, the STI gene, the STI protein, or both, are CDK4 / 6. Overexpression can be characterized by a +2 or +3 level. To measure the levels of multiplication or hyperexpression, any method customary in the art can be used. For example, multiplication can be measured by fluorescence of in situ hybridization (FISH). An advantageous method has been described by Coussens et al. In Science 230, 1132 (1032). Overexpression can be measured by immunohistochemistry (IHC). Coussens and others, in the same article, have also described an advantageous method. Alternatively, the level of overexpression of STl is inferred from clinical observations, without using the explicit measurement by IHC, but based instead on the patient's history, physical diagnosis, or other diagnostic elements. The antibody can advantageously be a mediator of antibody-dependent cellular cytotoxicity. In another aspect of the method of the invention, the combination is administered at least about once a day. In another aspect, the combination of the invention is administered at least about twice a day. The therapeutically effective amount of the first compound is approximately 25 mg / kg / day. In another aspect, the therapeutically effective amount of the first compound is about 50 mg / kg / day. The combination of the invention can be administered orally, buccally, sublingually, vaginally, intraduodenally, parenterally, topically, or rectally. Preferably, the formulation will be adapted to the particular mode of administration. The antibody combinations of the invention can be administered substantially simultaneously with the other compounds of the combination. The formulations of the individual components of the combination depend on the properties of each agent and the pharmacological effect desired by the administrator. The method of the invention is applicable to a human being. They can also treat beings that are not human. For example, the mammal can be a horse. The method of the invention is useful for administration to female mammals. The method can be useful also for males. The mammal can be an adult. In another aspect, infants, children, adolescents or the elderly can be treated with the methods of the invention. The methods of the invention are applicable to a wide variety of abnormal cell growth situations. In one aspect, methods and equipment are advantageously applied to cancers. The cancer may be selected from the group consisting of: lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vagina carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer , small bowel cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, soft tissue sarcoma, cancer of the urethra, cancer of the penis, cancer of the prostate, chronic or acute leukemia , lymphocytic lymphomas, bladder cancer, kidney or urethral cancer, renal cell carcinoma, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), lymphoma p CNS rimario, spinal axis tumors, brainstem glioma, pituitary adenoma, or a combination of one or more of the above cancers; Other cancers may also be susceptible to treatment with the methods of the invention. In one aspect, the cancer is selected from the group consisting of ovarian cancer and breast cancer. In another aspect, cancer is breast cancer. The method of the invention is also applicable, for example, adjuvant therapy, in which the mammal has received or is receiving sessions of chemotherapeutic agents. In this regard, the remaining cancer may be a minimal residual disease. In another aspect, the method of the invention be applied as a prophylactic measure. Thus, for example, the method can be applied to a mammal that presents remission of a cancer, in which no detectable disease can be detected. In one aspect of the methods of the invention, the amount of the active agents is at least sufficient to produce therapeutic synergy. Accordingly, the combination of the steps of the method of the invention is an improved treatment of a cancer, compared to any of said steps alone. The invention also comprises a kit containing: (a) a first agent, as described above, and (b) written instructions included in the kit together with (a), for simultaneous or sequential administration in the treatment of a Cancer. Thus, the written instructions can detail and qualify the modes of administration. In one aspect of the kit, the written instructions specify the administration of a cyclin-dependent kinase inhibitor, and a ST1. Advantageously, the written instructions specify the administration of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3- d] pyrimidin-7-one. In another particular aspect of the equipment, said equipment further comprises the administration of 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide or of? / - [(R) -2 , 3-dihydroxy-propoxy} -3,4-d-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide. On the other hand, the equipment may comprise a fluid for reconstituting the aforementioned active agents, if they are supplied in the dry state. The compounds of the present invention of combination are potent ST inhibitors of oncogenic and protooncogenic protein tyrosine kinases, and are therefore all adapted to the therapeutic use as antiproliferative agents (for example anticancer agents) in mammals, in particular in humans. In particular, the compounds of the present invention are useful in the prevention and treatment of various proliferative disorders in man such as malignant and benign tumors of kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic , lung, vulvar, thyroid, hepatic carcinomas, sarcomas, glioblastomas, head and neck, and other hyperplastic conditions such as benign hyperplasia of the skin (eg psoriasis) and benign prostatic hyperplasia (eg HBP) ). In addition, it is expected that the methods and equipment of the present invention may be effective against various leukemias and malignant lymphoid tumors. The compounds of the present invention of combination may also be useful in the treatment of additional disorders in which occurrences of expression, ligand / receptor interaction or aberrant activation or signaling, related to different protein tyrosine kinases are involved. Said disorders may include neuronal, glial, astrocytic, hypothalamic, and others of a glandular, macrophage, epithelial, stromal and blastocoelic nature, in which aberrant function, expression, activation or signaling of the specific ST1 is involved. In addition, the active compounds of the present invention may have therapeutic utility in inflammatory, angiogenic and immunological disorders involving tyrosine kinases, both identified and not yet identified, that are inhibited by the compounds of the present invention. The active compounds described encompass all pharmaceutically acceptable isotopic variations. An isotopic variation is a compound in which at least one atom has been replaced by an atom that has the same atomic number, but an atomic mass different from the atomic mass that is usually found in nature. Useful isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Illustrative isotopes may therefore include, without limitation, 2H, 3H, 13C, 14C, 15N, 170, 180, 32P, 35S, 18F, and 36CI. Substitution with isotopes such as deuterium, i.e., 2H, in the disclosed compounds, may provide certain therapeutic advantages resulting from increased metabolic stability, eg, increased in vivo half-life, or lower dosage requirements and, therefore, , it may be more useful in some circumstances. In addition, some isotopic variations, for example those that incorporate a radioactive isotope, are useful in studies of drug distribution and / or tissue substrates. The radioactive isotopes tritium, ie 3H and carbon 14, ie 14C, are especially useful for this purpose since they are easily incorporated and detection means are available. The isotopic variations of the described compounds can be prepared generally by conventional techniques known to those skilled in the art, or by procedures analogous to those described in the appended Examples, employing appropriate isotopic variations of appropriate reagents. The pharmaceutically acceptable solvates of the disclosed compounds include those in which the crystallization solvent may be substituted isotopically, for example D20, d6-acetone and d6-DMSO. The active compounds described can be administered as crystalline or amorphous products. They can be obtained, for example, as solid blocks, powders or films, by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. The combinations described can be administered alone or in combination with other drugs, and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" refers to any ingredient other than the active agents described herein and their salts. The choice of excipient will depend to a large extent on the particular mode of administration. The described compounds can be administered orally.

Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, by which the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid filled ones), chewing gums, multi and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesives), ovules, nebulizers and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as a soft or hard capsule filler, and typically comprise a carrier, for example water, EtOH, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid from, for example, an envelope. The disclosed compounds can also be used in rapidly dissolving and fast-disintegrating pharmaceutical forms, such as those described by Liang and Chen in Expert Opinion in Therapeutic Patents, (2001) 11 (6): 981-986. For dosage forms in tablets, and depending on the dosage, the drug may be from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disgregates include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will constitute from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the pharmaceutical form. Binders are generally used to impart cohesion qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may be from 0.2 wt% to 5 wt% of the tablet, and the glidants may be from 0.2 wt% to 1 wt% of the tablet. Generally, the tablets also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants generally constitute from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other ingredients may include preservatives, antioxidants, flavors, and colorants. The tablet mixtures can be compressed directly to form the tablets. Alternatively, tablet blends or portions of tablet blends can be granulated wet, dry, or melted, can be coagulated from the molten state, or can be extruded prior to forming the tablets. The final formulation may comprise one or more layers, and may be coated or uncoated. Illustrative tablets contain up to about 80% drug, from about 10% to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight of disintegrant, and about 0.25% by weight to about 10% by weight of lubricant. For additional details regarding the formulation of tablets, see H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets, Vol. 1 (1980). Solid formulations for oral administration can be formulated for immediate release and / or for modified release. Formulations with modified release include delayed, sustained, pulsed, controlled, directed and programmed release. For a general description of suitable modified release formulations see U.S. Pat. number 6,106,864. For details of other useful release technologies, such as high energy dispersions and osmotic and coated particles, see Verma et al., Pharmaceutical Technology On-line (2001) 25 (2): 1-14. As for a discussion of the use of chewing gum to achieve a controlled release, see WO 00/35298. The described compounds can also be administered directly into the bloodstream, into the muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle injectors (also with microneedles), needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and pH regulating agents (preferably at a pH of 3 to 9), but for some applications, may be more adequately formulated as a non-aqueous solution , sterile, or as a dry form that has to be used together with a suitable vehicle such as pyrogen-free sterile water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be carried out easily using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the disclosed compounds, used in the preparation of parenteral solutions, can be increased using suitable formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated to provide immediate and / or modified release, as described above. Thus, the described derivatives can be formulated in a more solid form, to be administered as an implanted reservoir that provides a prolonged release of the active compound.

The compounds of the invention can also be administered topically to the skin or mucosa, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Topical formulations may also include penetration enhancers (see, for example, the article by Finnin and Morgan in J. Pharm. Sci. (1999) 88 (10): 955-958 Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needleless injection (eg, POWDERJECT) or injection without needles Topical formulations can be formulated to provide immediate and / or modified release, as described above. The disclosed compounds can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example in a dry mixture with lactose, or as a mixed particulate component, for example mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurized container, a pump, a spray, a nebulizer, an atomizer (preferably an atomizer employing electrohydrodynamics to produce a fine mist), or a nebulizer, with or without the use of a suitable propellant, such as dichlorofluoromethane. The pressure vessel, pump, sprayer, atomizer or nebulizer contain a solution or suspension comprising the active compound, an agent to disperse, solubilize, or prolong the release of the active compound (e.g. EtOH or aqueous EtOH), one or more solvents that serve as propellants, and an optional surfactant, such as sorbitan trioleate or an oligo (lactic acid). Before use in a dry powder or in a suspension formulation, the medicinal substance is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable milling method, for example by spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules, vesicle containers (also known as blister packs) and cartridges (made, for example, with gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator, can be formulated to contain a powder mixture of the active compound, a suitable powder base such as lactose or starch, and a performance modifier such as L-leucine, mannitol or magnesium stearate. The lactose may be anhydrous or, preferably, monohydrated. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula 1 or formula 2, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Formulations for inhaled / intranasal administration can be formulated to be immediate release and / or modified using, for example, poly (DL-lactic-coglycolic acid) (PGLA). To the formulations of the invention directed to the inhaled / intranasal administration, suitable flavoring agents can be added, such as menthol and levomenthol, or sweeteners such as saccharin or sodium saccharin. In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that supplies a measured quantity. The units according to the invention are typically arranged to deliver a metered or "puffed" dose containing from 100 to 1000 μg of the pharmaceutically active ingredient. The total daily dose will typically be in the range of 100 μg to 10 mg, which can be administered in a single dose or, more commonly, in divided doses throughout the day. The active compounds can be administered rectally or vaginally, for example in the form of a suppository, vaginal suppository or enema. Cocoa butter is a traditional suppository base, but different alternatives can be used, as appropriate. Formulations for rectal / vaginal administration can be formulated to provide immediate and / or modified release, as described above. The disclosed compounds can also be administered directly into the eyes or ears, typically in the form of drops of a micronized suspension or a solution in sterile saline, pH adjusted, and isotonic. Other formulations suitable for ocular and otic administration include: ointments, biodegradable (e.g. absorbable gel sponge, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular material systems, such as niosomes or liposomes. A polymer such as a crosslinked poly (acrylic acid), polyvinyl alcohol, hyaluronic acid, a cellulosic polymer (for example hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose), or a heteropolysaccharide polymer (for example gellan gum) can be incorporated, together with a preservative such as benzalkonium chloride. These formulations can also be supplied by iontophoresis. Formulations for ocular / otic administration can be formulated to provide immediate and / or modified release, as described above. The disclosed compounds can be combined with soluble macromolecular entities such as cyclodextrin or polymers containing polyethylene glycol, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability. For example, it is found that drug-cyclodextrin complexes in general are useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. For these purposes, alpha-, beta- and gamma-cyclodextrins are commonly used. See, for example, international patent applications WO 91/11172, WO 94/02518 and WO 98/55148. The dosage of the individual compounds of the present combination invention will vary from about 0.01 mg per kg of body weight and per day, to about 100 mg per kg of body weight and per day. Typical doses for adults will be from about 0.1 mg to about 3000 mg per day. The amount of active component in a unit dose preparation can be varied or adjusted from about 0.1 mg to about 500 mg, preferably from about 0.6 mg to 100 mg, depending on the particular application and the potency of the active component. The composition may also contain, if desired, other compatible therapeutic agents. A subject in need of treatment is administered a dose of about 0.6 to about 500 mg per day, either once or in multiple doses over a 24-hour period. This treatment can be repeated at successive intervals for as long as necessary. The following protocols demonstrate the efficacy of the combinations of the invention.

Chemotherapeutic evaluation of a CDK-4 inhibitor in combination with the standard reference agent Taxotere, against advanced human breast carcinoma MDA-MB-435. Objective: To determine the in vivo efficacy of a CDK-4 inhibitor and the reference standard agent Taxotere, when administered as separate agents, and also together, in two combination schemes, against the solid human xenograft MDA-MB-435. Methods: Four hundred female SCID mice were received from the Charles River Breeding Laboratories on February 11, 2003. The mice were 21-28 days old when they arrived. All animals were examined before beginning the study, to ensure that they were healthy and acclimated to the laboratory environment. The mice are stabled in facilities with barriers, with food and water at their discretion, and a light / dark cycle of 12 hours. The animals were grouped at a rate of five per cage while they were in the tumor group, and at a rate of four per cage when they were randomized into study groups. Animal care was provided in accordance with the recommendations of the AAALAC. All protocols involving animals were reviewed and approved by the institutional committee on animal care and use. On day 0 (April 20, 2003) all mice (18-22 g) received a subcutaneous (SC) implant of an MDA-MB-435 tumor fragment, approximately 30 mg, from tumors weighing 1000 mg . The human solid tumor model MBA-MB-435, a breast carcinoma, had been developed from cell lines, and had been maintained in SCID mice. The tumor model had been serially transferred as subcutaneous implants of tumor fragments. The tumor source for this study was MDA-MB-435/14 (T, 1-29-03). Treatment was initiated when the tumor fragments reached a size of 200-250 mg. The animals were randomly mixed, and then separated into twenty-four groups of 8 mice. Each animal was weighed individually, and tumors were measured on the day of treatment initiation and then every 3-4 days during treatment. The dosing solutions were calculated according to the average weight of the group. 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-p-piperazin-1-yl-pyridin-2-ylamino) -8 / - -pyrido [2,3-d] pyrimidin-7 was prepared ona and Taxotere, according to the drug preparation forms, and in the manner shown in the drug preparation tables for chemotherapy. The compounds were administered as individual agents, with two different schemes. A group of animals first received 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrid [2, 3-d] pyrimid-7-one for 5 days, and then, after 24 hours, the standard reference agent (Taxotere) in an intravenous (IV) dose. The second set was administered the standard reference agent (Taxotere) in one dose, followed after 24 hours by 5 daily doses of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-pyr). perazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one. These programs were repeated three times. The solution of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidine 7-one was administered orally (PO) once a day, days 14-18, 21-25, and 28-32, or days 15-19, 22-26, and 29-33, depending on the treatment program. Taxotere was administered intravenously on days 19, 26, and 33, or on days 14, 21, and 28, according to the treatment program. An additional group of 16 mice, which received the two delivery vehicles (50 mM sodium lactate for 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridine), was included as a negative control. 2-ylammon) -8-pyrido [2,3-d] pyrimidin-7-one, pH 4.0, and Tween 80 / EtOH / water for Taxotere) orally on days 14-18, 21- 25, and 28-32, and intravenously on days 19, 26, and 33. The volume of oral administration was 0.5 ml, and the volume of intravenous administration was 0.2 ml. During the course of the study the animals were weighed at the time of calculating the treatment doses, and then every week. Tumors were measured every three or four days throughout the study. Every animal was inspected daily for clinical signs, and also after administering the compound. The data collection was done entirely in CRAAS, and all the printed reports were adequately documented in the study file (data notebook 83410x13). This study was carried out in accordance with the established standard departmental work procedures.

TABLE 1 Summary of the CCTM protocol Experiment number: 83410x13 Tumor: MDA- B-435 Mouse: CB17 SCID Sex: H cy. • ^ 1 Measurements: 2 times per week Total number of mice required: 400 (192 extra Total required drug: see below Weight: to start the treatment, v after weekly OD x 4 TO: 2/19/2003 PD0332991-0002B: 11.4 g required of Taxotere precursor, PD0323256: 96 mg of precursor Chemotherapeutic evaluation of a CDK-4 inhibitor in combination with the standard reference agent 5-fluorouracil (5-FU), against human colon carcinoma in an advanced state Colo-205 Objective: To determine the in vivo efficacy of the CDK-4 inhibitor 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidin-7-one and standard reference agent 5-fluorouracil (5-FU), when administered as separate agents, and also together, in two combination schemes, against the solid human xenograft Colo-205. Methods: Four hundred female SCID mice were received from the Charles River Breeding Laboratories on February 25, 2003. The mice were 21-28 days old when they arrived. All animals were examined before beginning the study, to ensure that they were healthy and acclimated to the laboratory environment. The mice were stabled in facilities with barriers, with food and water at their discretion, and a light / dark cycle of 12 hours. The animals were grouped at a rate of five per cage while they were in the tumor group, and at a rate of four per cage when they were randomized into study groups. Animal care was provided in accordance with the recommendations of the AAALAC. All protocols involving animals were reviewed and approved by the institutional committee on animal care and use. On day 0 (March 13, 2003) all mice (18-22 g) received a subcutaneous (SC) implant of a Colo-205 tumor fragment, approximately 30 mg, from tumors weighing 1000 mg. The Colo-205 human solid tumor model, a colon carcinoma, had been developed from cell lines, and had been maintained in SCID mice. The tumor model had been serially transferred as subcutaneous implants of tumor fragments. The tumor source for this study was Colo-205 / 09B (T, 2-11-03). Treatment was initiated when the tumor fragments reached a size of 200-250 mg. Animals were randomly mixed, and then classified into twenty-four groups of 8 mice. Each animal was weighed individually, and tumors were measured on the day of treatment initiation and then every 3-4 days during treatment. The dosing solutions were calculated according to the average weight of the group. 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] was prepared ] pyrimidin-7-one and (5-FU), according to the drug preparation forms, and in the manner shown in the drug preparation tables for chemotherapy. The compounds were administered as individual agents, with two different schemes. A group of animals first received 6-acetyl! -8-cyclopentyl-5-methyl-2- (5-p-piperazin-1-yl-pyridn-2-ylamino) -8 - / - pyrido [2,3-d] pyridin-7-one for 5 days, and then, after 24 hours, the standard reference agent (5-FU) in an intravenous (IV) dose. The second set was administered the standard reference agent (5-FU) in one dose, followed after 24 hours by 5 daily doses of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazine). 1-yl-pyridin-2-amyl) -8 - / - pyridyl [2,3-d] pyrimidin-7-one. These programs had been designed to be repeated three times, but because of the observed toxicity, only two administration cycles were completed. The solution of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyridmin N-7-one was administered orally (PO) once a day, on days 20-24 and 27-31, or on days 21-25 and 28-32, according to the treatment program. 5-FU was administered intravenously on days 25 and 32, or on days 20 and 27, according to the treatment program. An additional group of 16 mice, which received the two delivery vehicles (50 mM sodium lactate for 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-p), was included as a negative control. Ridin-2-ylamino) -8H-pyrid [2,3-d] pyrimidin-7-one, pH 4.0, and saline for 5-FU) orally on days 20-24, and 27-31, and intravenously on days 25 and 32. The volume of oral administration was 0.5 ml, and the volume of intravenous administration was 0.2 ml. During the course of the study the animals were weighed at the time of calculating the treatment doses, and then every week. Tumors were measured every three or four days throughout the study. Every animal was inspected daily for clinical signs, and also after administering the compound. The data collection was done entirely in CRAAS, and all the printed reports were adequately documented in the study file (data notebook 90663x15). This study was carried out in accordance with the established standard departmental work procedures.

TABLE 2 Summary of the CCTM protocol ET- Experiment number: Tumor: Col-205 Mouse: CB17 SCID 90663x12 Sex: H or CO Total number of mice required: 400 Measurements: 2 times per (192 extra) week Total required drug: see below Weight: to start treatment, and then weekly x 4 TO: March 2003 PD0332991-0002B: 11.4 g of 5FU precursor required , PD0037760: - precursor mg or Lp Chemotherapeutic evaluation of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 - / - [2,3-dlpyrimidin-7-one in combination with the standard reference agent carboplatin, against the human breast carcinoma in advanced stage MDA-MB-435. Objective: To determine the in vivo efficacy of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [ 2,3-d] pyrimidin-7-one and the standard reference agent carboplatin, when administered as separate agents, and also together, in two combination schemes, against the solid human xenograft MDA-MB-435 . Methods: Four hundred female SCID mice were received from the Charles River Breeding Laboratories on April 8, 2003. The mice were 21-28 days old when they arrived. All animals were examined before beginning the study, to ensure that they were healthy and acclimated to the laboratory environment. The mice were stabled in facilities with barriers, with food and water at their discretion, and a light / dark cycle of 12 hours. The animals were grouped at a rate of five per cage while they were in the tumor group, and at a rate of four per cage when they were randomized into study groups. Animal care was provided in accordance with the recommendations of the AAALAC. All protocols involving animals were reviewed and approved by the institutional committee on animal care and use. On day 0 (April 24, 2003) all mice (18-22 g) received a subcutaneous (SC) implant of an MDA-MB-435 tumor fragment, approximately 30 mg, from tumors weighing 1000 mg . The human solid tumor model MBA-MB-435, a breast carcinoma, had been developed from cell lines, and had been maintained in SCID mice. The tumor model had been serially transferred as subcutaneous implants of tumor fragments. The tumor source for this study was MDA-MB-435/17 (T, 4-2-03). Treatment was initiated when the tumor fragments reached a size of 200-250 mg. The animals were randomly mixed, and then separated into twenty-four groups of 8 mice. Each animal was weighed individually, and tumors were measured on the day of treatment initiation and then every 3-4 days during treatment. The dosing solutions were calculated according to the average weight of the group. 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7 was prepared -one and carboplatine, according to the drug preparation forms, and in the manner shown in the drug preparation tables for chemotherapy. The compounds were administered as individual agents, with two different schemes. A group of animals first received 6-acetyl-8-dclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one for 5 days, and then, after 24 hours, the standard reference agent (carboplatin) in an intravenous (IV) dose. The second set was administered the standard reference agent (carboplatin) in one dose, followed after 24 hours by 5 daily doses of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazyl). n-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidin-7-one. These programs were repeated three times. The solution of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] ] pyrimidin-7-one was administered orally (PO) once a day, days 14-18, 21-25, and 28-32, or days 15-19, 22-26, and 29-33, depending on the treatment program. Carboplatin was administered intravenously on days 19, 26, and 33, or on days 14, 21, and 28, according to the treatment program. An additional group of 16 mice, which received the two administration vehicles (50 mM sodium lactate for 6-acetyl-8-cyclopentyl-5-methyl-2 - (- p-piperazin-1-yl-pyrid), was included as a negative control. N-2-amylamino) -8H-pyrid [2,3-d] pyrimidin-7-one, pH 4.0, and saline solution for carboplatin) orally on days 14-18, 21-25 , and 28-32, and intravenously on days 19, 26 and 33. The volume of oral administration was 0.5 ml, and the volume of intravenous administration was 0.2 ml. During the course of the study the animals were weighed at the time of calculating the treatment doses, and then every week. Tumors were measured every three or four days throughout the study. Every animal was inspected daily for clinical signs, and also after administering the compound. The data collection was done entirely in CRAAS, and all the printed reports were adequately documented in the study file (data notebook 90663x15). This study was carried out in accordance with the established standard departmental work procedures.

Chemotherapeutic evaluation of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 - / - pyrid [2,3-d1pyrimidn-7-one and the MEK inhibitor? / - f (R) -2,3-dihydroxy-propoxp-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide against human colon carcinoma in advanced state Colo-205. Objective: To determine the in vivo efficacy of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2- (5-p-piperazin-1-ylpyridin-2-ylamine) - 8H-pyrido [2,3-d] pyrimidin-7-one and the MEK inhibitor N - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide, when administered daily for 15 days as separate agents, and also together, in combination, against the solid human xenograft Colo-205. Methods: Four hundred female SCID mice were received from the Charles River Breeding Laboratories on June 17, 2003. The mice were 21-28 days old when they arrived. All animals were examined before beginning the study, to ensure that they were healthy and acclimated to the laboratory environment. The mice were stabled in facilities with barriers, with food and water at their discretion, and a light / dark cycle of 12 hours. The animals were grouped at a rate of five per cage while they were in the tumor group, and at a rate of four per cage when they were randomized into study groups. Animal care was provided in accordance with the recommendations of the AAALAC. All protocols involving animals were reviewed and approved by the institutional committee on animal care and use. On day 0 (July 2, 2003) all mice (18-22 g) received a subcutaneous (SC) implant of a Colo-205 tumor fragment, approximately 30 mg, from tumors weighing 1000 mg. The Colo-205 human solid tumor model, a colon carcinoma, had been developed from cell lines, and had been maintained in SCID mice. The tumor model had been serially transferred as subcutaneous implants of tumor fragments. The tumor source for this study was Colo-205 / 13B (T, 6-3-03). Treatment was initiated when the tumor fragments reached a size of 200-250 mg. The animals were randomly mixed, and then separated into twenty-four groups of 8 mice. Each animal was weighed individually, and tumors were measured on the day of treatment initiation and then every 3-4 days during treatment. The dosing solutions were calculated according to the average weight of the group. 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-plperazin-1-1-pyrid-2-ylamine) -8 / - / - pyr Do [2,3-d] pyrimidin-7-one and N - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo- fenllamyl) -benzamide according to the drug preparation forms, and in the manner shown in the drug preparation tables for chemotherapy. The solutions were administered by oral gavage (PO) once a day for 15 consecutive days. Always 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 - / - pyrido [2,3-d] pyr was first administered Midin-7-one, followed, within one hour, by N - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-) iodo-phenylamino) -benzamide. An additional group of 16 mice, which received the two administration vehicles (50 mM sodium lactate for 6-acetyl-8-cyclopentyl-5-methyl-2 - (- piperazin-1-yl), was included as a negative control. -pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one, pH 4.0, and HMPT for? / - [(R) -2,3-dihydroxy-propoxy] -3,4-d-fluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide) orally, with the same daily treatment program. All administration volumes were 0.5 ml. During the course of the study the animals were weighed at the time of calculating the treatment doses, and then every week. Tumors were measured every three or four days throughout the study. Every animal was inspected daily for clinical signs, and also after administering the compound. All the data collection was done in CRAAS, and all the printed reports were adequately documented in the study file (data notebook 90665x15). This study was carried out in accordance with the established standard departmental work procedures.

TABLE 3 Summary of the CCTM protocol MM- Experiment number: Tumor: Colo-205 Mouse: CB17 SCID 90665x15 Sex: H N3 í- Total number of mice required: 400 (192 extra) Measurements: 2 times per week Required total drug: see below Weight: to start the treatment, and then weekly x 4 PARA: 7/2/003 PD0332991-0054: 11, 000 mg of parent required - received from CM, lot Q, 78.2% P. Mek inhibitor Lp: PD0325910-000: 1000 mg of progenitor - in Lab, lot S or T Note: The evolution of tumors will be monitored up to 200-250 mg.

Chemotherapeutic evaluation of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3 -d] pyrimidin-7-one in combination with the standard reference agent Camptosar (CPT-11), against human colon carcinoma in advanced stage Colo-205. Objective: To determine the in vivo efficacy of the inhibitor of CDK-4 6-acetyl-8-cyclopentyl-5-methyl-2 - (- piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [ 2,3-djpirimidin-7-one and the standard reference agent Camptosar, irinotecan (CPT-11), when administered as separate agents, and also together, in two combination schemes, against the solid human xenograft Colo-205. Methods: Three hundred female SCID mice were received from the Charles River Breeding Laboratories on July 8, 2003. The mice were 21-28 days old when they arrived. All animals were examined before beginning the study, to ensure that they were healthy and acclimated to the laboratory environment. The mice were stabled in facilities with barriers, with food and water at their discretion, and a light / dark cycle of 12 hours. The animals were grouped at a rate of five per cage while they were in the tumor group, and at a rate of four per cage when they were randomized into study groups. Animal care was provided in accordance with the recommendations of the AAALAC. All protocols involving animals were reviewed and approved by the institutional committee on animal care and use.

On day O (July 25, 2003) all mice (18-22 g) received a subcutaneous (SC) implant of a Colo-205 tumor fragment, approximately 30 mg, from tumors weighing 1000 mg. The Colo-205 human solid tumor model, a colon carcinoma, had been developed from cell lines, and had been maintained in SCID mice. The tumor model had been serially transferred as subcutaneous implants of tumor fragments. The tumor source for this study was Colo-205 / 14B (T, 7-2-03). Treatment was initiated when the tumor fragments reached a size of 200-250 mg. The animals were randomly mixed, and then separated into seventeen groups of 8 mice. Each animal was weighed individually, and tumors were measured on the day of treatment initiation and then every 3-4 days during treatment. The dosing solutions were calculated according to the average weight of the group. 6-Acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pirldo [2,3-d] pyrimidin-7-one and CPT- were prepared 11, according to the drug preparation forms, and in the manner shown in the drug preparation tables for chemotherapy. The compounds were administered as separate agents, with two different schemes. A group of animals were first administered 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidine. -7-one for 5 days, they were left without treatment for two days, and then they were administered for a further 5 days, and then, after 2 days, they were given the standard reference agent (CPT-11) in five days. daily intravenous doses. The second set was administered the standard reference agent (CPT-11) in five doses, one each day, followed after 2 days by 6-acetyl-8-cyclopentyl-5-methyl-2- ( 5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrid [2, 3-d] pirimi-din-7-one administered once a day for 5 days, they were left for two days without treatment, and then they were administered for 5 more days. The solution of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidin-7- Ona was administered orally (PO) once a day, days 17-21 and 24-28, or days 24-28 and 31-35, according to the treatment program. CPT-11 was administered intravenously on days 17-21 or days 31-35, according to the treatment program. An additional group of 16 mice, which received the two administration vehicles (50 mM sodium lactate for 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazine-1 - L-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimid-7-one, pH 4.0, and saline for CPT-11) orally on days 17-21 , and 24-28, and intravenously on days 31-35. The volume of oral administration was 0.5 ml, and the volume of intravenous administration was 0.2 ml. During the course of the study the animals were weighed at the time of calculating the treatment doses, and then every week. Tumors were measured every three or four days throughout the study. Every animal was inspected daily for clinical signs, and also after administering the compound. The data collection was done entirely in CRAAS, and all the printed reports were adequately documented in the study file (data notebook 90666x07). This study was carried out in accordance with the established standard departmental work procedures.

TABLE 4 Summary of the CCTM protocol MM- Experiment No.: 90666x07 Tumor. Colo-205 Mouse: CB17 SCID Sex: H OR Total number of mice required: 300 (148 measurements: 2 times per week extra) Total required drug: see below Weight: to start the treatment, and then weekly x 4 PARA: 7/25/2003 PD0332991: 6000 mg required - use PF -0080665-01, lot 1 (80.42% P) -in the Camptosar shelf (CPT-11): PD0205014-000: 700 mg - in the laboratory lot V Note: The evolution of tumors up to 200-250 will be followed mg.

NO NO Preparations The following preparations are intended to be illustrative and not limiting, and represent specific embodiments of the present invention.

Preparation 1 Preparation of 4- [6- (6-bromo) -8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-d1-pyrimidin-2-ylamino] -f-butyl ester -pyridin-3-yl-piperazin-1-carboxylic acid A suspension of 6-bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8 was heated under nitrogen in an oil bath for 7 hours. - / - pyrido [2,3-c] pyrimidin-7-one (10.00 g, 0.027 mol, prepared as in Example 6 of WO 01/707041, which is incorporated herein by reference) and 10.37 g (0.0373 mol) of 4- (6-amino-pyridin-3-yl) -piperazin-1-carboxylic acid f-butyl ester in toluene (100 ml). Thin layer chromatography (SiO2, 10% MeOH in DCM) indicated the presence of the two starting materials. The suspension was refluxed for a further 18 hours. The resulting suspension was cooled to room temperature and filtered to give 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dhh) butyl ester. Hydrochloride [2,3-c | pyridin-2-ylamino) -pyridin-3-yl] -piperazin-1-carboxylic acid (5.93 g, 38%). Melting point > 250 ° C. MS (APCl) M ++ 1: calculated 584.2, found 584.2.

Preparation 2 Preparation of f-butyl ester of 4-acid. { 6- [8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7,8-dihydro-pyrido [2,3-c] pyrimidin-2-ylaminol-pyridin-3-pyridin; l} -piperazin-1-carboxylic acid A suspension of 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-) t-butyl ester was refluxed for 3.5 hours. dihydro-pyrido [2,3-d] pyrimidin-2-yl-amino) -pyridin-3-yl] -piperazin-1-carboxylic acid (5.93 g, 0.010 mol, prepared as in Example 1), tetrakis (triphenylphosphine) palladium (0) (1.40 g, 0.00121 mol), and tributyl (1-ethoxy-vinyl) tin (5.32 ml, 0.0157 mol) in toluene (30 ml) . The mixture was cooled and filtered to provide a solid. Purification of the solid by chromatography on silica gel using a gradient of 5% -66% ethyl acetate / hexane over the course of 15 minutes gave 4-butyl-butyl ester. { 6- [8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methyl-7-oxo-7,8-dihydro-pyrid [2,3-c] p Rimidin-2-ylammon] -pyridin-3-il} -piper-zin-1-carboxylic acid as a yellow foam (4.50 g, 78%). MS (APCl) M ++ 1: calculated 576.2, found 576.3.

Preparation 3 Preparation of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyrido [2,3-opy] hydrochloride Midin-7-one Hydrogen chloride gas was bubbled into a solution, cooled in an ice bath, of 4-f-butyl ester. { 6- [8-cyclopentyl-6- (1-ethoxy-vinyl) -5-methy1-7-oxo-7,8-dihydro-pyrid [2,3-d] pyrimidine- 2-ylamino] -pyridin-3-yl} -piperazine-1-carboxylic acid (4.50 g, 0.00783 mol, prepared as in Example 2) in DCM (100 ml). The resulting suspension was capped, stirred at room temperature overnight, and then diluted with diethyl ether (200 ml). The solid was isolated by filtration, washed with diethyl ether, and dried to provide the hydrochloride salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-p-piperazin-1-yl-pyridin-2). -ylamino) -8 - / - pyrid [2,3-d] pyridin-7-one as a yellow solid (4.01 g, 92%). Melting point 200 ° C. HPLC, inverted phase C18, gradient 10% -95% 0.1% TFA / CH3CN in 0.1% TFA / H2O over the course of 22 minutes: 99.0% at 11.04 minutes. MS (APCl) M ++ 1: calculated 448.2, found 448.3. Analysis, calculated for C 24 H 29 N 7 • 2-2.4 H 20 1.85 HCl: C, 51.64; H, 6.44; N, 17.56, Cl (total), 11.75. Experimental: C, 51.31; H, 6.41; N, 17.20; Cl (total), 12.11.

Preparation 4 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyridoi2.3-c | pirimin-7-one (Form B) To a suspension of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / -pyrido [2,3-d] pyrimidin-7-one (7.0 g, 15.64 mmol, prepared as in Example 3, after being in contact with NaOH) dispersed in 250 mL of water, were added dropwise. ml of a 0.52 M solution of isethionic acid in MeOH (15.64 mmol) to a pH of 5.2. The solution was filtered through a glass (thin) filter, and the clear solution was lyophilized to provide 9.4 g of the amorphous salt. The amorphous salt (3.16 g) was mixed with 25 ml of MeOH and, after almost complete dissolution, a new precipitate formed. Another 25 ml of MeOH was added, and the mixture was stirred at a temperature in the range of 46 ° C to 49 ° C for four hours. The mixture was slowly cooled to 32 ° C, and left in a cold room (+ 4 ° C) overnight. A sample was taken for powder X-ray diffraction (PXRD), which indicated the formation of Form B. The mixture was filtered, and the precipitate was dried overnight at 50 ° C in a vacuum oven. This provided 2.92 g of the mono-isethionate salt of the compound of Formula 1, with a yield of 92%. HPLC - 99.25%, PXRD - Form B, CHNS and H-NMR were consistent with the structure.

Preparation 5 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 / - / - pyridof2,3-cppirimidin- 7-one (Form B) MeOH (100 ml) was placed in a 250 ml flask equipped with a mechanical stirrer, thermocouple / controller, condenser, and heating mantle, and preheated to 35 ° C. A salt of amorphous isethionate (2 g, prepared as in Example 4) was slowly added in three equal portions, with intervals of 25 to 30 minutes between additions. The reaction mixture was stirred at 35 ° C overnight, and then cooled. A sample was filtered and examined by PXRD. It was pure Form B. The entire reaction mixture was used as a seed for Form B in a larger scale experiment.

Preparation 6 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3- c] pyrimidin-7-one (Form B) MeOH (50 ml) was placed in a 250 ml flask equipped with a magnetic stirrer, condenser, thermocouple / controller, and heating mantle, and preheated to 40 ° C. A salt of amorphous isethionate (1 g, prepared as in Example 4) was added slowly in three equal portions, with intervals of 30 minutes between the portions, and then stirred overnight at 40 ° C. The reaction was monitored by Raman in-situ spectroscopy. A sample was taken, filtered, and analyzed by PXRD. It was pure Form B for both PXRD and Raman spectroscopy. The mixture was cooled to 25 ° C at a rate of 3 ° C / hour, cooled to -10 ° C, filtered, and dried under vacuum to provide 0.85 g of the crystalline product of Form B.

Preparation 7 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8- -pyrid [2,3-c-pyrimidin-7-one (Form B) The free base (Formula 1, 0.895 mg, 2 mmol) was mixed with 10 ml of MeOH, and seeded with 33 mg of a sodium salt. mono-isethionate of the compound of Formula 1 (Form B). Then, in equal portions and over a period of 75 minutes, 5.6 ml of a 0.375 M solution of isethionic acid in MeOH (2.1 mmol) was added. The mixture was stirred for an additional 1 hour and a sample was taken for analysis by PXRD. This confirmed the formation of crystalline form B. The mixture was stirred at room temperature overnight, and another PXRD analysis was performed. There was no change in the crystalline form. The mixture was cooled overnight in a refrigerator at -8 ° C, filtered, and dried at 50 ° C in a vacuum oven, to provide 1053 g (91.8% of theory) of the above-mentioned compound (Form B) . HPLC -99.8%, CHNS, H-NMR, IR are consistent with the structure, PXRD - Form B.

Preparation 8 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-p-piperazin-1-yl-pyridin-2-ylamino) -8t- [2.3-c / | pyrimidin-7-one (Form A) An amorphous isethionate salt (47 mg, prepared as in Example 4) was mixed with 4 ml of EtOH in a 15 ml flask. ml equipped with a magnetic stirrer, thermocouple and condenser. The mixture was heated to reflux, which caused an almost transparent solution to form. After refluxing for 10-15 min, the mixture became turbid. It was cooled slowly to 50 ° C, and seeded at 69 ° C with Form A. The mixture was kept at 50 ° C for 5 hours, and allowed to cool to room temperature overnight. The mixture was then cooled to 1 ° C with an ice bath, kept for 1.5 hours, filtered, washed with 0.5 ml of cold EtOH, dried in air, and then dried in a 70 ° vacuum oven. C overnight, to provide 38.2 mg of a fine crystalline material. It was noted by PXRD that the crystalline material was mono-isethionate salt Form A. The H-NMR was consistent with the mono-isethionate salt, and indicated the presence of residual EtOH at a ratio of approximately 5.9 mol% or 0.6 % in weigh.

Preparation 9 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-1-pyridin-2-ylamino) -8 - / - pyridine [2,3-c] pyridin-7-one (Form D) A salt of amorphous setionate (9.0 g, prepared as in Example 4) was added to 300 ml of MeOH. stirred and heated to 63.8 ° C (reflux). Two 50 ml portions of MeOH were added to the slightly turbid mixture. The hot mixture was filtered to a 2 liter flask equipped with a mechanical stirrer. The mixture was briefly heated to reflux, and then cooled to 60 ° C. IPA (100 ml) was added to the mixture. The mixture was again heated to 60 ° C, and an additional 110 ml of IPA was added. A precipitate was started at 59.7 ° C. The mixture was again heated to 67.5 ° C, cooled to 50 ° C, and kept overnight. The next morning a sample was taken for analysis by PXRD. The mixture was cooled to 25 ° C at a rate of 3 ° C / hour, and another sample was taken for PXRD when the mixture had reached 28 ° C. The mixture was allowed to cool to room temperature overnight. A precipitate was isolated, and dried in a vacuum oven at 65 ° C and 30 Torr. This procedure provided 7.45 g (82.8% yield) of crystalline compound (Form D according to PXRD analysis). The samples analyzed previously were also Form D. The HPLC analysis showed a purity of 98.82%, and the CHNS microanalysis was within a margin of +/- 0.4%. A suspension of isethionate salt Form A, B, and D in MeOH provided substantially pure Form B in less than three days.

Preparation 10 Preparation of isethionic acid (2-hydroxy-ethanesulfonic acid) In a 5-liter round bottom flask, with four nozzles, equipped with a mechanical stirrer, thermocouple, gas bubbler, and an outlet to the atmosphere through a water trap , charged 748 g (5.05 mole) of sodium isethionate (ALDRICH), and 4 liters of IPA. The mixture was stirred at room temperature. An ice bath was used to keep the internal temperature below 50 ° C while introducing 925 g (25.4 moles) of gaseous hydrogen chloride (ALDRICH) into the system, at such a rate that it dissolved as quickly as it was added. (as appreciated by the absence of bubbling through the water trap). HCl gas was added to saturate the system (which was appreciated by the start of bubbling through the water trap). During the addition of HCl, the temperature was raised to 45 ° C. The mixture was cooled to room temperature, and filtered through a filter with a coarse frit. The cake was washed with 100 ml of IPA, and the cloudy filtrate was filtered through a 10-20 μm filter. In a rotary evaporator, the resulting clear and colorless filtrate was concentrated under reduced pressure., while keeping the bath temperature below 50 ° C. The 1.07 kg resulting from clear, slightly yellow oil was diluted with 50 ml of tap water and 400 ml of toluene and concentrated under reduced pressure in a rotary evaporator for three days, keeping the bath temperature below 50 ° C. The resulting 800 g of clear, slightly yellow oil was diluted with 500 ml of toluene and 250 ml of IPA and concentrated under reduced pressure in a rotary evaporator for 11 days, keeping the bath temperature below 50 ° C. The resulting 713 g of clear, slightly yellow oil was 81% by weight (580 g, yield 91.1%) and contained 7.9% by weight of water and 7.5% by weight of IPA.

Preparation 11 Preparation of 4- butyl ester of acid. { 6-r6- (1-butoxy-vinyl) -8-cyclopentyl-5-methyl-7-oxo-718-dihydro-pyrido-2,3-Q-pyrimidin-2-ylamino-1-pyridin-3 -ylVpiperazin-1 -carbo-xyly A five-liter, three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet / outlet concentrated with the atmosphere through the atmosphere was placed under nitrogen atmosphere. a silicone oil bubbler, and charged with 4- [6- (6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyridyl) -butyl ester. [2,3- d] pyridin-2-ylamino) -pyridin-3-yl] -piperazin-1-carboxylic acid (300 g, 0.51 mol, prepared as in Example 2), butyl vinyl ether (154 g, 1.54 moles, ALDRICH), n-butanol (1.5 liters, ALDRICH), and diisopropylethylamine (107 ml, 0.62 moles, ALDRICH). The suspension was placed under about 50 Torr vacuum, and then it was filled with nitrogen three times. Thereto was added 8.3 g (0.01 mole) of bis- (diphenylphosphinoferrocene) dichloride-palladium dichloromethane (Johnson Matthey, lot 077598001), and the resulting mixture was purged three more times, in the manner described above. The mixture was then heated to 95 ° C and stirred for 20 hours. The resulting red, fluid suspension was diluted with 2 liters of heptane and cooled to approximately 5 ° C. At this temperature, 400 ml of saturated aqueous potassium carbonate was added, and the mixture was filtered, rinsing with 250 ml of heptane. After drying in an oven for 16 hours at 45 ° C, 231.7 g (75% yield) of the title compound was obtained as a yellow solid.

Preparation 12 Preparation of a mono-isethionate salt of 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-p. ridor2,3-lpyrimidin-7-one (Form B) A 22 liter, three-neck round bottom flask equipped with a mechanical stirrer, thermocouple, and concentrated nitrogen inlet / outlet was placed under nitrogen atmosphere. atmosphere through a bubbler with silicone oil, and charged with 4- (6- (6- (1-butoxy-vinyl) -8-cyclopentyl) -butyl ester. -met.l-7-oxo-7,8-d¡h¡dro-pyrido [2,3-d] pyrimidin-2-ylamino) -pyridin-3-yl] -piperazin -1-carboxylic acid (725 g, 1.20 moles, prepared as in Example 11), and MeOH (14 liters). The suspension was stirred at room temperature while adding a solution of isethionic acid (530 g, 4.20 mol, prepared as in Example 10), MeOH (1.5 L), and water (70 mL, 3.89 mol). The resulting suspension was heated to 55 ° C over the course of 30 minutes, and then stirred at 55 ° C for 30 minutes. A solution of 175 g (1.73 mol) of Et3N (ALDRICH) in 200 mL of MeOH was added to the suspension while it was cooling to 30 ° C. The suspension was maintained at 30 ° C while a solution of 128 g (1.26 mol) of Et 3 N in 2 liters of MeOH was added dropwise over the course of 6 hours. A sample of the resulting suspension was taken to determine the crystalline form (Form B). The suspension was cooled, kept at 5 ° C for 15 minutes, and then filtered through a thick frit filter. The resulting filter cake was washed with multiple 200 ml washes of cold MeOH. The solid product was dried at 55 ° C under vacuum to provide 710 g (91% yield) of the compound as yellow crystals. It should be understood that the above description is intended to be illustrative and not restrictive. Many modalities will be apparent to those skilled in the art after reading the above description. Therefore, the scope of the invention should not be determined by reference to the foregoing description, but should be determined with reference to the appended claims, together with the full scope of equivalents to which said claims are entitled. Descriptions of all articles and references, including granted patents, patent applications and patent publications, are incorporated herein by reference in their entirety and for all purposes.

Preparation 13 N - [(R) -2,3-Dihydroxy-propoxp-3,4-d-fluoro-2- (2-fluoro-4-vodo-phenylamino) -benzamide (Form IV) To a flask containing acid 3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzoic acid (2.6 kg, 6.6 mol) and?,? '- carbonyldiimidazole (1.1 kg, 6.8 mol) under nitrogen atmosphere, 12 liters of nitrogen were added. dry acetonitrile. After stirring at 22 ° ± 5 ° C for about 90 minutes, a solution of (7? -0- (2,2-dimethyl- [1, 3] dioxolan-4-ylmethyl) -hydroxylamine in toluene was added ( total volume 8.5 liters, approximately 8 moles of amine) The solution was stirred for at least 6 hours at 22 ° ± 5 ° C. Aqueous hydrochloric acid (9 liters, 1.5 molar) was added, and after stirring for about 5 minutes, The layers were separated, aqueous hydrochloric acid (9 liters, 1.5 molar) was added to the remaining upper layer and, after stirring for about 20 hours, the layers were separated, the remaining top layer was concentrated by vacuum distillation, and then diluted with 15 liters of toluene and 2 liters of ethanol, the mixture was heated to 35-45 ° C, diluted with 20 liters of warm water, and then cooled to 0-5 ° C. The product was isolated by filtration, and washed with 2 liters of toluene.The product was recrystald by dissolving it in 12 liters of toluene and 2 liters of ethanol (at 50 ° ± 5 ° C), by adding 10 liters of water, and cooling to 0-5 ° C. After isolating the product by filtration and washing with toluene, the product was dried in a vacuum oven, yielding 2.6 kg of N - [(R) -2,3-dihydroxypropoxy] -3,4-difluoro-2- (2- fluoro-4-iodo-phenylamino) -benzamide. 2.4 kg of the preceding compound, as a mixture of different crystalline forms, were stirred in a mixture of 10 liters of water and 1 liter of ethanol at 35 + 5 ° C for 20-30 hours, and then cooled to 25 + 5C. The product was isolated by filtration, washed with 1 liter of water, and then dried at 65 ° C in a vacuum oven. This resulted in 2.3 kg of material containing more than 90% Form IV. Note: DSC analysis shows a melting onset at 110 ° C, and only a small peak amount with melting onset at 117 ° C.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a combination comprising a selective inhibitor of CDK and one or more signal transduction inhibitors, for the preparation of a medicament for treating abnormal cell growth in a patient.

2. The use claimed in claim 1, wherein the medicament comprises a selective inhibitor of CDK-4, CDK-6 inhibitor or CDK-4/6 inhibitor, and one or more signal transduction inhibitors. .

3. The use claimed in claim 2, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-pperazin-1) -yl-pyridin-2-ylammon) -8 / - / - pyrido [2,3-d] pyrimidin-7-one and one or more signal transduction inhibitors.

4. The use claimed in claim 3, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1- l-pyridin-2-ylamino) -8H-pyrido [2,3-d] pyrimidin-7-one and a MEK inhibitor.

5. The use claimed in claim 4, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-p) Ridin-2-amyl) -8 - / - pyrid [2,3-d] pyrimidin-7-one and the MEK inhibitor 2- (2-chloro-4-) iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide.

6. The use claimed in claim 4, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridine) -2-¡llanono) -8 / - / - pyrida [2,3-d] pyrimidin-7-one and the inhibitor of MEK / V - [(R) -2,3-dihydroxy-propoxy] -3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino) -benzamide.

7. The use claimed in claim 3, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridine) -2-ylamino) -8 / - / - pyrido [2,3-d] pyrimidin-7-one and a signal transduction inhibitor selected from the group consisting of Raf kinase inhibitor, Akt inhibitor and inhibitor of mTOR.

8. The use claimed in claim 7, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin- 2-ylammon) -8H-pyridono [2,3-d] pyrimidin-7-one and a kinase inhibitor Raf or mTOR, selected from the group consisting of BAY 43-9006, rapamycin, CCI 779, Rad001 or Arry 142886.

9. The use claimed in claim 3, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl -2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrid [2,3-d] pyrimidin-7-one and one or more inhibitors of signal transduction selected from the group consisting of bcr-abl tyrosine-clnase inhibitors, PDGFR inhibitors, c-Kit inhibitors, erbB inhibitors, VEGF-R inhibitors, FGFR inhibitors and IGF1-R inhibitors.

10. The use claimed in claim 9, wherein the medicament comprises the inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-pperazin-1-yl-pyridine) -2-ylamino) -8 / - pyrida [2,3-d] pyrimidin-7-one and an inhibitor of PDGFR, erbB, or VEGF-R selected from the group consisting of CP-868,596, ST-1571 , PTK-787, PKC-412, Herceptin (trastuzumab), Erbitux, Iressa (gefitinib), Tarceva (erlotinib), EKB-569, PKI-166, GW-572016, E-2-methoxy-N- (3- { 4- [3-methyl-4- (6-methyl-pyridin-3-yloxy) -phenylamino] -quinazolin-6-yl] -allyl) -aceta-mide, CI-1033, CP -547,632, PTK 787, ZD 6474, PKC 412 and Avastin (bevacizumeb). 11.- The use of a combination of an inhibitor of CDK4 / 6 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-1-pyridin -2-amino) -8 - / - pyrido [2,3-djpyrimidin-7-one and a multi-directed kinase inhibitor for the preparation of a medicament for treating abnormal cell growth in a patient. 12. The use claimed in claim 11, wherein the medicament comprises the inhibitor of CDK 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-p) Ridin-2-ylamino) -8H-pyrid [2,3-d] pyridin-7-one and a multi-directed kinase inhibitor that is SU11248 or Gleevec. 13. The use claimed in any of the claims 1, 5 or 11, wherein the medicament comprises one or more additional therapeutic agents selected from the group consisting of an antitumor agent, alkylating agent, antimetabolite, antibiotic, antitumor agent derived from plants, camptothecin derivative, interferon, and response modifier. biological 14. The use claimed in any of claims 1, 5 or 11, wherein the medicament further comprises one or more additional therapeutic agents selected from the group consisting of cisplatin, oxaliplatin, carboplatin, cyclophosphamide, 5-fluorouracil, capecitabine , cytosine arabinoside, hydroxyurea, N- (5- [N- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) -N-methylamino] -2-tenoyl) -L-glutamic acid, adriamycin, bleomycin, interferon, Nolvadex (tamoxifen) and Casodex (4'-cyano-3- (4-fluorophenylsulfoni ^ -hydroxy ^ -methyl-S'-rifluoromethyl propionanilide) 15.- A pharmaceutical combination comprising an amount of 6 -acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8 - / - pyrido [2,3-cf] pyrimidin-7- One or a sephionate salt thereof and an amount of one or more signal transduction inhibitors selected from the group consisting of tyrosine kinase inhibitors, MEK inhibitors, tyrosine kinase inhibitors, bcr-abl, PDGFR inhibitors, c-Kit inhibitors, erbB inhibitors, VEGF-R inhibitors, Hsp 90 inhibitors, Aurora kinase inhibitors, FLT-3 inhibitors, n-Ras inhibitors, PI3 kinase inhibitors, kinase inhibitors Raf, Akt inhibitors, mTOR inhibitors, and multi-targeted kinase inhibitors.