ES2349763T3 - TREATMENT OF SOLID TUMOR DISEASES WITH COMBINATIONS INCLUDING IMATINIB AND AN EFLUJO PUMP INHIBITOR. - Google Patents

Abstract

Use of a combination comprising (a) N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl) -4- (3-pyridyl) -2 pyrimidin-amine as the sole ingredient active that inhibits the BCRP efflux pump, (b) at least one compound that inhibits an efflux pump selected from MDR1 and MRP2 selected from the group consisting of: (1) [3'-deoxy-3'-oxo- MeBmt] 1-cyclosporine, (2) [3'-deoxy-3'-oxo-MeBmt] 1 - [Val] 2-cyclosporin, (3) [3'-deoxy-3'-oxoMeBmt] 1 - [Nva] 2-cyclosporine, (4) Cycle- [Pec-MeVal-Val-MeAsp (f3-Pt-Bu) -Melle-Melle-Gly-MeVal-Tyr (Me) -L- Lact], (5) cycle- [Pec -MeVal-Val-MeAsp-Melle-Melle-Gly-MeVal-Tyr (Me) -D-Lact], and (6) verapamil, (c) optionally an anti-neoplastic agent, (d) optionally an alkylating agent, and (e) optionally hydroxyurea, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, and optionally at least one pharmaceutical vehicle amente acceptable; for simultaneous, separate or sequential use in the preparation of a medicament for the treatment of a solid tumor disease.

Description

The invention relates to the treatment of a warm-blooded animal, especially a human, presenting a solid tumor disease comprising the use of a combination comprising (a) N- {5- [4- (4-methyl-piperazinomethyl) ) -benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidin-amine as the only active ingredient that inhibits the BCRP efflux pump, (b) at least one compound that inhibits the efflux pump active in the cerebral blood barrier of MDR1 and MRP2 selected from the group consisting of: (1) [3'-deoxy-3'-oxo-MeBmt] 1 cyclosporin, (2) [3'-deoxy-3'-oxo-MeBmt] 1- [Val] 2-cyclosporine, (3) [3'-deoxy-3'oxoMeBmt] 1- [Nval] 2-cyclosporine, (4) cyclo- [Pec-MeVal-Val-MeAsp (β-Pt-Bu ) -MelleMelle-Gly-MeVal-Tyr (Me) -L-Lact], (5) cycle- [Pec-MeVal-Val-MeAsp-Melle-Melle-GlyMeVal-Tyr (Me) -D-Lact], and ( 6) verapamil, (c) optionally an antineoplastic agent, especially as defined in this invention, (d) optionally an alkylating agent and (e) optionally, h Idroxyurea for the treatment of a solid tumor disease.

The N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl} 4- (3-pyridyl) -2-pyrimidin-amine (imatinib mesylate, STI571) mesylate salt is Marketed under the name Glivec® (Gleevec®), Gliveec® is a tyrosine kinase inhibitor suitable for the treatment of chronic myeloid leukemia and GIST (gastrointestinal stromal tumors). New clinical studies in patients with glioblastoma multiforme (GBM) show response in terms of bursting and progression-free survival when Glivec® is administered together with hydroxyurea (G. Dresemann, ASCO 2004, summary 1550; Reardon et al. J Clin Oncol. 20 of December 2005, 23 (36); 9359-68; Dresemann, Ann Oncol. October 2005, 16 (10): 1702-8). Because ST1571 brain uptake is rather limited, as shown in animal studies, this also limits the pharmacological effect of Glivec®. It was suggested to improve imatinib mesylate brain penetration by co-administration of a BCRP inhibitor and, optionally, a P-gp inhibitor (“The effect of Bcrpi (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): implications for the use of BCRP and P-gp inhibitors to enable the brain penetration of imatinib in patients. ”Breedveld P, Puim D, Cipriani G, Wielinga P, van Tellingen O, Schinkel AH et al. Cancer Res. 2005, April 1; 65 (7): 2577-82). Breedveld P. et al. describes the effect of inhibitors of P-gp and Bcrp1 on intravenous imatinib brain penetration in mice. The authors show that the elacridar inhibitor significantly increases imatinib brain penetration (see Figure 4a).

Attention should be paid to the fact that elacriding in both a Bcrp1 and P-gp inhibitor, as cited by the same authors on page 2581, right part, last sentence of the third paragraph. Therefore it is not clear whether the effect shown by elacridar is due to a P-gp or Brcp1 inhibitor. The authors concluded that the positive effect of the drug was due to the inhibition of Brcp1 and not P-gp. Therefore, the person skilled in the art when reading document D1 would probably avoid using a P-gp inhibitor only in combination with imatinib, but it focuses on Bcrp1 inhibitors, or at least in the combination of a Brcp1 inhibitor. and a P-gp inhibitor with imatinib.

WO 2006/012958 shows the use of a combination comprising a) a BCRP (breast cancer resistance protein) inhibitor, b) imatinib and c) a P-gp (P-glycoprotein) and imatinib inhibitor and a additional BCRP inhibitor.

Mahon, F-X et al. Blood, volume 101, 2003, number 6, pages 2368-2373 analyzes the effect of imatinib on cell viability in a CML cell line that overexpresses P-gp (K562 / DOX) that was treated with verapamil or PSC833 (waltzpodar). The study differs from the indications of the present application in that the authors look only at the toxic effect of imatinib on cell lines derived from CML in an in vitro model in which P-gp is artificially overexpressed.

Dai H. et al., J. Pharm. Exp. Ther., Vol. 304, 2003, number 3, pages 10851092 refers to the question of whether the imatinib drug is an efflux target mediated by P-gp in the blood-brain barrier. Mainly, the study examines the role of P-gp in a knocked out mouse model, in which the imatinib distribution in blood-brain is analyzed after drug administration. The combinations claimed in this document show a surprisingly better effect on the imatinib brain / plasma distribution than the P-gp inhibitor LY335979.

N- {5- [4- (piperazino-methyl) -benzoylamido] -2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine (CGP74588) is an active metabolite of imatinib.

Surprisingly it has now been found that the co-administration of STI571 with at least one compound that inhibits an active efflux pump in the selected cerebral blood barrier of MDR1 and MRP2 selected from the group consisting of (1) [3'-deoxy-3 '-oxo-MeBmt] 1-cyclosporine, (2) [3'-deoxy-3'-oxoMeBmt] 1- [Val] 2-cyclosporine, (3) [3'-deoxy-3'-oxo-MeBmt] 1 - [Nval] 2-cyclosporine, (4) cyclo- [Pec-MeVal-Val-MeAsp (β-Pt-Bu) -Melle-Melle-Gly-MeVal-Tyr (Me) -L-Lact], (5) cycle- [Pec-MeVal-Val-MeAsp-Melle-Melle-Gly-MeVal-Tyr (Me) -D-Lact], and (6) verapamil, represents a route to significantly improve brain penetration of ST1571 also in the absence of any active ingredient that inhibits BCRP other than ST1571 itself. Hence, the present invention relates in a first aspect to the use of a combination comprising (a) N- {5- [4- (4-methyl-piperazinomethyl) -benzoylamido] -2-methylphenyl) -4- (3 -pyridyl) -2-pyrimidin-amine, as the only active ingredient that inhibits the BCRP efflux pump, (b) at least one compound that inhibits the active efflux pump in the MDR1 and MRP2 cerebral blood barrier selected from the group consisting of: (1) [3'-deoxy-3'-oxo-MeBmt] 1 cyclosporin, (2) [3'-deoxy-3'-oxo-MeBmt] 1- [Val] 2-cyclosporine, (3) [ 3'-deoxy-3'oxoMeBmt] 1- [Nval] 2-cyclosporine, (4) cycle- [Pec-MeVal-Val-MeAsp (β-Pt-Bu) -MelleMelle-Gly-MeVal-Tyr (Me) - L-Lact], (5) cycle- [Pec-MeVal-Val-MeAsp-Melle-Melle-GlyMeVal-Tyr (Me) -D-Lact], and (6) verapamil, (c) optionally an antineoplastic agent, especially as defined in this invention, (d) optionally an alkylating agent and (e) optionally, hydroxyurea, in which the compounds may also be present in the form of their s Pharmaceutically acceptable ales or any hydrate thereof, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the preparation of a medicament for the treatment of solid tumor disease.

MDR1 and MRP2 efflux pumps are known to be active in the cerebral blood barrier. Hence, the present invention is particularly useful for the treatment of a solid tumor disease located in the central nervous system (CNS), especially glioma, such as glioblastoma multiforme. As used herein, the term "glioma" includes all primary intrinsic neoplasms of the brain and spinal cord, for example, astrocytomas, ependymomas, neurocytomas or meningiomas. In a broader aspect the combinations as described in this invention can be used for any solid tumor disease by preventing efflux of N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl ) -4- (3-pyridyl) -2-pyrimidin-amine in the tumor cells.

The term "solid tumor" as used in the present invention especially means breast cancer, colon cancer and in general of the GI tract, lung cancer, particularly small cell lung cancer, and non-lung cancer. small cells, head and neck cancer, urogenital cancer, for example, cervical, uterine, ovarian, testicular, prostate or bladder cancer, Hodgkin's disease or Kaposi's sarcoma. Depending on the type of tumor and the particular combination used, a reduction in tumor volume can be obtained.

The combinations of the present invention can be used in the form of a combined preparation or a pharmaceutical composition.

The term "a combined preparation" as used herein especially defines a "kit of parts" in the sense that the components of the combination (a), (b), (c), (d) and ( e) as defined above they can be dosed independently or with the use of different fixed combinations with different amounts of the components of the combination a), (b), (c), (d) and (e), that is, simultaneously or at different times of time. The parts of the parts kit can be administered, for example, simultaneously or in chronological phases, that is at different times and with the same or different time intervals for any part of the parts kit. Most preferably, the time intervals are selected such that the effect on the disease treated in the combined use of the parts is longer than the effect that would be obtained with use of only any one of the components of the combination. The ratio of the total amounts of the components of the combination (a), (b), (c), (d) and (e) can be varied in relation to each of those administered in the combined preparation, for example, in order to cover the needs of a subpopulation of patients to be treated or the needs of the individual patient whose different needs may be due to the particular disease, age, sex, body weight, etc. from the patients. Preferably, there is at least one beneficial effect, for example, a mutual improvement of the effect of the components of the combination (a), (b), (c), (d) and (e), in particular a synergism, for example , a more than additive effect, additional advantageous effects, less side effects, a combined therapeutic effect in an ineffective dosage of one or both of the components of the combination (a), (b), (c), (d) and (e), and most preferably a strong synergism of the components of the combination (a), (b), (c), (d) and (e).

The term "treatment" includes the treatment of a patient in need thereof which results in a delay in the progression of solid tumor disease. The term "progression delay" as used herein means administration of the combination to patients who are in a pre-stage or in a previous phase of the disease to be treated, in which it is diagnosed. to patients, for example, a pre-form of the corresponding disease or those patients who are in a state, for example, during a medical treatment or a state resulting from an accident, under which the development of a disease is likely correspondent.

It will be understood that references to the components of the combination are understood to also include pharmaceutically acceptable salts or prodrugs. If the components of the combination have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts may also be formed which have, if desired, an additionally present basic center. A combination component (a), (b), (c) or

(d) having an acid group (for example COOH) can also form salts with bases. N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2pyrimidin-amine, that is, component of the combination (a), is preferably used in the present invention in the form of its monomesylate salt (STI571).

N-phenyl-2-pyrimidin-amine derivatives are especially described in US 5,521,184. N- {5- [4- (4-methyl-piperazino-methyl) benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine can be prepared as described in US 5,521. 184 The mon- monosylate salt of N- {5- [4- (4-methyl-piperazino-methyl) benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidin-amine can be prepared and formulated, for example , as described in examples 4 and 6 of WSO 99/03854 or as described in WO 03/090720. N- {5- [4 (piperazino-methyl) -benzoylamido] -2-methylphenyl} -4- (3-pyridyl) -2-pyrimidine-amine (CGP74588) can be prepared as described in US 2004-0102453 .

A compound is selected that inhibits the efflux pump MDR1 (P-gp inhibitor) of verapamil, [3'-deoxy-3'-oxo-MeBmt] 1-cyclosporine, [3'-deoxy-3'-oxoMeBmt] 1 - [Val] 2-cyclosporine and [3'-deoxy-3'-oxo-MeBmt] 1 [Nva] 2-cyclosporine, such cyclosporins are described in EP 0296122 in example H as cyclosporins 1.37, 1.38 and 1.39, respectively, as well as cycle- [Pec-MeValVal-MeAsp ([beta] -Pt-Bu) -Melle-Melle-Gly-MeVal-Tyr (Me) -L-Lact] and cycle- [Pec-MeValVal-MeAsp- Melle-Melle-Gly-MeVal-Tyr (Me) -D-Lact], described in EP 0360760 as examples 52 and 1 (first compound), respectively. With regard to all aspects of the present invention, it is preferably used as a P-gp [3'-deoxy-3'-oxo-MeBmt] 1- [Val] 2-cyclosporin A inhibitor, also known as waltzpodar, hereinafter also designated as PSC833, known from EP 296122 (example H). PSC833 can be administered in the form of the galenic composition described in WO 93/20833.

The term "alkylating agents" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide and melphalan. Cyclophosphamide can be administered, for example, in the form as it is marketed, for example, under the trade name CYCLOSTINTM. Ifosfamide can be administered, for example, in the form as it is marketed, for example, under the trade name HOLOXANTM. A preferred alkylating agent is iemozoiomide.

The term "antineoplastic agents" as used herein includes, but is not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubular active agents, antineoplastic antimetabolites, platinum compounds, compounds which reduce the activity of protein kinase and additional anti-angiogenic compounds, gonadorelin agonists, anti-androgens, bisphosphonates and trastuzumab.

The term "aromatase inhibitors" as used herein refers to compounds that inhibit the production of estrogen, that is, the conversion of androstenedione and testosterone substrates to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, vorozole, fadrozole, anastrozole and, most especially, letrozole. Exemestane can be administered, for example, in the form as it is marketed, for example, under the trade name AROMASINTM. Formestane can be administered, for example, in the form as it is marketed, for example, under the trade name LENTARONTM. Fadrozol can be administered, for example, in the form as it is marketed, for example, under the trade name AFEMATM. Anastrozole can be administered, for example, in the form as it is marketed, for example, under the trade name ARIMIDEXTM. Letrozole can be administered, for example, in the form as it is marketed, for example, under the trade name FEMARATM or FEMARTM. Letrozole has been specifically described in European Patent No. 0236940 published on September 16, 1987, as well as in United States Patent No. 4,978,672 published on December 18, 1990, and Japanese Patent Number 2018112 all of them a Applicant's name. Aminoglutehimide can be administered, for example, in the form as it is marketed, for example, under the trade name ORIMETENTM.

The term "antiestrogens" as used herein refers to compounds that antagonize the effect of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is marketed, for example, under the trade name NOLVADEXTM. Raloxifene hydrochloride can be administered, for example, in the form as it is marketed, for example, under the trade name EVIST ATM. Fulvestrant can be formulated as described in US 4,659,516 or it can be administered, for example, in the form as it is marketed, for example, under the trade name FASLODEXTM.

The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, irinotecan, 9 nitrocamptothecin and the PNU-166148 macromolecular camptothecin conjugate (compound A1 in WO 99/17804). Irinotecano can be administered, for example, in the way it is marketed, for example, under the trade name CAMPTOSARTM. Topotecan can be administered, for example, in the way it is marketed, for example, under the trade name HYCAMTINTM.

The term "topoisomerase Ii inhibitors" as used herein includes, but is not limited to, anthracyclines doxorubicin (including liposomal formulation, for example CALYXTM), epirubicin, idarubicin and nemorubicin, anthraquinones mitoxantrone and losoxantrone, and the etoposide and teniposide podophyllotoxins. Etoposide can be administered, for example, in the form as it is marketed, for example, under the trade name ETOPOFHOSTM. Teniposide can be administered, for example, in the form as it is marketed, for example, under the trade name VM 26-BRISTOLTM. Doxorubicin can be administered, for example, in the form as it is marketed, for example, under the trade name ADRIBLASTINTM. Epirubicin can be administered, for example, in the form as it is marketed, for example, under the trade name FARMORUBICINTM. Idarubicin can be administered, for example, in the form as it is marketed, for example, under the trade name ZAVEDOSTM. Mitoxantrone can be administered, for example, in the form as it is marketed, for example, under the trade name NOVANTRONTM.

The term "microtubular active agents" refers to microtubule stabilization agents and microtubule destabilizing agents that include, but are not limited to, paclitaxel and docetaxel taxanes, vinca alkaloids, for example, vinblastine, especially vinblastine sulfate , vincristine especially vincristine sulfate, and vinorelbine and epothilones. Paclitaxel (Taxol® is a natural product with antitumor activity. TAXOL is obtained by a semi-synthetic method of Taxus baccata. The chemical name of paclitaxel is 5 (beta), 20-epoxy-1,2- (alpha), 4,7- (beta), 10 (beta), 13 (alpha) -hexahydroxitax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R, 3S) -N-benzoyl-3 "phenylisoserine. Docetaxel may be administered, for example, in the form as it is marketed, for example, under the trade name TAXOTERETM. Vinblastine sulfate may be administered, for example, in the form as it is marketed, for example, under the name commercial VINBLASTIN RPTM Vincristine sulfate can be administered, for example, in the form as it is marketed, for example, under the trade name FARMISTINTM.

The term "antineoplastic antimetabolites" includes, but is not limited to, 5-fluorouracil, capecitabine, gemcitabine, methotrexate and edatrexate. Capecitabine can be administered, for example, in the form as it is marketed, for example, under the trade name XELODATM. Gemcitabine can be administered, for example, in the form as it is marketed, for example, under the trade name GEMZARTM. The term "platinum compounds" as used herein includes, but is not limited to, carboplatin, cisplatin and oxaliplatin. Carboplatin can be administered, for example, in the form as it is marketed, for example, under the trade name CARBOPLATTM. Oxaplatin can be administered, for example, in the form as it is marketed, for example, under the trade name ELOXATINTM.

The term "compounds that reduce the activity of the protein kinase and additional anti-angiogenic compounds" as used herein includes, but are not limited to, compounds that reduce the activity of the epidermal growth factor (EGF) of the factor. of epidermal growth (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and / or anti-angiogenic protein kinase C compounds that have another mechanism for their activity.

Compounds that reduce VEGF activity are especially compounds that inhibit VEGF receptor tyrosine kinase, compounds that inhibit a VEGF receptor and compounds that bind VEGF, and are in particular those compounds, proteins and monoclonal antibodies described in general and specifically in WO 98/35958, WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0769947; those that describe M. Prewett et al. in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al. in Proc. Natl Acad. Sci. USA, vol. 93 pages 14765-14770, December 1996, by Z. Zhu et al. in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al. in Toxicologic Pathology, vol. 27, number 1, pages 14-21, 1999; in WO 00/37502 and WO 94/10202; AngiostatinTM, described by M.S. O'Reilly et al., Cell 79, 1994, 315-328; and EndostatinTM, described by M.S. O'Reilly et al., Cell 88, 1997, 277-285; Compounds that reduce the activity of the epidemic growth factor (EGF) are especially compounds that inhibit the EGF receptor tyrosine kinase, compounds that inhibit the EGF receptor and compounds that bind to EGF and are in particular those compounds described in general and specifically in WO 97/02266, EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980; compounds that reduce the activity of protein kinase C are especially those derived from stauro-sporin described in EP 0296110 (pharmaceutical preparation described in WO 00/48571) whose compounds are inhibitors of protein kinase C; In all cases of references to patent applications or scientific publications, the claims of compounds and the final products of the embodiments are particularly given, the subject matter of the final products. Pharmaceutical preparations and claims of such patent publications are incorporated into the present application by reference to said publications. The corresponding stereoisomers are also included as well as the corresponding crystalline modifications, for example, solvates and polymorphs, which are described therein. The compounds used as active ingredients in the combinations disclosed herein can be prepared and administered as described in the cited documents, respectively.

Additional anti-angiogenic compounds are thalidomide (THALOMID), SU5416, and celecoxib (Celebrex);

The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin is described in US 4,100,274 and can be administered, for example, in the form as it is marketed, for example, under the trade name ZOLADEXTM. Abarelix can be formulated, for example, as described in US 5,843,901.

The term "anti-androgens" as used herein includes, but is not limited to, bicalutamide (CASODEXTM), which can be formulated, for example, as described in US 4,636,505.

The term "bisphosphonates" as used herein includes, but is not limited to, etridonic acid, clodronium acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. "Etridonic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name DIDRONELTM. "Clodronic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name BONEFOSTM. "Tiludronic acid" may be administered, for example, in the form as it is marketed, for example, under the trade name SKELIDTM. "Pamidronic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name AREDIATM. "Alendronic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name FOSAMAXTM. "Ibandronic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name BONDRANATTM. "Risedronic acid" may be administered, for example, in the form as it is marketed, for example, under the trade name ACTONELTM. "Zoledronic acid" can be administered, for example, in the form as it is marketed, for example, under the trade name ZOMETATM. "Zoledronic acid" has been specifically described in European Patent No. 0275821, published on July 27, 1988, as well as in United States Patent No. 4,939,130 issued on July 3, 1990, and the Japanese patent number 2744238 all in the name of the applicant. The term "zoledronic acid" also includes pharmacologically acceptable salt or any hydrate thereof such as anhydrous zoledronic acid, zoledronic acid monohydrate, disodium zeldronate, trisodium zeldronate.

"Trastuzumab" may be administered, for example, in the form as it is marketed, for example, under the trade name HECEPTINTM.

The structure of active agents identified by code numbers, generic or trade names can be found in the current edition of the “The Merck Index” compendium or databases, for example, international patents (for example, IMS Word Publications).

A combination comprising (a) N- {5- [4- (4-methyl-piperazino-methyl) benzoylamido] -2-methylphenyl) -4- (3-pyridyl) -2-pyrimidin-amine, as the sole ingredient active that inhibits the BCRP efflux pump, (b) at least one compound that inhibits the active efflux pump selected from MDR1 and MRP2 selected from the group consisting of: (1) [3'-deoxy-3'-oxo-MeBmt ] 1-cyclosporine, (2) [3'-deoxy-3'-oxoMeBmt] 1- [Val] 2-cyclosporine, (3) [3'-deoxy-3'-oxoMeBmt] 1- [Nval] 2-cyclosporine , (4) cycle [Pec-MeVal-Val-MeAsp (β-Pt-Bu) -Melle-Melle-Gly-MeVal-Tyr (Me) -L-Lact], (5) cycle [Pec-MeVal-Val- MeAsp-Melle-Melle-Gly-MeVal-Tyr (Me) -D-Lact], and (6) verapamil, (c) optionally an antineoplastic agent, especially as defined in this invention, and (d) optionally an alkylating agent and (e) optionally, hydroxyurea, in which the compounds may also be present in the form of their pharmaceutically acceptable salts or any hydrate thereof, and optionally at least A pharmaceutically acceptable vehicle, for simultaneous use, separately or sequentially, will hereinafter be referred to as a COMBINATION OF THE INVENTION.

It can be demonstrated by the established test models and in particular those test models described in this invention that a COMBINATION OF THE INVENTION results in a significant improvement of STI571 uptake in solid tumor cells and STI571 brain penetration. Improved uptake and penetration results in a more effective treatment of solid tumor diseases, especially solid tumor diseases of the central nervous system. This advantage gives rise to the additional benefit that lower doses of the active ingredients of the COMBINATION OF THE INVENTION can be used for the same clinical effect, for example, that the necessary dosages are not only often smaller but can be applied less frequently therefore reducing the incidence of side effects. This is in line with the wishes and requirements of the patients to be treated.

The person skilled in the art is fully qualified to select a relevant test model to test the therapeutic indications and beneficial effects cited above and hereinafter. The pharmacological activity of a COMBINATION OF THE INVENTION may, for example, be demonstrated in a clinical study or in a test procedure as described essentially below.

The study in FVB mice described in the following examples of cerebral perfusion in situ indicates that the transport of imatinib through the blood-brain barrier is limited by saturable processes

image 1

Experiments in mdr1a1b (- / -) FVB mice strongly suggest that P-glycoprotein and breast cancer resistance protein are involved. In FVB-type mice, co-perfusion of 10 µM waltz with 0.5 µM imatinib can markedly improve imatinib distribution in the brain.

Suitable clinical studies are, for example, non-randomized open-label dose scale studies in patients with glioblastoma multiforme. Such studies demonstrate in particular the improved brain penetration of STI571 and the therapeutic efficacy of a COMBINATION OF THE INVENTION. The beneficial effects in solid tumor diseases can be determined directly by the results of these of these studies or by changes in the study design that are known as such by a person skilled in the art.

The COMBINATION OF THE INVENTION can also be applied in combination with surgery, moderate prolonged total body hyperthermia and / or irradiation therapy.

In one embodiment of the invention the chemotherapeutic agent is an antineoplastic agent selected from aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubular active agents, antineoplastic antimetabolites, platinum compounds, compounds that reduce protein activity kinase and additional antiangiogenic compounds, gonadorelin agonists, anti-androgens, bisphophonates and trastuzumab. In such an embodiment the antineoplastic agent is especially selected from pamidronic acid, zoledronic acid and letrozole, preferably zoledronic acid and letrozole.

A preferred embodiment of the invention relates to the use of a COMBINATION OF THE INVENTION for the treatment of glioma. Preferably in such an embodiment the COMBINATION OF THE INVENTION comprises hydroxyurea.

It is an object of the present invention to provide a pharmaceutical composition comprising an amount, which is therapeutically effective against a solid tumor disease comprising the COMBINATION OF THE INVENTION. In this composition, the components of the combination (a), (b), (c) and

(d) they can be administered together, one after the other or separately in a combined unit dosage form or in separate unit dosage forms. The unit dosage form can also be a fixed combination.

The pharmaceutical compositions for separate administration of the components of the combination (a), (b), (c), (d) and (e) and for administration in a fixed combination, ie a unique galenic composition comprising the At least two components of the combination according to the invention can be prepared in a manner known per se and are suitable for enteric administration such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including human, comprising a therapeutically effective amount of at least one component of the pharmacologically active combination alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteric or parenteral application.

The new pharmaceutical composition contains, for example, from about 10% to about 100%, preferably from about 20% to about 60% of the active ingredients. Pharmaceutical preparations for combination therapy for enteric or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and additionally ampoules. If not indicated otherwise, they are prepared in a known manner as is, for example by means of conventional mixing, granulation, sugar coating, solution or lyophilization procedures. It will be appreciated that the unit content of a combination component contained in an individual dose of each dosage form does not need in its own constitution an effective amount since the necessary effective amount can be achieved by administration of a plurality of dosage units.

In particular, a therapeutically effective amount of each of the components of the combination of the COMBINATION OF THE INVENTION can be administered simultaneously or sequentially and in any order, and the components can be administered separately or as a fixed combination. For example, the method of treating a solid tumor disease according to the invention may comprise (i) administration of the combination partner (a) in free form or pharmaceutically acceptable salt and (ii) administration of the combination partners ( b), (c), (d) or (e) in free form or pharmaceutically acceptable salt, simultaneously or sequentially or in any order, in therapeutically effective amounts, preferably in synergistically effective amounts, for example, in corresponding daily dosages at the amounts described in this invention. The individual combination components of the COMBINATION OF THE INVENTION may be administered separately at different times during the course of therapy or concurrently in divided or unique combination forms. In addition, the term administration also comprises the use of a prodrug of a component of the combination that is transformed in vivo into the component of the combination as such. The present invention should therefore be understood as comprising all simultaneous or alternating treatment regimens and the term "administration" should be interpreted in accordance with the foregoing.

The effective dosage of each of the combination components used in the COMBINATION OF THE INVENTION may vary depending on the particular compound or pharmaceutical composition used, the mode of administration, the condition in question, the severity of the condition that be concerned. Therefore, the dosage regimen of the COMBINATION OF THE INVENTION is selected according to a variety of factors including the route of administration and the renal and hepatic function of the patient. A physician, clinician or veterinarian skilled in the art can easily determine and prescribe the effective amount of simple active ingredients required to prevent, counteract or reverse the progress of the condition. The optimum precision to achieve the concentration of the active ingredients within the range that gives efficacy without toxicity requires a regime based on the kinetic parameters of bioavailability of the active ingredient at the target sites. When the combination components used in the COMBINATION OF THE INVENTION in the form of commercial simple drugs are administered, their dosage and mode of administration may take place in accordance with the information provided in the indications of the respective marketed drug package, with the in order to give rise to the beneficial effect described in this invention, if not otherwise cited in the present invention.

N- {5- [4- (4-Methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl} 4- (3-pyridyl) -2-pyrimidine-amine monomesylate is preferably administered to a human in a dosage in the range of about 25 to 1000 mg / day, more preferably 50 to 800 mg / day and most preferably 100 to 400 mg / day. Unless indicated otherwise, the compound is preferably administered one to four times a day.

Fadrozol can be administered orally to a human in a dosage range ranging from about 0.5 to about 10 mg / day, preferably from about 1 to about 2.5 mg / day.

Letrozole can be administered orally to a human in a dosage range ranging from about 0.1 to about 10 mg / day, preferably from about 0.5 to about 5 mg / day, most preferably from about 1 to about 2.5 mg / day Examples of compositions containing letrozole are well known in the art, for example Physicians ’Desk Reference Copyright © 2001 (Medical Economics Company Inc.). Simple doses of zoledronic acid should preferably not exceed 8 mg; preferably from 4 mg, more preferably from about 0.5 to about 4 mg. Compositions containing zoledronic acid are described in the art, for example, in international patent application US 01/14886 filed May 5, 2001 and published November 29, 2001.

Exemestane can be administered orally to a human in a dosage range ranging from about 5 to about 200 mg / day, preferably from about 10 to about 25 mg / day, or parenterally from about 50 to about 500 mg / day, preferably from about 100 to about 250 mg / day. If the drug could be administered in a separate pharmaceutical composition, it can be administered in the manner described in GB 2,177,700.

Formestane can be administered parenterally to a human in a dosage range ranging from about 100 to about 500 mg / day, preferably from about 250 to about 300 mg / day.

Anastrozole can be administered orally to a human in a dosage range ranging from about 0.25 to 20 mg / day, preferably from about 0.5 to about 2.5 mg / day.

Aminoglutehemide can be administered to a human in a dosage range that ranges from about 200 to 500 mg / day. Tamoxifen citrate can be administered to a human in a dosage range that ranges from approximately 10 to 40 mg / day.

Vinblastine can be administered to a human in a dosage range that ranges from approximately 1.5 to 10 mg / m2 day.

Vincristine sulfate can be administered parenterally to a human in a dosage range that ranges from about 0.025 to 0.05 mg / kg body weight * week.

Vinorelbine can be administered to a human in a dosage range that ranges from approximately 10 to 50 mg / m2 day.

Etoposide phosphate can be administered to a human in a dosage range ranging from about 25 to 115 mg / m2 day, for example 56.8 or 113.6 mg / m2 day.

Teniposide can be administered to a human in a dosage range that ranges from approximately 75 to 150 mg approximately every two weeks.

Doxorubicin can be administered to a human in a dosage range ranging from about 10 to 100 mg / m2 day, for example 25 or 50 mg / m2 day.

Epirubicin can be administered to a human in a dosage range that ranges from approximately 10 to 200 mg / m2 day. Idarubicin can be administered to a human in a dosage range that ranges from approximately 0.5 to 50 mg / m2 day.

Mitoxantrone can be administered to a human in a dosage range that ranges from approximately 2.5 to 25 mg / m2 day.

Paclitaxel can be administered to a human in a dosage range ranging from about 50 to 300 mg / m2 day.

Docetaxel can be administered to a human in a dosage range that ranges from approximately 25 to 100 mg / m2 day.

Cyclophosphamide can be administered to a human in a dosage range that ranges from approximately 50 to 1500 mg / m2 day.

Mefalano can be administered to a human in a dosage range that varies from approximately 0.5 to 10 mg / m2 day.

5-Fluorouracil can be administered to a human in a dosage range ranging from about 50 to 1000 mg / m2 day, for example 500 mg / m2 day.

Capecitabine can be administered to a human in a dosage range that varies from about 10 to 1000 mg / m2 day.

Gemcitabine hydrochloride can be administered to a human in a dosage range that varies from approximately 1000 mg / week.

Methotrexate can be administered to a human in a dosage range that varies from about 5 to 500 mg / m2 day.

Topotecan cannot be administered to a human in a dosage range that varies from about 1 to 5 mg / m2 day.

Irinotecano can be administered to a human in a dosage range that varies from approximately 50 to 350 mg / m2 day.

Carboplatin can be administered to a human in a dosage range that ranges from approximately 200 to 400 mg / m2 approximately every four weeks.

Cisplatin can be administered to a human in a dosage range that ranges from approximately 25 to 75 mg / m2 approximately every three weeks.

Oxaliplatin can be administered to a human in a dosage range that ranges from approximately 50 to 85 mg / m2 every two weeks.

Alendronic acid can be administered to a human in a dosage range that ranges from about 5 to 10 mg / day.

Clodronic acid can be administered to a human, for example, in a dosage range ranging from about 750 to 1500 mg / day.

Etridonic acid can be administered to a human in a dosage range that ranges from about 200 to 400 mg / day. Ibandronic acid can be administered to a human in a dosage range that varies from approximately 1 to 4 mg every three to four weeks.

Risedronic acid can be administered to a human in a dosage range that ranges from about 20 to 30 mg / day.

Pamidronic acid can be administered to a human in a dosage range that ranges from approximately 15 to 90 mg every three to four weeks.

Tiludronic acid can be administered to a human in a dosage range that ranges from approximately 200 to 400 mg / day.

Trastuzumab can be administered to a human in a dosage range that varies from about 1 to 4 mg / m2 week.

Bicalutamide can be administered to a human in a dosage range that ranges from approximately 25 to 50 mg / m2 day.

Paclitaxel can be administered to a human in a dosage range ranging from about 135 mg / m2 to about 175 mg / m2 administered intravenously every 3 weeks, or 100 mg / m2 every 2 weeks. The succinate salt described in example 62 of WO 98/35958 can be administered to a human in a dosage range of from about 50 to 1500, more preferably from about 100 to 750, and most preferably from 250 to 500, mg / day.

Additionally, the present invention concerns the use of a COMBINATION OF THE INVENTION for the treatment of a solid tumor disease and for the preparation of a medicament for the treatment of a solid tumor disease.

Furthermore, the present invention provides a commercial package comprising as active ingredients COMBINATION OF THE INVENTION, together with instructions for simultaneous, separate or sequential use thereof in the treatment of a solid tumor disease.

The following example illustrates the invention described above, but not intended to limit the scope of the invention in any way. Other test models known as such by the person skilled in the art in the corresponding art can also determine the beneficial effects of the COMBINATION OF THE INVENTION. Abbreviations AUC area under the concentration curve - time AUCult area under the concentration-time curve from zero to the last point

of measured time% CV coefficient of variation HPLC high performance liquid chromatography Kp partition constant LOQ detection limit PEG polyethylene glycol Rsq square correlation coefficient (statistical goodness of

adjustment) SD standard deviation of mean T1 / 2z apparent elimination half-period Vdss steady-state distribution volume Example 1: brain perfusion in situ in mice

Imatinib 0.5 µmol / L is administered to FVB mice using the in situ brain perfusion technique. After 1 minute of perfusion, the cerebral uptake of the drug is low (net transport constant - 1 µl / g / s). When 25 µM waltzpodar is co-perfused, imatinib brain uptake is improved by a factor of 2.5. Example 2: In vivo study in mice

Imatinib 12.5 mg / kg is administered intravenously to FVB mice: 1 h after the dose, the brain's penetration of the drug is low (brain-to-plasma concentration ratios <0.10). When 10 mg / kg of waltzpodar is administered intravenously 1 h after the dose, imatinib brain penetration is improved by a factor of 4 to 5. Example 3: In vivo study in rats

The pharmacokinetic parameters in imatinib blood and brain can be studied in Hanover Wistar rats for 24 hours. The drug (12.5 mg / kg) is administered intravenously with or without waltzpodar (10 mg / kg).

Group A: Rats successively receive [14C] STI571, 12.5 mg-base / kg (approx. 7.4 MBq / kg) in 0.9% saline solution by injection into an exposed saphenous vein (2 ml / kg ) and a mixture of ethanol - PEG 200 - 5% glucose (2: 6: 2 v / v / v) by injection into the other (2 ml / kg).

Group B: Rats successively receive [14C] STI571, 12.5 mg-base / kg (approx. 7.4 MBq / kg) in 0.9% saline solution by injection into an exposed saphenous vein (2 ml / kg ) and PSC833 (waltzpodar) 10 mg / kg in ethanol - PEG 200 - 5% glucose (2: 6: 2 v / v / v) by injection in the other (2 ml / kg).

Group C: Rats receive 10 mg / kg of [14C] inulin (approx. 1.9 MBq / kg; PerkinElmer, Boston, USA) in 0.9% saline solution by injection into the exposed saphenous vein.

At 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, rats of group A and B are sacrificed after anesthesia (n = 3 per group), while mice of group C are sacrificed 0 , 08 hours after administration (n = 3). Blood, plasma, brain are collected from each animal.

All samples are analyzed in relation to total radioactivity by liquid scintillation counting (LSC). Briefly, 50 µl of blood samples are successively mixed and incubated with 0.5 ml of Soluene 350-isopropanol 1: 1 (v / v), 0.2 ml of 30% H2O2 (overnight), 0, 5 ml of 2 N HCl (20 minutes) and 5 ml of IrgaSafe (Packard) (overnight). 50 µl of plasma samples are successively mixed and incubated with 0.5 ml of Soluene 350-isopropanol 1: 1 (v / v) overnight, 0.5 ml of 2N HCl (20 minutes) and 5 ml of IrgaSafe (during the night). 250 µl of brain homogenate sample is treated with 2 ml of Soluene 350 (overnight), 0.5 ml of 2N HCl (20 minutes) and 17.5 ml of Irgasafe (overnight). All samples are counted in Tricarb (Packard) liquid scintillation analyzers. Conventional automatic external techniques (inactivation compensation) are used to determine the efficiency of the respective radiometric analysis; the observed data (cpm) are transformed into disintegrations per minute (dpm).

In group A and B the samples are also analyzed in relation to unmodified STI571 by reverse dilution of isotopes based on liquid chromatography procedure (LC-RID). Briefly, the concentrations of unmodified STI571 in blood (200 µl), plasma (200 µl) and brain (500 µl homogenate) are determined by liquid chromatography procedure - reverse isotope dilution (LC-RID). The procedure involves the addition of 2.5 µg of non-radiolabeled STI571 to each sample as an internal standard. All blood samples were doped with 100 µl of water for hemolysis while all samples were analyzed directly. After adding 100 µl of pH 12 concentrated buffer and 4 ml of tert-butyl methyl ether, all samples were stirred for 15 minutes and centrifuged (6000 g, 10 minutes, 22 ° C). The organic phase is separated and evaporated in a vacuum centrifuge. The residues are dissolved in 250 µl of acetonitrile-water (30:70 v / v) followed by 75 µl of n-hexane. The reconstituted samples are then shaken and centrifuged (13000 g, 4 minutes, 22 ° C), the upper hexane layer is removed and 150 µl is analyzed in HPLC. STI571 is separated from potential metabolites and endogenous compounds on an analytical Symmetry C-18 column, 3.5 µM, 150 x 46 mm (Waters, Milford, USA) equipped with a C-18 Symmetry pre-column, 5 µM, 20 x 3.9 mm (Waters, Milford, USA) at 10 ° C. The mobile phases A and B comprise water with 0.2% formic acid and acetonitrile with 0.2% formic acid, respectively. The effluent is controlled with a UV detection device at 270 nm. The retention time of the STI571 peak is approximately 20 minutes. The peak corresponding to the unmodified compound is collected in a polyethylene vial using a fraction collector and the radioactivity of the drug is analyzed by LSC. The concentration of [14C] STI571 in each sample is calculated.

Imatinib brain penetration is only low. Valspodar has no significant impact on imatinib plasma pharmacokinetic parameters but strongly increases its penetration in the brain (brain-to-plasma concentration or AUC ratios x 5-6).

More specifically after intravenous bolus administration of 12.5 mg / kg of STI571:

-STI571 is distributed moderately in tissues (Vdss = 3.9 Ukg). The

penetration of unmodified SIT571 in the brain is low, that is, its ratio

AUC brain-to-blood, Kp, is 0.14.

-The brain exposure to metabolites related to STI571 is low, it is

In other words, their brain-to-blood AUC ratio, Kp, is 0.07.

After intravenous bolus administration of 12.5 mg / kg of STI571 and 10

mg / kg PSC833:

-The arrangement of metabolites related to STI571 looks slightly

modified Blood exposure to metabolites is multiplied by a

factor of 1.3 in blood and 1.5 in plasma.

-The unmodified brain penetration of STI571 is greatly improved with

PSC833 (Tables 1 and 2), that is, their brain-to-blood AUC ratio, Kp, is 0.64. Cmax is also reached 15 minutes after the dose but is multiplied with a factor of 3.7, that is, 4052 ng-eq / g in radioactivity relative to the compound or 3277 ng / g in unmodified STI571. Similarly, brain exposure to unmodified STI571 is markedly improved (i.e., 5.4 fold increase) and brain-blood concentration ratios for unmodified STI571 range from 0.55 to 0.95 (i.e. , increase 4.8 times on average). PSC833 does not significantly modify the removal slope of unmodified STI571 in brain to blood (t1 / 2z = 2.4 hours).

-After intravenous administration of 12.5 mg / kg of [14C] STI571 in rats, the fraction of unmodified STI571 among total radioactivity is more important in brain than in blood or plasma, that is, 80% versus 65 %

or 66% respectively. This demonstrates that STI571 metabolites weakly penetrate the brain compartment as confirmed by low metabolite concentrations in the brain. The brain penetration of metabolites related to STI571 is greatly increased by PSC833, that is, its brain-to-blood AUC ratio, Kp, is 0.31. Hence, the exposure in the brain is multiplied by 6.8 and the ratios of brain-to-blood Kp (table 3) in 4.4.

Example 4: accumulation of CCP74588 in rat C6 glioma cells Rat C6 glioma cells are used as a glioma model in studies in

In vitro or in vivo, to investigate the effect of this combination on cell proliferation.

Rat C6 glioma cells are maintained in modified Dulbecco medium with high glucose content supplemented with 10% fetal bovine serum and 2 nM Lglutamine in a humidified atmosphere of 95% air-5% CO 2. All accumulation tests are carried out in confluent cultures. For this purpose the cells are seeded in 24-well plates at a density of 100 * 103 cells / cm2 and allowed to proliferate in culture medium for 48 hours. The accumulation of CGP74588 (0.5 to 50 µM) is measured after 0.5, 1, 2, 4, 8 or 16 minutes of incubation in a conventional medium that does not contain serum. For competition trials, cultures with different concentrations of the different competitors are pre-incubated for 15 minutes. The accumulation of CGP74588 (1.5 - 50 µM) is measured after 1 minute of incubation in the presence of hydroxyurea (1, 10, 100 or 1000 µM), waltzpodar (1 or 10 µM), zosuquidar (1 or 10 µM) , elacridar (1 or 10 µM), carbamazepine (10 or 100 µM) or phenytoin (10 or 100 µM). The cell accumulation of

1.5 µM CGP745888 in C6 cells that have been pre-incubated with hydroxyurea (1, 10, 100 or 1000 µM) for 48 hours. The accumulation of CGP74588 in rat C6 cells is concentration dependent, suggesting that one or more saturable transport systems

5 influence their uptake in these cells. The accumulation of CGP74588 in rat C6 cells after 1 minute of incubation is significantly increased after 15 minutes of preincubation of the cells with waltzpodar, zosuquidar and elacridar. All these three inhibitors have a similar accumulation effect of CGP74588 at the same concentration (mean increase of 1.7 times at 1 µM and increase

10 medium 2.3 times at 10 µM).

Table 1: Group B radioactive brain kinetic parameters

Concentrations of compound-related radioactivity (ng-eq / g) in the brain corrected for blood contamination (4.7%) and pharmacokinetic parameters after intravenous administration of 12.5 mg / kg of [14C] STI471 and 10 mg / kg from

15 PSC833 to male Hanover Wistar rats (n = 3 per time point)

Weather

Data Half DT % CV

(h)

Individual

0.25

4321 4767 3069 4052 881 22

0.5

3987 3205 4123 3772 495 13

one

2583 2504 3362 2816 474 17

2

1655 2716 2102 2158 533 25

4

850 875 924 883 38

4

8

378 429 294 367 68 19

24

75 92 104 91 fifteen 16

Tmax

0.25

Cmax

4052

Cmax / dose

324

AUCult

10795

AUC

12192

AUC / dose

975

T1 / 2z

2.6

AUCcerebro / blood

0.51

AUCcerebro / plasma

0.39

to

Rsq> 0.97. LOQ = 27 ng-eq / g before correction of vascular contamination.

Tmax in h, Cmax in ng / g, Cmax / dose in (ng / g) / (mg / kg), AUCult and AUC in h ng-eq / g, AUC / dose in (h ng-eq / g) / (mg / kg), t1 / 2z in h, AUCcerebro / blood or plasma is the ratio of AUCcerebro versus AUCsangre or plasma for radioactivity related to compound. To achieve pmol / g concentrations, these levels are multiplied in ng-eq / g by the factor of 2.03.

Table 2: STI571 brain kinetic parameters in group A

STI571 concentrations in brain corrected for blood contamination (4.7%) and pharmacokinetic parameters after intravenous administration of 12.5 mg / kg of [14C] STI471 to male Hanover Wistar rats (n = 3 per

time point)

Weather

Data Half DT % CV

(h)

Individual

0.25

746 494 1438 893 488 55

0.5

652 717 229 533 265 fifty

one

540 506 604 550 fifty 9

2

402 275 322 333 64 19

4

102 112 131 115 14 12

8

52 33 29 38 12 32

24

<LOQ <LOQ <LOQ - - -

Tmax

0.25

Cmax

893

Cmax / dose

71

AUCult

1678

AUC

1802

AUC / dose

144

T1 / 2z

2.2

fno modified

79.9

AUCcerebro / blood

0.14

AUCcerebro / plasma

0.11

to

Rsq> 0.97. LOQ = 49 ng-eq / g before correction of vascular contamination. Tmax in h, Cmax in ng / g, Cmax / dose in (ng / g) / (mg / kg), AUCult and AUC in h ng-eq / g, AUC / dose in (h ng-eq / g) / (mg / kg), t1 / 2z in h. fno modified = fraction not changed (%)

based on cerebral AUC drug parent / radioactivity. AUCcerebro / blood or plasma is the ratio of AUCcerebro versus AUCsangre or plasma for STI571. To achieve pmol / g concentrations, these levels are multiplied in ng / g by 2.03 factor.

Table 3: Brain penetration of STI571-related metabolites in group B

[A] blood-brain concentration ratios for metabolites related to STI571 after intravenous administration of 12.5 mg / kg of [14C] STI471 and 10 mg / kg of PSC833 to male Hanover Wistar rats (n = 3 per time point)

Average Data Time DT% CV

(h) Individuals

0.25 0.54 0.62 0.28 0.48 0.18 37 0.5 0.49 0.35 0.43 0.42 0.07 16 1 0.26 0.41 0.47 0, 38 0.11 28 2 0.31 0.50 0.38 0.40 0.10 24 4 0.27 0.23 0.27 0.25 0.03 10 8 0.40 0.39 0.24 0 , 34 0.09 26 24 nd nd nd -

[B] brain-in-plasma concentration ratios for metabolites related to

STI571 after intravenous administration of 12.5 mg / kg of [14C] STI471 and 10 10 mg / kg of PSC833 to male Hanover Wistar rats (n = 3 per time point)

Weather

Data Half DT % CV

(h)

Individual

0.25

0.38 0.34 0.18 0.30 0.11 35

0.5

0.32 0.27 0.28 0.29 0.03 9

one

0.15 0.23 0.28 0.22 0.06 28

2

0.21 0.32 0.24 0.25 0.06 2. 3

4

0.20 0.13 0.17 0.17 0.03 twenty-one

8

0.26 0.27 0.15 0.23 0.07 29

24

nd nd nd - - -

nd = not determined

Claims (9)

1. Use of a combination comprising

(to)

N- {5- [4- (4-methyl-piperazino-methyl) -benzoylamido] -2-methylphenyl) -4- (3-pyridyl) -2pyrimidin-amine as the only active ingredient that inhibits the BCRP efflux pump,

(b)

at least one compound that inhibits an efflux pump selected from MDR1 and MRP2 selected from the group consisting of:

(one)

[3’-desoxi-3’-oxo-MeBmt] 1-cyclosporine,

(2)

[3’-desoxi-3’-oxo-MeBmt] 1- [Val] 2-cyclosporine,

(3)

[3’-desoxi-3’-oxoMeBmt] 1- [Nva] 2-cyclosporine, (4) Cycle- [Pec-MeVal-Val-MeAsp (f3-P-t-Bu) -Melle-Melle-Gly-MeVal-Tyr (Me) -L- Lact], (5) cycle- [Pec-MeVal-Val-MeAsp-Melle-Melle-Gly-MeVal-Tyr (Me) -D-Lact], Y

(6)

verapamil,

(C)

optionally an anti-neoplastic agent,

(d)

optionally an alkylating agent, and

(and)

optionally hydroxyurea, in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt or any hydrate thereof, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use in the preparation of a medicament for the treatment of a solid tumor disease.

2.

The use according to claim 1 wherein N- {5- [4- (4-methylpiperazino-methyl) -benzoylamido] -2-methylphenyl) -4- (3-pyridyl) -2-pyrimidine-amine is used in the form of its monomethanesulfonate salt.

3.

The use according to any one of claims 1, 2, wherein the solid tumor disease is located in the central nervous system.

Four.

The use according to any one of claims 1, 2, wherein the solid tumor disease is glioma.

5.

The use according to claims 3 or 4, wherein the combination comprises an alkylating agent, especially temozolomide.

6. The use according to any one of claims 3 to 5, wherein the combination comprises hydroxyurea. 7. The use according to any one of the preceding claims, wherein the combination comprises a compound that inhibits the MDR1 efflux pump selected from verapamil, 3'-deoxy-3'-oxo-MeBmt] 1-cyclosporine, [3'-deoxy 10 3’-oxo-MeBmt] 1- [Val] 2-cyclosporine and [3’-deoxy-3’-oxo-MeBmt] 1- [Nva] 2-cyclosporine. 8. The use according to any one of the preceding claims, wherein the combination comprises a compound that inhibits the MDR1 reflux pump, wherein said compound is waltzpodar (PSC833). fifteen 9. The use according to any one of the preceding claims, wherein 25 to 1000 mg / day of N- {5- [4- (4-methylpiperazino-methyl) -benzoylamido monomesylate] -2- methylphenyl) -4- (3-pyridyl) -2-pyrimidin-amine to a human patient. twenty