MX2007003459A - Thermodynamically stable form of bay 43-9006 tosylate - Google Patents

Abstract

The present invention relates to a novel form, thermodynamically stable at room temperature, of the tosylate salt of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide, to processes for its preparation, to medicaments comprising it and to its use in the control of disorders.

Description

THERMALLY STABLE FORM OF A TOSILATE SALT FIELD OF THE INVENTION The present invention relates to a new form, terraodynamically stable at room temperature, of the tosylate salt of 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders. BACKGROUND OF THE INVENTION The tosylate salt of 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide is mentioned in WO 03/068228 and WO 03/047579 and corresponds to the compound of formula (I): WO 03/068228 relates, inter alia, to the use of the compound of formula (I) for the treatment of disorders in which angiogenesis plays a role REF .: 180398 important, for example in the growth of tumors. Document 03/047579 relates to arylureas in combination with cytotoxic or cytostatic compounds for the treatment of cancer. The compound 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide is described in WO 00/42012 and corresponds to the compound of the formula (II): The compounds and their salts, described in WO 00/42012, for example tosylates, are described therein as inhibitors of the enzyme Raf kinase and can be used for the treatment of disorders, for example cancer. The compound of formula (II) is prepared in the manner described in WO 00/42012. The compound of formula (I) is prepared according to a general conventional procedure for the preparation of tosylate salts, as described in example 1 of the working examples. In this process, the compound of formula (I) is obtained in the form of a polymorph crystal which is referred to hereinafter as polymorph II. The polymorph II has a transition point of 194SC and an X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum and characteristic NIR spectrum (Table 1-6, Fig. 1-6). It has been discovered that polymorph II is metastable. Surprisingly, two more polymorphs and two solvates of the compound of formula (I) have been discovered. The compound of formula (I) in polymorph I melts to decomposition at 223-2319C, the compound of formula (I) in polymorph III melts at 187-190aC. The monomethanol solvate of the compound of formula (I) contains 4.8% methanol and the monoethanol solvate of the compound of formula (I) contains 6.7% ethanol. The polymorph I of the invention of the compound of formula (I) is thermodynamically stable at room temperature and is stable during storage even after processing it via suspensions and, therefore, is particularly suitable for use in pharmaceutical formulations, for example suspensions or creams, but also in other preparations which are prepared by the suspended active ingredient, for example in aqueous granulation or wet milling. The present invention provides the compound of formula (I) in polymorph I. The use of the invention of the compound of formula (I) in stable polymorph I ensures that an unwanted conversion to another polymorph and an associated change in the properties of the compound of formula (I), for example solubility or bioavailability. This increases the safety and quality of the preparations comprising the compound of the formula (I) and reduces the risk to the patient. The polymorph I of the compound of formula (I), compared to polymorph II, polymorph III, the ethanol solvate and methanol, has an X-ray diffractogram, a NIR spectrum, a FIR spectrum and a clearly differentiable Raman spectrum ( Fig. 2-6). The compound of the formula (I) in polymorph I melts to decomposition at 223-2312C and, therefore, is clearly distinguishable from polymorph II (conversion temperature at 194SC) and polymorph III (melting point 187-190 SC) ). Unlike solvent-free forms, the ethanol solvate of the compound of the formula (I) and the methanol solvate of the compound of the formula (I) have mass losses in the thermogravimetric analysis (TGA) of 6.7% and 4.8%, respectively (Fig. 1). The compound of the formula (I) of the invention in polymorph I is used with high purity in pharmaceutical formulations. For reasons of stability, a pharmaceutical formulation comprises the compound of formula (I) primarily in polymorph I and without otherwise significant fractions, for example from another polymorph or from a solvate of the compound of formula (I). The pharmaceutical composition preferably contains more than 90 percent by weight, more preferably more than 95 weight percent, of the compound of the formula (I) in the polymorph I with respect to the total amount of the compound of the formula (I) present in the composition. Treatment method: The present invention further provides the use of the compound of the formula (I) in polymorph I for the treatment of disorders. Preference is given to the use for the treatment of disorders exhibiting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, for example leukemia, or for the treatment of carcinoma, for example carcinoma of the lung, pancreas, thyroid gland, kidney or intestine, or for the treatment of the growth of carcinogenic cells. The present invention further provides the use of the compound of the formula (I) in polymorph I for the preparation of a pharmaceutical composition for the treatment of disorders. Preference is given to the use for the treatment of disorders exhibiting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, for example leukemia, or for the treatment of carcinoma, for example carcinoma of the lung, pancreas, thyroid gland, kidney or intestine, or for the treatment of the growth of carcinogenic cells. The compound of the formula (I) in polymorph I of the present invention can be used to treat, modulate and / or prevent any disease or condition mediated by one or more cellular signal transduction pathways involving raf, VEGFR, PDGFR, p38 and / or flt-3 kinases. The term "mediated" indicates, for example, that the signaling molecule is part of the pathway that is aberrant or altered in the disease and / or condition. While not wishing to be bound by any theory or mechanism of action, it has been found that the compounds of the present invention possess the ability to modulate the activity of the raf, VEGFR, PDGFR, p38 and / or flt-3 kinases. The methods of the present invention, however, are not limited to any particular mechanism or to how the compounds achieve their therapeutic effect. By the term "modular" it is meant that the functional activity of the route (or a component thereof) is changed in comparison with its normal activity in the absence of the compound. This effect includes any quality or degree of modulation, including increase, agonization, increase, enhancement, facilitation, stimulation, decrease, blockage, inhibition, reduction, decrease, antagonization, etc. By the term "kinase activity" is meant a catalytic activity in which an adenosine triphosphate (ATP) phosphate is transferred to an amino acid residue ( example, serine, threonine or tyrosine) in a protein substrate. A compound can modulate kinase activity, for example by inhibiting it by competing directly with ATP for the cavity of the ATP-binding kinase, producing a conformational change in the structure of the enzyme that affects its activity (for example, by altering the three-dimensional structure biologically active), etc. The kinase activity can be determined routinely using conventional assay methods. Kinase assays typically comprise the enzyme kinase, substrates, buffers, and components of a detection system. A disease or condition "mediated" by raf, VEGFR, PDGFR, p38 and or flt-3 indicates that one of these receptors is a part of a signal transduction pathway that is involved in any aspect of the disease phenotype (e.g. when a defect in the receptor itself is involved in "causing" the disease, when the stimulation of the receptor by its ligand induces motility, migration and / or cell proliferation that produces a disease phenotype, when the stimulation or phosphorylation of the receptor results in restenosis result, any functional activity of raf, VEGFR, PDGFR, p38 and / or flt-3 which, when expressed in an inappropriate manner, results in a disease symptom and / or phenotype). The term "treat" is used conventionally, for example the management or care of a subject for the purpose of combating, mitigating, reducing, alleviating, improving the state of, etc., of a disease or disorder. The diseases and conditions. which may be treated include any of those mentioned above and subsequently, as well as: The diseases associated with Raf include, for example, cell proliferation disorders, cancer, tumors, etc.; Diseases associated with VEGFR-2 include, for example, cancer, tumor growth, inflammatory diseases, rheumatoid arthritis, retinopathy, psoriasis, glomerulonephritis, asthma, chronic bronchitis, atherosclerosis, rejection of transplants, conditions involving angiogenesis, etc .; Diseases associated with VEGFR-3 include, for example, cancer, corneal disease, inflamed cornea, corneal transplantation, lymphatic hyperplasia, conditions involving lymphangiogenesis, etc .; Diseases associated with PDGFR-beta include, for example, diseases or conditions characterized by cell proliferation, cell matrix production, cell movement, and / or production of extracellular matrix. Specific examples include, for example, tumors, malignancies, cancer, metastasis, myeloid leukemia chronic, inflammation, renal disease, diabetic nephropathy, mesangial proliferative glomerulonephritis, fibrotic diseases, atherosclerosis, restenosis, arteriesclerosis related to hypertension, arteriesclerosis by venous bypass graft, scleroderma, interstitial lung disease, synovial disorders, arthritis, leukemia, lympholas, etc.; Diseases associated with Flt-3 include, for example, immune-related disorders, disorders of blood cells, conditions involving the development of hematopoietic cells (e.g., T cells, B cells, dendritic cells), cancer, anemia, HIV , acquired immunodeficiency syndrome, etc. Diseases associated with p38 include inflammatory disorders, immunomodulatory disorders, and other disorders that have been linked to the abnormal production of cytokines, especially TNF-alpha, or the abnormal activity of MMP. These disorders include, but are not limited to, rheumatoid arthritis, COPD, osteoporosis, Crohn's disease and psoriasis. The methods of the present invention include modulating the proliferation of tumor cells, including the inhibition of cell proliferation. The latter indicates that the growth and / or differentiation of tumor cells decreases, decreases, decreases, slows down, etc.

The term "proliferation" includes any procedure that relates to growth and cell division, and includes differentiation and apoptosis. As discussed above, raf kinases play a key role in the activation of the cytoplasmic signaling cascade involved in cell proliferation, differentiation and apoptosis. For example, studies have found that inhibiting c-raf by anti-sense oligonucleotides can block cell proliferation. Any amount of inhibition is considered therapeutic. The methods of the present invention also include treating mammalian hyperproliferative disorders. Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and distant metastases. These disorders also include lymphomas, sarcomas and leukemias. Any tumor or cancer can be treated, including, but not limited to, cancers having one or more mutations in rafts, VEFGR, PDGFR, p38 and / or flt-3, as well as any member upstream or downstream of the trafficking routes. signage of which they are part. As discussed above, a cancer can be treated with a compound of the present invention independently of the mechanism responsible for it. Cancers of any organ can be treated, including cancers of, but not limited to, for example, colon, pancreas, breast, prostate, bone, liver, kidney, lung, testes, skin, pancreas, stomach, colorectal cancer, renal cell carcinoma, carcinoma. hepatocellular, melanoma, etc. Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. Examples of cancers of the respiratory tract include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma. Examples of brain cancers include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor. Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to, anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small bowel, and salivary gland cancers. Urinary tract tumors include, but are not limited to, cancers of the bladder, penis, kidney, renal pelvis, ureter, and urethra. Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (carcinoma of liver cells with or without a fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinomas. Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head and neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, and / or oropharyngeal cancers, and cancer of the lips and oral cavity. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, lymphoma of cutaneous T cells, Hodgkin's disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute or chronic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, undifferentiated AML, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia , or erythroleukemia, megakarioblastic leukemia, etc. In addition to inhibiting the proliferation of tumor cells, the compounds of the present invention can also cause regression of tumors, for example, a decrease in the size of a tumor, or in the extent of cancer in the body. The present invention also relates to methods of modulating angiogenesis and / or lymphangiogenesis in a system comprising cells, comprising administering to the system an effective amount of a compound described herein. A system comprising cells can be an in vivo system such as a tumor in a patient, isolated organs, tissues, or cells, in vitro assay systems (CAM, BCE, etc.), animal models (e.g., cancer models, in vivo, subcutaneous), hosts in need of treatment (e.g., hosts suffering from diseases having an angiogenic component and / or lymphangiogenic, such as cancer), etc. Inappropriate and ectopic expression of angiogenesis (eg, abnormal angiogenesis) can be harmful to an organism. Numerous pathological conditions are associated with the growth of foreign blood vessels. These include, for example, diabetic retinopathy, neovascular glaucoma, psoriasis, retrolateral fibroplasias, angiofibroma, inflammation, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue stimulates growth, leading to rapid tumor growth and metastasis. In addition, the growth of new blood and lymphatic vessels in a tumor provides an escape route for renegade cells, stimulating metastasis and the consequent spread of cancer. The methods of the present invention also relate to treating and / or preventing disorders or conditions associated with, or resulting from, vascular hyperpermeability. For example, VEGF increases the permeability of endothelial cells. Consequently, any condition that As a result, the release of VEGF, especially in higher than normal amounts, may be associated with vascular hyperpermeability and the detrimental effects that accompany it. The present invention, however, provides treatment or prevention of any condition or disorder associated with, or resulting from, vascular hyperpermeability, regardless of the mechanism of action. The formation of edema is a life-threatening complication of various diseases of the central nervous system, including head injuries, tumors, stroke, hypoxia, and altitude sickness. The underlying cause of edema is vascular hyperpermeability. The compounds of the present invention can be used to treat and / or prevent vascular hyperpermeability, by treating and / or preventing, therefore, the edema and the detrimental effects related thereto. Other hyperpermeability conditions (or conditions that cause vascular hyperpermeability) include, but are not limited to, tissue edema (eg, lung, kidney, brain, etc.), vasogenic cerebral edema, chronic inflammation, wound healing, ischemia, tumors, atherosclerosis, peripheral vascular disease, ascites, effusions, exudates, nephrotic edema, primary glomerular disease, peripheral arterial disease, diabetic retinopathy, diabetic retinal disease, obstruction of the Respiratory tract during asthma and other pulmonary disorders, circulatory collapse in septicemia, acute lung injury, acute respiratory insufficiency syndrome, etc. Tests for vascular permeability can be performed routinely, for example Heiss et al., J. Clin. Invest., 98: 1400-1408, 1996; Fischer et al., Am. J. Physiol., 276 (4 Pt 1); C812-20, 1999; Fischer et al., Am. J. Physiol. Cell. Physiol., 279: C935-C944, 2000. The compound of the formula (I) in the polymorph I of this invention also has a broad therapeutic activity to treat or prevent the progression of a large set of diseases, such as inflammatory conditions, coronary restenosis, angiogenesis associated with tumors, atherosclerosis, autoimmune diseases, inflammation, certain kidney diseases associated with the proliferation of glomerular or mesangial cells, and ocular diseases associated with the proliferation of retina vessels, psoriasis, liver cirrhosis, diabetes, atherosclerosis, restenosis , vascular graft restenosis, stent stenosis, angiogenesis, eye diseases, pulmonary fibrosis, obliterative bronchiolitis, glomerular nephritis, rheumatoid arthritis. The present invention also provides treatment, prevention, modulation, etc., of one or more of the following conditions in humans and / or other mammals: retinopathy, including diabetic retinopathy, ischemic retinal vein occlusion, premature retinopathy and age-related macular degeneration; rheumatoid arthritis, psoriasis, or bullous disorder related to the formation of subepidermal blisters, including bullous pemphigoid, erythema multiforme, or dermatitis herpetiformis, rheumatic fever, bone resorption, postmenopausal osteoporosis, septicemia, severe negative septicemia, septic shock, endotoxic shock, toxic shock, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-Herxheimer reaction, asthma, respiratory distress syndrome in adults, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, pneumoconiosis of coal workers, alveolar injury, liver failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria (Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), heart failure c ongestive, injury after heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelination and loss of oligodendrocytes in multiple sclerosis), advanced cancer, malignant lymphoid tumor, pancreatitis, healing of damaged wounds in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, intestinal necrosis, injury / radiation toxicity after administration of monoclonal antibodies, host reaction to graft (reperfusion injury due to ischemia and rejection of kidney allografts , liver, heart, and skin), lung allograft rejection (obliterative bronchitis), or complications due to total hip replacement, and an infectious disease selected from tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga resulting from infection by Trypanosoma cruzi, effects of Shiga-type toxin resulting from infection by E. coli, effects of enterotoxin A resulting from infection by Staphylococcus, meningococcal infection, and infections of Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, the flu, encephalomyelitis virus Theiler, and the human immunodeficiency virus (HIV), papilloma, blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, cancer of the neck, cancer of bladder, breast cancer, coloreetal cancer, thyroid cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease, Burkitt's disease, arthritis, rheumatoid arthritis, diabetic retinopathy, angiogenesis, restenosis, stent restenosis, vascular graft restenosis, pulmonary fibrosis, liver cirrhosis, atherosclerosis, glomerulonephritis, diabetic nephropathy, thrombotic microangiopathy syndromes, transplant rejection, psoriasis, diabetes, wound healing, inflammation, and neurodegenerative diseases, hyperimmune disorders, hemangioma, myocardial angiogenesis, coronary and cerebral collateral vascularization, ischemia, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, premature retinopathy, wound healing, diseases related to Helicobacter ulcer, fractures, endometriosis, a diabetic condition, fever due to cat scratches, thyroid hyperplasia, asthma or edema after burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, respiratory distress syndrome in adults, ascites, an ocular affection, a cardiovascular disease, Crow-Fukase disease (POEMS), Crohn's disease, glomerulonephritis, osteoarthritis, multiple sclerosis, rejection of grafts, Lyme disease, septicemia, von Hippel Lindau disease, pemphigus, Paget's disease, polycystic kidney disease, sarcoidosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, radiation, hypoxia, preeclampsia, menometrorrhagia, endometriosis, Herpes simplex infection, ischemic retinopathy, corneal angiogenesis, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, toxoplasmosis, and effusions and edema associated with tumors. The present invention also provides a method for the prevention or treatment of diseases, especially the diseases mentioned above, by using an effective amount of the compound of the formula (I) in polymorph I. Combination with other pharmaceutical agents: The compound of the formula I) in polymorph I of this invention can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination does not cause unacceptable side effects. This may be of particular relevance for the treatment of hyperproliferative diseases such as cancer. In this case, the compound of this invention can be combined with known cytotoxic agents, inhibitors of signal transduction, with other anticancer agents, or with antiemetics, as well as with mixtures and combinations thereof. In one embodiment, the compound of the formula (I) in the Polymorph I of the present invention can be combined with cytotoxic anti-cancer agents. Examples of such agents can be found in the 11th Edition of Merck Index (1996). These agents include, but are not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine and vindesine. Other suitable cytotoxic drugs for use with the compounds of the invention include, but are not limited to, compounds recognized for use in the treatment of neoplastic diseases in The Pharmacological Basis of Therapeutics by Goodman and Gilman (Ninth Edition, 1996, McGraw-Hill) . These agents include, but are not limited to, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2 ', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxyinoniladenine, ethinylestradiol, 5-fluorodeoxyuridine, 5-fluoro-deoxyuridine monophosphate, Fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa , trimethylmelamine, uridine and vinorelbine. In another embodiment, the compound of the formula (I) in the polymorph I of the present invention can be combined with antiemetics. Suitable antiemetics for use with the compounds of the invention include, but are not limited to, antihistamines, Hi receptor blockers, 5-HT3 antagonists, neuroleptics, anticholinergics, dopamine antagonists, serotonin antagonists, glucocorticoids or cannabinoids. These agents include, but are not limited to, meclozin, dimenhydrinate, phenothiazine derivatives (eg, tiethylperazine, triflupromazin), benzamide or benzimidazole derivatives (eg metoclopramid, bromoprid, domperidon), butyrophenones, scopalamin, pyridoxine, chlorphenoxy, granisetron, ondansetron, tropisetron, and dexametason. Preference is given to antiemetics: granisetron, ondansetron, tropisetron, or dexametason. "Combination" means for the purposes of the invention not only a dosage form that contains all the components (the so-called fixed combinations), and combination packages containing the components separated from each other, but also components that are administered simultaneously or sequentially, as long as they are used for the prophylaxis or treatment of the same disease. The active ingredients of the combination according to the invention can be converted in a known manner into the customary formulations, which can be liquid or solid formulations. Examples are tablets, coated tablets, pills, capsules, granules, aerosols, syrups, emulsions, suspensions, solutions. As the combination according to the invention is well tolerated and in some cases is effective even at low dosages, a wide range of formulation variants is possible. Therefore, one possibility is to formulate the individual active ingredients of the combination according to the invention separately. In this case, it is not absolutely necessary to take the individual active ingredients at the same time; on the contrary, sequential intake can be advantageous to achieve optimal effects. It is appropriate for such separate administration to combine the formulations of the individual active ingredients, for example tablets or capsules, simultaneously together in a suitable primary container. The active ingredients are present in the primary packaging in each case in different containers that can be, for example, tubes, bottles or blister packs. Said packaging separately from the components in the joint primary package is also called kit. Additional formulation variants that are suitable and preferred for the combination according to the invention are also fixed combinations. "Fixed combination" is intended herein to mean pharmaceutical forms in which the components are present together in a fixed proportion of quantities. Said fixed combinations may be, for example, in the form of oral solutions, although preferably they are solid oral pharmaceutical preparations, for example capsules or tablets. Pharmaceutical Compositions: The invention also relates to pharmaceutical compositions containing the compound of the formula (I) in the polymorph I of the present invention and methods of administration to a patient in need of a pharmaceutical composition of this invention. A patient, for the purpose of this invention, is a mammal, including a human being, in need of treatment for the particular condition or disease. The pharmaceutical compositions of the present invention are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of the formula (I) in the polymorph I of the present invention. A pharmaceutically acceptable carrier is any vehicle that is relatively non-toxic and harmless to a patient at concentrations consistent with an effective activity of the active ingredient such that any side effects attributable to the vehicle do not adversely affect the beneficial effects of the active ingredient. A pharmaceutically effective amount of the compound is the amount that produces a result or that exerts an influence on the particular condition being treated.

The compound of the formula (I) in polymorph I can be administered in a suitable manner, for example orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally or otically, or in the form of an implant or stent. For these routes of application, the compounds of the invention can be administered in suitable administration forms. For oral administration, suitable administration forms are those that function according to the prior art and supply the compound of formula (I) in polymorph I in a rapid and / or modified manner, for example tablets (coated or uncoated tablets). Coated, for example with coatings resistant to gastric juices or which have delayed dissolution or which are insoluble and which control the release of the compound of the invention), rapidly disintegrating tablets in the oral cavity or films / wafers, films / freeze-dried, capsules (for example hard or soft gelatin capsules) ), tablets coated with sugar, granules, pills, powders, suspensions or aerosols. Parenteral administration can take place by avoiding an absorption step (e.g., in an intravenous, intraarterial, intracardiac, intraspinal or intralumbar fashion) or with inclusion of absorption (e.g., in an intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal fashion). Suitable administration forms for parenteral application include injection and infusion preparations in the form of suspensions, freeze-dried or sterile powders. Suitable for the other routes of administration, for example, medicinal forms for inhalation (including powder inhalers, nebulizers), tablets for lingual, sublingual or buccal administration, films / wafers or capsules, suppositories, preparations for the ear or the eye, vaginal capsules, aqueous suspensions (lotions, agitated mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), pastes, fine powders, implants or stents.

The compound of the invention can be converted into the aforementioned application forms. This can take place in a known manner by mixing it with inert, non-toxic, pharmaceutically suitable excipients. These excipients include carriers, (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbithane oleate), binders (e.g., polyvinyl pyrrolidone) ), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxides), and substances for masking flavors and / or odors. The present invention further provides medicaments comprising at least the compound of the formula (I) in the polymorph I, typically together with one or more inert, non-toxic, pharmaceutically suitable excipients, for example binders, fillers, etc., and to the use of the same for the purposes mentioned above. Dosage of the pharmaceutical compositions of the present invention: Based on known conventional laboratory techniques for evaluating compounds useful for the treatment of any of the above-mentioned disorders previously, by conventional toxicity tests and by conventional pharmacological tests to determine the treatment of the conditions identified above in mammals, and by comparing these results with the results of known medicaments used to treat these conditions, the effective dose of the drugs can be easily determined. compounds of this invention for the treatment of each of the desired indications. The amount of active ingredient to be administered in the treatment of one of these conditions can vary widely according to considerations such as the particular compound and dosage unit employed, the mode of administration, the treatment period, the age and sex of the patient. treated, and the nature and extent of the condition treated. The total amount of active ingredient to be administered may vary from about 0.001 mg / kg to about 200 mg / kg, and preferably from about 0.1 mg / kg to about 50 mg / kg of body weight per day. A unit dosage may preferably contain from about 5 mg to about 4000 mg of active ingredient, and may be administered one or more times per day. The daily dosage for oral administration will preferably be from 0.1 to 50 mg / kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques will preferably be from 0.1 to 10 mg / kg of total body weight. The daily rectal dosage regimen will preferably be from 0.1 to 50 mg / kg of total body weight. The daily vaginal dosing regimen will preferably be from 0.1 to 50 mg / kg of total body weight. The daily topical dosing regimen will preferably be 0.1 to 10 mg / kg administered between one and four times a day. The transdermal concentration will preferably be that necessary to maintain a daily dose of 0.1 to 10 mg / kg. The daily inhalation dosage regimen will preferably be from 0.1 to 10 mg / kg of total body weight. Other dosages and amounts can be selected routinely. However, in some cases it may be advantageous to deviate from the specified amounts, depending on the body weight, the route of administration, the individual behavior towards the active ingredient, the type of preparation and the time or interval during which the administration is carried out. . For example, less than the minimum amounts mentioned above may be sufficient in some cases, while the specified upper limit has to be exceeded in other cases. In the case of administration of relatively large amounts, it may be advisable to divide these into several doses individual during the day. Preparation method: The invention further provides a process for preparing the compound of the formula (I) in the polymorph I, by processing the compound of the formula (I) in the polymorph II, obtained as described in example 1, in a inert solvent at a temperature of, for example, 50 SC up to the reflux temperature of the solvent, preferably 60 to 80 eC, in the absence of crystals of a solvate of the compound of the formula (I), for example in the absence of crystals of the solvate of methanol or of the ethanol solvate of the compound of the formula (I), for up to one day. The mixture is cooled from -30aC to room temperature, preferably from -25SC to 102C, and the crystals are isolated and dried. The compound of formula (I) is thus obtained in polymorph I. The invention also provides a process for preparing the compound of formula (I) in polymorph I, by processing the compound of formula (I) in polymorph II, obtained as described in example 1, in an inert solvent at a temperature of, for example, from 10aC to the reflux temperature of the solvent, preferably at room temperature, for up to one day. Subsequently, the mixture is seeded with crystals of the compound of the formula (I) in the polymorph (I) and stirred or stir, for example at room temperature, for 1 hour to 14 days, preferably 2 hours to 7 days. The crystals are isolated and dried. The compound of the formula (I) is thus obtained in the polymorph I. The invention also provides a process for preparing the compound of the formula (I) in the polymorph.

I, processing the compound of the formula (I) in the polymorph II, obtained as described in example 1, in an inert solvent until the desired degree of conversion is obtained, preferably up to the quantitative conversion to polymorph I. If appropriate, crystals of the compound of the formula (I) are added in the polymorph I. The resulting crystals are isolated and, to remove the solvent present, they are dried to a constant weight at room temperature or at an elevated temperature, for example from 40 to 80 ° C. The compound of formula (I) is thus obtained in polymorph I. By processing the compound of the formula (I) in the polymorph II in an inert solvent, it means that for example the compound of the formula (I) in the polymorph II is completely dissolved (solution) or only in part (suspension). The mixture can, for example, be stirred or stirred. Suitable inert solvents are lower alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, or ketones such as acetone, or alkanes such as n-pentane, cyclopentane, n-hexane, cyclohexane, or tetrahydrofuran, or acetonitrile, or toluene, or ethyl acetate, or mixtures of the aforementioned solvents, or mixtures of the mentioned solvents with water. Preference is given to methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, toluene, ethyl acetate, mixtures of the solvents mentioned or mixtures of the solvents mentioned with water. Isopropanol, ethyl acetate or a mixture thereof are most preferably used as inert solvents. Preference is given to the preparation of the compound of the formula (I) in the polymorph I by processing the compound of the formula (I) in the polymorph II, obtained as described in example 1, in methanol, ethanol, a mixture of both solvents or a mixture of both solvents with water, preferably a 1: 1 mixture with water, and stirring or stirring at a temperature of from 50 ° C. to the reflux temperature of the solvent, preferably 60 to 80 SC, in the absence of crystals of a solvent. solvate of the compound of the formula (I), for example in the absence of crystals of the methanol solvate or of the ethanol solvate of the compound of the formula (I), for up to one day. The crystals are cooled from -302C to room temperature, preferably from -259C to 10aC, they are isolated and dried. The compound of formula (I) is thus obtained in polymorph I. More preferably isopropanol, ethyl acetate or a mixture thereof is used as the solvent. Preference is also given to the preparation of the compound of the formula (I) in the polymorph I by processing the compound of the formula (I) in the polymorph II, obtained as described in example 1, in methanol, ethanol, a mixture of both solvents or a mixture of both solvents with water, and stirring or stirring at a temperature of from 102 ° C to the reflux temperature of the solvent, preferably at room temperature, for up to 1 day. The mixture is subsequently seeded with crystals of the compound of the formula (I) in the polymorph I and stirred or stirred, for example at room temperature, for 1 hour to 14 days, preferably 2 hours to 7 days. The crystals are isolated and dried. The compound of formula (I) is thus obtained in polymorph I. More preferably isopropanol, ethyl acetate or a mixture thereof is used as the solvent. Preference is also given to the preparation of the compound of the formula (I) in the polymorph I by processing the compound of the formula (I) in the polymorph II, obtained as described in example 1, in an inert solvent other than methanol and / or ethanol, preferably isopropanol, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, toluene, or a mixture thereof and stirring or stirring at a temperature of from 10 ° C to the reflux temperature of the solvent, preferably from room temperature to 90 ° C, for up to 2 weeks, preferably 1 day up to a week. If appropriate, the mixture is co to room temperature and the crystals are isolated and dried. The compound of formula (I) is thus obtained in polymorph I. More preferably isopropanol, ethyl acetate or a mixture thereof is used as the solvent. The compound of the formula (I) can also be prepared in the polymorph I by heating the compound of the formula (I) in the polymorph II up to 195 to 222 aC, preferably from 195 to 215 QC, for example at a heating rate of 10. eC at 30aC per minute, preferably from 152C to 25fiC per minute, and subsequently cooling to 10SC to 30aC, preferably at room temperature, for example at a cooling rate of 12C to 4aC per minute, preferably from C to 3SC per minute. The compound of the formula (I) in the polymorph III can be prepared by processing the compound of the formula (I) in the polymorph II in an inert solvent, for example methanol. The filtration is done after 1 day to 1 week, and the product is dried and heat treated at 145 to 160 BC for 15 minutes to 1 hour. The compound of the formula (I) is obtained, thus, in polymorph III. The methanol solvate of the compound of the formula (I) can be prepared by processing the compound of the formula (I) in the polymorph II in methanol. After 1 week, filtration is performed, and the product is dried and stored in a methanol atmosphere for 5 hours to 1 week. The methanol solvate of the compound of the formula (I) is thus obtained with a methanol content of 4.8% by weight. The ethanol solvate of the compound of the formula (I) can be prepared by processing the compound of the formula (I) in the polymorph II in ethanol. After 1 week, the filtration is carried out and the product is dried. The ethanol solvate of the compound of the formula (I) is thus obtained with an ethanol factor of 6.7 weight percent. The procedures are generally carried out at atmospheric pressure. However, it is also possible to work at a high pressure or at a reduced pressure (for example in a range of 0.5 to 5 bar (50 to 500 kPa)). The weight data in the tests and in the examples that follow are, unless otherwise indicated, percentages by weight; The parts are parts by weight. The proportions of solvents, dilution ratios and the concentration data of the liquid / liquid solutions are based on the volume in each case.

Working examples Thermograms were obtained using a differential scanning calorimeter DSC 7 or Pyris-1 and TGA 7 thermogravimetric analyzer from Perkin-Elmer. X-ray diffractograms were recorded on a Stoe transmission diffractometer. The IR, FIR, NIR and Raman spectra were recorded using Fourier spectrometers IFS 66v (IR, FIR), IFS 28 / N (NIR) and RFS 100 (Raman) from Bruker. Example 4 tosylate li. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} - -me ilpyridine-2-carboxamide in polymorph II 903 g of 4- are charged initially. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide, prepared as described in WO 00/42012, in 2700 ml of ethanol. 451.7 g of p-toluenesulfonic acid monohydrate are dissolved in 1340 g of ethanol and added dropwise at room temperature. The suspension is stirred at room temperature for 1 hour, then it is removed by filtration with suction, and the residue is washed three times with 830 ml each of ethanol. The drying is carried out at 502C under reduced pressure with air supply. 1129.6 g of the title compound are obtained in polymorph II.

Example 2; Preparation of tosylate 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -methylpyridine-2-carboxamide in polymorph I Example 2.1 5 mg of the tosylate salt of 4 are heated. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II to 2002C at a heating rate of 20sC / min and subsequently cooled to room temperature at a cooling rate of 22C / min. The sample is thermoanalytically tested (DSC) and corresponds to the title compound in polymorph I. EXAMPLE 2.2 75 mg of the tosylate salt of 4 are dissolved. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino} carboni1) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II in 10 ml of ethanol / water (1: 1) at about 80 ° C and filtered. The mixture is divided into two samples and sample A is crystallized in a refrigerator at + 82C and sample B in a freezer at -20aC. After vaporization of the solvent mixtures, the two crystals of samples A and B are tested thermoanalytically (DSC). Both samples correspond to the title compound in polymorph I. Example 2.3 In each case, 400 mg of the salt is suspended. tosylate of 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II in a) 8 ml of methanol and b) in 8 ml of ethanol and each is stirred at room temperature for 2 hours. Each of the suspensions is seeded with 2 mg of the title compound in polymorph I and subsequently stirred at room temperature for 1 week. After filtration, the solid residues of the two samples are dried at room temperature. Each of the residues is thermoanalytically tested (DSC) and corresponds to the title compound in polymorph I. Example 2.4 200 mg of the tosylate salt of 4 are suspended. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} N-methylpyridine-2-carboxamide in polymorph II in 5 ml of ethanol / water (1: 1 v / v) and stirred at room temperature for 2 hours. The suspension is seeded with 2 mg of the title compound in polymorph I and subsequently stirred at room temperature for 1 week. After filtration, the solid residue is dried at room temperature. The residue is thermoanalytically tested (DSC) and corresponds to the title compound in polymorph I. Example 2.5 50 mg of the tosylate salt of 4 are mixed in each case. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II with 2 ml in each case of a) isopropanol, b) acetone, c) tetrahydrofuran, d) acetonitrile, e) ethyl acetate and f) toluene, and in each case they are stirred at room temperature for 6 days. In the case of c) tetrahydrofuran and f) toluene, an additional 1 ml of the particular solvent is added. Each of the suspensions is filtered and the particular residues are dried at room temperature. Each residue is tested by X-ray diffractometry and corresponds to the title compound in polymorph I. Example 2.6 200 mg of the tosylate salt of 4 is suspended. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II in 4 ml of toluene and the suspension is stirred at 80 aC for one week. After cooling to room temperature, the residue is filtered, dried at room temperature and tested by X-ray diffractometry. The title compound is obtained in polymorph I. EXAMPLE 3; Preparation of tosylate 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph III 3.5 g of the tosylate salt of 4 are suspended. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N- methylpyridine-2-carboxamide in polymorph II in 15 ml of methanol and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature. Subsequently, the product is heat treated at 150 ° C for 30 minutes. The residue is analyzed by X-ray diffractometry and corresponds to the title compound in polymorph III. Example 4: Preparation of the methanol solvate of the tosylate of 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -JV-methylpyridine-2-carboxamide 3.5 g of the tosylate salt of 4 are suspended. { 4 - [( { [4-chloro-3- (trifluoromethyl) phenyl] amino} carboni1) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II in 15 ml of methanol and stirred at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature. Subsequently, the product is stored in a desiccator with a methanol atmosphere for one day. The residue is analyzed by x-ray diffractometry and corresponds to the methanol solvate of the title compound with a methanol content of 4.8 percent by weight.

Example 5; Preparation of the tosylate ethanol solvate of 4-. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino.} Carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide 3 g of the tosylate salt of 4 are suspended. { 4- [( { [4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N-methylpyridine-2-carboxamide in polymorph II in 15 ml of ethanol and stir at room temperature. After one week, the suspension is filtered and the residue is dried at room temperature. The residue is analyzed by x-ray diffractometry and corresponds to the ethanol solvate of the title compound with an ethanol content of 6.7 weight percent.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows DSC and TJA thermograms of the compound (I) · Figure 2 shows X-ray diffraction patterns of compound (I). Figure 3 shows IR spectra of compound (I). Figure 4 shows Raman spectra of compound (I). Figure 5 shows FIR spectra of compound (I). Figure 6 shows NIR spectra of compound (I).

Table 1: Differential Scan Calorimetry and Thermogravimetry conversion point Table 2: X-ray diffractometry 4 Table 4: Raman spectroscopy Table 5: FIR spectroscopy Table 6: NIR spectroscopy It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

2. Having described the invention as above, it is declared as property contained in the following claims: 1. A compound characterized in that it is of formula (I) in polymorph I. 2. A preparation of the compound of the formula (I) in polymorph I, characterized in that it comprises processing the compound of the formula (I) in the polymorph II in an inert solvent until the quantitative conversion to polymorph I.
3. 3. The preparation of the compound of the formula (I) in the polymorph I according to claim 2, characterized in that the compound of the formula (I) in the polymorph II is processed in an inert solvent and is seeded with crystals of the compound of the formula (I) in polymorph I.
4. 4. The preparation of the compound of the formula (I) in polymorph I, characterized by the compound of formula (I) in polymorph II being heated to 195-222 ° C at a heating rate of 10 to 30 ° C per minute and subsequently cooled to 10 to 30 ° C at a cooling rate from 1 to 4 aC per minute.
5. 5. A compound of the formula (I) in polymorph I, characterized in that it is for the treatment of disorders presenting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, carcinoma or growth of carcinogenic cells.
6. 6. A compound of the formula (I) in polymorph I according to claim 5, characterized in that it is for the treatment of leukemia or for the treatment of carcinoma of the lung, pancreas, thyroid gland, kidney or intestine.
7. 7. The use of the compound of the formula (I) in polymorph I for the preparation of a pharmaceutical composition for the treatment of disorders exhibiting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, carcinoma or growth of carcinogenic cells.
8. 8. The use of the compound of the formula (I) in polymorph I for the preparation of a pharmaceutical composition according to claim 7 for the treatment of leukemia or for the treatment of carcinoma of lung, pancreas, thyroid gland, kidney or intestine.
9. 9. A pharmaceutical composition characterized in that it comprises the compound of the formula (I) primarily in polymorph I and without significant fractions of another form of the compound of the formula (I).
10. 10. The pharmaceutical composition according to claim 9, characterized in that it contains more than 90 weight percent of the compound of the formula (I) in the polymorph I with respect to the total amount of the compound of the formula (I) present in the composition.
11. 11. The pharmaceutical composition according to one of claims 9 or 10, characterized in that it is for the treatment of disorders.
12. 12. The pharmaceutical composition according to one of claims 9 to 11, characterized in that it is for the treatment of disorders exhibiting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, carcinoma or growth of carcinogenic cells.
13. 13. The pharmaceutical composition according to one of claims 9 to 12, characterized in that it is for the treatment of leukemia or for the treatment of carcinoma of the lung, pancreas, thyroid gland, kidney or intestine.
14. 14. The pharmaceutical composition in accordance with a of claims 9 to 13, characterized in that it comprises one or more inert, non-toxic, pharmaceutically suitable excipients.
15. 15. A method characterized in that it is for the treatment of disorders exhibiting abnormal processes of angiogenesis or hyperpermeability, bone marrow diseases, carcinoma or growth of carcinogenic cells, using an effective amount of the compound of the formula (I) in the polymorph I or of a pharmaceutical composition as defined in one of claims 9 to 14.
16. 16. The method according to claim 15, characterized in that it is for the treatment of leukemia or for the treatment of carcinoma of the lung, of the pancreas, of the thyroid gland, of the kidney or of the intestine.
17. 17. A compound of the formula (I) in polymorph I, characterized in that it can be obtained by dissolving or suspending the compound of the formula (I) in the polymorph II in an inert solvent and stirring or stirring until the quantitative conversion to polymorph I.
18. 18. A compound of the formula (I) according to claim 17, characterized in that it can be obtained by dissolving or suspending the compound of the formula (I) in the polymorph II in an inert solvent and by seeding it with crystals of the compound of the formula (I) in polymorph I.
19. 19. A combination characterized in that it comprises the compound of the formula (I) in polymorph I and one or more other pharmaceutical agents. The combination according to claim 19, characterized in that the one or more other pharmaceutical agents are cytotoxic agents, signal transduction inhibitors, anti-cancer agents, or antiemetics. 21. The pharmaceutical composition according to one of claims 9 to 14, characterized in that it comprises one or more other pharmaceutical agents. 22. The pharmaceutical composition according to claim 21, characterized in that the one or more other pharmaceutical agents are cytotoxic agents, signal transduction inhibitors, anti-cancer agents, or antiemetics.