WO2007059155A1 - Traitement de cancers a resistance a des agents chimiotherapeutiques - Google Patents

Traitement de cancers a resistance a des agents chimiotherapeutiques Download PDF

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Publication number
WO2007059155A1
WO2007059155A1 PCT/US2006/044238 US2006044238W WO2007059155A1 WO 2007059155 A1 WO2007059155 A1 WO 2007059155A1 US 2006044238 W US2006044238 W US 2006044238W WO 2007059155 A1 WO2007059155 A1 WO 2007059155A1
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cancer
recurrent
acid
tumor
stage
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PCT/US2006/044238
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English (en)
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Scott Wilhelm
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Bayer Pharmaceuticals Corporation
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Publication of WO2007059155A1 publication Critical patent/WO2007059155A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Cancer is a class of diseases characterized by two heritable properties: (1) uncontrolled cell division and (2) the ability of these cells to invade other tissues, either by direct growth into adjacent tissue (invasion) or by migration of cells to distant sites (metastasis).
  • the hyper-proliferative properties initially give rise to a tumor or neoplasm.
  • a tumor is considered a cancer when its cells acquire the ability to invade surrounding tissues, e.g., by breaking loose and entering the blood or lymph systems, or by forming secondary tumors at other sites in the body.
  • the unregulated growth is caused by damaged DNA, resulting in mutations to vital genes that control cell division, the cell cycle, among other functions.
  • One or more of these mutations which can be inherited or acquired, can lead to uncontrolled cell division and cancer.
  • Cancers can be classified according to the tissue and cell type from which they arise. Cancers developing from epithelial cells are called carcinomas, and those from connective and muscle cells are called sarcomas. Additional cancers include those arising from hematopoietic cells (e.g., leukemia) and cancers of the nervous system.
  • carcinomas those from epithelial cells
  • connective and muscle cells are called sarcomas.
  • Additional cancers include those arising from hematopoietic cells (e.g., leukemia) and cancers of the nervous system.
  • cancers appear to arise during a process in which an initial population of abnormal cells evolve into more aberrant cells through successive cycles of mutation and selection. More than 100 different genes have been identified which, when mutant, result in cancer. These so-called cancer-critical genes fall into two broad classes: oncogenes and tumor suppressor genes. Many cancer-critical genes play a role in the regulation of cell divisions, a highly complicated process involving multiple and parallel pathways. These include growth factors, cytokines, hormones, etc. [0005] Cancer can cause many different symptoms, depending on the site and character of the malignancy and whether there is metastasis. A definitive diagnosis usually requires the microscopic examination of tissue obtained by biopsy. Once diagnosed, cancer is usually treated with surgery, chemotherapy and/or radiation.
  • Cancer is one of the leading causes of death in developed countries. It is estimated by the National Cancer Institute that approximately 9.8 million Americans were alive in January 2001 with a history of cancer. About 1,372,910 new cases of cancer were expected to be diagnosed in 2005, alone. In 2005, almost 600,000 Americans died of cancer, about 1 out of every 4 deaths. Many forms of cancer are associated with environmental factors, which may be avoidable. Smoking tobacco leads to more cancers than any other environmental factor.
  • kinase inhibitors are being used successfully to treat cancers; however, some patients acquire a resistance to the drug's activity.
  • the present invention provides methods of treating a cancer in a subject in need thereof, comprising administering an effective amount of sorafenib to a subject having a cancer, wherein said cancer has acquired resistance to a kinase inhibitor.
  • a kinase inhibitor is any drug or agent (e.g., anti-sense; small molecules; antibodies; etc) which blocks or reduces the activity of a kinase. This includes, tyrosine kinases, serine-threonine kinases, receptor kinases, non-receptor kinases, etc.
  • kinase activity refers to the ability of a polypeptide to catalyze the transfer of a phosphate from one molecule to another.
  • GIST gastrointestinal stromal tumors
  • CML chronic myelogenous leukemia
  • imatinib STI571 or Gleevac
  • STI571 or Gleevac imatinib
  • a tyrosine kinase inhibitor that inhibits the kinase activity of BCR- ABL, ABL, KIT, and PDGFR.
  • a study of GIST patients with acquired resistance to imatinib showed secondary mutations in the KIT kinase domain. See, e.g., Antonescu et al, Clin. Cancer Res., 11(11):41824190, 2005.
  • a second site mutation in BCR-ABL is the predominant mechanism of imatinib resistance in CML. See, e.g., Gorre et al., Science, 293:876-880, 2001 who describe a mutation T315I associated with imatinib resistance.
  • Acquired resistance has also been observed with other cancer drugs, including patients treated with EGFR-kinase inhibitors, such as gefitinib (Iressa) or erlotinib (Tarceva).
  • Resistance mutations often occur in the kinase catalytic domain interfering or weakening the interaction with its inhibitor. Resistance mutations have been reported for number of kinases, including, BCR-ABL, KIT, PGF receptor, and EGF receptor. These secondary mutations often occur in the "gatekeeper” residue, the amino acid residue that "guards" the ATP-binding pocket and which also can comprise the site which interacts with the inhibitor. See, e.g., Noble et a!., Science, 303: 1800-1805, 2004.
  • the present invention relates to using sorafenib to treat a cancer which has acquired resistance to a kinase inhibitor, irrespective of the molecular mechanism responsible for it.
  • mutations which can lead to resistance and which can be treated in accordance with the presence invention include, e.g., KIT mutations, such as primary or secondary mutations in residues 654, 670, 816, 820, 822, 823, from residues about 650-654, about 670-674, from about 816-824, in the A-loop (activation), V654A, T670I, D816G, D816E, D820E, D820Y, N822K, and Y823D, etc.
  • KIT mutations such as primary or secondary mutations in residues 654, 670, 816, 820, 822, 823, from residues about 650-654, about 670-674, from about 816-824, in the A-loop (activation), V654A, T670I, D816G, D816E, D820E, D820Y, N822K, and Y823D, etc.
  • Such mutations, when secondary, can
  • mutations which lead to gefitinib and erlotinib resistance include, e.g., mutations at residue 670, such as T790M (see also, Carter et al., Proc. Natl. Acad. ScL, 102:11011-11016, 2005).
  • Examples of kinase targets to which resistance can be acquired included, but are not limited to, e.g., PDGFR-alpha, PDGFR-beta, EGFR, VEGFR, VEGFR1,
  • VEGFR2 VEGFR2, VEGFR3, HER-2, KIT, FLT3, C-MET, FGFR, FGFR1, FGFR3, C-FMS, RET,
  • Associated cancers include, but are not limited to, CML (chronic myeloid leukemia), ALL (acute lymphoblastic leukemia),
  • AML acute myelogenous leukemia
  • T-ALL T-CeII acute lymphoblastic leukemia
  • ALCL acute lymphoblast cell leukemia
  • EMS 8p11 myeloproliferative syndrome
  • aCML atypical chronic myelogenous leukemia
  • MM multiple myeloma
  • T-lymphoma
  • MDS myelodysplastic (syndrome), HES (hypereosinophilic syndrome), SM (systemic mastocytosis), and CMML (chronic myelomonocytic leukemia), IMT (inflammatory myofibroblastic tumor), NSCLC (non-small cell lung cancer), glioblastoma, SCCHN
  • squamous cell carcinoma of the head and neck ovarian cancer
  • RCC renal cell carcinoma
  • pancreatic cancer colorectal cancer
  • breast cancer lung cancer
  • GIST seminoa, sarcomas, musculoskeletal tumors, gastric cancer, renal papillary carcinoma, malignant melanoma
  • PTC papillary thyroid cancer
  • congenital fibrosarcoma mesoblastic nephroma, secretory breast carcinoma, osteosarcoma
  • PAIS pulmonary artery intimal sarcoma
  • DFSP dermatofibrosarcoma protuberans
  • FMTC Familial medullary thyroid carcinoma
  • MEN-2B radiation associated papillary thyroid cancer, astrocytoma, breast cancer, prostate cancer, renal cancer, etc. See, e.g., Krause et al.,
  • Diseases which can be treated in accordance with present invention include, e.g., diseases which are treated with imatinib, such as, but not limited to: Accelerated
  • Lymphoblastic Leukemia Acute Lymphoblastic Leukemia in Remission; Acute
  • Lymphocytic Leukemia Acute Monoblastic and Acute; Monocytic Leukemia; Acute
  • Diseases which can be treated in accordance with present invention include, e.g., diseases which are treated with gefitinib, such as, but not limited to: Adenocarcinoma of the Colon; Adenocarcinoma of the Esophagus; Adenocarcinoma of the Lung; Adenocarcinoma of the Prostate; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Advanced Non-Nasopharyngeal Head and Neck Carcinoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglima; Anaplastic Thyroid Cancer; Bladder Cancer; Brain Tumor; Breast Cancer; Breast Cancer in Situ; Breast Neoplasms; Bronchoalveolar Cell Lung Cancer; Cancer of the Fallopian Tube; Carcinoma, Squamous Cell; Cervix Neoplasms; Colon Cancer; Colorectal Cancer; Epithelial Mesothelioma; Esophageal Cancer; Esophagogastric Cancer; Follicular Thyroid
  • Diseases which can be treated in accordance with present invention include, e.g., diseases which are treated with tarceva, such as, but not limited to: Adenocarcinoma; Adenocarcinoma of the Colon; Adenocarcinoma of the Esophagus; Adenocarcinoma of the Lung; Adenocarcinoma of the Pancreas; Adenocarcinoma of the Prostate; Adenocarcinoma of the Stomach; Adenosquamous Cell Lung Cancer; Adult Giant Cell Glioblastoma; Advanced Adult Primary Liver Cancer; Advanced NSCLC; Advanced Solid Tumors; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Andrigen Deprivation Therapy; Bladder Cancer; Brenner Tumor; Bronchoalveolar Cell Lung Cancer; Childhood Brain Tumor; Childhood Cerebellar Astrocytoma; Childhood Cerebral Astrocytoma; Childhood Ependymoma; Childhood Malignant;
  • tyrosine kinase inhibitors and other kinase inhibitors include, but are not limited to, e.g., ABX-EGF, adaphostin, AEE788, AG 013736, AG 490, AG 825, AG 957, AG 1024, AG 1296, aloisine, aloisine A, alsterpaullone, aminogenistein, AMG 706, AMN107, API-2, AP23573, apigenin, ARRY-142886 (AZD6244), arctigenin, AY- 22989, AZD0530, AZD1152, AZD2171, bevacizumab, bisindolylmaleimide IX, BMS- 354825, BMS-387032, BMS-599626, Bryostatin 1 , CCI779, CEP-701, CEP-7055, cetuximab, 2C4, chelerythrine, CHIR-258,
  • tyrosine kinase inhibitors include, e.g., AEE788, AMG 706, AMN107, ARRY-142886 (AZD6244), AZD2171 , AZD0530, bevacizumab, BMS- 354825, BMS-599626, CCI779, CEP-7055, cetuximab, CHIR-258, CM 033, CP-724714, CP-547-632, erlotinib (tarceva or OSI774), gefltinib (Iressa), GW572016, GW786034, imatinib mesylate (STI57 or Gleevec), lapatinib ditosylate (GSK572016), PD 0173074, PD 0325901, PKC412, PTK787, rapamyci ⁇ , sunitinib (sutent), SU5416, SU11248, SU6668, trastuzum
  • tyrosine kinase inhibitors include, e.g., 17-DMAG; 17- AAG; AG 9; AG 10; AG 1; AG 18; AG 30; AG 43; AG 82; AG 99; AG 112; AG 126; AG 183; AG 213; AG 370: AG 490; AG 494; AG 527; AG 537; AG 538; AG 555; AG 556; AG 592; AG 825; AG 835; AG 879; AG 957; AG 957; AG 1024; AG 1288; AG 1295; AG 1296; AG 1387; AG 1433; AG 1478; AGL 2043; AGL 2263; Aminogenistein; BPDQ; BPIQ-I; BPIQ-II; 4-[(3'-Bromo-4'-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (WHI- P154); 4-[(3-Bromophenyl)amino]-6,7
  • tyrosine kinase inhibitors include, but are not limited to, Herbimycin A (Streptomyces sp.); 1,2,3,4,5,6-HexabromocycJohexane; HNMPA-(AM)3; (5-Hydroxy-1 H-2-indolyl)(1 H-2-indolyl)-methanone; 4-(4'-Hydroxyphenyl)amino-6,7- dimethoxyquinazoline (WHI-P131); IGF-1R Inhibitor, PPP; l-OMe-AG 538; (Z,E)-3- (lmidazol-4-ylmethylene)indolin-2-one; [2-(1 H-2-lndolylcarbonyl)-1 H-5-indoIyl]butanoate; lndirubin Derivative E804; K-252a, Nocardiopsis sp.; Lavendus
  • the present invention provides methods of treating cancers which have acquired resistance to a kinase inhibitor comprising, e.g., comprising administering to a subject in need thereof an effective amount of sorafenib, wherein the cancer is treated.
  • the phrase "effective amount” indicates the amount of sorafenib which is effective to treat any symptom or aspect of the cancer. Effective amounts can be determined routinely. Further guidance on dosages and administration regimens is provided below.
  • treating is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving, etc., one or more of the symptoms associated with a cancer, including all cancers mentioned herein and in Table 1.
  • Administering effective amounts of sorafenib can treat one or more aspects of the cancer disease, including, but not limited to, causing tumor regression; causing cell death; causing apoptosis; causing necrosis; inhibiting cell proliferation; inhibiting tumor growth; inhibiting tumor metastasis; inhibiting tumor migration; inhibiting tumor invasion; reducing disease progression; stabilizing the disease; reducing or inhibiting angiogenesis; prolonging patient survival; enhancing patient's quality of life; reducing adverse symptoms associated with cancer; and reducing the frequency, severity, intensity, and/or duration of any of the aforementioned aspects.
  • Any cancer can be treated in accordance of the present invention, irrespective of the type or cause of the cancer, and irrespective of the genetic lesions associated with it (see, e.g., Atlas of Genetics and Cytogenetics in Oncology and Haematology on the worldwide web at infobiogen.fr/services/chromcancer/ for an atlas of genes involved in cancer).
  • pre-cancerous cells, tumors, neoplasms, and non-malignant tumors can also be treated.
  • Cancers which can be treated include, e.g., cancers which are primary; which arise from a primary tumor at a secondary metastatic site; which have been treated by surgery (e.g., entirely removed, surgical resection, etc); which have been treated by chemotherapy, radiation, radiofrequency ablation, and/or any other adjunct to drug therapy; which have acquired drug-resistance; which are refractory to a chemotherapeutic agent.
  • any subject can be in accordance with the present invention, including, e.g., mammals, such as dogs, cats, horses, rats, mice, monkeys, and humans.
  • the present invention also relates to treating a cancer which has acquired resistance to any agent targeted at the RAS-RAF-MEK-ERK pathway.
  • Agents include any compound which is an inhibitor of any component of the aforementioned pathway.
  • the present invention also provides methods of treating a cancer in a subject in need thereof, comprising administering an effective amount of sorafenib to said subject having a cancer, wherein said cancer is refractory to a chemotherapeutic agent.
  • refractory means, e.g., that the cancer (including a tumor and/or any metastasis thereof), upon treatment with at least one chemotherapeutic shows no or only weak anti-cancer (e.g., anti-proliferative response) (such as, no or only weak inhibition of tumor growth) after the treatment with such an agent.
  • chemotherapeutic agents include, but are not limited to, e.g., alkylating agents (e.g., cyclophosphamide, ifosfamide, melphalan, chlorambucil, aziridines, epoxides, alkyl sulfonates), cisplatin and its analogues (e.g., carboplatin, oxaliplatin), antimetabolitites (e.g., methotrexate, 5-fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine), toposiomerase interactive agents (e.g., camptothecin, irinotecan, topotecan, etoposide, teniposide, doxorubicin, daunorubicin),
  • alkylating agents e.g., cyclophosphamide, ifosfamide, melphalan, chlorambucil, aziridines, e
  • sorafenib refers to the tosylate salt of the compound N- ⁇ -chloro-S- ⁇ rifluoromethyOphe ⁇ yll-NH ⁇ - ⁇ -carbamoyl-i-oxo ⁇ pyridyloxy)]phenyl ⁇ urea of the formula I .below including all polymorphs, hydrates, solvates or combinations thereof.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfo ⁇ ic acid, 1- naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid,, and mandelic acid.
  • inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulfo ⁇ ic acid, 1- naphthalenesulf
  • salts of inorganic bases include salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N.N-dicyclohexylamine, lysine, pyridine, N,N-dirnethylaminopyridine (DMAP), 1 ,4- diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene
  • alkaline cations e
  • Solvates for the purposes of the invention are those forms of the compound where solvent molecules form a complex in the solid state and include, but are not limited to for example ethanol and methanol. Hydrates are a specific form of solvates, where the solvent molecule is water. [0032] Without further elaboration, it is believed that one skilled in the art can, using the prceeding description, utilize the following invention to its fullest extent. The following specific preferred embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in anyway whatsoever.
  • the organic layer is sequentially washed with a saturated NH 4 CI solution then a saturated NaCI solution, dried (MgSO-O, and concentrated under reduced pressure.
  • the crude product is purified using MPLC chromatography (Biotage ® ; gradient from 100% EtOAc to followed by 10% MeOH / 50% EtOAc / 40% hexane) to give the 4-chloro-5-trifluoromethylaniline as a brown solid (510 mg, 58%).
  • Step 3 Preparation of N-[4-chloro-3-(trifluor ⁇ methyl)phenyl]-N'- ⁇ 4-[2- carbamoyl-(4-pyr ⁇ dyloxy)]phenyl ⁇ urea
  • sorafenib in the polymorph I is as follows: [0047] Heating 5mg of "Sorafenib,”[tosylate salt of 4- ⁇ 4-[( ⁇ [4-chloro-3- (trifluoromethyl)phenyl]amino ⁇ carbonyl)amino]-phenoxy ⁇ -N-methylpyridine-2- carboxamide] in the polymorph Il to 200 0 C at a heating rate of 20°C/min and subsequently cooling to room temperature at a cooling rate of 2°C/min. The sample is tested thermoanalytically (DSC) and corresponds to the title compound in the polymorph I.
  • DSC thermoanalytically
  • the specific dose level and frequency of dosage may vary, depending upon a variety of factors, including the activity of the active agent, its metabolic stability and length of action, rate of excretion, mode and time of administration, the age, body weight, health condition, gender, diet, baseline hematologic and biologic parameters (e.g., WBCs, granulocytes, platelets, hemoglobin, creatinine, bilirubin, albumin, etc.), etc., of the subject, and the severity, intensity, stage of the cancer, primary site of cancer, size of cancer lesion, presence or extent of metastases, surgical status, disease progression (i.e., aggressive), etc. of the disease.
  • WBCs granulocytes, platelets, hemoglobin, creatinine, bilirubin, albumin, etc.
  • the compound of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, intrathecal, intratumoral, etc. Sorafenib can be administered directly to the site of a tumor, either pre- or post-operatively. It can be administered alone, or in combination with any ingredient(s), active or inactive.
  • any effective route including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, spray, inhalation, subcutaneous, intravenous, intramuscular, buccal,
  • Sorafenib can be administered by the oral route using the pharmaceutical composition of the present invention will generally range, based on body weight, from about 0.01 mg/kg to about 50 mg/kg; from about 1 mg/kg to about 40 mg/kg; from about 5 mg/kg to about 30 mg/kg; from about 10 to about 25 mg/kg; about 10 mg/kg; about 20 mg/kg; about 25 mg/kg; about 30 mg/kg; etc.
  • any suitable dosing interval can be used in accordance with the present invention.
  • the compound can be administered once, twice (BID), three, four, etc., times a day.
  • BID twice
  • about 100, about 200, about 400 mg, about 500 mg, about 600 mg, or about 800 mg can be administered one, twice, or three times daily.
  • Sorafenib can be administered at any suitable time.
  • it can be administered routinely as other chemotherapeutic agents; it can be administered as a bolus prior to a surgical intervention; prior to or after radiation, radiofrequency ablation and other energy treatments; post-operatively; pre-operatively; etc.
  • Sorafenib can be further combined with any other suitable additive or pharmaceutically acceptable carrier.
  • suitable additives include any of those used conventionally, such as those described in Remington: The Science and Practice of
  • the compounds can be in any suitable form, without limitation.
  • Forms suitable for oral use include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups and elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Compounds can be formulated with other ingredients, e.g., "pharmaceutically acceptable carriers” or “excipierits” to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
  • pharmaceutically acceptable carriers e.g., "pharmaceutically acceptable carriers” or “excipierits” to indicate they are combined with the active drug and can be administered safely to a subject for therapeutic purposes.
  • these include, but are not limited to, antioxidants, preservatives, dyes, tablet-coating compositions, plasticizers, inert carriers, excipients, polymers, coating materials, osmotic barriers, devices and agents which slow or retard solubility, etc.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example magnesium stearate, stearic acid or talc.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylceilulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example poly
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p- hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent exemplified by those already mentioned above.
  • Additional excipients for example, sweetening, flavoring and coloring agents, may also be present.
  • the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbfc acid.
  • compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug.
  • suppositories for rectal or vaginal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of the invention may also be administrated transdermal ⁇ using methods known to those skilled in the art (see, for example; Chie ⁇ ; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157 3Mar94).
  • a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bactericides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
  • a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
  • Suitable solvents for processing transdermal delivery systems include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
  • lower alcohols such as ethanol or isopropyl alcohol
  • lower ketones such as acetone
  • lower carboxylic acid esters such as ethyl acetate
  • polar ethers such as tetrahydrofuran
  • lower hydrocarbons such as hexane, cyclohexane or benzene
  • halogenated hydrocarbons such as dichloromethane, chloroform, trichlor
  • Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
  • Suitable penetration enhancing materials for transdermal delivery system include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tertbutyl or monogiycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid
  • Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
  • Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
  • Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene copolymers, and natural and synthetic rubbers.
  • Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
  • compositions comprising precursors can also be formulated for controlled release, where release of the active ingredient is regulated or modulated to achieve a desired rate of delivery into the systemic circulation.
  • a controlled release formulation can be pulsed, delayed, extended, slow, steady, immediate, rapid, fast, etc. It can comprise one or more release formulations, e.g. extended- and immediate- release components. Extended delivery systems can be utilized to achieve a dosing internal of once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, etc.
  • the dosage form/delivery system can be a tablet or a capsule suited for extended release, but a sustained release liquid or suspension can also be used.
  • a controlled release pharmaceutical formulation can be produced which maintains the release of, and or peak blood plasma levels of sorafenib.
  • compositions according to the invention at least 80% of the sorafenib exists in the stable polymorph I form and most preferably sorafenib is present in a micronized form.
  • Micronization can be achieved by standard milling methods, preferably by air chat milling, known to a skilled person.
  • the micronized form can have a mean particle size of from 0.5 to 10 ⁇ m, preferably from 1 to 6 ⁇ m, more preferably from 1 to 3 ⁇ m.
  • the indicated particle size is the mean of the particle size distribution measured by laser diffraction known to a skilled person (measuring device: HELOS, Sympatec).
  • compositions which are preferred comprise sorafenib, a compound of formula (I) or another pharmaceutically acceptable salt of a compound of formula I in a portion of at least 40%, preferably at least 45%, more preferably at least 50%, even more preferably at least 55%, by weight of the composition. Amounts of at least 62%, or at least 69%, or at least 75% by weight of the composition can be used under certain circumstances. Methods for preparing such formulations are disclosed in provisional application Serial No. 60/658,827, filed March 7, 2005, which is incorporated herein by reference.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions et des procédés destinés à traiter un cancer avec du sorafenib. N'importe quel cancer peut être traité, même ceux ayant acquis une résistance à un autre agent thérapeutique, tel que les inhibiteurs de kinase. Le sorafenib peut également être utilisé afin de traiter des cancers devenus réfractaires à d'autres agents chimiothérapeutiques.
PCT/US2006/044238 2005-11-14 2006-11-14 Traitement de cancers a resistance a des agents chimiotherapeutiques WO2007059155A1 (fr)

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US60/735,853 2005-11-14
US78534706P 2006-03-24 2006-03-24
US60/785,347 2006-03-24

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Cited By (14)

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WO2008089388A2 (fr) * 2007-01-19 2008-07-24 Bayer Healthcare Llc Traitement de cancers présentant une résistance à des agents chimiothérapeutiques
WO2008089389A3 (fr) * 2007-01-19 2009-01-08 Bayer Healthcare Llc Traitement de cancers à résistance acquise aux inhibiteurs kit
WO2009017838A2 (fr) * 2007-08-01 2009-02-05 Exelixis, Inc. Combinaisons d'inhibiteurs jak-2 et d'autres agents
WO2010019701A2 (fr) * 2008-08-14 2010-02-18 Concert Pharmaceuticals, Inc. Dérivés de diaryl urée
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
CN102875460A (zh) * 2012-05-17 2013-01-16 上海奥博生物医药技术有限公司 一种制备索拉非尼的方法
CN103254126A (zh) * 2008-09-19 2013-08-21 苏州泽璟生物制药有限公司 氘代的ω-二苯基脲及衍生物以及包含该化合物的药物组合物
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
WO2014152330A1 (fr) * 2013-03-15 2014-09-25 Stc.Unm Traitement à base d'arsenic de cancers et de troubles inflammatoires
US9737488B2 (en) 2005-03-07 2017-08-22 Bayer Healthcare Llc Pharmaceutical composition for the treatment of cancer

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WO2005009367A2 (fr) * 2003-07-17 2005-02-03 Ambit Biosciences Corporation Traitement de maladies au moyen d'inhibiteurs de kinase

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US7838541B2 (en) 2002-02-11 2010-11-23 Bayer Healthcare, Llc Aryl ureas with angiogenesis inhibiting activity
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
US9737488B2 (en) 2005-03-07 2017-08-22 Bayer Healthcare Llc Pharmaceutical composition for the treatment of cancer
WO2008089388A2 (fr) * 2007-01-19 2008-07-24 Bayer Healthcare Llc Traitement de cancers présentant une résistance à des agents chimiothérapeutiques
US8680124B2 (en) 2007-01-19 2014-03-25 Bayer Healthcare Llc Treatment of cancers with acquired resistance to kit inhibitors
WO2008089389A3 (fr) * 2007-01-19 2009-01-08 Bayer Healthcare Llc Traitement de cancers à résistance acquise aux inhibiteurs kit
WO2008089388A3 (fr) * 2007-01-19 2008-12-31 Bayer Healthcare Llc Traitement de cancers présentant une résistance à des agents chimiothérapeutiques
WO2009017838A3 (fr) * 2007-08-01 2009-07-02 Exelixis Inc Combinaisons d'inhibiteurs jak-2 et d'autres agents
WO2009017838A2 (fr) * 2007-08-01 2009-02-05 Exelixis, Inc. Combinaisons d'inhibiteurs jak-2 et d'autres agents
WO2010019701A3 (fr) * 2008-08-14 2010-08-26 Concert Pharmaceuticals, Inc. Dérivés de diaryl urée
WO2010019701A2 (fr) * 2008-08-14 2010-02-18 Concert Pharmaceuticals, Inc. Dérivés de diaryl urée
CN103254126A (zh) * 2008-09-19 2013-08-21 苏州泽璟生物制药有限公司 氘代的ω-二苯基脲及衍生物以及包含该化合物的药物组合物
CN102875460A (zh) * 2012-05-17 2013-01-16 上海奥博生物医药技术有限公司 一种制备索拉非尼的方法
WO2014152330A1 (fr) * 2013-03-15 2014-09-25 Stc.Unm Traitement à base d'arsenic de cancers et de troubles inflammatoires

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