WO2003095448A1 - Derives de pyridinyl amino pyrimidine utilises dans le traitement des troubles de l'hyperproliferation - Google Patents

Derives de pyridinyl amino pyrimidine utilises dans le traitement des troubles de l'hyperproliferation Download PDF

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WO2003095448A1
WO2003095448A1 PCT/US2003/013604 US0313604W WO03095448A1 WO 2003095448 A1 WO2003095448 A1 WO 2003095448A1 US 0313604 W US0313604 W US 0313604W WO 03095448 A1 WO03095448 A1 WO 03095448A1
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Prior art keywords
halo
phenyl
limited
compounds
agents
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PCT/US2003/013604
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English (en)
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Jill E. Wood
Yuanwei Chen
Jianqing Chen
Donglei Liu
Sharad K. Verma
Barry Hart
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Bayer Pharmaceuticals Corporation
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Priority to AU2003231231A priority Critical patent/AU2003231231A1/en
Publication of WO2003095448A1 publication Critical patent/WO2003095448A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel pyridinyl amino pyrimidine compounds, pharmaceutical compositions containing such compounds, and the use of those compounds and/or compositions for treating hyper-proliferative disorders.
  • One embodiment of this invention relates to a compound of Formula 1(a) or 1(b)
  • X is halo
  • R 1 is selected from morpholinyl, NHC(O)(CrC 6 )alkyl and O — phenyl wherein said phenyl is optionally substituted with a substituent selected from (C C 6 )alkyl, (C C 6 )alkoxy, halo, and CF 3 ;
  • R 2 is in each instance independently selected from SO 2 NH 2 and halo;
  • R 3 is selected from H, (C C 6 )alkoxy, CF 3 and halo;
  • R 4 is a substituent selected from C(O)OH, NHC(O)-phenyl, a five membered heterocycle, and imadazo[1 ,2-a]pyridinyl; or a pharmaceutically acceptable salt thereof.
  • Formula I(a) and Formula l(b) may also be referred to herein severally and collectively as Formula I.
  • (C ⁇ -C 6 )alkyl means linear or branched saturated carbon groups having from about 1 to about 6 C atoms. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, and the like.
  • (CrC 6 )alkoxy means a linear or branched saturated carbon group having from about 1 to about 6 C atoms, said carbon group being attached to an O atom.
  • the O atom is the point of attachment of the alkoxy substituent to the pyridyl ring.
  • alkoxy substituents include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, fet -butoxy, and the like.
  • halo means an atom selected from Cl, Br, and F.
  • 5 memebered heterocycle means an aryl ring containing 5 atoms, 1 , 2, or 3 of which are heteroatoms selected from N, O and S, the rest of the atoms in the ring being C, with the proviso that said ring may contain no more than 1 O atom or 1 S atom.
  • the heteroaromatic ring may be attached to the phenyl ring of the core molecule at any available C or N atom.
  • lmidaol[1 ,2-a]pyridine can be attached to the phenyl ring of the core molecule through any available C on its five-membered ring.
  • R group is attached at a specific point of attachment of a phenyl ring (e.g., R 1 and R 3 )
  • the substituent(s) may be attached to the phenyl ring at any available C atom, preferably at the 3, 4, or 5 C.
  • each is selected independently from the other so that they may be the same or different.
  • Representative compounds of Formula l(a) are shown in Table I.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention.
  • Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • pharmaceutically acceptable salts of the compounds of Formula I are also within the scope of this invention.
  • pharmaceutically acceptable salt refers to either inorganic or organic acid or base salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlor
  • the compounds of this invention may be prepared by standard techniques known in the art and by known processes analogous thereto.
  • the compounds of this invention can be synthesized according to the General Method described further below.
  • the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
  • Thin-layer chromatography was performed on Whatman ® pre-coated glass- backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science ® silica gel.
  • Proton ( 1 H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric G/V-Omega 300 (300 MHz) spectrometer with either Me 4 Si ( ⁇ 0.00) or residual protonated solvent (CHCI 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • HPLC - electrospray mass spectra for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.
  • R 1 , R 2 , R 3 and R 4 are as illustrated in Examples 1-20 and Tables 1-2.
  • Step 2 To a suspension of 5-bromo-2-chloro-4-(4-fluoroanilino)pyrimidine (8.0 g, 26.4 mmol) and 3-amino-5-(4-chlorophenyloxy)pyridine (6.8 g, 26.4 mmol) in t-BuOH (275 mL) was added cone. HCI (1.0 mL). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature.
  • the precipitate was filtered to give the HCI salt of final product.
  • the HCI salt was suspended in EtOAc (300 mL) and 1 N NaOH (26 mL) and water (200 mL) were added. The mixture was stirred for 10 min until it became clear, and then the layers were separated using a separatory funnel. The organic layer was dried over MgSO 4) concentrated under reduced pressure, the residue was washed with MeOH and dried in vacuo to give 9.0 g (70%) of ⁇ /-(5-bromo-2- ⁇ [6-(4-chlorophenoxy)-3- pyridinyl]amino ⁇ -4-pyrimidinyl)- ⁇ /-(4-fluorophenyl)amine. R f 0.77 (1/1 EtOAC/Hex).
  • a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
  • a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, and isolating the salt thus formed.
  • the free base is treated with anhydrous HCI in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt.
  • the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt.
  • compositions of the compounds of this invention are provided.
  • the compounds of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment (including prophylactic treatment) for the particular condition or disease.
  • compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt or ester thereof, of the present invention.
  • a pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylim
  • compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material are, for example, cocoa butter and polyethylene glycol.
  • Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11 , 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3 ); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methyl
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not
  • compositions according to the present invention can be illustrated as follows: Sterile Injectable Solution
  • a suitable amount of pure active ingredient is dissolved in sterile, injectable water to a desired concentration, for example from about 1.0 mg/ml to about 50.0 mg/ml.
  • U.S. P. grade sodium chloride crystals (NaCI) is added to the solution such that the final concentration of NaCI is 0.9% by weight of water.
  • the pH of the solution is adjusted to range between approximately pH 2.0 and pH 6.0 by the addition of pure (99.999%purity) hydrochloric acid.
  • the solution is sterilized via filtration through a sterile 0.22 micron filter.
  • the sterile solution is stored in sealed sterile vials wherein each vial contains the desired dosage unit of active ingredient per ml of injection solution.
  • U.S. P. grade sodium chloride (NaCI) is dissolved in sterile, injectable water to a final concentration of 0.9% NaCI by weight of water.
  • An amount of pure (99.999% purity) hydrochloric acid is added to the NaCI solution to obtain a final pH in the range of approximately pH2.0 to pH6.0.
  • An amount of U.S. P. grade potassium chloride crystals (KCL) is dissolved in the solution such that the final concentration of KCI is 0.1% by weight.
  • From 0.5 part to about thirty parts by weight of active ingredient (depending on the desired end dosage unit) is added to the solution and is completely dissolved by agitation.
  • the pH of the solution is adjusted again to between pH2.0 and pH6.0 using pure hydrochloric acid.
  • the solution is sterilized via filtration through a sterile 0.22 micron filter and stored in sealed sterile injection vials, each containing approximately 0.5 mg to approximately 30 mg active ingredient, depending on the final dosage unit desired in the sterile injection solution.
  • a 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary.
  • the solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.
  • a sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention
  • a large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and
  • aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders.
  • This method comprises administering to a mammalian patient, including a human, in need thereof, an amount of a compound, a pharmaceutically acceptable salt thereof, or a composition of this invention that is effective to treat or prevent the disorder.
  • the present invention also relates to a method for using the compounds and compositions of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to delay or diminish the onset of the disorder.
  • the present compounds and compositions exhibit anti-proliferative activity and are thus useful to treat the disorders that are described below and/or otherwise known in the art.
  • Hyper-proliferative disorders include diseases or conditions whose progression proceeds, at least in part, via proliferation.
  • Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
  • the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
  • taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
  • taxotere Bissery et al. Anti Cancer Drugs 1995, 6(3), 339
  • topoisomerase inhibitors Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93 were demonstrated with the use of in vitro tumor proliferation assays.
  • the following assays are two methods by which compound activity relating to treatment of the disorders identified herein can be determined.
  • HCT116 cells are seeded at a density of 3000 cells per well in 100 uL DMEM universal growth medium in 96-well culture plates and incubated overnight at 37 °C in 5% CO 2 in a humidified incubator. T 0 MTS measurements are taken as described below. Cells are treated with test compounds serially diluted at10 uM, 5, 2.5, 1.25, 0.6uM, duplicate; Final concentration of DMSO in each well is 0.1% and incubated for 3 days at 37 °C in 5% CO 2 in a humidified incubator.
  • MTS reagent CellTiter 96 Aqueous One Solution Cell Proliferation Assay
  • This assay may also be run using HT1080 or DLD-1 cell lines following the same procedure.
  • In vivo assay Groups of female Ncr nude mice [Taconic Laboratories, NY] are inoculated with 3x10 6 cells of HCT- 16, a CRC xenograft on day 0. When tumors reach a 75 to 150 mm 3 in size (typically 6-8 days), animals are administered compounds of interest p.o. in a Cremaphor (12.5%; Sigma Aldrich, St. Louis, MO): Ethanol (12.5%): Saline (75%) vehicle for 14 days. The treatment volumes are 0.1mLI-test article/1 Og body weight. A group of 10 untreated animals is included to assess tumor response to test article vehicles. During the course of the study the animals tumor growth measurements and body weights are determined twice a week. All animals are observed for clinical signs daily and after compound administration. Tumor volume is calculated using the ellipsoid formula:
  • D diameter of the tumor at major axis
  • d diameter of the tumor at minor axis
  • Representative compounds of this invention demonstrated an IC 50 under 20 ⁇ M in assays such as those described above. Based upon the above and other standard laboratory techniques known to evaluate compounds useful for the prevention and/or treatment of the diseases or disorders described above by standard toxicity tests and by standard pharmacological assays for the determination of the prevention and/or treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for prevention and/or treatment of each desired indication.
  • the amount of the active ingredient to be administered in the prevention and/or treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient treated, and the nature and extent of the condition to be prevented and/or treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 300 mg/kg, and preferably from about 0.10 mg/kg to about 150 mg/kg body weight per day.
  • a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of administration and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional prevention and/or treatment tests.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the compounds of this invention can be combined with other anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
  • anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment and/or prevention of neoplastic diseases in Goodman and Gilman's The
  • anti-hyper-proliferative agents suitable for use with the composition of this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

Abstract

La présente invention concerne un composé de la formule I(a) ou I(b), dans laquelle X est halo; R1 est choisi entre morpholinyle, NHC(O)(C1-C6)alkyle et O-phényle où ledit phényle est facultativement substitué par un substituant choisi entre (C1-C6)alkyle, (C1-C6)alcoxy, halo, et CF3; R2 est dans chaque cas choisi indépendamment entre SO2NH2 et halo; R3 est choisi entre H, (C1-C6)alcoxy, CF3 et halo; R4 est un substituant choisi entre C(O)OH, NHC(O)-phényle, un hétérocycle à cinq chaînons, et un imadazo[1,2-a]pyridinyle; ou un sel pharmaceutiquement acceptable de ce dernier.
PCT/US2003/013604 2002-05-06 2003-05-02 Derives de pyridinyl amino pyrimidine utilises dans le traitement des troubles de l'hyperproliferation WO2003095448A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016894A1 (fr) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidine diamines utiles dans le cadre du traitement de maladies neoplasiques, de troubles inflammatoires et de troubles du systeme immunitaire
US7109337B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7109335B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7145008B2 (en) 2004-05-14 2006-12-05 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7208499B2 (en) 2004-05-14 2007-04-24 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7235562B2 (en) 2004-05-14 2007-06-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
WO2008106635A1 (fr) * 2007-03-01 2008-09-04 Supergen, Inc. Dérivés de pyrimidine-2,4-diamine et leur utilisation en tant qu'inhibiteurs de la kinase jak2
CN1858857B (zh) * 2005-05-03 2010-04-14 海力士半导体有限公司 具有一致编程速度的非易失性存储设备
US7820648B2 (en) 2005-12-21 2010-10-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7943627B2 (en) 2002-03-15 2011-05-17 Novartis Ag 2,4-diaminopyrimidine derivatives
US7964592B2 (en) 2003-03-14 2011-06-21 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
US8039479B2 (en) 2006-12-08 2011-10-18 Irm Llc Compounds and compositions as protein kinase inhibitors
CN107434779A (zh) * 2011-12-21 2017-12-05 洛桑联邦理工学院(Epfl) Notch信号通路抑制剂及其在癌症治疗中的用途
US10202356B2 (en) 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
WO2020135488A1 (fr) * 2018-12-26 2020-07-02 上海喆邺生物科技有限公司 Dérivé de 2,4-diaminopyrimidine et son application
US11013741B1 (en) 2018-04-05 2021-05-25 Sumitomo Dainippon Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
DK1534286T3 (da) 2002-07-29 2010-04-26 Rigel Pharmaceuticals Inc Fremgangsmåder til behandling eller forebyggelse af autoimmune sygdomme med 2,4-pyrimidindiamin-forbindelser
UA80767C2 (en) * 2002-12-20 2007-10-25 Pfizer Prod Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CA2533377C (fr) 2003-07-30 2012-11-27 Rigel Pharmaceuticals, Inc. Methodes de traitement ou de prevention de maladies auto-immunes a l'aide de composes de 2,4-pyrimidinediamine
WO2006004776A1 (fr) 2004-06-29 2006-01-12 Rigel Pharmaceuticals, Inc. Composés de 4-pyrimidineamine et leurs utilisations en tant qu’agent anti-prolifération
US20060051406A1 (en) * 2004-07-23 2006-03-09 Manjeet Parmar Formulation of insoluble small molecule therapeutics in lipid-based carriers
GB0419161D0 (en) * 2004-08-27 2004-09-29 Novartis Ag Organic compounds
GB0419160D0 (en) * 2004-08-27 2004-09-29 Novartis Ag Organic compounds
WO2006037117A1 (fr) * 2004-09-27 2006-04-06 Amgen Inc. Composes heterocycliques substitues et procedes d'utilisation
DK1814878T3 (da) 2004-11-24 2012-05-07 Rigel Pharmaceuticals Inc Spiro-2, 4-pyrimidindiamin-forbindelser og anvendelser deraf
EP2161275A1 (fr) 2005-01-19 2010-03-10 Rigel Pharmaceuticals, Inc. Promédicaments de composés de 2,4-pyrimidinédiamine et leurs utilisations
US20060247263A1 (en) * 2005-04-19 2006-11-02 Amgen Inc. Substituted heterocyclic compounds and methods of use
RU2485106C2 (ru) 2005-06-08 2013-06-20 Райджел Фамэсьютикэлз, Инк. Соединения, проявляющие активность в отношении jak-киназы (варианты), способ лечения заболеваний, опосредованных jak-киназой, способ ингибирования активности jak-киназы (варианты), фармацевтическая композиция на основе указанных соединений
US20070203161A1 (en) * 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US8604042B2 (en) 2005-11-01 2013-12-10 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
JP2009518443A (ja) 2005-12-06 2009-05-07 リゲル ファーマシューティカルズ インコーポレーティッド 脂質を主材料とする担体に内封された、不溶性小分子治療剤の製剤
TW200736232A (en) * 2006-01-26 2007-10-01 Astrazeneca Ab Pyrimidine derivatives
WO2007098507A2 (fr) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions et méthodes destinées à l'inhibition de la voie jak
WO2007105023A1 (fr) * 2006-03-15 2007-09-20 Csir Modulation de l'activite phosphoryl transferase de la glutamine synthetase
GB2451594A (en) * 2006-03-15 2009-02-04 Csir Modulation of phosphoryl transferase activity of glutamine synthetase
WO2008049123A2 (fr) 2006-10-19 2008-04-24 Rigel Pharmaceuticals, Inc. Compositions et procédés pour l'inhibition de la voie jak
WO2008051547A1 (fr) 2006-10-23 2008-05-02 Cephalon, Inc. Dérives bicycliques fusionnes de 2,4-diaminopyrimidine utilises comme inhibiteurs de alk et c-met
EP1939185A1 (fr) * 2006-12-20 2008-07-02 Bayer Schering Pharma Aktiengesellschaft Nouveaux hetaryl-phénylènediamine-pyrimidines en tant qu'inhibiteurs de protéine kinase pour le traitement du cancer
WO2008077810A2 (fr) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Dérivés de spiropipéridine
FR2911137B1 (fr) * 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de 2,4-dianilinopyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
EP1969929A1 (fr) 2007-03-12 2008-09-17 Bayer CropScience AG Phénylamidine substituée et son utilisation en tant que fongicide
BRPI0810411B8 (pt) * 2007-04-18 2021-05-25 Pfizer Prod Inc derivados de sulfonil amida para o tratamento de crescimento celular anormal, seu sos, bem como composição farmacêutica
AU2016201820B2 (en) * 2007-04-18 2018-03-08 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
AU2014201847B2 (en) * 2007-04-18 2015-12-24 Pfizer Products Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
EP2231620A1 (fr) 2007-12-03 2010-09-29 Boehringer Ingelheim International GmbH Nouveaux composés
JP5306373B2 (ja) 2008-01-11 2013-10-02 エフ．ホフマン−ラ ロシュ アーゲー アミロイドβのモジュレーター
AU2009216851B2 (en) 2008-02-22 2013-11-07 F. Hoffmann-La Roche Ag Modulators for amyloid beta
JP5802127B2 (ja) 2008-04-16 2015-10-28 ポートラ ファーマシューティカルズ， インコーポレイテッド Ｓｙｋ又はｊａｋキナーゼ阻害剤としての２，６−ジアミノ−ピリミジン−５−イル−カルボキサミド類
ES2546502T3 (es) 2008-04-16 2015-09-24 Portola Pharmaceuticals, Inc. 2,6-Diamino-pirimidin-5-il-carboxamidas como inhibidores de syk o JAK quinasas
US8138339B2 (en) 2008-04-16 2012-03-20 Portola Pharmaceuticals, Inc. Inhibitors of protein kinases
CA2723185A1 (fr) 2008-04-22 2009-10-29 Portola Pharmaceuticals, Inc. Inhibiteurs de proteines kinases
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
AU2009248923B2 (en) 2008-05-21 2015-01-29 Takeda Pharmaceutical Company Limited Phosphorous derivatives as kinase inhibitors
DE102008049323A1 (de) * 2008-09-29 2010-04-01 Henkel Ag & Co. Kgaa Neue Entwicklerkomponenten
CN102177151A (zh) 2008-10-09 2011-09-07 弗·哈夫曼-拉罗切有限公司 β-淀粉样蛋白的调节剂
WO2010052199A1 (fr) 2008-11-10 2010-05-14 F. Hoffmann-La Roche Ag Modulateurs de la gamma secrétase hétérocyclique
CA2749195C (fr) * 2009-01-15 2017-03-07 Rigel Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase c et leurs utilisations
US8933227B2 (en) 2009-08-14 2015-01-13 Boehringer Ingelheim International Gmbh Selective synthesis of functionalized pyrimidines
JP5539518B2 (ja) 2009-08-14 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ２−アミノ−５−トリフルオロメチルピリミジン誘導体の位置選択的調製
CA2784807C (fr) 2009-12-29 2021-12-14 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinase raf de type ii
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
JP5607241B2 (ja) 2010-05-21 2014-10-15 ケミリア・エービー 新規ピリミジン誘導体
WO2012061418A2 (fr) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Benzamides et nicotinamides en tant que modulateurs de syk
WO2012061415A1 (fr) 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Oxypyrimidines en tant que modulateurs de syk
EP2975027A1 (fr) 2010-11-01 2016-01-20 Portola Pharmaceuticals, Inc. Nicotinamides comme modulateurs de la kinase jak
AU2010363329A1 (en) 2010-11-07 2013-05-09 Targegen, Inc. Compositions and methods for treating myelofibrosis
BR112013024378A2 (pt) 2011-03-24 2016-12-13 Chemilia Ab novos derivados de pirimidina
US9249124B2 (en) 2011-03-30 2016-02-02 H. Lee Moffitt Cancer Center And Research Institute, Inc. Aurora kinase inhibitors and methods of making and using thereof
KR101884010B1 (ko) 2011-05-04 2018-07-31 어리어드 파마슈티칼스, 인코포레이티드 Egfr-유도된 암의 세포 증식을 억제하는 화합물
WO2013013188A1 (fr) 2011-07-21 2013-01-24 Tolero Pharmaceuticals, Inc. Inhibiteurs de protéine kinase hétérocycliques
WO2013074986A1 (fr) * 2011-11-17 2013-05-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs de la kinase c-jun-n-terminale (jnk)
EA026939B1 (ru) 2011-11-23 2017-06-30 Портола Фармасьютикалз, Инк. Пиразиновые ингибиторы киназы
JP6469567B2 (ja) 2012-05-05 2019-02-13 アリアド・ファーマシューティカルズ・インコーポレイテッド Ｅｇｆｒ発動性がんの細胞増殖阻害用化合物
KR101446742B1 (ko) * 2012-08-10 2014-10-01 한국화학연구원 Ｎ2,ｎ4-비스(4-(피페라진-1-일)페닐)피리미딘-2,4-디아민 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물
WO2014058921A2 (fr) 2012-10-08 2014-04-17 Portola Pharmaceuticals, Inc. Inhibiteurs substitués de pyrimidinyl kinase
US9758522B2 (en) 2012-10-19 2017-09-12 Dana-Farber Cancer Institute, Inc. Hydrophobically tagged small molecules as inducers of protein degradation
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
JP6491202B2 (ja) 2013-10-18 2019-03-27 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド サイクリン依存性キナーゼ７（ｃｄｋ７）の多環阻害剤
WO2015058126A1 (fr) 2013-10-18 2015-04-23 Syros Pharmaceuticals, Inc. Composés hétéroaromatiques utiles dans le traitement de maladies prolifératives
US10106507B2 (en) 2014-08-03 2018-10-23 H. Lee Moffitt Cancer Center and Research Insitute, Inc. Potent dual BRD4-kinase inhibitors as cancer therapeutics
AU2015371251B2 (en) 2014-12-23 2020-06-11 Dana-Farber Cancer Institute, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
WO2016160617A2 (fr) 2015-03-27 2016-10-06 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinases cycline-dépendantes
EP3347018B1 (fr) 2015-09-09 2021-09-01 Dana-Farber Cancer Institute, Inc. Inhibiteurs de kinases cycline-dépendantes
WO2017066428A1 (fr) 2015-10-13 2017-04-20 H. Lee Moffitt Cancer Center & Research Institute, Inc. Inhibiteurs de brd4-kinase à utiliser en tant qu'agents thérapeutiques anticancéreux
EP3630291B1 (fr) 2017-05-26 2024-01-10 Cancer Research Technology Limited Dérivés de la benzimidazolone en tant qu'inhibiteurs du récepteur bcl6
ES2930804T3 (es) 2017-06-30 2022-12-22 Beijing Tide Pharmaceutical Co Ltd Inhibidor de proteína cinasa asociada a RHO, composición farmacéutica que lo comprende, así como método de preparación y uso del mismo
WO2019000683A1 (fr) 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Inhibiteur de protéine kinase associée à rho, composition pharmaceutique contenant celui-ci, son procédé de préparation et ses applications
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
CN109776522B (zh) * 2017-10-30 2020-12-29 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
CA3095580A1 (fr) 2018-04-13 2019-10-17 Sumitomo Dainippon Pharma Oncology, Inc. Inhibiteurs de kinase pim pour le traitement de neoplasmes myeloproliferatifs et de fibrose associee au cancer
WO2020006724A1 (fr) * 2018-07-05 2020-01-09 清华大学 Composé de dégradation ciblée de protéine fak et utilisation associée
AU2020221247A1 (en) 2019-02-12 2021-08-05 Sumitomo Pharma Oncology, Inc. Formulations comprising heterocyclic protein kinase inhibitors
CN114105887B (zh) * 2021-09-16 2023-12-01 沈阳药科大学 一种氨基嘧啶衍生物及其制备方法和用途

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (fr) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
WO1995009852A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Autres derives pyrimidine et leur preparation
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
WO2000039101A1 (fr) * 1998-12-24 2000-07-06 Astrazeneca Ab Composes de pyrimidine
WO2001064656A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di-(hetero-) arylamino (-oxy)-5 pyrimidines substitutees utilisees comme agents antineoplasiques
WO2001064655A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy) pyrimidines substitues en 5, utilises comme agents antineoplasiques
WO2001064654A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab Composes de pyrimidine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040141A1 (fr) * 2001-09-28 2003-05-15 Bayer Pharmaceuticals Corporation Composes d'oxazolyl-phenyl-2,4-diamino-pyrimidine, et methodes de traitement de troubles hyperproliferatifs
EP1578722A4 (fr) * 2001-10-12 2006-09-06 Irm Llc Squelettes d'inhibiteurs de kinase et leurs methodes de preparation
JP4460292B2 (ja) * 2001-10-17 2010-05-12 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト ピリミジン誘導体、これらの化合物を含む医薬組成物、その使用及びその調製方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (fr) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
WO1995009852A1 (fr) * 1993-10-01 1995-04-13 Ciba-Geigy Ag Autres derives pyrimidine et leur preparation
WO1997019065A1 (fr) * 1995-11-20 1997-05-29 Celltech Therapeutics Limited 2-anilinopyrimidines substituees utiles en tant qu'inhibiteurs de proteine kinase
WO2000039101A1 (fr) * 1998-12-24 2000-07-06 Astrazeneca Ab Composes de pyrimidine
WO2001064656A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2,4,di-(hetero-) arylamino (-oxy)-5 pyrimidines substitutees utilisees comme agents antineoplasiques
WO2001064655A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab 2, 4-di(hetero-)arylamino (-oxy) pyrimidines substitues en 5, utilises comme agents antineoplasiques
WO2001064654A1 (fr) * 2000-03-01 2001-09-07 Astrazeneca Ab Composes de pyrimidine

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943627B2 (en) 2002-03-15 2011-05-17 Novartis Ag 2,4-diaminopyrimidine derivatives
US8431589B2 (en) 2002-03-15 2013-04-30 Novartis Ag 2,4-diaminopyrimidine derivatives
US7741336B2 (en) 2002-12-20 2010-06-22 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7109337B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7109335B2 (en) 2002-12-20 2006-09-19 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7351712B2 (en) 2002-12-20 2008-04-01 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7674796B2 (en) 2002-12-20 2010-03-09 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7964592B2 (en) 2003-03-14 2011-06-21 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
US8263590B2 (en) 2003-03-14 2012-09-11 Carlos Garcia-Echeverria Pyrimidine derivatives
US7893074B2 (en) 2003-08-15 2011-02-22 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
EP2287156A1 (fr) * 2003-08-15 2011-02-23 Novartis AG Composés de 2,4-di(phenylamino)pyrimidine er leur utilisation dans le traitement de maladies néoplastiques, inflammatoires et du système immunitaire
WO2005016894A1 (fr) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidine diamines utiles dans le cadre du traitement de maladies neoplasiques, de troubles inflammatoires et de troubles du systeme immunitaire
US7235562B2 (en) 2004-05-14 2007-06-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US7208499B2 (en) 2004-05-14 2007-04-24 Pfizer Inc. Pyrimidine derivatives for the treatment of abnormal cell growth
US7145008B2 (en) 2004-05-14 2006-12-05 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
CN1858857B (zh) * 2005-05-03 2010-04-14 海力士半导体有限公司 具有一致编程速度的非易失性存储设备
US7820648B2 (en) 2005-12-21 2010-10-26 Pfizer Inc Pyrimidine derivatives for the treatment of abnormal cell growth
US8039479B2 (en) 2006-12-08 2011-10-18 Irm Llc Compounds and compositions as protein kinase inhibitors
US8377921B2 (en) 2006-12-08 2013-02-19 Irm Llc Compounds and compositions as protein kinase inhibitors
US8399450B2 (en) 2006-12-08 2013-03-19 Irm Llc Compounds and compositions as protein kinase inhibitors
US8957081B2 (en) 2006-12-08 2015-02-17 Irm Llc Compounds and compositions as protein kinase inhibitors
US8372858B2 (en) 2006-12-08 2013-02-12 Irm Llc Compounds and compositions as protein kinase inhibitors
WO2008106635A1 (fr) * 2007-03-01 2008-09-04 Supergen, Inc. Dérivés de pyrimidine-2,4-diamine et leur utilisation en tant qu'inhibiteurs de la kinase jak2
CN107434779B (zh) * 2011-12-21 2021-07-13 洛桑联邦理工学院(Epfl) Notch信号通路抑制剂及其在癌症治疗中的用途
CN107434779A (zh) * 2011-12-21 2017-12-05 洛桑联邦理工学院(Epfl) Notch信号通路抑制剂及其在癌症治疗中的用途
CN113616648A (zh) * 2011-12-21 2021-11-09 洛桑联邦理工学院(Epfl) Notch信号通路抑制剂及其在癌症治疗中的用途
US10202356B2 (en) 2013-03-14 2019-02-12 Tolero Pharmaceuticals, Inc. JAK2 and ALK2 inhibitors and methods for their use
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US11013741B1 (en) 2018-04-05 2021-05-25 Sumitomo Dainippon Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11400091B2 (en) 2018-04-05 2022-08-02 Sumitomo Pharma Oncology, Inc. AXL kinase inhibitors and use of the same
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same
WO2020135488A1 (fr) * 2018-12-26 2020-07-02 上海喆邺生物科技有限公司 Dérivé de 2,4-diaminopyrimidine et son application

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WO2004046118A2 (fr) 2004-06-03

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