WO2007143483A2 - Procédé de traitement du cancer - Google Patents

Procédé de traitement du cancer Download PDF

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Publication number
WO2007143483A2
WO2007143483A2 PCT/US2007/070032 US2007070032W WO2007143483A2 WO 2007143483 A2 WO2007143483 A2 WO 2007143483A2 US 2007070032 W US2007070032 W US 2007070032W WO 2007143483 A2 WO2007143483 A2 WO 2007143483A2
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WIPO (PCT)
Prior art keywords
cancer
formula
compound
mammal
salt
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PCT/US2007/070032
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English (en)
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WO2007143483A3 (fr
Inventor
Bonnie F. Whitehead
Peter T.C. Ho
Albert Benjamin Suttle
Arundathy Nirmalini Pandite
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of WO2007143483A2 publication Critical patent/WO2007143483A2/fr
Publication of WO2007143483A3 publication Critical patent/WO2007143483A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method of treating cancer in a mammal by administration of pyrimidine derivatives and quinazoline derivatives.
  • the method relates to a method of treating cancer by administration of 5-[[4-[(2,3-dimethyl- 2H-indazol-6-yl)methylamino]-2-pyhmidinyl]amino]-2-methylbenzenesulfonamide or salts or solvates thereof, and N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine, or salts or solvates thereof.
  • cancer results from the deregulation of the normal processes that control cell division, differentiation and apoptotic cell death.
  • Apoptosis (programmed cell death) plays essential roles in embryonic development and pathogenesis of various diseases, such as degenerative neuronal diseases, cardiovascular diseases and cancer.
  • vascular endothelial growth factor and its receptors, termed vascular endothelial growth factor receptor(s) (VEGFRs).
  • VEGFR1 Flt-1
  • VEGFR2 Flk-1 and KDR
  • VEGFR3 Flt-4
  • antagonism of the VEGFR kinase domain is believed to block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis, and other signaling pathways mediated by VEGF, thereby providing a potent treatment for many types of cancer.
  • the erbB family of protein tyrosine kinases is another group of kinases that has been implicated in human malignancies. Elevated Erb-B1 (EGFR) receptor activity has, for example, been implicated in non-small cell lung, bladder, renal cell, and head and neck cancers. Increased c-Erb-B2 activity is associated with breast, ovarian, gastric and pancreatic cancers. Consequently, inhibition of such protein tyrosine kinases should provide a treatment for disorders characterized by aberrant Erb family protein kinase activity.
  • Combination therapy is rapidly becoming the norm in cancer treatment, rather than the exception. Oncologists are continually looking for anti-neoplastic compounds which when utilized in combination provides a more effective and/or enhanced treatment to the individual suffering the effects of cancer. Typically, successful combination therapy provides improved and even synergistic effect over monotherapy.
  • chemotherapeutic agents that provide clinical benefit in human patients.
  • multiple drug combinations that include 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyrimidinyl]amino]-2-methylbenzenesulfonamide or salts or solvates thereof, and N- ⁇ 3- chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine, or salts or solvates thereof, are described.
  • novel cancer treatment methods which include administration of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- pyhmidinyl]amino]-2-methylbenzenesulfonamide or salts or solvates thereof, and N- ⁇ 3- chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine, or salts or solvates thereof.
  • a method of treating susceptible cancers in a mammal comprising: administering to the mammal a compound of formula (I)
  • neoplasm refers to an abnormal growth of cells or tissue and is understood to include benign, i.e., non-cancerous growths, and malignant, i.e., cancerous growths.
  • neoplastic means of or related to a neoplasm.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • tumors are frequently metastatic, in that a first (primary) locus of tumor growth spreads to one or more anatomically separate sites.
  • a tumor or “a cancer” in a subject includes not only the primary tumor, but metastatic tumor growth as well.
  • a reference to “tumor” or “cancer” is not limited to tumors or cancers that are or may become metastatic.
  • the present invention provides methods for the treatment of several conditions or diseases, all of which comprise the step of administering a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II) or a salt or solvate thereof.
  • treatment refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrance of the condition in a previously afflicted subject.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compounds of formula (I) or a salt thereof or a compound of formula (II) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • the methods of cancer treatment disclosed herein include administering a compound of formula (I):
  • the salt of the compound of formula (I) is a hydrochloride salt.
  • the salt of the compound of formula (I) is an anhydrous or hydrous form of the monohydrochloride salt.
  • the monohydrochloride salt of the compound of formula (I) has the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyhmidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride and is illustrated as formula (T)
  • the salt of the compound of formula (I) is a monohydrochloride anhydrate.
  • the monohydrochloride anhydrate salt of the compound of formula (I) has the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyhmidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride anhydrate.
  • the solvate of the compound of formula (I) is a monohydrochlohde monohydrate of the compound of formula (I).
  • the monohydrochlohde monohydrate of the compound of formula (I) has the chemical name 5-( ⁇ 4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl ⁇ amino)-2- methylbenzenesulfonamide monohydrochlohde monohydrate, as illustrated in formula (I")
  • the salt of the compound of formula (II) is a tosylate salt.
  • the salt of the compound of formula (II) is an anhydrous or hydrous form of the ditosylate salt.
  • the ditosylate salt of the compound of formula (II) has the chemical name N- ⁇ 3-chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate and is illustrated as formula (M')
  • the salt of the compound of formula (II) is a ditosylate anhydrate.
  • the ditosylate anhydrate salt of the compound of formula (M) has the chemical name N- ⁇ 3-chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate.
  • the solvate of the compound of formula (II) is a monohydrate of the ditosylate salt.
  • the monohydrate of the ditosylate salt of the compound of formula (II) has the chemical name N- ⁇ 3-chloro-4- [(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]- 4-quinazolinamine ditosylate monohydrate and is illustrated as formula (N")
  • the methods of cancer treatment disclosed herein include administering any one or more of a compound of formula (I) or a salt or salvate thereof, a compound of formula (T), or a compound of formula (I"), in combination with any one or more of a compound of formula (II) or a salt or solvate thereof, a compound of formula (N'), or a compound of formula (N").
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in a compound of the present invention.
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochlohde, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, o
  • compositions include a compound of formula (I) or salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients, or a compound of formula (II) or salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the pharmaceutical composition may include a compounds of formula (I) and formula (II), or salts or solvates thereof, and one or more pharmaceuticall acceptable carriers, diluents, or excipients.
  • the carher(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5mg to 1 g, preferably 10mg to 500mg, of a compound of formula (I) or formula (II), or 0.5mg to 1 g, preferably 10mg to 500mg of each compound of formula (I) and formula (II) wherein the compounds are in a single unit dose.
  • the contents of each unit dose may depend on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • the compounds of formula (I) and formula (II) may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intraveneous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination.
  • the method of the present invention may also be employed with other therapeutic methods of cancer treatment.
  • combination therapy with other chemotherapeutic, hormonal, antibody agents as well as surgical and/or radiation treatments other than those mentioned above are envisaged.
  • Anti-neoplastic therapies are described for instance in International Application No. PCT US 02/01 130, filed January 14, 2002, published as WO 02/056912 on July 25, 2002, which is incorporated by reference herein to the extent that it relates to anti-neoplastic therapies.
  • Combination therapies according to the present invention thus include the administration of at least one compound of formula (I) and formula (II) as well as optional use of other therapeutic agents including other anti-neoplastic agents.
  • Such combination of agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order, both close and remote in time.
  • the amounts of the compounds of formula (I) and formula (II) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the agents for use according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • Agents for use according to the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists that may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bactehostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dhed (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • specific compounds of formula (I) and formula (II) are administered to a mammal.
  • the amount of one of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the mammal, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the amount will be at the discretion of the attendant physician or veterinarian.
  • the compound of formula (I) will be given in the range of 0.1 to 2000 mg per day and more usually in the range of 10 to 1000 mg per day, and the compound of formula (II) will be given in the range of 0.1 to 2000 mg per day and more usually in the range of 10 to 1800 mg per day.
  • the methods of the present invention are useful for treating many types of susceptible cancers, including but not limited to the following: brain cancer, including glioblastoma multiforme (GBM); neuroendocrine cancer; pancreatic cancer; prostate cancer; myeloma; breast cancer; lung cancer, including non-small cell and mesothelioma; ovarian cancer; kidney cancer, including renal cell carcinoma; gallbladder cancer; liver cancer, including hepatocellular and cholangio; cervical cancer; bladder cancer; head and neck cancer; gastric cancer, including esophageal, stomach, and intestinal; colorectal cancer; skin cancer; smooth muscle cancer and desmoid tumors; bone cancer, including giant cell tumors and osteosarcoma; sarcoma; and thyroid cancer.
  • GBM glioblastoma multiforme
  • neuroendocrine cancer pancreatic cancer
  • prostate cancer myeloma
  • breast cancer lung cancer, including non-small cell and mesothelioma
  • the treatment may be a first line therapy.
  • the treatment may be an adjunctive therapy.
  • the treatment may be an adjuvant therapy.
  • a method of treating a susceptible cancer in a mammal wherein the susceptible cancer is susceptible to VEGF-R and ErbB inhibition.
  • the kidneys are a pair of bean-shaped organs located on each side of the spine that filter blood and eliminate waste in the urine through a complex system of filtration tubules. All of the blood in the body passes through the kidneys approximately 20 times an hour. Renal cell carcinoma (RCC) is an uncommon form of cancer that is most often characterized by the presence of cancer cells in the lining of the kidney's filtration tubules. Cancer that has spread outside the kidney to several and/or distant sites in the body is referred to as metastatic RCC.
  • RCC Renal cell carcinoma
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is renal cell cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is renal cell cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Melanoma is a very serious form of skin cancer. It begins in melanocytes — cells that make the skin pigment called melanin. Although melanoma accounts for only about 4% of all skin cancer cases, it causes most skin cancer-related deaths.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is melanoma comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is melanoma comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is melanoma comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Sarcoma is a general class of uncommon cancers in which the cancer cells arise from or resemble normal cells in the body known as connective tissue.
  • Normal connective tissues include fat, muscle, blood vessels, deep skin tissues, nerves, bones, and cartilage. Cancers of cells which resemble any of these normal tissues are known as sarcomas.
  • Sarcomas are sub-classified based upon the specific type of cell that makes up the cancer. For example, leiomyosarcoma is a malignant tumor that develops from smooth muscle tissue. Chondrosarcoma is a tumor of cells that form cartlidge.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is sarcoma comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is sarcoma comprising: administering to the mammal a compound of formula (I') and a compound of formula (M").
  • Desmoid tumors are aggressive fibromatoses. Local invasiveness characterizes this low grade tumor. They typically arise in skeletal muscles or their fascia, and they are of connective tissue origin. Growth is relatively slow compared with most tumors, but aggressive accelerated growth has also been seen. Desmoid tumors are almost always non-metastatic, but deeply infiltrating lesions can invade into surrounding muscle. The mainstay of treatment has always been surgery, and treatment aims to have a curative effect with a good functional and cosmetic outcome. The problem lies therein, because these tumors are very infiltrative by nature and potentially require a large volume of resection to obtain a negative margin (if using surgery alone). As an attempt to maintain a functional and cosmetic outcome, many have tried to use radiation therapy (RT) as an adjunct for patients who have a positive margin, subtotal resection, or unresectable disease.
  • RT radiation therapy
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is a desmoid tumor comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is a desmoid tumor comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is a desmoid tumor comprising: administering to the mammal a compound of formula (T) and a compound of formula (II").
  • Lung cancer is the uncontrolled growth of abnormal cells in one or both of the lungs. While normal lung tissue cells reproduce and develop into healthy lung tissue, these abnormal cells reproduce rapidly and never grow into normal lung tissue. Lumps of cancer cells (tumors) then form and disrupt the lung, making it difficult to function properly.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is lung cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is lung cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Stomach cancer also called gastric cancer
  • gastric cancer is a cancer that begins in the lining of the stomach.
  • stomach cancer is still a prominent cause of cancer mortality, especially in developing countries. It occurs most frequently in men over the age of 40, and often presents as later stage disease, since the early stage signs and symptoms frequently go unnoticed.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • colorectal cancer Cancer of the colon or rectum is called colorectal cancer.
  • the cancer occurs when tumors grow in the lining of the large intestine, or large bowel. Occurrence rates are similar between men and women, and risk for the cancer increases after the age of 50.
  • colorectal cancer is the fourth most common cancer in the United States.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is colorectal cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Neuroendocrine tumor refers to the type of cell that a tumor grows from rather than where that tumor is located.
  • Neuroendocrine cells produce hormones or regulatory proteins, and so tumors of these cells usually have symptoms that are related to the specific hormones that they produce.
  • Neuroendocrine cells have roles both in the endocrine system and the nervous system. They produce and secrete a variety of regulatory hormones, or neuropeptides, which include neurotransmitters and growth factors. When these cells become cancerous, they grow and overproduce their specific neuropeptide.
  • Neuroendocrine tumors are generally rare.
  • one type of neuroendocrine tumor is a carcinoid tumor. This type of tumor can occur in the intestinal tract, appendix, rectum, bronchial tubes, or ovary. Most carcinoid tumors secrete serotonin. When the blood concentration of this hormone is high enough, it causes carcinoid syndrome. This syndrome refers to a variety of symptoms that are caused by the excessive amount of hormone secreted rather than the tumor itself
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is neuroendocrine cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is neuroendocrine cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (N").
  • Cancer of the pancreas is a disease in which cancer (malignant) cells are found in the tissues of the pancreas.
  • the pancreas is about 6 inches long and is shaped something like a thin pear, wider at one end and narrowing at the other.
  • the pancreas lies behind the stomach, inside a loop formed by part of the small intestine.
  • the broader right end of the pancreas is called the head, the middle section is called the body, and the narrow left end is the tail.
  • the pancreas has two basic jobs in the body. It produces juices that help digest food, and hormones (such as insulin) that regulate how the body stores and uses food.
  • the area of the pancreas that produces digestive juices is called the exocrine pancreas. About 95% of pancreatic cancers begin in the exocrine pancreas.
  • the hormone-producing area of the pancreas is called the endocrine pancreas. Only about 5% of pancreatic cancers start here, and include islet cell carcinomas.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (II").
  • Thyroid cancer is the uncontrolled growth of abnormal cells in the thyroid gland.
  • the thyroid gland is shaped like a butterfly and is located under the Adam's apple in the front of the neck.
  • the thyroid has two types of cells that produce two hormones that help to regulate body functions.
  • Follicular cells in the thyroid produce a hormone called thyroxine, or T-4, which controls the body's rate of metabolism.
  • Thyroid cancer is rare, accounting for only about 1 .5% of all types of cancer, and the illness is more common in women than in men
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is thyroid cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is thyroid cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is thyroid cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Breast cancer is a type of cancer where cells in the breast tissue divide and grow without the normal control. About 80 percent of breast cancers originate in the mammary ducts, while about 20 percent arise in the lobules. Cancerous tumors in the breast usually grow very slowly so that by the time one is large enough to be felt as a lump, it may have been growing for as long as ten years. Though breast cancer most often occurs in women, men make up approximately one percent of those diagnosed with breast cancer.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is breast cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is breast cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Head and neck cancer is the term given to a variety of malignant tumors that develop in the oral cavity (mouth), pharynx (throat), paranasal sinuses (small hollow spaces around the nose lined with cells that secrete mucus), nasal cavity (airway just behind the nose), larynx ("Adam's apple” or voice box), and salivary glands (parotid, submanidular, sublingual glands that secrete saliva). Some also include skin tumors of the face and neck and tumors of the cervical lymph nodes.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (N").
  • GBM glioblastoma multiforme
  • AA anaplastic astrocytoma
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Cervical cancer is cancer of the uterine cervix, the portion of the uterus attached to the top of the vagina. Ninety percent of cervical cancers arise from the flattened or "squamous" cells covering the cervix. Most of the remaining 10% arise from the glandular, mucus-secreting cells of the cervical canal leading into the uterus.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (M), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (M").
  • Bladder cancer tends to occur most commonly in individuals over 60 years of age. Cigarette smoking and exposure to certain industrially used chemicals (derivatives of compounds called arylamines) are strongly associated with the development of bladder cancer. The vast majority (approximately 90%) of these cancers originate in the lining cells of the bladder, known as urothelium or transitional epithelium.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (T) and a compound of formula (II").
  • Esophageal cancer is a malignant tumor of the esophagus, the muscular tube that transports food from the mouth to the stomach. Esophageal cancer is relatively uncommon in the United States, and occurs most often in men over 50 years old. It affects less than 5 in 100,000 people. There are two main types of esophageal cancer, squamous cell carcinoma and adenocarcinoma. These two types are distinguished by the way they look under the microscope.
  • Squamous cell cancer is associated with smoking and alcohol consumption.
  • the incidence of this disease in the United States has remained relatively constant, while the incidence of adenocarcinoma of the esophagus has risen dramatically.
  • Barrett's esophagus a complication of gastroesophageal reflux disease (GERD)
  • GFD gastroesophageal reflux disease
  • Risk factors for adenocarcinoma of the esophagus include male gender, obesity, western diet, and smoking.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is esophageal cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (II").
  • Heptoma is cancer of the hepatocytes. (The main functioning liver cell). Hepatoma is primary liver cancer. Hepatoma usually grows in the liver as a ball-like tumor, invading the normal tissue surrounding it. A history of infection with the hepatitis B virus puts individuals at risk of developing heptoma.
  • Cholangiocarcinoma originates in the bile ducts and is often caused by infestation with the liver fluke Clonorchis (a parasite). The cancer grows along the bile ducts in sheets or lines, and is hard to find on X-ray studies.
  • Liver cancer is much more prevalent in many of the developing countries than in the industrialized world. Its incidence is highest in subSaharan Africa, China, southern Asia, and Japan. Japan is the exception of the industrialized countries. China accounts for about 45% of the world's cases.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is liver cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is liver cancer comprising: administering to the mammal a compound of formula (I) or a salt or solvate thereof, and a compound of formula (II), or a salt or solvate thereof, and at least one anti-neoplastic therapy.
  • a method of treating a susceptible cancer in a mammal, wherein said cancer is liver cancer comprising: administering to the mammal a compound of formula (T) and a compound of formula (II").
  • L (liters); ml. (milliliters); ⁇ l_ (microliters); psi (pounds per square inch);
  • Tr retention time
  • RP reverse phase
  • DCM dichloromethane
  • DCE dichloroethane
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • HOAc acetic acid
  • TMSE (2-(tri methyl si IyI )ethyl ); TMS (thmethylsilyl); TIPS (triisopropylsilyl); TBS (f-butyldimethylsilyl);
  • the free base, salts and solvates of the compound of formula (I) may be prepared, for example, according to the procedures of International Patent Application No. PCT/US01 /49367 filed December 19, 2001 , and published as WO 02/0591 10 on August 1 , 2002, and International Patent Application No. PCT/US03/1921 1 filed June 17, 2003, and published as WO 03/106416 on December 24, 2003.
  • Thmethyl orthoformate (1 1 mmol, 1 .17 g) was added over a 2 min period to a solution of boron trifluoride etherate (12.5 mmol, 1.77 g in methylene chloride (2.0 mL) which had been cooled to -30 0 C. The mixture was warmed to 0 0 C for 15 min and was then cooled to -70 0 C. The nitro indazole (10 mmol, 1.77 g) was slurried in methylene chloride (30 mL) and was added all at once to the cooled mixture. The mixture was stirred at -70 0 C for 15 min and at ambient temperature for 17 h. After 17 h the mixture was red and heterogeneous.
  • the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) and the organic layer separated.
  • the aqueous layer was extracted with methylene chloride (30 mL).
  • the methylene chloride layers were combined and extracted with water (30 mL).
  • the methylene chloride layer was distilled under reduced pressure until ⁇ 10 mL remained.
  • Propanol (10 mL) was added and the remainder of the methylene chloride removed under reduced pressure, resulting in a yellow slurry.
  • the product was isolated by filtration to give 2,3-dimethyl-6- nitro-2H-indazole (65 %, 7mmol, 1.25 g) as a light yellow powder.
  • the methylene chloride layers were combined and back extracted with water (20 ml_).
  • the methylene chloride layer was treated with propanol (10 mL) and the methylene chloride was removed by distillation under reduced pressure.
  • the solid was isolated by filtration and the yellow solid washed with heptane (5 mL) and air-dried.
  • the 2,3-dimethyl-6-nitro-2/-/-indazole product (70%, 0.97 g) was obtained as a light yellow solid.
  • reaction mixture was stirred at 68 - 72 0 C until ⁇ 1.5% by area of the starting product of Intermediate Example 4 was remaining by HPLC analysis (Typically, this reaction is complete in > 8 hrs).
  • the reaction mixture was cooled to 20 0 C over ca. 30 min and stirred at 20 - 22 0 C for 40 min.
  • the product was then isolated by filtration and the filter cake washed with ethanol (20 ml_, 3.3 volumes). The wet cake was dried under vacuum at 45 - 50 0 C.
  • the solids were blown in the filter- dryer with nitrogen at 25°C until the LOD was less than 25%.
  • Acetonithle 300 mL was charged to the solids in filter-dryer, and stirred at 60 0 C for at least 8 hours or until the form conversion was complete (no monohydrate remaining) as observed by DATR to form 5-( ⁇ 4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyhmidinyl ⁇ amino)-2- methylbenzenesulfonamide monohydrochloride anhydrate.
  • the contents of the filter- dryer were cooled to ⁇ 30°C, and the filtrate was pushed off using nitrogen pressure.
  • the free base and HCI salts of the compound of formula (II) may be prepared according to the procedures of International Patent Application No. PCT/EP99/00048, filed January 8, 1999, and published as WO 99/35146 on July 15, 1999, referred to above. A schematic of such procedures is presented in Scheme A following. The specific page references given are to WO 99/35146.
  • the free base of the compound of formula Il is used as an example of the general scheme. The following procedures are also described in International Patent Application No. PCT/US2006/014447.
  • Procedure A Reaction of an amine with a bicyclic species containing a 4- chloropyhmidine ring (p. 55, lines 21 -33, p. 69, lines 30-34 and p. 74, line 35 - p. 75, line 4).
  • Procedure B Reaction of Procedure A product with heteroaryl tin reagent (p.55, line 33 - p. 56, line 9)
  • the ditosylate salts including the anhydrous and hydrated forms thereof, of the compound of formula (II) may be prepared according to the procedures of International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002 and International; patent Application No. PCT/US03/10747, filed April 8, 2003, and published as WO 03/086467 on October 23, 2003.
  • a further process is illustrated in Scheme B following.
  • Scheme B following illustrates the preparation of the ditosylate salt of the compound of formula (II).
  • the preparation proceeds in four stages: Stage 1 : reaction of quinazoline (I), which is prepared from 3H-6-iodoquinazolin-4-one (I'), with amine (II) to give iodoquinazoline (III); Stage 2: preparation of the corresponding aldehyde salt (V) by reaction of iodoquinazoline (III) and boronic acid (IV) followed by treatment with p- toluenesulfonic acid salt; Stage 3: preparation of the ditosylate salt of GW572016 (Vl) from aldehyde salt (V); and Stage 4: recrystallization of the GW572016 ditosylate salt (Vl).
  • Scheme C shows an alternate preparation of the ditosylate salt of the compound of formula (II).

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Abstract

La présente invention concerne un procédé de traitement du cancer chez un mammifère par administration de dérivés de pyrimidine et de dérivés de quinazoline. En particulier, le procédé concerne un procédé de traitement du cancer par administration de 5-[[4-[(2,3-diméthyl-2H-indazol-6-yl)méthylamino]-2-pyrimidinyl]amino]-2-méthylbenzène-sulfonamide ou des sels ou solvates de celui-ci, et de N-{3-chloro-4-[(3-fluorobenzyl)oxy]phényl}-6-[5-({[2-(méthanesulfonyl)-éthyl]amino}méthyl)-2-furyl]-4-quinazolinamine, ou des sels ou solvates de celle-ci.
PCT/US2007/070032 2006-06-01 2007-05-31 Procédé de traitement du cancer Ceased WO2007143483A2 (fr)

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WO2011058179A1 (fr) * 2009-11-16 2011-05-19 Ratiopharm Gmbh 5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide
WO2011069053A1 (fr) 2009-12-04 2011-06-09 Teva Pharmaceutical Industries Ltd. Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl
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US8252805B2 (en) 2008-05-07 2012-08-28 Teva Pharmaceutical Industries Ltd. Forms of lapatinib ditosylate and processes for preparation thereof
WO2009140144A1 (fr) * 2008-05-15 2009-11-19 Teva Pharmaceutical Industries Ltd. Formes du lapatinib cristallin et leurs procédés de préparation
WO2010023187A1 (fr) * 2008-08-25 2010-03-04 Ratiopharm Gmbh Composition pharmaceutique contenant de la n-[3-chloro-4-[(3-fluorophényl)méthoxy]phényl]-6-[5[[[2-(méthylsulfonyl)éthyl]amino]méthyl]-2-furyl]-4-quinazolinamine
US8586091B2 (en) 2008-08-25 2013-11-19 Ratiopharm Gmbh Pharmaceutical composition comprising N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-quinazolinamine
EP2158912A1 (fr) * 2008-08-25 2010-03-03 Ratiopharm GmbH Composition pharmaceutique comportant de la N-[3-chhloro-4-[3-fluorophenyl)methoxy)phenyl]6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine
EP2158913A1 (fr) * 2008-08-25 2010-03-03 Ratiopharm GmbH Composition pharmaceutique comportant de la N-[3-chhloro-4-[3-fluorophenyl)methoxy)phenyl]6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine
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US20120197019A1 (en) * 2009-10-23 2012-08-02 Dharmesh Surendra Bhanushali Compositions and processes
WO2011058179A1 (fr) * 2009-11-16 2011-05-19 Ratiopharm Gmbh 5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide
WO2011069053A1 (fr) 2009-12-04 2011-06-09 Teva Pharmaceutical Industries Ltd. Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl
US20130303560A1 (en) * 2011-02-01 2013-11-14 Sunnybrook Research Institute Combination
WO2014170910A1 (fr) 2013-04-04 2014-10-23 Natco Pharma Limited Procédé de préparation du lapatinib
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