WO2009073224A1 - Procédés de traitement de certaines maladies à l'aide de dérivés de la pyrimidine - Google Patents

Procédés de traitement de certaines maladies à l'aide de dérivés de la pyrimidine Download PDF

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Publication number
WO2009073224A1
WO2009073224A1 PCT/US2008/013445 US2008013445W WO2009073224A1 WO 2009073224 A1 WO2009073224 A1 WO 2009073224A1 US 2008013445 W US2008013445 W US 2008013445W WO 2009073224 A1 WO2009073224 A1 WO 2009073224A1
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Prior art keywords
cancer
pharmaceutically acceptable
subject
acceptable salt
compound
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PCT/US2008/013445
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English (en)
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Patrick Zarrinkar
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Ambit Biosciences Corp.
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Publication of WO2009073224A1 publication Critical patent/WO2009073224A1/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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Definitions

  • VX-680 also known as MK-0457
  • US2004/0049032 and related applications (e.g., US 2006/0270660 and WO 04/000833) as an Aurora kinase inhibitor.
  • the compound VX-680 has the structure of Formula I:
  • D VX-680 was tested in an in-vitro competition binding assay against a panel of approximately three hundred distinct human protein kinases, including lipid kinases and disease-relevant mutant variants, and additional off-targets were identified for this compound.
  • PLK4 serine/threonine nonreceptor tyrosine kinase 4 (Polo-like kinase 4, also known as SAK).
  • PLK4 is a member of the polo-like kinases, a family having the common feature of polo boxes (PB) which are regions of similarity at the C-terminal end that are capable of binding to mitotic structures.
  • PB polo boxes
  • DDRl receptor tyrosine kinase
  • Discoidin Domain Receptor 1 Another off-target kinase identified for VX-680 is the receptor tyrosine kinase DDRl, or Discoidin Domain Receptor 1.
  • DDRl appears in five splice variant forms, Ia, Ib, Ic, Id and Ie, of which DDRIa and DDRIb are the most well studied (Vogel et al., FASEB J., 1999, 13 (Suppl.), S77-S82; Alves et al., FASEBJ., 2001, 15, 1321-1323).
  • Collagens serve as natural ligands for DDRl , and a related member, DDR2 (Vogel, FASEB J, 1999, 13 (Suppl.), S77-S82).
  • DDRl plays a role in the extension of granule neuron axon in response to the abundant collagen found in the pia, which suggests that the receptor plays a role in the development of the neural circuitry of the cerebellum (Bhatt et al. Genes & Dev. 2000, 14, 2216-2228).
  • DDRl may therefore provide another mechanistic target for the treatment or prevention of arteriosclerosis and restenosis.
  • DDRl may also serve as a clinical target for idiopathic pulmonary fibrosis (IPF), a disease with high morbidity and mortality among patients 65 and older. Hallmarks of disease include an expansion of fibroblastic cells, excessive deposition of ECM and collagen in the lung, and gradual replacement of the alveoli by scar tissue.
  • IPF idiopathic pulmonary fibrosis
  • mice lacking the receptor were resistant to bleomycin-induced lung inflammation and fibrosis (Avivi- Green, et al, Am. JRespir. Crit. Care Med. 2006 174, 420-427).
  • Fibroblast obtained from IPF patients predominantly express DDRIb, and DDR activation inhibited Fas ligand-induced apoptosis (Matsuyama et al., Am J Pathol 2006 168, 866-877).
  • DDRl is involved in metastasis (Vogel, FASEB J., 1999, 13 (Suppi), S77-S82). Overexpression of DDRl have been found in primary breast cancer, ovarian cancer, esophageal cancer, and pediatric brain cancer (Barker et al., Oncogene, 1995, //, 569-575; Laval et al., Cell Growth DiJf. 1994, 5, 1 173-1 183; Nemoto et al., Pathobioi, 1997, 65, 165-203; Weiner et al., Pediatr. Neurosurg., 1996, 25, 64-72).
  • DDRl is up-regulated two fold while DDR2 is down-regulated two fold and although DDR2 was not predictive of patient survival, DDRl was associated with overall and disease free survival and no DDR mutations were observed (Ford et al., Brit J Cancer 2007, 96, 808-814).
  • a method of modulating DDRl kinase in a cell or a subject which comprises contacting the cell or administering to the subject a therapeutically effective amount of the compound of Formula I:
  • Also provided herein is a method of modulating DDRl kinase in a host, which comprises contacting the DDRl kinase in the host with the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of modulating DDRl kinase, which comprises contacting the DDRl kinase with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • Also provided herein is a method of modulating PLK4 kinase in a cell or a subject, which comprises contacting the cell or administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of modulating FLK4 kinase in a host, which comprises contacting the FLK.4 kinase in the host with the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method of modulating FLK4 kinase, which comprises contacting the FLK4 kinase with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • Also provided herein is a method for treating a cardiovascular condition in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Also provided herein is a method for treating atherosclerosis in a subject , which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a method for treating restenosis in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • a method for treating idiopathic pulmonary fibrosis (IPF) in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • cancers of the breast, ovaries, esophagus, head and neck, brain, liver, lung, or colon which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Each method provided herein may further comprise administering a second therapeutic agent.
  • the second therapeutic agent is an anticancer agent.
  • the second therapeutic agent is a lipid lowering agent, anti -hypertensives, anti-platelet agent, or anti-coagulants.
  • anticancer agent is meant to include anti-proliferative agents and chemotherapeutic agents, including antimetabolites (e.g., 5-fluoro uracil, methotrexate, and fludarabine), antimicrotubule agents (e.g., vinca alkaloids, such as vincristine and vinblastine; and taxanes, such as paclitaxel and docetaxel), alkylating agents (e.g., mechlorethamine, chlorambucil, cyclophosphamide, melphalan, melphalan, ifosfamide, carmustine, and nitrosoureas, such as carmustine, lomustine, bischloroethylnitrosurea, and hydroxyurea), platinum agents (e.g., cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), and CI-973), anthracyclines (e.g.,
  • anti-coagulants is meant to include heparin or warfarin
  • anti-hypertensives is meant to include diuretics (i.e. thiazide and thiazide-like diuretics), beta-blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, ACE inhibitors, calcium channel blockers, and angiotensin receptor blockers (saltans), aldosterone antagonists, and vasodilators.
  • diuretics i.e. thiazide and thiazide-like diuretics
  • beta-blockers alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, ACE inhibitors, calcium channel blockers, and angiotensin receptor blockers (saltans), aldosterone antagonists, and vasodilators.
  • anti-platelet agents is meant to include acetylsalicylic acid
  • DDRl kinase refers to all mammalian isoforms, splice variants, polymorphisms, and mutant forms of the DDRl kinase, including, e.g., DDRIa, DDRIb, DDRIc, DDRId, and DDRIe.
  • lipid lowering agent is meant to include HMG-CoA reductase inhibitors (including statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altocor, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor)), bile acid binding resins (including cholestyramine (Questran) colesevelam (WelChol) and colestipol (Colestid)), cholesterol absorption inhibitors (including ezetimibe (Zetia)), fibrates (including fenofibrate (Lof ⁇ bra, TriCor) and gemfibrozil (Lopid)) and niacin (vitamin B3).
  • statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altocor, Mevacor), pravastatin (Pravachol),
  • treat means to include alleviating or abrogating the disease in question, or one or more of the symptoms associated with the diseases; or alleviating or eradicating the cause(s) of the disease.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • each component is "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • PLK4 kinase refers to all mammalian isoforms, splice variants, polymorphisms, and mutant forms of the PLK4 kinase.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • subject cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the subject is a mammalian subject.
  • the subject is a human.
  • the term "host” refers to a unicellular or multicellular organism in which a virus can replicate, including, but not limited to, a cell, cell line, and animal, such as human.
  • the compound of Formula I is intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified.
  • structural isomers of the compound of Formula I are interconvertible via a low energy barrier, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety.
  • the compound of Formula I may exhibit more than one type of isomerism.
  • the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; and "Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley- VCH and VHCA, Zurich, 2002).
  • Suitable pharmaceutically acceptable acid salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionat
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(
  • the compound of Formula I can also be synthesized using other methods known in the art.
  • the starting material 1 may be prepared according to Koppel et al. (J. Org. Chem. 1961, 26, 792- 803). Other starting materials are either commercially available or can be readily prepared.
  • compositions which comprise the compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient, in combination with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition comprises at least one nonrelease controlling excipients or carriers.
  • the pharmaceutical composition comprises at least one release controlling and at least one nonrelease controlling excipients or carriers.
  • the amount of the compound of Formula I in the pharmaceutical compositions provided herein varies depending upon factors, including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the mode of administration.
  • the pharmaceutical composition is formulated in a dosage of between about 0.01 to about 100 mg/kg body weight/day of the compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition which comprises the compound of Formula I, or a pharmaceutically acceptable salt thereof, and lactic acid.
  • the lactic acid-containing composition can be prepared by the steps of a) preparing a lactic acid aqueous solution at a concentration, such as about 20 mg/mL; b) adding the appropriate amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, into the lactic acid solution to achieve a desired final concentration of the compound of Formula I in the solution, such as about 25 mg/mL; and c) adding the appropriate amount of sugar to achieve a desired final concentration, such as about 10, about 15, about 50, or about 100 mg/mL, depending on the desired tonicity.
  • Mechanical methods can be used to facilitate the mixing and solublization of the compound of Formula I and excipients.
  • the pH value of the solution can also be adjusted to a desired value.
  • a lyophilized pharmaceutical composition for reconstitution with sterile water for injection which comprises the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the lyophilized composition can be prepared by the steps of a) preparing a first solution of the pharmaceutically acceptable carrier; and b) adding the appropriate amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, into the first solution to generate a second solution; c) sterilizing and filtering the second solution; and d) lyophilizing the sterilized second solution to form a white powder.
  • An exemplary lyophilized composition is illustrated as follows:
  • a lyophilized pharmaceutical composition for reconstitution with sterile water for injection which comprises the compound of Formula I, or a pharmaceutically acceptable salt thereof, and mannitol.
  • the lyophilized composition can be prepared by the steps of a) preparing a first solution of mannitol; and b) adding the appropriate amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof, into the first mannitol solution to generate a second solution; c) sterilizing and filtering the second solution from the last step; and d) lyophilizing the sterilized second solution to form a white powder.
  • An exemplary lyophilized composition is illustrated as follows:
  • the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered alone, or in combination with one or more other active ingredients (i.e., other therapeutic agents).
  • the pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical compositions may also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsed-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126).
  • the pharmaceutical compositions are provided in a dosage form for oral administration. In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration.
  • compositions provided herein may be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to a physically discrete unit suitable for administration to human and animal subjects, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit-dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit- dosage forms packaged in a single container to be administered in segregated unit- dosage form.
  • Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • compositions provided herein may be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxye
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include colloidal silicon dioxide, CAB-O-SIL ®
  • Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN ® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN ® 80), and triethanolamine oleate.
  • Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of nonaqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric- coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled- release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol. or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable nonaqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly-alkylene glycol including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol
  • formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as but
  • compositions provided herein may be provided as non- effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed- , controlled, targeted-, and programmed-release forms.
  • compositions provided herein may be co- formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action.
  • compositions provided herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.
  • compositions provided herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see. Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Water-miscible vehicles include, but are not limited to, ethanol, 1,3- butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N- dimethylacetamide, and dimethyl sulfoxide.
  • liquid polyethylene glycol e.g., polyethylene glycol 300 and polyethylene glycol 400
  • propylene glycol e.g., N-methyl-2-pyrrolidone, N,N- dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents include those described herein. including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including ⁇ - cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ - cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • cyclodextrins including ⁇ - cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutylether- ⁇ - cyclodextrin, and sulfobutylether 7- ⁇ -cyclodextrin (CAPTISOL ® , CyDex, Lenexa, KS).
  • compositions provided herein may be formulated for single or multiple dosage administration.
  • the single dosage formulations are packaged in an ampoule, a vial, or a syringe.
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed- , controlled, targeted-, and programmed-release forms.
  • the pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include polymethylmethacrylate, polybutyl- methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulf ⁇ te.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • the pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane.
  • the pharmaceutical compositions may also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein, a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • compositions provided herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.
  • compositions provided herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • A) cardiovascular disorder including arteriosclerosis, atherosclerosis, and restenosis;
  • cancer including breast cancer (including primary breast cancer), ovarian cancer, head and neck cancer (including esophageal cancer), brain cancer (including pediatric brain cancer), liver cancer, lung cancer including non small cell lung cancer (nsclc), colon cancer (including colorectal cancer).
  • breast cancer including primary breast cancer
  • ovarian cancer including head and neck cancer
  • head and neck cancer including esophageal cancer
  • brain cancer including pediatric brain cancer
  • liver cancer including lung cancer including non small cell lung cancer (nsclc), colon cancer (including colorectal cancer).
  • nsclc non small cell lung cancer
  • colon cancer including colorectal cancer
  • a method of modulating DDRl kinase in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • a method of modulating DDRl kinase in a host which comprises contacting the DDRl kinase in the host with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • DDRl kinase which comprises contacting the DDRl kinase with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • the FLK4 kinase in a host which comprises contacting the FLK4 kinase in the host with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • FLK4 kinase which comprises contacting the FLK4 kinase with the compound of Formula I or a pharmaceutically acceptable salt thereof. Further provided herein is a method wherein the contacting is done in an in vivo or in vitro system.
  • a method for treating a cardiovascular condition in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • a method for treating atherosclerosis in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • a method for treating restenosis in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • a method for treating idiopathic pulmonary fibrosis (IPF) in a subject which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1 ,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • a method for treating cancer such as cancers of the breast, ovaries, esophagus, head and neck, brain, liver, lung, or colon, in a subject, which comprises administering to the subject a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the therapeutically effective amount of the compound of Formula I is 1 to 1,500 mg/m 2 per day, including about 3, 30, 60, 90, 180, 190, 240, 300, 350, 400, 500, 600, 700, 750, 900, 850, 1200 or 1500 mg/m 2 per day of the compound of Formula I or a pharmaceutically acceptable salt.
  • Each method provided herein may further comprise administering a second therapeutic agent:
  • the second therapeutic agent is an anticancer agent.
  • the second therapeutic agent is a lipid lowering agent, anti-hypertensives, anti-platelet agent, or anti-coagulants.
  • the mammal is a human.
  • the administered dose of the compound of Formula I can also be expressed in units other than as mg/m 2 , such as mg.
  • mg mg
  • One of ordinary skill in the art would readily know how to convert doses between mg/m 2 and mg/kg for a given height or weight of a subject ⁇ see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of about 25 to about 4,000 mg/m 2 for a 65 kg human approximately equals to that of about 0.66 to about 105 mg/kg.
  • the compound of Formula I can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a disease described herein.
  • the term "in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
  • therapies e.g., prophylactic and/or therapeutic agents
  • the route of administration of the compound of Formula I is independent of the route of administration of a second therapy.
  • each method provided herein may independently, further comprise the step of administering a second therapeutic agent.
  • the second therapeutic agent is a lipid lowering agent.
  • lipid lowering agent is an HMG-CoA reductase inhibitors (including statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altocor, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor) or simvastatin (Zocor)).
  • statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Altocor, Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor) or simvastatin (Zocor)
  • lipid lowering agent is a bile acid binding resin (including cholestyramine (Questran) colesevelam (WelChol) or colestipol (Colestid)).
  • the lipid lowering agent is a cholesterol absorption inhibitor (including ezetimibe (Zetia)), fibrates (including fenofibrate (Lofibra, TriCor) or gemfibrozil (Lopid)).
  • the lipid lowering agent is niacin (vitamin B3).
  • the second therapeutic agent is an antihypertensive.
  • the second therapeutic agent is a diuretic (including thiazide or thiazide-like diuretics).
  • the second therapeutic agent is a beta-blockers.
  • the second therapeutic agent is an alpha blockers.
  • the second therapeutic agent is a sympathetic nerve inhibitor.
  • the second therapeutic agent is an ACE inhibitor.
  • the second therapeutic agent is a calcium channel blocker.
  • the second therapeutic agent is an angiotensin receptor blockers (saltans).
  • the second therapeutic agent is an aldosterone antagonist.
  • the second therapeutic agent is a vasodilator.
  • the second therapeutic agent is an anti-platelet agent.
  • the anti-platelet agent is acetylsalicylic acid (aspirin).
  • the anti-platelet agent is clopidogrel.
  • the anti-platelet agent is ticlopidine.
  • the anti-platelet agent is dipyridamole.
  • the second therapeutic agent is an anticoagulants.
  • the anti-coagulant is heparin.
  • the anti-coagulant is warfarin (including Coumadin).
  • the second therapeutic agent is an anticancer agent.
  • the anticancer agent is an antimetabolite, including, but not limited to, 5-fluoro uracil, methotrexate, and fludarabine.
  • the anticancer agent is an antimicrotubule agent, including, but not limited to, vinca alkaloids (e.g., vincristine and vinblastine) and taxanes (e.g., paclitaxel and docetaxel).
  • the anticancer agent is an alkylating agent, including, but not limited to, cyclophosphamide, melphalan, carmustine, and nitrosoureas (e.g., bischloroethylnitrosurea and hydroxyurea).
  • the anticancer agent is a platinum agent, including, but not limited to, cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), and CI-973.
  • the anticancer agent is an anthracycline, including, but not limited to, doxrubicin and daunorubicin.
  • the anticancer agent is an antitumor antibiotic, including, but not limited to, mitomycin, idarubicin, adriamycin, and daunomycin.
  • the anticancer agent is a topoisomerase inhibitor, e.g., etoposide and camptothecins.
  • the anticancer agent is selected from the group consisting of adriamycin, busulfan, cytarabine, cyclophosphamide, dexamethasone, fludarabine, fluorouracil, hydroxyurea, interferons, oblimersen, platinum derivatives, taxol, topotecan, and vincristine.
  • the anticancer agent is an AbI kinase inhibitor.
  • the AbI kinase inhibitor is selected from the group consisting of imatinib, BMS354825 (dasatinib), AMN107 (nilotinib), AP23464, AZDO53O, CGP76030, ONOl 2380, INN-0406 (NS- 187), SKI-606 (bosutinib), and pyrrolo[2,3-d]pyrimidines including PD 166326, PDl 73955 and PD 180970.
  • the AbI kinase inhibitor is imatinib.
  • the AbI kinase inhibitor is dasatinib. In yet another embodiment, the AbI kinase inhibitor is nilotinib. In yet another embodiment, the AbI kinase inhibitor is AP23464. In yet another embodiment, the AbI kinase inhibitor is AZD0530. In yet another embodiment, the AbI kinase inhibitor is CGP76030. In yet another embodiment, the AbI kinase inhibitor is SKI-606. In yet another embodiment, the AbI kinase inhibitor is ONOl 2380. In yet another embodiment, the AbI kinase inhibitor is INN-0406 (NS-187).
  • the AbI kinase inhibitor is a pyrrolo[2,3-d]pyrimidine. In another embodiment, the AbI kinase inhibitor is PD 166326. In yet another embodiment, the AbI kinase inhibitor is PDl 73955. In still another embodiment, the AbI kinase inhibitor is PD 180970.
  • Radiotherapy e.g., gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
  • endocrine therapy biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF))
  • TNF tumor necrosis factor
  • hyperthermia and cryotherapy agents to attenuate any adverse effects (e.g., antiemetics)
  • chemotherapeutic drugs including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, and gemcitabine), spindle poisons (vinblastine, vincris
  • Binding reactions were assembled by combining kinase, liganded affinity beads, and test compounds in 1 x binding buffer (20 % SeaBlock, 0.17x PBS, 0.05 % Tween 20, 6 mM DTT). Test compounds were prepared as 100 x stocks in DMSO and rapidly diluted into the aqueous environment. DMSO was added to control assays lacking a test compound.
  • Blank fields indicate combinations that were tested but for which interaction was weak (K d > 10 ⁇ M) or was not detected in a primary screen (10 ⁇ M).

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Abstract

L'invention concerne des procédés de traitement de l'athérosclérose, de la resténose, de la fibrose pulmonaire idiopathique et de certains cancers.
PCT/US2008/013445 2007-12-07 2008-12-05 Procédés de traitement de certaines maladies à l'aide de dérivés de la pyrimidine WO2009073224A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019094819A3 (fr) * 2017-11-09 2020-03-26 Abon Pharmaceuticals, Llc Systèmes d'administration par voie intraveineuse pour médicaments de chimiothérapie
EP3752161A4 (fr) * 2018-02-15 2021-12-22 Children's Hospital Medical Center Méthodes de traitement de la fibrose
WO2022182918A1 (fr) * 2021-02-25 2022-09-01 Icahn School Of Medicine At Mount Sinai Méthodes pour inhiber une inflammation et une progression de plaques d'athérosclérose et des événements cardiovasculaires chez des patients atteints d'une maladie cérébrovasculaire et cardiovasculaire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004000833A1 (fr) * 2002-06-20 2003-12-31 Vertex Pharmaceuticals Incorporated Procedes pour la preparation de pyrimidines substituees et derives de pyrimidines utilises comme inhibiteurs des proteine-kinases
WO2004076412A2 (fr) * 2003-02-26 2004-09-10 Sugen, Inc. Composes d'aminoheteroaryle utilises en tant qu'inhibiteurs de proteine kinase
WO2007059299A1 (fr) * 2005-11-16 2007-05-24 Vertex Pharmaceuticals Incorporated Aminopyrimidines utiles en tant qu’inhibiteurs de la kinase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004000833A1 (fr) * 2002-06-20 2003-12-31 Vertex Pharmaceuticals Incorporated Procedes pour la preparation de pyrimidines substituees et derives de pyrimidines utilises comme inhibiteurs des proteine-kinases
WO2004076412A2 (fr) * 2003-02-26 2004-09-10 Sugen, Inc. Composes d'aminoheteroaryle utilises en tant qu'inhibiteurs de proteine kinase
WO2007059299A1 (fr) * 2005-11-16 2007-05-24 Vertex Pharmaceuticals Incorporated Aminopyrimidines utiles en tant qu’inhibiteurs de la kinase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019094819A3 (fr) * 2017-11-09 2020-03-26 Abon Pharmaceuticals, Llc Systèmes d'administration par voie intraveineuse pour médicaments de chimiothérapie
EP3752161A4 (fr) * 2018-02-15 2021-12-22 Children's Hospital Medical Center Méthodes de traitement de la fibrose
WO2022182918A1 (fr) * 2021-02-25 2022-09-01 Icahn School Of Medicine At Mount Sinai Méthodes pour inhiber une inflammation et une progression de plaques d'athérosclérose et des événements cardiovasculaires chez des patients atteints d'une maladie cérébrovasculaire et cardiovasculaire

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