USRE41065E1 - Alkynl and azido-substituted 4-anilinoquinazolines - Google Patents

Alkynl and azido-substituted 4-anilinoquinazolines Download PDF

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USRE41065E1
USRE41065E1 US12/038,530 US3853008A USRE41065E US RE41065 E1 USRE41065 E1 US RE41065E1 US 3853008 A US3853008 A US 3853008A US RE41065 E USRE41065 E US RE41065E
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amine
quinazolin
ethynylphenyl
ethynyl
phenyl
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Rodney Caughren Schnur
Lee Daniel Arnold
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Pfizer Inc
OSI Pharmaceuticals LLC
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OSI Pharmaceuticals LLC
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Priority claimed from PCT/IB1995/000436 external-priority patent/WO1996030347A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • This invention relates to 4-(substituted phenylamino) quinazoline derivatives which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
  • a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on activation, leads to the formation of malignant tumor cells).
  • oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation.
  • the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
  • Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer.
  • epidermal growth factor receptor which possesses tyrosine kinase activity is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
  • inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells.
  • erbstatin a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor.
  • EGFR epidermal growth factor receptor tyrosine kinase
  • This invention relates to compounds of the formula and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
  • Preferred compounds of formula I include those wherein R 2 is hydrogen and R 4 is -(ethynyl)-R 11 .
  • R 1 is independently selected from hydrogen, hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R 5 optionally substituted with halo, —OR 6 , carboxy, or —C(O)NH 2 ; —OR 5 optionally substituted with halo, —OR 6 , —OC(O)R 6 , —NR 6 R 6 , or A; —NR 6 R 6 , —C(O)NR 6 R 6 , —SR 5 , phenyl-(C 2 -C 4 )-alkoxy wherein said phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from halo, R 5 or —OR 5 .
  • the invention further relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically-effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
  • the invention further relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of claim 1 .
  • the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is cancer.
  • the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is said cancer is brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological or thyroid cancer.
  • the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is noncancerous.
  • the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is a benign hyperplasia of the skin or prostate.
  • the invention further relates to a process for preparing a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • Preferred processes for preparing the compound of formula I include those wherein each aryl group is selected from phenyl, naphth-1-yl and naphth-2-yl.
  • halo as used herein, unless otherwise indicated, means chloro, bromo, iodo, or fluoro.
  • alkyl as used herein, unless otherwise indicated, means straight chained, cyclic or branched, saturated or unsaturated hydrocarbon moiety with the proviso that said alkyl must comprise three or more carbon atoms if it is branched or cyclic.
  • reaction-inert solvent refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
  • the Formula I compounds, pharmaceutically acceptable salts and prodrugs thereof may be prepared by any process known to be applicable to the preparation of chemically-related compounds.
  • the active compounds may be made from the appropriately substituted quinazoline using the appropriately substituted amine.
  • the reaction may be effected in the presence of a base, preferably an alkali or alkaline earth metal carbonate or hydroxide or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N-dimethylaniline.
  • bases are hereinafter refered to as suitable bases.
  • the reaction mixture is maintained at a temperature from about ambient to about the reflux temperature of the solvent, preferably from about 35° C. to about reflux, until substantially no remaining 4-haloquinazoline can be detected, typically about 2 to about 24 hours.
  • the reaction is performed under an inert atmosphere such as dry nitrogen.
  • the reactants are combined stoichiometrically.
  • an amine base is used for those compounds where a salt (typically the HCl salt) of an amine 4 or 5 is used, it is preferable to use excess amine base, generally an extra equivalent of amine base. (Alternatively, if an amine base is not used an excess of the amine 4 or 5 may be used).
  • a sterically hindered amine 4 such as a 2-alkyl-3-ethynylaniline
  • very reactive 4-haloquinazoline it is preferable to use t-butyl alcohol or a polar aprotic solvent such as DMF or N-methylpyrrolidin-2-one as the solvent.
  • a 4-substituted quinazoline 2 wherein X is hydroxyl or oxo (and the 2-nitrogen is hydrogenated) is reacted with carbon tetrachloride and an optionally substituted triarylphosphine which is optionally supported on an inert polymer (e.g. triphenylphosphine, polymer supported, Aldrich Cat. No.
  • 36,645-5 which is a 2% divinylbenzene cross-linked polystyrene containing 3 mmol phosphorous per gram resin) in a solvent such as carbon tetrachloride, chloroform, dichloroethane, tetrahydrofuran, acetonitrile or other aprotic solvent or mixtures thereof.
  • a solvent such as carbon tetrachloride, chloroform, dichloroethane, tetrahydrofuran, acetonitrile or other aprotic solvent or mixtures thereof.
  • the reaction mixture is maintained at a temperature from about ambient to reflux, preferably from about 35° C. to reflux, for 2 to 24 hours.
  • This mixture is reacted with the appropriate amine or amine hydrochloride 4 or 5 either directly or after removal of solvent, for example by vacuum evaporation, and addition of a suitable alternative solvent such as a (C 1 -C 6 ) alcohol, DMF, N-methylpyrrolidin-2-one, pyridine or 1-4 dioxane.
  • a suitable alternative solvent such as a (C 1 -C 6 ) alcohol, DMF, N-methylpyrrolidin-2-one, pyridine or 1-4 dioxane.
  • the reaction mixture is maintained at a temperature from about ambient to the reflux temperature of the solvent preferably from about 35° C. to about reflux, until substantially complete formation of product is acheived, typically from about 2 to about 24 hours.
  • the reaction is performed under an inert atmosphere such as dry nitrogen.
  • Compound 3 is converted to compounds of formula 1 wherein R 4 is R 11 ethynyl, and R 11 is as defined above, by reaction with a suitable palladium reagent such as tetrakis (triphenylphosphine)palladium or bis(triphenylphosphine) palladium dichloride in the presence of a suitable Lewis acid such as cuprous chloride and a suitable alkyne such as trimethylsilylacetylene, propargyl alcohol or 3-(N,N-dimethylamino)-propyne in a solvent such as diethylamine or triethylamine.
  • a suitable palladium reagent such as tetrakis (triphenylphosphine)palladium or bis(triphenylphosphine) palladium dichloride in the presence of a suitable Lewis acid such as cuprous chloride and a suitable alkyne such as trimethylsilylacetylene, propargyl alcohol or 3-(N
  • Compounds 3, wherein Y is NH 2 may be converted to compounds 1 wherein R 4 is azide by treatment of compound 3 with a diazotizing agent, such as an acid and a nitrite (e.g., acetic acid and NaNO 2 ) followed by treatment of the resulting product with an azide, such as NaN 3 .
  • a diazotizing agent such as an acid and a nitrite (e.g., acetic acid and NaNO 2 ) followed by treatment of the resulting product with an azide, such as NaN 3 .
  • the reduction may conveniently be carried out by any of the many procedures known for such transformations.
  • the reduction may be carried out, for example, by hydrogenation of the nitro compound in a reaction-inert solvent in the presence of a suitable metal catalyst such as palladium, platinum or nickel.
  • a further suitable reducing agent is, for example, an activated metal such as activated iron (produced by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
  • the reduction may be carried out by heating a mixture of the nitro compound and the activated metal with concentrated hydrochloric acid in a solvent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example, 50° to 150° C., conveniently at or near 70° C.
  • alkali metal dithionites such as sodium dithionite
  • alkali metal dithionites such as sodium dithionite
  • nitrogen protecting groups can be used.
  • groups include (C 1 -C 6 )alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbonyl, O-nitrophenylsulfonyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl.
  • the addition of the nitrogen protecting group may be carried out in a chlorinated hydrocarbon solvent such as methylene chloride or 1,2-dichloroethane, or an ethereal solvent such as glyme, diglyme or THF, in the presence or absence of a tertiary amine base such as triethylamine, diisopropylethylamine or pyridine, preferably triethylamine, at a temperature from about 0° C. to about 50° C., preferably about ambient temperature.
  • the protecting groups are . conveniently attached using Schotten-Baumann conditions.
  • the protecting group may be removed by deprotecting methods known to those skilled in the art such as treatment with trifluoroacetic acid in methylene chloride for the tert-butoxycarbonyl protected products.
  • the cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation.
  • Treatment of the protected formula I derivative with molten pyridine hydrochloride (20-30 eq.) at 150° to 175° C. may be employed for O-dealkylations.
  • the cleavage reaction may be carried out, for example, by treatment of the protected quinazoline derivative with an alkali metal (C 1 -C 4 )alkylsulphide, such as sodium ethanethiolate or by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide.
  • the cleavage reaction may also, conveniently, be carried out by treatment of the protected quinazoline derivative with a boron or aluminum trihalide such as boron tribromide. Such reactions are preferably carried out in the presence of a reaction-inert solvent at a suitable temperature.
  • Suitable oxidizing agents are known in the art for the oxidation of sulfanyl to sulphinyl and/or sulphonyl, e.g., hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum.
  • the oxidation is generally carried out under as mild conditions as possible using the stoichiometric amount of oxidizing agent in order to reduce the risk of over oxidation and damage to other functional groups.
  • the reaction is carried out in a suitable solvent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature from about ⁇ 25° to 50° C., preferably at or near ambient temperature, i.e., in the range of 15° to 35° C.
  • a milder oxidizing agents should be used such as sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
  • the compounds of formula I containing a (C 1 -C 4 )alkylsulphonyl group may be obtained by oxidation of the corresponding (C 1 -C 4 )alkylsulphinyl compound as well as of the corresponding (C 1 C 4 )alkylsulfanyl compound.
  • Suitable acylating agents are any agents known in the art for the acylation of amino to acylamino, for example, acyl halides, e.g., a (C 2 -C 4 )alkanoyl chloride or bromide or a benzoyl chloride or bromide, alkanoic acid anhydrides or mixed anhydrides (e.g., acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (C 1 -C 4 )alkoxycarbonyl halide, for example (C 1 -C 4 ) alkoxycarbonyl chloride, in the presence of a suitable base.
  • acyl halides e.g., a (C 2 -C 4 )alkanoyl chloride or bromide or a benzoyl chloride or bromide
  • alkanoic acid anhydrides or mixed anhydrides e.g., acetic anhydride or the mixed anhydr
  • a suitable acylating agent is, for example, a cyanate, e.g., an alkali metal cyanate such as sodium cyanate, or an isocyanate such as phenyl isocyanate.
  • N-sulfonylations may be carried out with suitable sulfonyl halides or sulfonylanhydrides in the presence of a tertiary amine base.
  • the acylation or sulfonylation is carried out in a reaction-inert solvent and at a temperature in the range of about ⁇ 30° to 120° C., conveniently at or near ambient temperature.
  • R 1 is (C 1 -C 4 )alkoxy or substituted (C 1 -C 4 )alkoxy or R 1 is (C 1 -C 4 )alkylamino or substituted mono-N- or di-N,N-(C 1 -C 4 )alkylamino, are prepared by the alkylation, preferably in the presence of a suitable base, of a corresponding compound wherein R 1 is hydroxy or amino, respectively.
  • Suitable alkylating agents include alkyl or substituted alkyl halides, for example, an optionally substituted (C 1 -C 4 )alkyl chloride, bromide or iodide, in the presence of a suitable base in a reaction-inert solvent and at a temperature in the range of about 10° to 140° C., conveniently at or near ambient temperature.
  • alkyl or substituted alkyl halides for example, an optionally substituted (C 1 -C 4 )alkyl chloride, bromide or iodide
  • R 1 is a carboxy substituent or a substituent which includes a carboxy group
  • R 1 is a (C 1 -C 4 )alkoxycarbonyl substituent or a substituent which includes a (C 1 -C 4 )alkoxycarbonyl group.
  • the hydrolysis may conveniently be performed, for example, under basic conditions, e.g., in the presence of alkali metal hydroxide as illustrated in the accompanying Examples.
  • Suitable acylating agents known in the art for acylation of hydroxyaryl moieties to alkanoyloxyaryl groups include, for example, (C 2 -C 4 )alkanoyl halides, (C 2 -C 4 )alkanoyl anhydrides and mixed anhydrides as described above, and suitable substituted derivatives thereof may be employed, typically in the presence of a suitable base.
  • (C 2 -C 4 )alkanoic acids or suitably substituted derivatives thereof may be coupled with a Formula I compound wherein R 1 is hydroxy with the aid of a condensing agent such as a carbodiimide.
  • suitable carbamoylating agents are, for example, cyanates or alkyl or arylisocyanates, typically in the presence of a suitable base.
  • suitable intermediates such as the chloroformate or carbonylimidazolyl derivative of a compound of Formula I in which R 1 is hydroxy may be generated, for example, by treatment of said derivative with phosgene (or a phosgene equivalent) or carbonyidiimidazole. The resulting intermediate may then be reacted with an appropriate amine or substituted amine to produce the desired carbamoyl derivatives.
  • the activation and coupling of formula I compounds wherein R 1 is carboxy may be performed by a variety of methods known to those skilled in the art. Suitable methods include activation of the carboxyl as an acid halide, azide, symmetric or mixed anhydride, or active ester of appropriate reactivity for coupling with the desired amine. Examples of such types of intermediates and their production and use in couplings with amines may be found extensively in the literature; for example M. Bodansky and A. Bodansky, “The Practice of Peptide Synthesis”, Springer,-Verlag, New York, 1984. The resulting formula I compounds may be isolated and purified by standard methods, such as solvent removal and recrystallization or chromatography.
  • Certain Formula I quinazolines can exist in solvated, as well as unsolvated forms, such as the hydrated forms. It is to be understood that the invention encompasses all such solvated, as well as unsolvated forms, which possess activity against hyperproliferative diseases.
  • a suitable pharmaceutically-acceptable salt of a compound of formula I is, for example, an acid-addition salt of a corresponding compound which is sufficiently basic, e.g., an acid-addition salt with, for example, an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid.
  • an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid.
  • a suitable pharmaceutically-acceptable base-addition salt of a compound of formula I which is acidic is an alkali metal salt, for example, a lithium, sodium or potassium salt; an alkaline earth metal salt, for example, a calcium or magnesium salt; an ammonium salt; or a salt with an organic base which affords a physiologically-acceptable cation for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. All such salts are within the scope of this invention and they can be prepared by conventional methods.
  • they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate.
  • the salts are recovered by filtration; by precipitation with a non-solvent, preferably an etheral or hydrocarbon solvent, followed by filtration and by evaporation of a solvent, or, in the case of aqueous solutions, by lyophilization.
  • Some of the compounds of Formula I have asymmetric carbon atoms.
  • Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se., for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers mixtures and pure enantiomers are considered as part of the invention.
  • the active compounds of this invention are potent inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases such as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer) in mammals, particularly humans.
  • EGFR epidermal growth factor receptor
  • erbB2 HER3, or HER4
  • antiproliferative agents e.g., anticancer
  • the compounds of this invention are therapeutants or prophylactics for the treatment of a variety of human tumors (renal, liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, various head and neck tumors), and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., BPH). It is, in addition, expected that a quinazoline of the present invention may possess activity against a range of leukemias and lymphoid malignancies.
  • the active compounds may also be expected to be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions, activation or signalling events related to various protein tyrosine kinases, whose activity is inhibited by the agents of Formula I, are involved.
  • Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases may be involved.
  • compounds of Formula I may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases which are inhibited by compounds of Formula I.
  • the in vitro activity of the active compounds in inhibiting the receptor tyrosine kinase may be determined by the procedure detailed below.
  • Activity of the active compunds, in vitro can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., Lys 3 -Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et. al., J. Biol. Chem. 267 (29), 20638-47 (1992)) on tyrosine by epidermal growth factor receptor kinase by a test compound relative to a control.
  • an exogenous substrate e.g., Lys 3 -Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et. al., J. Biol. Chem. 267 (29), 20638-47 (1992)
  • Affinity purified, soluble human EGF receptor (96 ng) is obtained according to the procedure in G. N. Gill, W.
  • the phosphorylation reaction is initiated by addition of 20 ⁇ l 33 P-ATP/substrate mix (120 ⁇ M Lys 3 -Gastrin (sequence in single letter code for amino acids, KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 ⁇ M ATP, 2 ⁇ Ci ⁇ -[ 33 P]-ATP) to the EGFr/EGF mix and incubated for 20 minutes at room temperature.
  • the reaction is stopped by addition of 10 ⁇ l stop solution (0.5M EDTA, pH 8; 2mM ATP) and 6 ⁇ l 2N HCl.
  • the tubes are centrifuged at 14,000 RPM, 4° C., for 10 minutes.
  • Such assays allow the determination of an approximate IC 50 value for the in vitro inhibition of EGFR kinase activity.
  • IC 50 0.0001 ⁇ 30 ⁇ M.
  • Activity of the active compounds, in vivo can be determined by the amount of inhibition of tumor growth by a test compound relative to a control.
  • the tumor growth inhibitory effects of various compounds are measured according to the methods of Corbett T. H., et al. “Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure”, Cancer Res., 35, 2434-2439 (1975) and Corbett, T. H., et al., “A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother. Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors are induced in the left flank by s.c.
  • test animals injection of 1 ⁇ 10 6 log phase cultured tumor cells (human MDA-MB-468 breast or human HN5 head and neck carcinoma cells) suspended in 0.10 ml RPMI 1640.
  • active compound formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into saline or, alternatively, 1:9 dilution into 0.1% Pluronic® P105 in 0.9% saline
  • ip intraperitoneal
  • oral po
  • the flank site of tumor implantation provides reproducible dose/response effects for a variety of chemotherapeutic agents, and the method of measurement (tumor diameter) is a reliable method for assessing tumor growth rates.
  • Administration of the active compounds can be effected by any method which enables delivery of the compounds to the site of action (e.g., cancer cells). These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, etc.
  • the amount of active compound administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physician.
  • an effective dosage is in the range of approximately 0.001-100 mg/kg, preferably 1 to 35 mg/kg in single or divided doses. For an average 70 kg human, this would amount to 0.05 to 7 g/day, preferably 0.2 to 2.5 g/day.
  • the composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
  • the pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
  • compositions according to the invention may contain 0.1%-95% of the compound, preferably 1%-70%.
  • the composition or formulation to be administered will contain a quantity of active compound in an amount effective to alleviate or reduce the signs in the subject being treated, i.e., hyperproliferative diseases, over the course of the treatment.
  • Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents.
  • the pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • excipients such as citric acid
  • disintegrants such as starch, alginic acid and certain complex silicates
  • binding agents such as sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.
  • Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
  • hyperproliferative disease treatment described above may be applied as a sole therapy or may involve, in addition to the active compound, one or more other antitumor substances. Such conjoint treatment may be achieved by way of the simultaneous, sequential, cyclic or separate dosing of the individual components of the treatment.
  • High pressure liquid chromatography used in the following examples and preparations was effected according to the following method unless modified in specific examples.
  • Perkin-Elmer Pecosphere® 3 ⁇ 3C cartridge column (3mm ⁇ 3cm, C18; available from Perkin Elmer Corp., Norwalk, Conn. 06859) with a Brownlee (trademark) RP-8Newguard precolumn (7 micron, 3.2 mm ⁇ 15 mm, available from Applied Biosystems Inc. San Jose, Calif. 95134) which was previously equilibrated in pH 4.50, 200 mM ammonium acetate buffer.
  • Example 3 The title product of Example 3 (50 mg, 0.149 mmol), triphenylphosphine (60 mg, 0.225 mmol)), phthalimide (165 mg, 1.12 mmol) and diethyl azodicarboxylate (36 ⁇ L, 0.228 mmol) were stirred at room temperature in 3 mL of dry tetrahydrofuran for 16 hours.
  • reaction mixture was concentrated to a solid and flash chromatographed on silica gel eluted with 15% acetone:methylene chloride to afford pure solid [3-(2′- ⁇ phthalimidomethyl ⁇ -ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine which was converted to its hydrochloride salt by addition of 1 mL of anhydrous 1M HCl in methanol followed by 3 mL of isopropyl alcohol. The salt was collected by filtration, dried and used immediately in the next step; 15 mg. This 15 mg, 0.0323 mmol was treated with 0.5 ml of hydrazine hydrate and 1 mL of methanol for 0.5 hours.
  • reaction mixture was evaporated, in vacuo, and the product isolated by flash chromatography eluted with 10% methanol in methylene chloride. Pure title product was isolated after conversion to its hydrochloride salt with 1 mL of 1M HCl in methanol, precipitation with isopropyl alcohol and diethyl ether and drying, in vacuo,; 5.6 mg (47%) mp 275° C. dec.
  • the title product was prepared in the following three step sequence with out purification of the intermediates.
  • a mixture consisting of 3-bromo-2-methylaniline (1.00 g, 5.37 mmol), tetrakis(triphenylphosphine)palladium (200 mg), trimethylsilylacetylene (1.053 g, 10.75 mmol), 10 mL of dry, nitrogen purged diethylamine and cuprous iodide 910 mg) was refluxed for 16 hours, cooled and concentrated, in vacuo, to afford a residue which was partitioned between chloroform and 1N HCL.
  • Example 8 The title product of Example 8 (100 mg, 0.384 mmol), pyridine (140 ⁇ L, 1.68 mmol) and methanesulfonyl chloride (99 ⁇ L, 1.26 mmol) were refluxed in 10 mL of 1,2-dichloroethane for 7 hours. The reaction mixture was cooled and evaporated in a vacuo to a residue which was triturated in 10 mL of 1N HCl, filtered and dried in vacuo to yield (3-ethynylphenyl)-(6-methanesulfonylaminoquinazoline-4-yl)amine; 102 mg (78%) mp 248° C. dec.
  • the title product was prepared in the following three step sequence without purification of the intermediates.
  • a mixture consisting of 4-bromo-2-nitrotoluene (1.50 g, 6.94 mmol) tetrakis(triphenylphosphine)palladium (750 mg), trimethylsilylacetylene (3.00 mL, 21.21 mmol) and cuprous iodide (20 mg) in 20 mL of nitrogen purged, dry diethylamine was refluxed for 2 hours, cooled and concentrated, in vacuo, to afford a residue which was partitioned between 100 mL of ethyl acetate and 100 mL of 1N HCl.
  • 6-Methanesulfonyl-quinazolin-4-one 200 mg, 0.89 mmol
  • triphenyl phosphine 566 mg, 2.15 mmol
  • carbon tetrachloride 815 ⁇ L, 8.92 mmol
  • the solvent was vacuum evaporated to afford a residue. This was dissolved in 5 mL of isopropyl alcohol and 3-ethynylaniline (156 mg, 1.33 mmol) and heated at reflux for 16 hours.
  • the cooled reaction mixture was filtered, washed with a minimum of cold isopropyl alcohol and dried in vacuo at 70° C. for 16 hours to afford pure title product; 63 mg (20%) mp 281°-282° C.
  • 6-Ethanesulfanyl-quinazolin-4-one (100 mg, 0.48 mmol), triphenyl phosphine (305 mg, 1.16 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours.
  • the solvent was vacuum evaporated to afford a residue. This was dissolved in 5 mL of isopropyl alcohol and 3-ethynylaniline (68 mg, 0.58 mmol) and heated at reflux for 1 hour.
  • the cooled reaction mixture was filtered, washed with a minimum of cold isopropyl alcohol and dried in vacuo at 70° C. for 16 hours to afford pure title product; 70 mg (42%) mp 239°-40° C.
  • 3-(2′-Trimethylsilyl-ethynyl)-4-fluoroaniline was prepared from 3-bromo-4-fluoroaniline (7.0 gm, 36.8 mmol) tetrakis(triphenylphosphine)palladium (1.4 gm), trimethylsilyl-acetylene (7.2 gm, 74 mmol) and cuprous iodide (40 mg) in 140 mL of nitrogen purged dry diethylamine at reflux for 16 hours. The cooled reaction mixture was filtered through Celite and the Celite washed with ether.
  • 3-(Propyn-1-yl)aniline was prepared from 3-bromo-nitrobenzene in four steps.
  • 3-Bromo-nitrobenzene 5.0 gm, 24.7 mmol
  • tetrakis(triphenylphosphine)palladium 1.0 gm
  • trimethylsilyl-acetylene 3.6 gm, 37 mmol
  • cuprous iodide 20 mg
  • the cooled reaction mixture was vacuum evaporated, diluted with 50 mL of methylene chloride and 50 mL of 1N hydrochloric acid and filtered.
  • the title product was prepared from 4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxyethoxy)-quinazoline (399 mg, 1.26 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (515 mg; 94%; M.P. 215°-225° C. (dec); LC-MS: 398 (MH + ); anal. RP18-HPLC RT: 4.85 min.).
  • Example 29 The title product of Example 29 (200 mg, 0.456 mmol) was treated with cesuim acetate (1.75 g, 9.12 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N 2 for 16 hours. The reaction mixture was partitioned between brine and CHCl 3 , and the organic extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford an oil (277 mg) which was recrystallized from CH 2 Cl 2 /hexane. (184 mg; 90%; M.P. 137°-138° C.; LC-MS: 450 (MH + ); anal. RP18-HPLC RT: 4.64 min.).
  • Example 30 The title product of Example 30 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N 2 for 16 hours. The reaction mixture was partitioned between brine and CHCl 3 , and the organic extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford a residue (285 mg) which was recrystallized from ethylacetate/hexane. (134 mg; M.P. 84°-87° C.; LC-MS: 422 (MH + ); anal. RP18-HPLC RT: 4.38 min.).
  • This product was prepared from 4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline (600 mg, 1.89 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (737 mg; 90%; M.P. 225°-235° C. (dec); LC-MS: 398 (MH + ); anal. RP18-HPLC RT: 4.89 min.).
  • Example 34 The title product of Example 34 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N 2 for 16 hours. The reaction mixture was partitioned between brine and CHCl 3 , and the organic extract was washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to afford a residue (288 mg) which was recrystallized from ethyl acetate/hexanes. (134 mg; M.P.134°-135° C.; LC-MS: 422 (MH + ); anal. RP18-HPLC RT: 4.43 min.).
  • Example 35 The title product of Example 35 (149 mg, 0.354 mmol) in methanol (3 mL) was treated with 5M aqueous KOH (0.25 mL). The mixture was stirred at 20° C. for 30 minutes before removing the solvent in vacuo. The solid residue was washed with water to remove salts, and dried azeotropically by dissolution two times in acetonitrile and concentration in vacuo to afford 100 mg of title product as its free base. This material was converted to its HCl salt according to the method used in Example 28 (87 mg; 59%; M.P. 230°-235° C. (dec); LC-MS: 380 (MH + ); anal. RP18-HPLC RT: 3.42 min.).
  • Example 34 The title product of Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with N-methyl-piperazine (281 ⁇ L, 2.53 mmol) at 110° C. for 16 hours. The reaction mixture was partitioned between CHCl 3 and saturated aqueous NaHCO 3 . The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was chromatographed on silica using 15% methanol/CH 2 Cl 2 to provide 56 mg of pure product as its free base.
  • Example 34 The title product from Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl 3 and saturated aqueous NaHCO 3 . The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product (119 mg) was chromatographed on silica using 10% methanol/CH 2 Cl 2 to provide 85 mg of pure title product as its free base.
  • Example 30 The title product of Example 30 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl 3 and saturated aqueous NaHCO 3 . The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product (125 mg) was chromatographed on silica using 10% methanol/CH 2 Cl 2 to provide 86 mg of pure title product as its free base.
  • Example 33 The title product from Example 33 (149 mg, 0.354 mmol) in methanol (3 mL) was treated with 5M aqueous KOH (0.25 mL). The mixture was stirred at 20° C. for 30 minutes before removing the solvent in vacuo. The solid residue was washed with water to remove salts, and dried azeotropically by dissolution two times in acetonitrile and concentration in vacuo to afford 95 mg of title product as its free base. This material was converted to its HCl salt according to the method used in Example 28 (89 mg; 61%; M.P. 190°-215° C. (dec); LC-MS: 380 (MH + ); anal. RP18-HPLC RT: 3.66 min.).
  • This material was desilated directly by treatment with 2 mL of methanol containing 1 drop of water and 100 mg of potassium carbonate for 0.5 hours.
  • the heterogeneous reaction mixture was filtered through Celite and vacuum evaporated to a residue which was dissolved in excess 1N HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuo at 70° C. to afford the title product; 160 mg (75%); mp 258°-259.5° C.
  • 6-Methyl-quinazolin-4-one (350 mg, 2.18 mmol) was added to a suspension of polymer-supported triphenylphosphine (from Fluka, 3.63 g of about 3 mmol P/g resin; 10.9 mmol) in a mixture of CCl 4 (3.35 g, 21.80 mmol) and 1,2 dichloroethane (10 mL). The mixture was heated to 60° C. for 2 hours and then the polymer was removed by filtration and washed with dichloroethane. The filtrate was collected in a flask containing 3-ethynyl-aniline (0.644 g, 2.18 mmol) and concentrated to 5 mL by evaporation.
  • Example 34 The title product of Example 34 (150 mg, 0.34 mmol) was added to a solution of thiolactic acid (100 ⁇ L, 1.14 mmol) and KOH (150 mg, 2.7 mmol) in degassed DMF (5 mL)/H 2 O (0.5 mL). The reaction mixture was stirred at 50° C. under an atmosphere of N 2 for 72 hours and then cooled to room temperature. The pH of the mixture was adjusted to about 4.0 with acetic acid and then partitioned between CHCl 3 and brine. The organic extracts were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the title product was prepared from the title product of Example34 and mercaptoacetic acid according to the method of Example 45. (3%; LC-MS: 454 (MH + ); anal. RP-HPLC RT: 3.37 min).
  • Example 30 The title product of Example 30 (107 mg, 0.245 mmol) was treated with sodium ethoxide (0.582 mmol) in refluxing ethanol (3 mL) for 24 hours. The solvent was removed in vacuo and the product was isolated by flash chromatography on silica using 10% acetone/CH 2 Cl 2 to provide 30 mg of the 6-vinyloxy product (33%; M.P. 113°-114° C.; LC-MS: 362 (MH + ); anal. RP-HPLC RT: 4.84 min). The 6-(2-ethoxy-ethoxy) derivative eluted as a more polar product (45 mg) and was converted to its HCl salt according to the procedure described for Example28 (43%; M.P. 220°-225° C. (dec); LC-MS: 408 (MH + ); anal. RP-HPLC RT: 4.35 min).
  • the free base of this product was prepared from the title product of Example 30 and the sodium salt of pyrid-4-one as described for Example 50.
  • the free base was isolated by flash chromatography with 15% methanol/CHCl 3 and converted to the title product according to the procedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS: 457 (MH + ); anal. RP-HPLC RT: 3.45 min).
  • RP18-HPLC RT 5.82 min.
  • the analytical RP18-HPLC system consisted of a Waters 717 (trademark) autosampler, Waters 996 Photodiode Array Detector (trademark), and Waters 600 quarternary solvent delivery system, and was controlled by Millennium (trademark) software.
  • 6,7-Dibutoxyquinazolin-4-one (105 mg, 0.362 mmol), triphenylphosphine (208 mg, 0.796 mmol) and 5 mL of carbon tetrachloride were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (47 mg, 0.398 mmol) and refluxed for 3 hours.
  • 6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-one 200 mg, 0.739 mmol
  • triphenylphosphine 427 mg, 1.63 mmol
  • 0.7 mL of carbon tetrachloride 0.7 mL
  • the hot reaction mixture was filtered to isolate crude product which was column chromatographed on silica gel eluted with 5% methanol in chloroform. Fractions containing the pure product were concentrated in vacuo to afford the title product as a solid; 23 mg (8.4%); mp 230°-232° C.
  • This product was prepared from the title product of Example 30 and mercaptoacetic acid at 22° C. over 10 days according to the method outlined in Example 45. (16%; M.P. 98°-113° C. (dec); LC-MS 454 (MH + ); anal. RP-HPLC 3.24 min.)
  • the catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to a thick slurry which was diluted with ether (400 mL).
  • the solid white hydrochloride salt of ethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88%).
  • a portion of this material (42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were dissolved in formamide (63 mL) and the stirred mixture was heated to 160°-165° C. under an atmosphere of N 2 for 3 hours.

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Abstract

The invention relates to compounds of the formula
Figure USRE041065-20091229-C00001
and to pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, n and m are as defined herein. The compounds of formula I are useful in the treatment of hyperproliferative diseases, such as cancer. The invention further relates to processes of making the compounds of formula I and to methods of using such compounds in the treatment of hyperproliferative diseases.

Description

This application is a continuation-in-part of PCT international application number PCT/IB95/00436, filed Jun. 6, 1995, which designates the United States.
BACKGROUND OF THE INVENTION
This invention relates to 4-(substituted phenylamino) quinazoline derivatives which are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals.
Many of the current treatment regimes for cancer utilize compounds which inhibit DNA synthesis. Such compounds are toxic to cells generally but their toxic effect on the rapidly dividing tumor cells can be beneficial. Alternative approaches to anti-cancer agents which act by mechanisms other than the inhibition of DNA synthesis have been explored in order to enhance the selectivity of action against cancer cells.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR) which possesses tyrosine kinase activity is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor.
Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties. More recently five European patent publications, namely EP 0 566 226 A1, EP 0 602 851 A1, EP 0 635 507 A1, EP 0 635 498 A1 and EP 0 520 722 A1 have disclosed that certain quinazoline derivatives possess anti-cancer properties which result from their tyrosine kinase inhibitory properties. Also PCT publication WO 92/20642 discloses bis-mono and bicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitors.
Although the anti-cancer compounds described above make a significant contribution to the art there is a continuing search in this field of art for improved anti-cancer pharmaceuticals.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula
Figure USRE041065-20091229-C00002
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
    • m is 1, 2, or 3;
    • each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1-C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
    • or each R1 is independently selected from R9 and (C1-C4)-alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, —OR6, —NR6R6, —C(O)R7, —NHOR5, —OC(O)R6, cyano, A and —YR5; R5 is C1-C4 alkyl; R6 is independently hydrogen or R5; R7 is R5, —OR6 or —NR6R6; A is selected from piperidino, morpholino, pyrrolidino, 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1-C4 alkylene)(CO2H), phenoxy, phenyl, phenylsulfanyl, C2-C4 alkenyl, and -(C1-C4 alkylene)C(O)NR6R6; and Y is S, SO, or SO2; wherein the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by one to three substituents independently selected from halo and R9, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R9 groups may comprise a single R1 group;
    • or each R1 is independently selected from —NHSO2R5, phthalimido-(C1-C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-(C2-C4)-alkanoylamino wherein R10 is selected from halo, —OR6, C2-C4 alkanoyloxy, —C(O)R7, and —NR6R6; and wherein the foregoing R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1-C4 alkyl, cyano, methanesulfonyl and C1-C4 alkoxy;
    • or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
    • R2 is hydrogen or C1-C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5;
    • n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1-C6 alkyl, —NR6R6, and C1-C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5; and,
    • R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1-C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R6.
Preferred compounds of formula I include those wherein R2 is hydrogen and R4 is -(ethynyl)-R11.
Other preferred compounds of formula I include those wherein m is 1 or 2;
    • each R1 is independently selected from the group consisting of hydrogen, hydroxy, hydroxyamino, carboxy, nitro, carbamoyl, ureido, R5 optionally substituted with halo, —OR6, carboxy, —C(O)NR6R6, A or —NR6R6; —OR5 optionally substituted with halo, —OR6, —OC(O)R6, —NR6R6, or A; —NR6R6, —C(O)R6 R5, —SR5, phenyl-(C2-C4)-alkoxy, cyano, phenyl; —NHR5 optionally substituted with halo or R9 wherein said R9 is optionally substituted by R9; —NHOR5, —SR5, C1-C4 alkylsulfonylamino, phthalimido-(C1-C4)-alkylsulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, halo-(C2-C4)-alkanoylamino, hydroxy-(C2-C4)-alkanoylamino, (C2-C4)-alkanoyloxy-(C2-C4)-alkanoylamino, (C1-C4)-alkoxy-(C2-C4)-alkanoylamino, (C1-C4)-alkoxycarbonyl-(C2-C4)-alkanoylamino, carbamoyl-(C2-C4)-alkanoylamino, N-(C1-C4)-alkylcarbamoyl-(C2-C4)-alkanoylamino, N,N-di-[(C1-C4)-alkyl]carbamoyl-(C2-C4)-alkanoylamino, amino-(C2-C4)-alkanoylamino, (C1-C4)-alkyl-amino-(C2-C4)-alkanoylamino, and di-(C1-C4)-alkyl-amino-(C2-C4)-alkanoylamino, and wherein said phenyl or phenoxy or anilino substituent in the foregoing R1 groups is optionally substituted with one or two substituents independently selected from halo, C1-C4 alkyl and C1-C4 alkoxy;
    • each R3 is independently selected from hydrogen, methyl, ethyl, amino, halo and hydroxy; and,
    • R4 is ethynyl.
Other preferred compounds of formula I include those wherein each R1 is independently selected from hydrogen, hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R5 optionally substituted with halo, —OR6, carboxy, or —C(O)NH2; —OR5 optionally substituted with halo, —OR6, —OC(O)R6, —NR6R6, or A; —NR6R6, —C(O)NR6R6, —SR5, phenyl-(C2-C4)-alkoxy wherein said phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from halo, R5 or —OR5.
Other preferred compounds of formula I include those wherein R2 is hydrogen and R4 is azido.
Other preferred compounds of formula I include those wherein R3 is halo and R1 is hydrogen or —OR5.
Other preferred compounds of formula I include those wherein R1 is methoxy.
Specific preferred compounds of formula I include the following:
  • (6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine;
  • [3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine;
  • (3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;
  • (6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;
  • (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine;
  • (6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine;
  • (3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine;
  • (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine;
  • (3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;
  • (3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine;
  • (3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine;
  • (3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;
  • (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;
  • (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine;
  • (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
  • (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
  • (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
  • (3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine;
  • (6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine
  • (6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;
  • (6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine;
  • [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine;
  • [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine;
  • [6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • [6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • [6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • 2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol;
  • [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • [7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • [7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • 2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol;
  • 2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol;
  • 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol;
  • [6-(2-acetoxy-ethoxy)-7-(2 -methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
  • (3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;
  • (3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine;
  • (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
  • (6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
  • (6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
  • (6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine;
  • [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine;
  • (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;
  • [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; and
  • 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol.
Other specific preferred compounds of formula I include the following:
  • (6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;
  • (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine;
  • (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;
  • (6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine;
  • (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine;
  • (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;
  • (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
  • (6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; and
  • (6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine.
Other specific preferred compounds of formula I include the following:
  • (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
  • (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;
  • [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;
  • [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;
  • (6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
  • (3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine; and,
  • (6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine.
The invention further relates to a pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically-effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
The invention further relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of claim 1.
In a preferred embodiment, the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is cancer.
In another preferred embodiment, the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is said cancer is brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological or thyroid cancer.
In another preferred embodiment, the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is noncancerous.
In another preferred embodiment, the method of treating hyperproliferative disorders includes those wherein said hyperproliferative disorder is a benign hyperplasia of the skin or prostate.
The invention further relates to a process for preparing a compound of the formula
Figure USRE041065-20091229-C00003
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
    • m is 1, 2, or 3;
    • each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1-C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
    • or each R1 is independently selected from R9 and (C1-C4)-alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, —OR6, —NR6R6, —C(O)R7, —NHOR5, —OC(O)R6, cyano, A and —YR5; R5 is C1-C4 alkyl; R6 is independently hydrogen or R5; R7 is R5, —OR6 or —NR6R6; A is selected from piperidino, morpholino, pyrrolidino, 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1-C4 alkylene)(CO2H), phenoxy, phenyl, phenylsulfanyl, C2-C4 alkenyl, and -(C1-C4 alkylene)C(O)NR6R6; and Y is S, SO, or SO2; wherein the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by one to three substituents independently selected from halo and R9, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R9 groups may comprise a single R1 group;
    • or each R1 is independently selected from —NHSO2R5, phthalimido-(C1-C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-(C2-C4)-alkanoylamino wherein R10 is selected from halo, —OR6, C2-C4 alkanoyloxy, —C(O)R7, and —NR6R6; and wherein the foregoing R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1-C4 alkyl, cyano, methanesulfonyl and C1-C4 alkoxy;
    • or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
    • R2 is hydrogen or C1-C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5;
    • n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1-C6 alkyl, —NR6R6, and C1-C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5; and,
    • R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1-C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R6; which comprises
      • a) treating a compound of the formula
        Figure USRE041065-20091229-C00004
    • wherein R1 and m are as defined above, with CCl4 and (C6-C10aryl)3P, optionally supported on an inert polymer, wherein the aryl moieties of said (C6-C10aryl)3P are optionally substituted by C1-C6 alkyl; and
      • b) treating the product of step a) with a compound of the formula
        Figure USRE041065-20091229-C00005
    • wherein R2, R3 and n are as defined above, and J is Y or R4, wherein R4 is as defined above and wherein Y is NH2, Br, I or trifluoromethanesulfonyloxy, with the proviso that when J is Y then the product of step b) must further be treated with an alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an azide where Y is NH2.
Preferred processes for preparing the compound of formula I include those wherein each aryl group is selected from phenyl, naphth-1-yl and naphth-2-yl.
Other preferred processes for preparing the compound of formula I include those wherein each Ar in (C6-C10aryl)3P is phenyl.
Other preferred processes for preparing the compound of formula I include those wherein said (C6-C10aryl)3P is supported on an inert polymer.
Other preferred processes for preparing the compound of formula I include those wherein said inert polymer is a divinylbenzene-cross-linked polymer of styrene.
The term “halo”, as used herein, unless otherwise indicated, means chloro, bromo, iodo, or fluoro.
The term “alkyl”, as used herein, unless otherwise indicated, means straight chained, cyclic or branched, saturated or unsaturated hydrocarbon moiety with the proviso that said alkyl must comprise three or more carbon atoms if it is branched or cyclic.
As used herein, the expression “reaction-inert solvent” refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
Other features and advantages will be apparent from the specification and claims which describe the invention.
Figure USRE041065-20091229-C00006
DETAILED DESCRIPTION OF THE INVENTION
The Formula I compounds, pharmaceutically acceptable salts and prodrugs thereof (hereafter the active compounds) may be prepared by any process known to be applicable to the preparation of chemically-related compounds.
In general the active compounds may be made from the appropriately substituted quinazoline using the appropriately substituted amine.
As shown in the Scheme the appropriate 4-substituted quinazoline 2 wherein X is a suitable displaceable leaving group such as halo, aryloxy, alkylsulfinyl, alkylsulfonyl such as trifluoromethanesulfonyloxy, arylsulfinyl, arylsulfonyl, siloxy, cyano, pyrazolo, triazolo or tetrazolo, preferably a 4-chloroquinazoline, is reacted with the appropriate amine or amine hydrochloride 4 or 5, wherein R4 is as described above and Y is Br, I, or trifluoromethane-sulfonyloxy in a solvent such as a (C1-C6)alcohol, dimethylformamide (DMF), N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran (THF), 1-4 dioxane, pyridine or other aprotic solvent. The reaction may be effected in the presence of a base, preferably an alkali or alkaline earth metal carbonate or hydroxide or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morpholine, triethylamine, 4-dimethylamino-pyridine or N,N-dimethylaniline. These bases are hereinafter refered to as suitable bases. The reaction mixture is maintained at a temperature from about ambient to about the reflux temperature of the solvent, preferably from about 35° C. to about reflux, until substantially no remaining 4-haloquinazoline can be detected, typically about 2 to about 24 hours. Preferably, the reaction is performed under an inert atmosphere such as dry nitrogen.
Generally the reactants are combined stoichiometrically. When an amine base is used for those compounds where a salt (typically the HCl salt) of an amine 4 or 5 is used, it is preferable to use excess amine base, generally an extra equivalent of amine base. (Alternatively, if an amine base is not used an excess of the amine 4 or 5 may be used).
For those compounds where a sterically hindered amine 4 (such as a 2-alkyl-3-ethynylaniline) or very reactive 4-haloquinazoline is used it is preferable to use t-butyl alcohol or a polar aprotic solvent such as DMF or N-methylpyrrolidin-2-one as the solvent.
Alternatively, a 4-substituted quinazoline 2 wherein X is hydroxyl or oxo (and the 2-nitrogen is hydrogenated) is reacted with carbon tetrachloride and an optionally substituted triarylphosphine which is optionally supported on an inert polymer (e.g. triphenylphosphine, polymer supported, Aldrich Cat. No. 36,645-5, which is a 2% divinylbenzene cross-linked polystyrene containing 3 mmol phosphorous per gram resin) in a solvent such as carbon tetrachloride, chloroform, dichloroethane, tetrahydrofuran, acetonitrile or other aprotic solvent or mixtures thereof. The reaction mixture is maintained at a temperature from about ambient to reflux, preferably from about 35° C. to reflux, for 2 to 24 hours. This mixture is reacted with the appropriate amine or amine hydrochloride 4 or 5 either directly or after removal of solvent, for example by vacuum evaporation, and addition of a suitable alternative solvent such as a (C1-C6) alcohol, DMF, N-methylpyrrolidin-2-one, pyridine or 1-4 dioxane. Then, the reaction mixture is maintained at a temperature from about ambient to the reflux temperature of the solvent preferably from about 35° C. to about reflux, until substantially complete formation of product is acheived, typically from about 2 to about 24 hours. Preferably the reaction is performed under an inert atmosphere such as dry nitrogen.
When compound 4, wherein Y is Br, I, or trifluoromethanesulfonyloxy, is used as starting material in the reaction with quinazoline 2, a compound of formula 3 is formed wherein R1, R2, R3, and Y are as described above. Compound 3 is converted to compounds of formula 1 wherein R4 is R11ethynyl, and R11 is as defined above, by reaction with a suitable palladium reagent such as tetrakis (triphenylphosphine)palladium or bis(triphenylphosphine) palladium dichloride in the presence of a suitable Lewis acid such as cuprous chloride and a suitable alkyne such as trimethylsilylacetylene, propargyl alcohol or 3-(N,N-dimethylamino)-propyne in a solvent such as diethylamine or triethylamine. Compounds 3, wherein Y is NH2, may be converted to compounds 1 wherein R4 is azide by treatment of compound 3 with a diazotizing agent, such as an acid and a nitrite (e.g., acetic acid and NaNO2) followed by treatment of the resulting product with an azide, such as NaN3.
For the production of those compounds of Formula I wherein an R1 is an amino or hydroxyamino group the reduction of the corresponding Formula I compound wherein R1 is nitro is employed.
The reduction may conveniently be carried out by any of the many procedures known for such transformations. The reduction may be carried out, for example, by hydrogenation of the nitro compound in a reaction-inert solvent in the presence of a suitable metal catalyst such as palladium, platinum or nickel. A further suitable reducing agent is, for example, an activated metal such as activated iron (produced by washing iron powder with a dilute solution of an acid such as hydrochloric acid). Thus, for example, the reduction may be carried out by heating a mixture of the nitro compound and the activated metal with concentrated hydrochloric acid in a solvent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example, 50° to 150° C., conveniently at or near 70° C. Another suitable class of reducing agents are the alkali metal dithionites, such as sodium dithionite, which may be used in (C1-C4)alkanoic acids, (C1-C6)alkanols, water or mixtures thereof.
For the production of those compounds of Formula I wherein R2 or R3 incorporates a primary or secondary amino moiety (other than the amino group intended to react with the quinazoline), such free amino group is preferably protected prior to the above described reaction followed by deprotection, subsequent to the above described reaction with 4-(substituted)quinazoline 2.
Several well known nitrogen protecting groups can be used. Such groups include (C1-C6)alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbonyl, O-nitrophenylsulfonyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl. The addition of the nitrogen protecting group may be carried out in a chlorinated hydrocarbon solvent such as methylene chloride or 1,2-dichloroethane, or an ethereal solvent such as glyme, diglyme or THF, in the presence or absence of a tertiary amine base such as triethylamine, diisopropylethylamine or pyridine, preferably triethylamine, at a temperature from about 0° C. to about 50° C., preferably about ambient temperature. Alternatively, the protecting groups are . conveniently attached using Schotten-Baumann conditions.
Subsequent to the above described coupling reaction, of compounds 2 and 5, the protecting group may be removed by deprotecting methods known to those skilled in the art such as treatment with trifluoroacetic acid in methylene chloride for the tert-butoxycarbonyl protected products.
For a description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis” Second Ed., John Wiley & Sons, New York, 1991.
For the production of compounds of Formula I wherein R1 or R2 is hydroxy, cleavage of a Formula I compound wherein R1 or R2 is (C1-C4)alkoxy is preferred.
The cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation. Treatment of the protected formula I derivative with molten pyridine hydrochloride (20-30 eq.) at 150° to 175° C. may be employed for O-dealkylations. Alternatively, the cleavage reaction may be carried out, for example, by treatment of the protected quinazoline derivative with an alkali metal (C1-C4)alkylsulphide, such as sodium ethanethiolate or by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide. The cleavage reaction may also, conveniently, be carried out by treatment of the protected quinazoline derivative with a boron or aluminum trihalide such as boron tribromide. Such reactions are preferably carried out in the presence of a reaction-inert solvent at a suitable temperature.
Compounds of formula I, wherein R1 or R2 is a (C1-C4) alkylsulphinyl or (C1-C4)alkylsulphonyl group are preferably prepared by oxidation of a formula I compound wherein R1 or R2 is a (C1-C4)alkylsulfanyl group. Suitable oxidizing agents are known in the art for the oxidation of sulfanyl to sulphinyl and/or sulphonyl, e.g., hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is generally carried out under as mild conditions as possible using the stoichiometric amount of oxidizing agent in order to reduce the risk of over oxidation and damage to other functional groups. In general, the reaction is carried out in a suitable solvent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature from about −25° to 50° C., preferably at or near ambient temperature, i.e., in the range of 15° to 35° C. When a compound carrying a sulphinyl group is desired a milder oxidizing agents should be used such as sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. The compounds of formula I containing a (C1-C4)alkylsulphonyl group may be obtained by oxidation of the corresponding (C1-C4)alkylsulphinyl compound as well as of the corresponding (C1C4)alkylsulfanyl compound.
Compounds of formula I wherein R1 is optionally substituted (C2-C4)alkanoylamino, ureido, 3-phenylureido, benzamido or sulfonamido can be prepared by acylation or sulfonylation of a corresponding compound wherein R1 is amino. Suitable acylating agents are any agents known in the art for the acylation of amino to acylamino, for example, acyl halides, e.g., a (C2-C4)alkanoyl chloride or bromide or a benzoyl chloride or bromide, alkanoic acid anhydrides or mixed anhydrides (e.g., acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (C1-C4)alkoxycarbonyl halide, for example (C1-C4) alkoxycarbonyl chloride, in the presence of a suitable base. For the production of those compounds of Formula I wherein R1 is ureido or 3-phenylureido, a suitable acylating agent is, for example, a cyanate, e.g., an alkali metal cyanate such as sodium cyanate, or an isocyanate such as phenyl isocyanate. N-sulfonylations may be carried out with suitable sulfonyl halides or sulfonylanhydrides in the presence of a tertiary amine base. In general the acylation or sulfonylation is carried out in a reaction-inert solvent and at a temperature in the range of about −30° to 120° C., conveniently at or near ambient temperature.
Compounds of Formula I wherein R1 is (C1-C4)alkoxy or substituted (C1-C4)alkoxy or R1 is (C1-C4)alkylamino or substituted mono-N- or di-N,N-(C1-C4)alkylamino, are prepared by the alkylation, preferably in the presence of a suitable base, of a corresponding compound wherein R1 is hydroxy or amino, respectively. Suitable alkylating agents include alkyl or substituted alkyl halides, for example, an optionally substituted (C1-C4)alkyl chloride, bromide or iodide, in the presence of a suitable base in a reaction-inert solvent and at a temperature in the range of about 10° to 140° C., conveniently at or near ambient temperature.
For the production of those compounds of Formula I wherein R1 is an amino-, oxy- or cyano-substituted (C1-C4)alkyl substituent, a corresponding compound wherein R1 is a (C1-C4)alkyl substituent bearing a group which is displacable by an amino-, alkoxy-, or cyano group is reacted with an appropriate amine, alcohol or cyanide, preferably in the presence of a suitable base. The reaction is preferably carried out in a reaction-inert solvent or diluent and at a temperature in the range of about 10° to 100° C., preferably at or near ambient temperature.
Compounds of Formula I, wherein R1 is a carboxy substituent or a substituent which includes a carboxy group are prepared by hydrolysis of a corresponding compound wherein R1 is a (C1-C4)alkoxycarbonyl substituent or a substituent which includes a (C1-C4)alkoxycarbonyl group. The hydrolysis may conveniently be performed, for example, under basic conditions, e.g., in the presence of alkali metal hydroxide as illustrated in the accompanying Examples.
Compounds of Formula I wherein R1 is amino, (C1-C4) alkylamino, di-[(C1-C4)alkyl]amino, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-(C1-C4) alkylpiperazin-1-yl or (C1-C4)alkysulfanyl, may be prepared by the reaction, in the presence of a suitable base, of a corresponding compound wherein R1 is an amine or thiol displaceable group with an appropriate amine or thiol. The reaction is preferably carried out in a reaction-inert solvent or diluent and at a temperature in the range of about 10° to 180° C., conveniently in the range 100° to 150° C.
Compounds of Formula I wherein R1 is 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl are prepared by the cyclisation, in the presence of a suitable base, of a corresponding compound wherein R1 is a halo-(C2-C4)alkanoylamino group. The reaction is preferably carried out in a reaction-inert solvent or diluent and at a temperature in the range of about 10° to 100° C., conveniently at or near ambient temperature.
For the production of compounds of Formula I in which R1 is carbamoyl, substituted carbamoyl, alkanoyloxy or substituted alkanoyloxy, the carbamoylation or acylation of a corresponding compound wherein R1 is hydroxy is convenient.
Suitable acylating agents known in the art for acylation of hydroxyaryl moieties to alkanoyloxyaryl groups include, for example, (C2-C4)alkanoyl halides, (C2-C4)alkanoyl anhydrides and mixed anhydrides as described above, and suitable substituted derivatives thereof may be employed, typically in the presence of a suitable base. Alternatively, (C2-C4)alkanoic acids or suitably substituted derivatives thereof may be coupled with a Formula I compound wherein R1 is hydroxy with the aid of a condensing agent such as a carbodiimide. For the production of those compounds of Formula I in which R1 is carbamoyl or substituted carbamoyl, suitable carbamoylating agents are, for example, cyanates or alkyl or arylisocyanates, typically in the presence of a suitable base. Alternatively, suitable intermediates such as the chloroformate or carbonylimidazolyl derivative of a compound of Formula I in which R1 is hydroxy may be generated, for example, by treatment of said derivative with phosgene (or a phosgene equivalent) or carbonyidiimidazole. The resulting intermediate may then be reacted with an appropriate amine or substituted amine to produce the desired carbamoyl derivatives.
Compounds of formula I wherein R1 is aminocarbonyl or a substituted aminocarbonyl can be prepared by the aminolysis of a suitable intermediate in which R1 is carboxy.
The activation and coupling of formula I compounds wherein R1 is carboxy may be performed by a variety of methods known to those skilled in the art. Suitable methods include activation of the carboxyl as an acid halide, azide, symmetric or mixed anhydride, or active ester of appropriate reactivity for coupling with the desired amine. Examples of such types of intermediates and their production and use in couplings with amines may be found extensively in the literature; for example M. Bodansky and A. Bodansky, “The Practice of Peptide Synthesis”, Springer,-Verlag, New York, 1984. The resulting formula I compounds may be isolated and purified by standard methods, such as solvent removal and recrystallization or chromatography.
The starting materials for the above described reaction schemes (e.g., amines, quinazolines and amine protecting groups) are readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, the preparation of 2,3-dihydro-1,4-benzoxazine derivatives are described in R. C. Elderfield, W. H. Todd, S. Gerber, Ch. 12 in “Heterocyclic Compounds”, Vol. 6, R. C. Elderfield ed., John Wiley and Sons, Inc., N.Y., 1957. Substituted 2,3-dihydrobenzothiazinyl compounds are described by R. C. Elderfield and E. E. Harris in Ch. 13 of Volume 6 of the Elderfield “Heterocyclic Compounds” book.
Certain Formula I quinazolines can exist in solvated, as well as unsolvated forms, such as the hydrated forms. It is to be understood that the invention encompasses all such solvated, as well as unsolvated forms, which possess activity against hyperproliferative diseases.
A suitable pharmaceutically-acceptable salt of a compound of formula I is, for example, an acid-addition salt of a corresponding compound which is sufficiently basic, e.g., an acid-addition salt with, for example, an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid. A suitable pharmaceutically-acceptable base-addition salt of a compound of formula I which is acidic is an alkali metal salt, for example, a lithium, sodium or potassium salt; an alkaline earth metal salt, for example, a calcium or magnesium salt; an ammonium salt; or a salt with an organic base which affords a physiologically-acceptable cation for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. All such salts are within the scope of this invention and they can be prepared by conventional methods. For example, they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration; by precipitation with a non-solvent, preferably an etheral or hydrocarbon solvent, followed by filtration and by evaporation of a solvent, or, in the case of aqueous solutions, by lyophilization.
Some of the compounds of Formula I have asymmetric carbon atoms. Such diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se., for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers mixtures and pure enantiomers are considered as part of the invention.
The active compounds of this invention are potent inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases such as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer) in mammals, particularly humans. In particular, the compounds of this invention are therapeutants or prophylactics for the treatment of a variety of human tumors (renal, liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, various head and neck tumors), and other hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., BPH). It is, in addition, expected that a quinazoline of the present invention may possess activity against a range of leukemias and lymphoid malignancies.
The active compounds may also be expected to be useful in the treatment of additional disorders in which aberrant expression ligand/receptor interactions, activation or signalling events related to various protein tyrosine kinases, whose activity is inhibited by the agents of Formula I, are involved.
Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases may be involved. In addition, compounds of Formula I may have therapeutic utility in inflammatory, angiogenic and immunologic disorders involving both identified and as yet unidentified tyrosine kinases which are inhibited by compounds of Formula I.
The in vitro activity of the active compounds in inhibiting the receptor tyrosine kinase (and thus subsequent proliferative response, e.g., cancer) may be determined by the procedure detailed below.
Activity of the active compunds, in vitro, can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., Lys3-Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et. al., J. Biol. Chem. 267 (29), 20638-47 (1992)) on tyrosine by epidermal growth factor receptor kinase by a test compound relative to a control. Affinity purified, soluble human EGF receptor (96 ng) is obtained according to the procedure in G. N. Gill, W. Weber, Methods in Enzymology 146, 82-88 (1987) from A431 cells (American Type Culture Collection, Rockville, Md.) and preincubated in a microfuge tube with EGF (2 μg/ml) in phosphorylation buffer+vanadate (PBV: 50 mM HEPES, pH 7.4; 125 mM NaCl; 24 mM MgCl2; 100 μM sodium orthovanadate), in a total volume of 10 μl, for 20-30 minutes at room temperature. The test compound, dissolved in dimethylsulfoxide (DMSO), is diluted in PBV, and 10 μl is mixed with the EGF receptor /EGF mix, and incubated for 10-30 minutes at 30° C. The phosphorylation reaction is initiated by addition of 20 μl 33P-ATP/substrate mix (120 μM Lys3-Gastrin (sequence in single letter code for amino acids, KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 μM ATP, 2 μCi γ-[33P]-ATP) to the EGFr/EGF mix and incubated for 20 minutes at room temperature. The reaction is stopped by addition of 10 μl stop solution (0.5M EDTA, pH 8; 2mM ATP) and 6 μl 2N HCl. The tubes are centrifuged at 14,000 RPM, 4° C., for 10 minutes. 35 μl of supernatant from each tube is pipetted onto a 2.5 cm circle of Whatman P81 paper, bulk washed four times in 5% acetic acid, 1 liter per wash, and then air dried. This results in the binding of substrate to the paper with loss of free ATP on washing. The [33P] incorporated is measured by liquid scintillation counting. Incorporation in the absence of substrate (e.g., lys3-gastrin) is subtracted from all values as a background and percent inhibition is calculated relative to controls without test compound present.
Such assays, carried out with a range of doses of test compounds, allow the determination of an approximate IC50 value for the in vitro inhibition of EGFR kinase activity. Although the inhibitory properties of the compounds of Formula I vary with structural change as expected, the activity generally exhibited by these agents, determined in the manner described above, is in the range of IC50=0.0001−30 μM.
Activity of the active compounds, in vivo, can be determined by the amount of inhibition of tumor growth by a test compound relative to a control. The tumor growth inhibitory effects of various compounds are measured according to the methods of Corbett T. H., et al. “Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure”, Cancer Res., 35, 2434-2439 (1975) and Corbett, T. H., et al., “A Mouse Colon-tumor Model for Experimental Therapy”, Cancer Chemother. Rep. (Part 2)”, 5, 169-186 (1975), with slight modifications. Tumors are induced in the left flank by s.c. injection of 1×106 log phase cultured tumor cells (human MDA-MB-468 breast or human HN5 head and neck carcinoma cells) suspended in 0.10 ml RPMI 1640. After sufficient time has elapsed for the tumors to become palpable (2-3 mm in diameter) the test animals (athymic mice) are treated with active compound (formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into saline or, alternatively, 1:9 dilution into 0.1% Pluronic® P105 in 0.9% saline) by the intraperitoneal (ip) or oral (po) routes of administration twice daily (i.e., every 12 hours) for 5 consecutive days. In order to determine an anti-tumor effect, the tumor is measured in millimeters with Vernier calipers across two diameters and the tumor size (mg) is calculated using the formula: Tumor weight=(length×[width]2)/2, according to the methods of Geran, R. I., et al. “Protocols for Screening Chemical Agents and Natural Products Against Animal Tumors and Other Biological Systems”, Third Edition, Cancer Chemother. Rep., 3, 1-104 (1972). Results are expressed as percent inhibition, according to the formula: Inhibition (%)=(TuWcontrol−TuWtest)/TUWcontrol×100%. The flank site of tumor implantation provides reproducible dose/response effects for a variety of chemotherapeutic agents, and the method of measurement (tumor diameter) is a reliable method for assessing tumor growth rates.
Administration of the active compounds can be effected by any method which enables delivery of the compounds to the site of action (e.g., cancer cells). These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, etc.
The amount of active compound administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physician. However an effective dosage is in the range of approximately 0.001-100 mg/kg, preferably 1 to 35 mg/kg in single or divided doses. For an average 70 kg human, this would amount to 0.05 to 7 g/day, preferably 0.2 to 2.5 g/day.
The composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Pharmaceutical compositions according to the invention may contain 0.1%-95% of the compound, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of active compound in an amount effective to alleviate or reduce the signs in the subject being treated, i.e., hyperproliferative diseases, over the course of the treatment.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences., Mack Publishing Company, Easter, Pa., 15th Edition (1975).
The hyperproliferative disease treatment described above may be applied as a sole therapy or may involve, in addition to the active compound, one or more other antitumor substances. Such conjoint treatment may be achieved by way of the simultaneous, sequential, cyclic or separate dosing of the individual components of the treatment.
High pressure liquid chromatography (HPLC) used in the following examples and preparations was effected according to the following method unless modified in specific examples. Perkin-Elmer Pecosphere® 3×3C cartridge column (3mm×3cm, C18; available from Perkin Elmer Corp., Norwalk, Conn. 06859) with a Brownlee (trademark) RP-8Newguard precolumn (7 micron, 3.2 mm×15 mm, available from Applied Biosystems Inc. San Jose, Calif. 95134) which was previously equilibrated in pH 4.50, 200 mM ammonium acetate buffer. Samples were eluted using a linear gradient of 0-100% acetonitrile/pH4.50, 200 mM NH4 acetate over 10 minutes with a flow rate of 3.0 mL/min. Chromatograms were generated over the range 240-400 nm using a diode array detector.
It should be understood that the invention is not limited to the particular embodiments shown and described herein, but that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the claims.
EXAMPLE 1 (4-Azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine Hydrochloride
4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 4-azidoaniline hydrochloride (200 mg, 1.11 mmol) were refluxed in 10 mL of isopropyl alcohol for 0.5 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 392 mg (98%); mp 200°-205° C. (dec).
EXAMPLE 2 (6,7-Dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine Hydrochloride
4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.12 mmol) and 3-ethynyl-aniline (137 mg, 1.17 mmol) were refluxed in 10 mL of isopropyl alcohol for 0.5 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 338 mg (99%); mp 269°-270° C.
EXAMPLE 3 (6,7-Dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine
A mixture of (3′-bromophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine hydrochloride (250 mg, 0.591 mmol), tetrakis(triphenylphosphine)palladium (100 mg), propargyl alcohol (600 μL), 7 mL of dry, nitrogen purged diethylamine and cuprous iodide (10 mg) was refluxed for 5 hours, cooled and filtered to afford solid title product which was washed two times with 2 mL of 50% diethylamine:methanol; 136 mg. The solid was recrystallized from methanol to give pure title product after drying, in vacuo,, at 70° C., 73 mg (37%); mp 267°-268° C.
EXAMPLE 4 [(3-(2′-Aminomethyl-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine Hydrochloride
The title product of Example 3 (50 mg, 0.149 mmol), triphenylphosphine (60 mg, 0.225 mmol)), phthalimide (165 mg, 1.12 mmol) and diethyl azodicarboxylate (36 μL, 0.228 mmol) were stirred at room temperature in 3 mL of dry tetrahydrofuran for 16 hours. The reaction mixture was concentrated to a solid and flash chromatographed on silica gel eluted with 15% acetone:methylene chloride to afford pure solid [3-(2′-{phthalimidomethyl}-ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine which was converted to its hydrochloride salt by addition of 1 mL of anhydrous 1M HCl in methanol followed by 3 mL of isopropyl alcohol. The salt was collected by filtration, dried and used immediately in the next step; 15 mg. This 15 mg, 0.0323 mmol was treated with 0.5 ml of hydrazine hydrate and 1 mL of methanol for 0.5 hours. The reaction mixture was evaporated, in vacuo, and the product isolated by flash chromatography eluted with 10% methanol in methylene chloride. Pure title product was isolated after conversion to its hydrochloride salt with 1 mL of 1M HCl in methanol, precipitation with isopropyl alcohol and diethyl ether and drying, in vacuo,; 5.6 mg (47%) mp 275° C. dec.
EXAMPLE 5 (3-Ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine Hydrochloride
4-Chloro-6-nitroquinazoline (1.06 g,5.00 mmol) and 3-ethynylaniline (1.00 g,5.30 mmol) were refluxed in 10 mL of isopropyl alcohol for 3 hours, cooled and, after 16 hours at room temperature, filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo, at 70° C., 1.27 g (78%); mp 255°-256° C.
EXAMPLE 6 (6,7-Dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine
The title product was prepared in the following three step sequence without purification of the intermediates. 4-Chloro-6,7-dimethoxyquinazoline (250 mg, 1.113 mmol) and 4-iodoaniline (268 mg, 1.224 mmol) were refluxed in 10 mL of isopropyl alcohol for 3 hours, cooled to room temperature and filtered to afford solid (4-iodophenyl)-(6,7-dimethoxyquinazoline-4-yl)amine hydrochloride which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 396 mg (76%). A mixture consisting of (4′-iodophenyl)-(6,7-dimethoxyquinazoline-4-yl)amine hydrochloride (250 mg, 0.564 mmol), tetrakis (triphenylphosphine)palladium (50 mg), trimethylsilylacetylene (160 μL, 1.13 mmol), 4 mL of dry, nitrogen purged diethylamine and cuprous iodide (10 mg) was refluxed for 2 hours, cooled and concentrated in vacuo, to afford a residue which was partitioned between chloroform and 1N HCL. Solid [4-(2′-{trimethylsilyl}-ethynyl) phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine formed at the interface of the two liquid phases and was filtered and dried in vacuo; 170 mg (80%).
[4-(2′-{Trimethylsilyl}ethynyl)phenyl]-(6,7-dimethoxyquinazoline-4-yl)amine (100 mg, 0.265 mmol) and anhydrous potassium carbonate (125 mg, 0.906 mmol) were stirred in 3 mL of methanol and 1 mL of water at room temperature for 2.5 hours. The reaction mixture was concentrated in vacuo, and partitioned between 20 mL of chloroform and 20 mL of 1N hydrochloric acid. The organic layer was dried with magnesium sulfate, filtered and vacuum evaporated to give the title product which was triturated with diethyl ether and dried in vacuo at 70° C.; 81 mg (90%) mp 239° C. dec.
EXAMPLE 7 (6,7-Dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine
The title product was prepared in the following three step sequence with out purification of the intermediates. A mixture consisting of 3-bromo-2-methylaniline (1.00 g, 5.37 mmol), tetrakis(triphenylphosphine)palladium (200 mg), trimethylsilylacetylene (1.053 g, 10.75 mmol), 10 mL of dry, nitrogen purged diethylamine and cuprous iodide 910 mg) was refluxed for 16 hours, cooled and concentrated, in vacuo, to afford a residue which was partitioned between chloroform and 1N HCL. The organic layer was washed with brine, dried with magnesium sulfate and vacuum evaporated to yield a residue, 3-[2′-(trimethylsilyl)ethynyl]-2-methylaniline which was purified by flash chromatography on silica gel eluted with 1:1 hexanes:methylene chloride; 200 mg (18%).
4-Chloro-6,7-dimethoxyquinazoline (104 mg, 0.466 mmol) and 3-[2′-(trimethylsilyl)ethinyl]-2-methylaniline (100 mg, 0.491 mmol) were refluxed in 3 mL of isopropyl alcohol for 16 hour, cooled to room temperature and filtered to afford a residue of solid {3-[2′-(trimethylsilyl)ethynyl]-2′-methylphenyl|}-(6,7dimethoxyquinazoline -4-yl)amine hydrochloride which was washed with 10 mL of isopropyl alcohol and triturated for 16 hours with diethyl ether. Thin layer chromatography on silica gel eluted with 9:1 chloroform:methanol indicated that the residue was impure product. The residue was purified by flash chromatography on silica gel eluted with 9:1 methylene chloride:methanol to afford after concentration and drying, in vacuo, pure product, 64 mg (33%). The product was dissolved in 3 mL of methanol and treated with 64 mg of anhydrous potassium carbonate at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and partitioned between 1N HCl and chloroform. Solid title product formed at the interface of the two liquid phases and was filtered and dried, in vacuo; 40 mg (84%) mp 225° C. dec.
EXAMPLE 8 (6-Amino-quinazolin-4-yl)-(3-ethynylphenyl)-amine
(3-Ethynyl-phenyl)-(6-nitro-quinazolin-4-yl)-amine hydrochloride (500 mg, 1.50 mmol) was dissolved in 10 mL of formic acid and treated portion-wise with sodium dithionite (1.10 g, 6.28 mmol) at room temperature. After 2 hours the mixture was quenched with 120 mL of water and filtered. The filtrate was evaporated in vacuo to a residue which was dissolved in 100 mL of 1:1 methanol:chloroform, filtered and evaporated in vacuo to a second residue. This was triturated with 200 mL of 5% sodium bicarbonate for 30 minutes, filtered, washed with water and dried in vacuo for 16 hours. Flash chromatography on silica gel eluted with ethyl acetate afforded pure (6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; 140 mg (34%); mp 165° C. dec.
EXAMPLE 9 (3-Ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl}-amine
The title product of Example 8 (100 mg, 0.384 mmol), pyridine (140 μL, 1.68 mmol) and methanesulfonyl chloride (99 μL, 1.26 mmol) were refluxed in 10 mL of 1,2-dichloroethane for 7 hours. The reaction mixture was cooled and evaporated in a vacuo to a residue which was triturated in 10 mL of 1N HCl, filtered and dried in vacuo to yield (3-ethynylphenyl)-(6-methanesulfonylaminoquinazoline-4-yl)amine; 102 mg (78%) mp 248° C. dec.
EXAMPLE 10 (3-Ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine Hydrochloride
4-Chloro-6,7-methylenedioxyquinazoline (200 mg, 1.04 mmol) and 3-ethynylaniline (127 mg, 1.09 mmol) were refluxed in 5 mL of isopropyl alcohol for 16 hour, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 266 mg (79%); mp >350° C.
EXAMPLE 11 ((6,7-Dimethoxyquinazolin-4-yl)-3-ethynyl-6-methylphenyl)-amine Hydrochloride
The title product was prepared in the following three step sequence without purification of the intermediates. A mixture consisting of 4-bromo-2-nitrotoluene (1.50 g, 6.94 mmol) tetrakis(triphenylphosphine)palladium (750 mg), trimethylsilylacetylene (3.00 mL, 21.21 mmol) and cuprous iodide (20 mg) in 20 mL of nitrogen purged, dry diethylamine was refluxed for 2 hours, cooled and concentrated, in vacuo, to afford a residue which was partitioned between 100 mL of ethyl acetate and 100 mL of 1N HCl. The organic layer was washed two times with 50 mL of 1N HCl followed by brine, dried with magnesium sulfate and vacuum evaporated to a residue. The residue was dissolved in 10 mL of ethyl acetate and diluted with 200 mL of petroleum ether. The solids were filtered off and the oil, obtained upon vacuum evaporation of the filtrate, solidified to give 4-[2′-(trimethylsilyl)ethinyl]-2-nitrotoluene. This product was reduced to the amino product by treatment with iron powder (1.76 g, 98.5 mmol) in 30 mL of methanol and 5 mL of concentrated hydrochloric acid at 80° C. for 2 hours. The cooled reaction mixture was filtered through Celite® and the filtrate was evaporated in vacuum. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered and vacuum evaporated to yield an oil, 5-[2′-(trimethylsilyl)ethynyl)-2-methylaniline which solidified upon standing: 1.37 g.
The above product (185 mg, 0.909 mmol) and 4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.890 mmol) were refluxed in tert-butyl alcohol for 16 hours. After cooling the reaction mixture was filtered to yield pure [2-methyl-5-(2′-{trimethylsilyl}-ethynyl)-phenyl]-(6,7-dimethoxyquinazoline-4-yl-amine hydrochloride after washing with ether and drying in vacuum; 326 mg (85%). The trimethylsilyl group was removed by dissolving the above product in 5 mL of methanol and 1 mL of water and treatment with potassium carbonate (320 mg). After stirring for 1 hour the mixture was filtered and concentrated in vacuo. The residue thus obtained was partitioned between 100 mL of methylene chloride and 100 mL of 1N HCl. The aqueous layer was extracted with an additional 100 mL of methylene chloride. The pooled organic layers were dried with magnesium sulfate, filtered and vacuum evaporated to a residue which was dissolved in anhydrous 1N HCl in methanol, concentrated and precipitated with ether. The solid title product was collected by filtration and washed with diethyl ether then dried in vacuo at 70° C.; 236 mg (88%) mp 266°-267° C.
EXAMPLE 12 (3-Ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine Hydrochloride
4-Chloro-7-nitroquinazoline (7.97 g, 38.0 mmol) and 3-ethynylaniline (4.54 g, 38.8 mmol) were refluxed in 125 mL of tert-butyl alcohol for 3 hours, cooled to room temperature and filtered to afford the title product as a solid which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 9.95 g (80%); mp 209°-210° C. dec.
EXAMPLE 13 (3-Ethynylphenyl)-[6-(4′-toluenesulfonylamino)-quinazolin-4-yl]-amine Hydrochloride
The title product of example 8 (0.201 mg, 0.774 mmol) and 4-toluenesulfonyl chloride (0.441 mg, 2.31 mmol) were refluxed in 3 mL of 1,2-dichloroethane and 0.5 mL of pyridine for 5 minutes. The reaction mixture was cooled to room temperature, diluted with 75 mL of ethyl acetate and washed two times with 75 mL of water once with 75 mL of 3% sodium bicarbonate and once with 75 mL of brine. The organic layer was dried with magnesium sulfate, filtered and vacuum evaporated to a residue which was purified by chromatography using a Chromatotron (trademark) eluted with ethyl acetate, to afford solid title product; 86.7 mg (27%) mp 220°-222° C.
EXAMPLE 14 (3-Ethynylphenyl)-{6-[2′-phthalimido-ethan-1′-ylsulfonylamino]quinazolin-4-yl}-amine Hydrochloride
The title product of example 8 (0.20 mg, 0.768 mmol) and 2-phthalimido-1-ethanesulfonyl chloride (0.615 mg, 2.25 mmol) were refluxed in 2 mL of 1,2-dichloroethane and 0.5 mL of pyridine for 16 hours, cooled to room temperature, diluted with 100 mL of chloroform and washed with 50 mL of 3% sodium bicarbonate and 50 mL of brine. The organic layer was dried with magnesium sulfate, filtered and vacuum evaporated to a residue which was dissolved in minimal methylene chloride and precipitated with petroleum ether, 188 mg. The precipitate was purified by chromatography using Chromatotron@ eluted with ethyl acetate, to afford the title product as a solid; 53.4 mg (14%) mp 197°-200° C.
EXAMPLE 15 (3-Ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine Hydrochloride
The title product of example 8, (0.302 mg, 1.16 mmol) and 3,5-dimethylpyrazole-1-carboxamidine (0.328 mg, 2.36 mmol) were refluxed in 10 mL of 1,2-dichloroethane and 0.97 mL of acetic acid for 24 hours, cooled to room temperature and filtered to yield the crude acetate of the title product. The product was dissolved in 35 mL of methanol and treated with 15 mL of anhydrous 1N HCl in methanol for 15 minutes and then precipitated with 75 mL of diethyl ether. Solid title product was collected by filtration and dried in vacuo at 70° C.; 91.2 mg (23%) mp>400° C.
EXAMPLE 16 (7-Aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine
The title product of example 12 (1.039 g, 3.18 mmol) was dissolved in 50 mL of tetrahydrofuran, 10 mL of methanol and 5 mL of chloroform at 50° C. Sodium dihydrogen phosphite (NaH2PO2, 3.822 g, 36 mmol) and 10% palladium on carbon (0.19 g) were added followed by dropwise addition of 10 mL of water. When 3 mL of water had been added the mixture became noticeably more homogeneous. After 1 hour the mixture was filtered through Celite. The Celite was washed thoroughly with methanol and chloroform. The combined organic solutions were vacuum evaporated to a residue which was triturated with water, 3% aqueous sodium bicarbonate and filtered. The solid title product was washed with water then diethyl ether and dried in vacuo, 1.054 gm (127%, wet). A portion of the above product was recrystallized from a minimum amount of hot ethanol and water to give, after removal of a small first crop of impure material, pure title product, (43%), mp 180° C. (dec).
EXAMPLE 17 (3-Ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine Hydrochloride
4-Chloro-7-methoxyquinazoline (274 mg, 3.72 mmol) and 3-ethynylaniline (436 mg, 3.72 mmol) were refluxed in 15 mL of tert-butyl alcohol for 3 hours, cooled and filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 977 mg (84%); mp 229°-231° C.
EXAMPLE 18 (6-Carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine Hydrochloride
4-Chloro-6-carbomethoxyquinazoline (100 mg, 0.450 mmol) and 3-ethynylaniline hydrochloride (53.4 mg, 0.456 mmol) were refluxed in 2 mL of tert-butyl alcohol for 2 hours, cooled, diluted with 2 mL of isopropyl alcohol and filtered to afford solid title product which was washed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 122 mg (80%); mp 232°-233° C. (dec).
EXAMPLE 19 (7-Carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine Hydrochloride
4-Chloro-7-carbomethoxyquinazoline (202 mg, 0.907 mmol) and 3-ethynylaniline (110 mg, 0.939 mmol) were refluxed in 4 mL of tert-butyl alcohol for 2 hours, cooled, diluted with 4 mL of isopropyl alcohol and filtered to afford solid title product which was washed with 10 mL of diethyl ether and dried, in vacuo, at 70° C., 248 mg (80%); mp 219.5°-221° C.
EXAMPLE 20 [6-,7-Bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine Hydrochloride
3-Ethynylaniline (37 mg, 0.32 mmol.), and 4-chloro-6,7-bis-(2-methoxy-ethoxy)quinazoline (90 mg, 0.29 mmol) were added to isopropanol (1.5 mL) containing pyridine (25 μL, 0.32 mmol) and the mixture was refluxed 4 hours under an atomospher of dry nitrogen. The solvent was removed, in vacuo, and the residue partitioned between 10% methanol in CHCl3 and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone in hexanes to afford 81 mg of the free base of the title product as a pale yellow solid. The free-base was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether, and titrated with 1M HCl in ether to precipitate the title product as its hydrochloride salt; 90 mg; 71%; mp 228°-230° C.
EXAMPLE 21 (3-Azidophenyl)-(6,7-dimethoxyquinazolin-4-yl) amine
4-Chloro-6,7-dimethoxyquinazoline (5.01 g, 22.3 mmol) was added in portions, over 1.5 hours, to m-phenylenediamine (2.66 g, 24.6 mmol) in refluxing isopropanol (100 mL) under an atmosphere of dry nitrogen. After the addition was complete the mixture was heated at reflux for 4 hours. The mixture was cooled to 20° C., and the precipitate was filtered, washed with chilled isopropanol and dried in vacuo to afford 6.97 g (93%) of (3-aminophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine hydrochloride (LC-MS: 297 (MH+). To a solution of the above product (50 mg, 0.169 mmol) in 80% acetic acid/H2O (2 mL), at 0° C., was added a solution of NaNO2 (18.4 mg, 0.186 mmol) in H2O (100 μL). After stirring 10 minutes at 0° C. a solution of NaN3 (12 mg, 0.185 mmol) in H2O (100 μL) was added. The mixture was allowed to warm to 20° C. and stirred for 1.5 hours. The reaction mixture was lyophilized and the residue partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic phase was wahsed further with brine, dried over Na2SO4, filtered, and concentrated, in vacuo. Recrystallization from CHCl3/hexanes afforded 36 mg of the title product as a white solid; mp 110°-113° C.
EXAMPLE 22 (3-Azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine
4-Chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) and 5-amino-3-chloroaniline (253 mg, 1.78 mmol) were combined in isopropanol (3 mL) and heated to reflux for 16 hours under an atmosphere of dry nitrogen. After cooling to 20° C. the mixture was diluted with methanol (5 mL) and the resulting precipitate was filtered and dried, in vacuo, to afford 252 mg (77%) of (3-amino-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)amine hydrochloride (mp. 298°-301° C.; LC-MS: 331 (MH+)). A portion of this product (175 mg, 0.476 mmol) was dissolved in 80% acetic acid/H2O (12 mL), cooled to 0° C., and a solution of NaNO2 (36 mg, 0.516 mmol) in H2O (300 μL) was added. The solution was stirred for 10 minutes at 0° C. and NaN3 (33 mg, 0.50 mmol) in H2O (300 μL) was added. The reaction mixture was allowed to warm to 20° C. and stirred 16 hours. The resulting precipitate was filtered and dissolved in 10% methanol in CHCl3 and the solution was washed with saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo to yield 59 mg (35%) of the title product as a yellow solid; mp 205°-206° C.
EXAMPLE 23 (3-Ethynylphenyl)-(6-methanesulfonyl-quinazolin-4-yl-amine Hydrochloride
6-Methanesulfonyl-quinazolin-4-one (200 mg, 0.89 mmol), triphenyl phosphine (566 mg, 2.15 mmol) and carbon tetrachloride (815 μL, 8.92 mmol) were refluxed in 3 mL of chloroform for 3.5 hours. The solvent was vacuum evaporated to afford a residue. This was dissolved in 5 mL of isopropyl alcohol and 3-ethynylaniline (156 mg, 1.33 mmol) and heated at reflux for 16 hours. The cooled reaction mixture was filtered, washed with a minimum of cold isopropyl alcohol and dried in vacuo at 70° C. for 16 hours to afford pure title product; 63 mg (20%) mp 281°-282° C.
EXAMPLE 24 (6-Ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine Hydrochloride
6-Ethanesulfanyl-quinazolin-4-one (100 mg, 0.48 mmol), triphenyl phosphine (305 mg, 1.16 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours. The solvent was vacuum evaporated to afford a residue. This was dissolved in 5 mL of isopropyl alcohol and 3-ethynylaniline (68 mg, 0.58 mmol) and heated at reflux for 1 hour. The cooled reaction mixture was filtered, washed with a minimum of cold isopropyl alcohol and dried in vacuo at 70° C. for 16 hours to afford pure title product; 70 mg (42%) mp 239°-40° C.
EXAMPLE 25 (6,7-Dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine Hydrochloride
4-Chloro-6,7-dimethoxyquinazoline (500 mg, 2.23 mmol) and 3-(2′-trimethylsilylethynyl)-4-fluoroaniline (507 mg, 2.44 mmol) were refluxed in 5 mL of tert-butyl alcohol for 16 hours, cooled and filtered to afford solid (6,7-dimethoxy-quinazolin-4-yl)-(3′-ethynyl-phenyl)-amine hydrochloride which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 832 mg (83%). This was reacted in 10 mL of methanol and 1 drop of water containing 250 mg of potassium carbonate for 3 hours. The mixture was filtered and the filtrate vacuum evaoprated. This residue was triturated for 1 hour with 1N hydrochloric acid, filtered and washed with a minimum amount of water then methanol and dried in vacuo; 506 mg (63%) mp 229° C. dec.
3-(2′-Trimethylsilyl-ethynyl)-4-fluoroaniline, used above, was prepared from 3-bromo-4-fluoroaniline (7.0 gm, 36.8 mmol) tetrakis(triphenylphosphine)palladium (1.4 gm), trimethylsilyl-acetylene (7.2 gm, 74 mmol) and cuprous iodide (40 mg) in 140 mL of nitrogen purged dry diethylamine at reflux for 16 hours. The cooled reaction mixture was filtered through Celite and the Celite washed with ether. The combined filtrates were vacuum evaporated to a residue which was purified by flash chromatography on silica gel eluted with 35% hexanes in methylene chloride. Fractions containing the pure 3-(2′-trimethylsilyl-ethynyl)-4-fluoroaniline were vacuum evaporated to a residue and used without further purification.
EXAMPLE 26 (6,7-Dimethoxy-quinazolin-4-yl)-(3-propyn-1-yl)phenyl)-amine Hydrochloride
4-Chloro-6,7-dimethoxyquinazoline (585 mg, 2.60 mmol) and 3-(propyn-1-yl)aniline (361 mg, 2.74 mmol) were refluxed in 5 mL of tert-butyl alcohol for 16 hours, cooled and filtered to afford solid (6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1-yl)phenyl)]-amine hydrochloride which was washed with 5 mL of isopropyl alcohol and 25 mL of ether then dried in vacuo at 70° C., 869 mg (94%); mp 260°-261° C.
3-(Propyn-1-yl)aniline, used above, was prepared from 3-bromo-nitrobenzene in four steps. 3-Bromo-nitrobenzene (5.0 gm, 24.7 mmol), tetrakis(triphenylphosphine)palladium (1.0 gm), trimethylsilyl-acetylene (3.6 gm, 37 mmol) and cuprous iodide (20 mg) in 20 mL of nitrogen purged, dry diethylamine at reflux for 16 hours. The cooled reaction mixture was vacuum evaporated, diluted with 50 mL of methylene chloride and 50 mL of 1N hydrochloric acid and filtered. The organic layer was collected and dried with magnesium sulfate filtered and vacuum evaporated to a residue. The 3-trimethylsilylethynylnitrobenzene was purified by flash chromatography on silica gel eluted with 2:1 hexanes:methylene chloride. Fractions containing the pure material were vacuum evaporated to afford pure 3-trimethylsilylethynyl nitrobenzene (4.6 gm). 4.0 gm of this were dissolved in 30 mL of methanol and 1 drop of water containing 1.16 gm of potassium carbonate. After one hour the mixture was vacuum evaporated and diluted with 100 mL of methylene chloride. The organic layer was washed with 100 mL of 1N hydrochloric acid, dried with magnesium sulfate, filtered and vacuum evaporated to a residue (2.96 gm). 790 mg of this was dissolved in 10 mL of benzene and treated with finely pulverized 87% potassium hydroxide (377 mg, 5.91 mmol), methyl iodide (2 mL) and 10 mg of 18-Crown-6 (Aldrich) at reflux for 16 hours. An additional 0.5 mL of methyl iodide were added and the reflux continued for an additional 2 hours. The cooled reaction mixture was vacuum evaporated to a residue which was diluted with 100 mL of methylene chloride and washed with 100 mL of 1N hydrochloric acid, dried with magnesium sulfate, filtered and vacuum evaporated to an oil. This was purified by flash chromatography on silica gel eluted with 1:1 hexanes:methylene chloride. Fractions containing pure 3-(propyn-1-yl)-nitrobenzene were vacuum evaporated to an oil which was used without further purification; 530 mg (61%). 3-(Propyn-1-yl)-nitrobenzene (530 mg, 3.3 mmol), iron powder (400 mg, 7.27 mmol), 3 mL of concentrated hydrochloric acid and 10 mL of methanol were refluxed for 1 hour. The reaction mixture was filtered and vacuum evaporated to a solid which was partitioned between 100 mL of methylene chloride and 100 mL of 1N sodium hydroxide. The two phases were filtered and then the organic phase was separated, dried with magnesium sulfate, filtered and vacuum evaporated to an oil which was used directly in the preparation of the title product; 321 mg (78%).
EXAMPLE 27 [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine Hydrochloride
4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (140 mg, 0.446 mmol) and 3-ethynyl-4-fluoroaniline (66 mg, 0.452 mmol) were reacted in refluxing isopropanol (3 mL) under an atmosphere of N2 for 16 hours. The solvent was removed in vacuo and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 116 mg of the pure title product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether and titrated with 1M HCl in ether to precipitate the title product as a white solid (99 mg; 50%; M.P. 170°-190° C. (dec); LC-MS: 412 (MH+); anal. RP18-HPLC RT: 4.33 min.).
EXAMPLE 28 [6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine Hydrochloride
4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (153 mg, 0.49 mmol), pyridine (40 μL) and 3-ethynyl-6-methylaniline (71 mg, 0.54 mmol) were reacted in DMF (3 mL) at 110° C. under an atmosphere of N2 for 36 hours. The solvent was removed in vacuo and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 40% acetone/CH2Cl2 to provide 40 mg (19%) of pure product as its free base. This oil was dissolved in a minimum volume of CHCl3, diluted with several volumes of ether, and triturated with 1M HCl in ether to precipitate the title product as a white solid (M.P. 170°-185° C. (dec); LC-MS: 408 (MH+); anal. RP18-HPLC RT: 3.93 min.).
EXAMPLE 29 [6,7-Bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine Hydrochloride
4-Chloro-6,7-bis-(2-chloro-ethoxy)-quinazoline (600 mg, 1.87 mmol) and 3-ethynyl-aniline (219 mg, 1.87 mmol) were reacted in refluxing isopropanol (15 mL) under an atmosphere of N2 for 2.5 hours. The mixture was cooled to 20° C. and the precipitated product was filtered, washed With isopropanol and ether and dried in vacuo. (707 mg; 86%; M.P. 230°-240° C. (dec); LC-MS: 402 (MH+); anal. RP18-HPLC RT: 5.35 min.).
EXAMPLE 30 [6-(2-Chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine Hydrochloride
The title product was prepared from 4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxyethoxy)-quinazoline (399 mg, 1.26 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (515 mg; 94%; M.P. 215°-225° C. (dec); LC-MS: 398 (MH+); anal. RP18-HPLC RT: 4.85 min.).
EXAMPLE 31 6,7-Bis(2-acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-quinazoline
The title product of Example 29 (200 mg, 0.456 mmol) was treated with cesuim acetate (1.75 g, 9.12 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford an oil (277 mg) which was recrystallized from CH2Cl2/hexane. (184 mg; 90%; M.P. 137°-138° C.; LC-MS: 450 (MH+); anal. RP18-HPLC RT: 4.64 min.).
EXAMPLE 32 2-[4-(3-Ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol Hydrochloride
6,7-Bis-(2-acetoxy-ethoxy)-4-(3-ethynyl-phenyl-amino)-quinazoline (199 mg, 0.443 mmol) in methanol (3 mL) was treated with 7M aqueous KOH (0.25 mL). The mixture was stirred at 20° C. for 2 hours before removing the solvent in vacuo. The solid residue was washed with water to remove salts, and dried azeotropically by dissolution two times in acetonitrile and concentration in vacuo to afford 116 mg of title product as its free base. This material was converted to its HCl salt according to the method used in Example 28 (115 mg; 65%; M.P.215°-218° C. (dec); LC-MS: 366 (MH+); anal. RP18-HPLC RT: 3.08 min.).
EXAMPLE 33 6-(2-Acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazoline
The title product of Example 30 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a residue (285 mg) which was recrystallized from ethylacetate/hexane. (134 mg; M.P. 84°-87° C.; LC-MS: 422 (MH+); anal. RP18-HPLC RT: 4.38 min.).
EXAMPLE 34 [7-(2-Chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine Hydrochloride
This product was prepared from 4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline (600 mg, 1.89 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (737 mg; 90%; M.P. 225°-235° C. (dec); LC-MS: 398 (MH+); anal. RP18-HPLC RT: 4.89 min.).
EXAMPLE 35 7-(2-Acetoxy-ethoxy)-4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazoline
The title product of Example 34 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a residue (288 mg) which was recrystallized from ethyl acetate/hexanes. (134 mg; M.P.134°-135° C.; LC-MS: 422 (MH+); anal. RP18-HPLC RT: 4.43 min.).
EXAMPLE 36 2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yl-oxy]-ethanol Hydrochloride
The title product of Example 35 (149 mg, 0.354 mmol) in methanol (3 mL) was treated with 5M aqueous KOH (0.25 mL). The mixture was stirred at 20° C. for 30 minutes before removing the solvent in vacuo. The solid residue was washed with water to remove salts, and dried azeotropically by dissolution two times in acetonitrile and concentration in vacuo to afford 100 mg of title product as its free base. This material was converted to its HCl salt according to the method used in Example 28 (87 mg; 59%; M.P. 230°-235° C. (dec); LC-MS: 380 (MH+); anal. RP18-HPLC RT: 3.42 min.).
EXAMPLE 37 (3-Ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine Dihydrochloride
The title product of Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with N-methyl-piperazine (281 μL, 2.53 mmol) at 110° C. for 16 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was chromatographed on silica using 15% methanol/CH2Cl2 to provide 56 mg of pure product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (65 mg; 48%; M.P. 130°-142° C. (dec); LC-MS: 462 (MH+); anal. RP18-HPLC RT: 3.69 min.).
EXAMPLE 38 (3-Ethynyl-phenyl)-[7-(2-imidazol-1-yl-ethoxy)-6-(2-methoxy-ethoxy)quinazolin-4-yl]-amine Dihydrochloride
The title product from Example 34 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (119 mg) was chromatographed on silica using 10% methanol/CH2Cl2 to provide 85 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (95 mg; 75%; M.P. 220°-227° C. (dec); LC-MS: 430 (MH+); anal. RP18-HPLC RT: 3.75 min.).
EXAMPLE 39 (3-Ethynyl-phenyl)-[6-(2-imidazol-1-yl-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-amine Dihydrochloride
The title product of Example 30 (110 mg, 0.253 mmol) in DMF (2 mL) was treated with imidazole (172 mg, 2.53 mmol) at 110° C. for 48 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (125 mg) was chromatographed on silica using 10% methanol/CH2Cl2 to provide 86 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid dihydrochloride salt (95 mg; 78%; M.P. 85°-100° C. (dec); LC-MS: 430 (MH+); anal. RP18-HPLC RT: 4.13 min.).
EXAMPLE 40 (3-Ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl-ethoxy)-quinazolin-4-yl]-amine Dihydrochloride
The title product from Example 30 (107 mg, 0.245 mmol) in DMF (2 mL) was treated with morpholine (214 μL, 2.45 mmol) at 80° C. for 24 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (168 mg) was chromatographed on silica using 7.5% methanol/CH2Cl2 to provide 65 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (88 mg; 59%; M.P. 115°-130° C. (dec); LC-MS: 449 (MH+); anal. RP18-HPLC RT: 4.00 min.).
EXAMPLE 41 2-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol Hydrochloride
The title product from Example 33 (149 mg, 0.354 mmol) in methanol (3 mL) was treated with 5M aqueous KOH (0.25 mL). The mixture was stirred at 20° C. for 30 minutes before removing the solvent in vacuo. The solid residue was washed with water to remove salts, and dried azeotropically by dissolution two times in acetonitrile and concentration in vacuo to afford 95 mg of title product as its free base. This material was converted to its HCl salt according to the method used in Example 28 (89 mg; 61%; M.P. 190°-215° C. (dec); LC-MS: 380 (MH+); anal. RP18-HPLC RT: 3.66 min.).
EXAMPLE 42 (6,7-Diethoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
6,7-Diethoxyquinazolin-4-one (120 mg, 0.512 mmol), triphenylphosphine (295 mg, 1.126 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours. The reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (66 mg, 0.563 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford solid title product which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 140 mg (75%); mp 269°-270° C.
EXAMPLE 43 (6,7-Diethoxy-quinazolin-4-yl)-(3-ethynyl-2-methyl-phenyl)-amine Hydrochloride
4-Chloro-6,7-diethoxyquinazoline (200 mg, 0.792 mmol) and 3-(2′-trimethylsilylethynyl-2-methyl-aniline (168 mg, 0.871 mmol) in 4 mL of tert-butyl alcohol was refluxed for 16 hours. The cooled reaction mixture was diluted with 5 mL of ethyl ether and filtered to afford solid (6,7-diethoxy-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethynyl)-2-methyl-phenyl)-amine hydrochloride which was washed with 10 mL of ethyl ether and dried in vacuo at 70° C. This material was desilated directly by treatment with 2 mL of methanol containing 1 drop of water and 100 mg of potassium carbonate for 0.5 hours. The heterogeneous reaction mixture was filtered through Celite and vacuum evaporated to a residue which was dissolved in excess 1N HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuo at 70° C. to afford the title product; 160 mg (75%); mp 258°-259.5° C.
EXAMPLE 44 (3-Ethynyl-phenyl)-(6-methyl-quinazolin-4-yl)-amine Hydrochloride
6-Methyl-quinazolin-4-one (350 mg, 2.18 mmol) was added to a suspension of polymer-supported triphenylphosphine (from Fluka, 3.63 g of about 3 mmol P/g resin; 10.9 mmol) in a mixture of CCl4 (3.35 g, 21.80 mmol) and 1,2 dichloroethane (10 mL). The mixture was heated to 60° C. for 2 hours and then the polymer was removed by filtration and washed with dichloroethane. The filtrate was collected in a flask containing 3-ethynyl-aniline (0.644 g, 2.18 mmol) and concentrated to 5 mL by evaporation. After 4 hours reflux under N2, followed by cooling to 20° C., the title product was collected by filtration (551 mg; 86%; M.P. 256°-257° C.; LC-MS: 260 (MH+); anal. RP-HPLC RT: 4.41 min).
EXAMPLE 45 2-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethylsulfanyl}-propionic Acid Ammonium Salt
The title product of Example 34 (150 mg, 0.34 mmol) was added to a solution of thiolactic acid (100 μL, 1.14 mmol) and KOH (150 mg, 2.7 mmol) in degassed DMF (5 mL)/H2O (0.5 mL). The reaction mixture was stirred at 50° C. under an atmosphere of N2 for 72 hours and then cooled to room temperature. The pH of the mixture was adjusted to about 4.0 with acetic acid and then partitioned between CHCl3 and brine. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative RP18 HPLC utilizing a gradient of 15% to 100% CH3CN/pH 4.5, 50 mM ammonium acetate followed by lyophilization of the appropriate pure fractions to afford the title product (28 mg; 18%; M.P. 95°-103° C. (dec); LC-MS: 468 (MH+); anal. RP-HPLC RT: 3.57 min).
EXAMPLE 46 {2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethylsulfanyl}-acetic Acid Ammonium Salt
The title product was prepared from the title product of Example34 and mercaptoacetic acid according to the method of Example 45. (3%; LC-MS: 454 (MH+); anal. RP-HPLC RT: 3.37 min).
EXAMPLE 47 4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-ol
This product was isolated as a more lipophilic product (by preparative RP18 HPLC) from the reaction used to generate the title product of Example 46 (5%; LC-MS: 336 (MH+); anal. RP-HPLC RT: 3.60 min).
EXAMPLE 48 (3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy-quinazolin-4-yl]-amine and [6-(2-ethoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethnynl-phenyl)-amine Hydrochloride
The title product of Example 30 (107 mg, 0.245 mmol) was treated with sodium ethoxide (0.582 mmol) in refluxing ethanol (3 mL) for 24 hours. The solvent was removed in vacuo and the product was isolated by flash chromatography on silica using 10% acetone/CH2Cl2 to provide 30 mg of the 6-vinyloxy product (33%; M.P. 113°-114° C.; LC-MS: 362 (MH+); anal. RP-HPLC RT: 4.84 min). The 6-(2-ethoxy-ethoxy) derivative eluted as a more polar product (45 mg) and was converted to its HCl salt according to the procedure described for Example28 (43%; M.P. 220°-225° C. (dec); LC-MS: 408 (MH+); anal. RP-HPLC RT: 4.35 min).
EXAMPLE 49 4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-ol Hydrochloride
(3-Ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-vinyloxy-quinazolin-4-yl]-amine (20 mg; from Example 48) was hydrolyzed by treatment with 6M HCl/methanol (30:70; 3 mL) at 50° C. for 5 days. The solution was concentrated in vacuo, and the residue was partitioned between CHCl3 and brine at a pH of about 7. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title product as its free base (15 mg), which was converted to its HCl salt according to the procedure described for Example 28 (M.P. 135°-150° C. (dec); LC-MS: 336 (MH+); anal. RP-HPLC RT: 3.77 min).
EXAMPLE 50 1-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethyl}-1H-pyridin-4-one Hydrochloride
NaH (30 mg of 60% in mineral oil, 0.77 mmol) was added to anhydrous DMF (2.0 mL) followed by pyrid-4-one (79 mg, 0.83 mmol). The mixture was stirred 40 minutes at 22° C. until all solids dissolved and the evolution of H2 ceased. The title product of Example 34 (120 mg, 0.28 mmol) and tetrabutylammonium iodide (15 mg) were added and the reaction mixture was stirred at 22° C. for 7 days under N2. Additional pyrid-4-one (79 mg) and NaH (30 mg of 60%) were dissolved in DMF (2 mL) and the solution was added to the reaction mixture. After another 4 days stirring the mixture was partitioned between CHCl3 and brine. The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica utilizing 10% methanol/CH2Cl2 to afford 65 mg of the free base of the title product which was converted to the mono-hydrochloride salt according to the procedure described for Example 28 (66 mg; M.P. 240°-248° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.23 min)
EXAMPLE 51 1-{2-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethyl}-1H-pyridin-4-one Hydrochloride
The free base of this product was prepared from the title product of Example 30 and the sodium salt of pyrid-4-one as described for Example 50. The free base was isolated by flash chromatography with 15% methanol/CHCl3 and converted to the title product according to the procedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.45 min).
EXAMPLE 52 (3-Ethynyl-phenyl)-(6-methoxy-quinazolin-4-yl)-amine Hydrochloride
A 25 mM solution of 6-methoxy-3H-quinazolin-4-one in 1,2-dichloroethane was added to polymer-supported triphenylphosphine (from Fluka, about 3 mmol P/g polymer; 2.5 mol equiv) and carbon tetrachloride (100 mole equiv). The reaction mixture was heated, with shaking, at 60° C. for 21 hours, cooled to 22° C., and a 30 mM solution of the 3-ethynylaniline (1.5 mole equiv) in t-butanol was added. The resulting mixture was then heated, with shaking, at 60° C. for 18 hours followed by cooling to 22° C. The polymer was filtered off and washed twice with methanol. The methanol washes were added to the filtrate and the solution was concentrated in vacuo to afford the title product (73%; LC-MS: 276 (MH+); anal. RP18-HPLC RT: 5.82 min). For these cases the analytical RP18-HPLC system consisted of a Waters 717 (trademark) autosampler, Waters 996 Photodiode Array Detector (trademark), and Waters 600 quarternary solvent delivery system, and was controlled by Millennium (trademark) software. The aliquots of samples were chromatographed using a linear gradient of 0% to 100% acetonitrile/0.2M ammonium acetate buffer (pH 4.5) over ten minutes at a flow rate of 3 ml/min. using a Perkin-Elmer Pecosphere (trademark) (3 mm×3 cm) C18 column.
The compounds of Examples 53-94, as their hydrochloride salts, were prepared in an analogous manner to that of Example 52 from the appropriate 3H-quinazolin-4-one derivative and 3-ethynyl-aniline:
HPLC
Exam- % LC-MS RT
ple Product Yield (MH+) (mins)
53 (6-Chloro-quinazolin-4-yl)-(3- 60 280, 282 6.44
ethynyl-phenyl)-amine
54 [7-Chloro-6-(2,5-dichloro- 51 456, 458 8.74
phenylsulfanyl)-quinazolin-4-yl]-
(3-ethynyl-phenyl)-amine
55 7-Chloro-4-(3-ethyl-phenylamino)- 12 305, 307 6.51
quinazolin-6-carbonitrile
56 [6-Bromo-7-(4-chloro-phenoxy)- 28 450, 452 8.05
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
57 [6-(4-Bromo-benzylsulfanyl)- 50 446, 448 7.99
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
58 (7-Bromo-6-methylsulfanyl- 46 370, 372 6.99
quinazolin-4-yl)-(3-ethynyl-
phenyl)-amine
59 {7-Chloro-6-[4-(4-chloro- 82 514, 516 9.45
phenylsulfanyl)-phenoxy]-
quinazolin-4-yl}-(3-ethynyl-
phenyl)-amine
60 (3-Ethynyl-phenyl)-(7- 88 354 7.40
phenylsulfanyl-quinazolin-4-yl)-
amine
61 (3-Ethynyl-phenyl)-(6-iodo- 64 372 6.81
quinazolin-4-yl)-amine
62 (3-Ethynyl-phenyl)-(6- 53 314 6.73
0trifluoromethyl-quinazolin-4-yl)-
amine
63 [7-Chloro-6-(4-(4-chloro- 78 406, 408 8.06
phenoxy)-quinazolin-4-yl]-(3-
ethynyl-phenyl)-amine
64 [7-Chloro-6-(4-chloro- 68 422, 424 8.45
phenylsulfanyl)-quinazolin-4-yl]-
(3-ethynyl-phenyl)-amine
65 [7-Chloro-6-(4-methoxy-phenoxy)- 88 402, 404 7.55
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
66 [7-Chloro-6-(4-fluoro-phenoxy)- 80 390 7.61
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
67 [6-(4-Chloro-phenoxy)-quinazolin- 79 372, 374 7.66
4-yl]-(3-ethynyl-phenyl)-amine
68 7-Bromo-4-(3-ethynyl- 61 431, 433 6.44
phenylamino)-quinazolin-6-
sulfonic acid
69 (6-Bromo-7-chloro-quinazolin-4- 80 358, 360 7.17
yl0-(3-ethynyl-phenyl)-amine
70 4-(3-Ethynyl-phenylamino)- 72 271 5.84
quinazolin-6-carbonitrile
71 [6-(4-Bromo-phenylsulfanyl)-7- 70 466, 468 8.56
chloro-quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
72 {6-[2-(4-Bromo-phenoxy)- 79 478, 478 8.11
ethylsulfanyl]-quinazolin-4-yl}-(3-
ethynyl-phenyl)-amine
73 4-[7-Chloro-4-(3-ethynyl- 85 427, 429 7.56
phenylamino)-quinazolin-6-
ylsulfanyl-methyl]-benzonitrile
74 [7-Chloro-6-(3-chloro-phenoxy)- 80 406, 408 8.10
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
75 [6-(3-Bromo-phenoxy)-7-chloro- 82 450, 452 8.22
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
76 (7-Chloro-6-phenoxy-quinazolin-4- 83 372, 374 7.59
yl)-3-ethynyl-phenyl)-amine
77 [7-Chloro-6-(4-methylsulfanyl- 86 418, 420 8.02
phenoxy)-quinazolin-4-yl]-(3-
ethynyl-phenyl)-amine
78 [7-Chloro-6-(4-methanesulfonyl- 73 450, 452 6.73
phenoxy)-quinazolin-4-yl]-(3-
ethynyl-phenyl)-amine
79 (7-Chloro-6-p-tolyloxy-quinazolin- 85 386, 388 4.95
4-yl]-(3-ethynyl-phenyl)-amine
80 (e-Ethynyl-phenyl)-[6-(4-phenoxy- 81 430 8.29
phenoxy)-quinazoin-4-yl]-amine
81 (7-Chloro-6-phenylsulfanyl- 80 388, 390 7.96
quinazolin-4-yl)-(3-ethynyl-
phenyl)-amine
82 [6-(3-Chloro-phenoxy)-quinazolin- 77 372, 374 7.71
4-yl]-(3-ethynyl-phenyl)-amine
83 [6-(3,5-Dichloro-phenoxy)- 61 406, 408 8.30
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
84 [6-(2-Chloro-phenoxy)-quinazolin- 70 372, 374 7.38
4-yl]-(3-ethynyl-phenyl)-amine
85 (7-Chloro-6-methanesulfonyl- 74 358, 360 5.74
quinazooin-4-yl)-(3-ethynyl-
phenyl)-amine
86 [6-(3,4-Dichloro-phenoxy)- 62 406, 408 8.14
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
87 [6-(4-Bromo-phenoxy)-quinazolin- 68 416, 418 7.81
4-yl]-(3-ethynyl-phenyl)-amine
88 [6-(4-Chloro-2-methyl-phenoxy)- 73 386, 388 8.02
quinazolin-4-yl]-(3-ethynyl-
phenyl)-amine
89 [7-Chloro-4-(3-ethynyl- 70 351 6.44
phenylamino)-quinazolin-6-
ylsulfanyl]-acetonitrile**
90 (6-Allylsulfanyl-quinazolin-4-yl)- 72 318 6.93
(3-ethynyl-phenyl)-amine
91 (7-Chloro-6-propylsulfanyl- 69 354, 356 7.79
quinazolin-4-yl)-(3-ethynyl-
phenyl)-amine
92 (7-Chloro-6-methyl-sulfanyl- 72 326, 328 6.94
quinazolin-4-yl)-(3-ethynyl-
phenyl)-amine
93 [7-Chloro-6-(2-methyl-sulfanyl- 71 386, 388 7.56
ethylsulfanyl)-quinazolin-4-yl]-(3-
ethynyl-phenyl)-amine
94 (6-Chloro-7-methoxy-quinazolin-4- 87 310, 312 6.65
yl)-(3-ethynyl-phenyl)-amine
**[7-Chloro-4-(3-ethynyl-phenylamino)-quinazolin-6-ylsulfanyl]-acetonitrile was obtained from 2-(7-chloro-4-oxo-3,4-dihydro-quinazolin-6-ylsulfanyl)-acetamide under these conditions.
EXAMPLE 95 (6,7-Dibutoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
6,7-Dibutoxyquinazolin-4-one (105 mg, 0.362 mmol), triphenylphosphine (208 mg, 0.796 mmol) and 5 mL of carbon tetrachloride were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (47 mg, 0.398 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford solid (6,7-dibutoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 92 mg (60%); mp 247°-248° C.
EXAMPLE 96 (6,7-Diisopropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
6,7-Diisopropoxyquinazolin-4-one (55 mg, 0.210 mmol), triphenylphosphine (121 mg, 0.462 mmol) and 3 mL of carbon tetrachloride were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (30 mg, 0.257 mmol) and refluxed for 3 hours. The cooled reaction mixture was vacuum evaporated to afford the solid title product which was column chromatographed on silica gel eluted with 5% acetone in methylene chloride containing 0.25% triethylamine. Fractions containing the pure product were concentrated in vacuo to a solid which was dissolved in 2 mL of 1N HCl in methanol, precipitated with ethyl ether, filtered and dried in vacuo at 70° C. to afford the title product; 140 mg (75%); mp 241°-242° C.
EXAMPLE 97 (6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
6-Chloro-7-(2-methoxyethylsulfanyl)-quinazolin-4-one (200 mg, 0.739 mmol), triphenylphosphine (427 mg, 1.63 mmol) and 0.7 mL of carbon tetrachloride were refluxed in 4 ml of 1,2-dichloroethane for 4 hours, concentrated in vacuo to a residue, diluted with 4 mL of isopropyl alcohol and 3-ethynylaniline (129 mg, 1.104 mmol) and refluxed for 16 hours. The hot reaction mixture was filtered to isolate crude product which was column chromatographed on silica gel eluted with 5% methanol in chloroform. Fractions containing the pure product were concentrated in vacuo to afford the title product as a solid; 23 mg (8.4%); mp 230°-232° C.
EXAMPLE 98 (6,7-Bis-[2-methoxyethoxy]-quinazolin-4-yl)-(3-ethynyl-2-methyl-phenyl)-amine
6,7-Bis-[2-methoxyethoxy]-4-chloro-quinazoline (90 mg, 0.288 mmol) and 3-(2′-trimethylsilylethynyl-2-methyl-aniline (62 mg, 0.317 mmol) were refluxed in 4 mL of tert-butyl alcohol for 16 hours. The cooled reaction mixture was diluted with 1 mL of isopropyl alcohol and filtered to afford solid (6,7-bis-(methoxyethoxy)-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethyn-1yl) -2-methyl-phenyl)-amine hydrochloride which was washed with 10 mL of ethyl ether and dried in vacuo at 70° C.; 70 mg. Of this material 51 mg was desilated by treatment with in 3 mL of methanol containing 1 drop of water and 50 mg of potassium carbonate for 0.5 hours at room temperature. The heterogeneous reaction mixture was filtered through celite and vacuum evaporated to a residue which was dried in vacuo at 70° C. to afford the title product as a dry foam; 38 mg (75%); mp 232° C.
EXAMPLE 99 (6,7-Bis-[2-methoxyethoxy]-quinazolin-4-yl)-(3-ethynyl-5′-fluoro-phenyl)-amine Hydrochloride
6,7-Bis[2-methoxyethoxy]-4-chloro-quinazoline (90 mg, 0.288 mmol) and 3-(2′-trimethylsilylethynyl-5-fluoro-aniline (69 mg, 0.317 mmol) were refluxed in 3 mL of tert-butyl alcohol for 5 hours. The cooled reaction mixture was diluted with 2 mL of isopropyl alcohol and filtered to afford solid (6,7-bis-methoxyethoxy-quinazolin-4-yl)-(3-(2′-trimethylsilyl-ethynyl)-5′-fluoro-phenyl)-amine hydrochloride which was washed with 10 mL of ethyl ether and dried in vacuo at 70° C.; 131 mg. All of this material was desilated by dissolution in 3 mL of methanol containing 1 drop of water and 35 mg of potassium carbonate for 0.5 hours at room temperature. The reaction mixture was adjusted to pH 2.5 with aqueous 1N hydrochloric acid and filtered. The solid was dried in vacuo at 70° C. to afford the title product; 92 mg (78%); mp 249°-250° C.
EXAMPLE 100 (7-Propylsulfanyl-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
7-Propylsulfanyl-quinazolin-4-one (300 mg, 1.36 mmol), triphenylphosphine (785 mg, 2.99 mmol), 1.31 mL of carbon tetrachloride and 5 mL of chloroform were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 5 mL of isopropyl alcohol and 3-ethynylaniline (175 mg, 1.49 mmol) and refluxed for 3 hours. The cooled reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluted with 10% methanol in chloroform. Fractions containing the pure title product, as the frree amine, were concentrated in vacuo to afford solid which was added to 3 mL of 1N HCl in methanol. This solution was evaporated in vacuo to a residue which was triturated with 4 mL of hot isopropyl alcohol cooled and filtered. The solid thus obtained was dried in vacuo at 70° C. to afford pure title product; 239 mg (55%); mp 229°-230° C.
EXAMPLE 101 [7-(2-Methoxyethylsulfanyl)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine Hydrochloride
In the same manner as Example 42 [7-(2-methoxyethylsulfanyl)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine hydrochloride was prepared from 7-(2-methoxyethylsulfanyl)-quinazolin-4-one (200 mg, 0.847 mmol), triphenylphosphine (533 mg, 2.03 mmol) and 3 mL of carbon tetrachloride in 74% yield; 233 mg; mp 208°-209° C.
EXAMPLE 102 (7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
7-Chloro-6-nitro-quinazolin-4-one (1.002 g, 4.44mmol), phosphorous oxychloride (11.5 g, 7.51 mmol) and phosphorous pentachloride (1.62 g, 7.74 mmol) were refluxed for 2 hours and the reaction mixture was concentrated in vacuo to a residue which was triturated with toluene and then again with chloroform and dried in vacuo to afford crude 4,7-dichloro-6-nitro-quinazoline. This was dissolved in 35 mL of isopropyl alcohol and 3-ethynylaniline (639 mg, 5.45 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford the title product as a solid which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 1.055 g (66%); mp 230.8°-232.6° C.
EXAMPLE 103 (6-Amino-7-chloro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine Hydrochloride
(7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (166 mg, 0.295 mmol) and sodium dithionite (207 mg, 1.19 mmol) were stirred in 1.5 mL of formic acid for 4 hours at room temperature. 45 mL of methanol were added to the reaction mixture which was set aside for 16 hours at room temperature. The precipitate thus obtained was filtered, triturated with 3% sodium bicarbonate for 0.5 hours and refiltered. The solid was dissolved in 20 mL of 1N HCl in methanol and precipitated with 200 mL of ethyl ether. This was filtered and dried in vacuo at 70° C. to afford the title product, 72 mg (83%); mp 260°-265° C.
EXAMPLE 104 (3-Ethynyl-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine
(7-Chloro-6-nitroquinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (100 mg, 0.306 mmol and dry sodium methoxide (120 mg, 2.22 mmol) were stirred in 2 mL of dry 2-methylpyrrolidin-1-one for 8 hours at 30° C. To the cooled reaction mixture 0.93 mL of 3N and 1 mL of water were added. The mixture was diluted with 60 mL of water and extracted with two time 60 mL of ethyl acetate. The pooled organic layers were washed with three times 50 mL of water and 50 mL of brine, dried with magnesium sulfate, filtered and vacuum evaporated to afford the title product as a solid; 80 mg (82%); mp 213°-218° C. dec.
EXAMPLE 105 {2-[4-(3-Ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethylsulfanyl}-acetic Acid Ammonium Salt
This product was prepared from the title product of Example 30 and mercaptoacetic acid at 22° C. over 10 days according to the method outlined in Example 45. (16%; M.P. 98°-113° C. (dec); LC-MS 454 (MH+); anal. RP-HPLC 3.24 min.)
PREPARATION 1 6,7-Bis(2-methoxy-ethoxy)-quinazolone
To ethyl 3,4-dihydroxybenzoate (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) and tetrabutylammonium iodide (750 mg) in degassed acetone (400 mL) was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture was stirred under N2 at reflux for 64 hours. Ether (600 mL) was added to the mixture and after stirring 30 minutes at 20° C. the precipitated salts were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated with hexane (500 mL) for 30 minutes and the white solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (55.5 g; 93%; M.P. 50°-51° C.). A portion of this product (45.7 g, 0.158 mol) in acetic acid (150 mL) was treated dropwise with conc. HNO3 (40 mL) at 5° C. and the solution stirred 24 hours before pouring into cold H2O (1.6 L). The mixture was extracted with ethyl acetate (1.1 L), and the organic phase was washed three times with 200 mL H2O, and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate (54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 mL) containing 1 equivalent of HCl (generated in the ethanol by prior addition of 11 mL acetyl chloride), PtO2.H2O (1.0 g) was added, and the mixture was hydrogenated under 45 psi H2 for 6 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to a thick slurry which was diluted with ether (400 mL). The solid white hydrochloride salt of ethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88%). A portion of this material (42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were dissolved in formamide (63 mL) and the stirred mixture was heated to 160°-165° C. under an atmosphere of N2 for 3 hours. H2O (200 mL) was added and after cooling the precipitated crude title product was recovered by filtration, washed with cold H2O, and dried in vacuo. The filtrate was extracted five times with CHCl3, and the pooled organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue and crude quinazolone precipitate were combined, triturated in hot acetonitrile (250 mL) for 30 minutes, cooled to 20° C. and treated with ether (250 mL). After cooling to 4° C. the white solid was filtered and dried in vacuo (30.4 g, 86%; GC-MS m/z 294 (M+)).
PREPARATION 2 4-Chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline
To 6,7-bis(2-methoxy-ethoxy)-quinazolone (500 mg, 1.7 mmol), from Preparation 1, in CHCl3 (10 mL) containing one drop of DMF was added oxalylchloride (490 μL, 5.6 mmol) in several portions over 5 minutes. Once foaming ceased the solution was refluxed 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in 1,2-dichloroethane (20 mL) and washed two times with 80 mL saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, and concentrated in vacuo to afford solid title product (520 mg, 92%; M.P. 108°-109° C.).
PREPARATION 3 4-Chloro-6,7-bis-(2-chloro-ethoxy)-quinazoline, 4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazoline and 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline and 4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline
6,7-Bis(2-methoxy-ethoxy)-quinazolone (5.4 g, 18.3 mmol), from Preparation 1, and pyridine (3.0 mL, 37 mmol) were heated in refluxing POCl3 (22 mL) under an atmosphere of dry nitrogen for 2.5 hours. Following concentration of the mixture in vacuo at 60° C. the residue was dissolved in CHCl3 (150 mL) and carefully added in portions with stirring to cold saturated aqueous NaHCO3 (100 mL). The mixture was stirred 10 min. after the addition was complete and the organic phase was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was flash chromatographed on silica using a gradient of 20% to 60% ethyl acetate/hexanes to afford 3.41 g of 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 234 mg of 4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazoline, 532 mg of 4-chloro-7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazoline, and 330 mg of 4-chloro-6,7-bis-(2-chloroethoxy)-quinazoline.

Claims (35)

1. A compound of the formula
Figure USRE041065-20091229-C00007
or a pharmaceutically acceptable salt thereof wherein:
m is 1, 2, or 3;
each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1-C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
or each R1 is independently selected from R9 and C1-C4-alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, —OR6, —NR6R6, —C(O)R7, —NHOR5, —OC(O)R6, cyano, A and —YR5; R5 is C1-C4 alkyl; R6is independently hydrogen or R5; R7 is R5, —OR6 or —NR6R6; A is selected from piperidino, morpholino, pyrrolidino, 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1-C4 alkylene) (CO2H), phenoxy, phenyl, phenylsulfanyl, C2-C4 alkenyl, and -(C1-C4 alkylene)C(O)NR6R6; and Y is S, SO, or SO2; wherein the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by one to three halo substituents and the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by 1 or 2 R9 groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom;
or each R1 is independently selected from —NHSO2R5, phthalimido-(C1-C4) -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-(C2-C4) -alkanoylamino wherein R10 is selected from halo, —OR6, C2-C4 alkanoyloxy, —C(O)R7, and —NR6R6; and wherein said —NHSO2R5, phthalimido-(C1-C4-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-(C2-C4)-alkanoylamino R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1-C4 alkyl, cyano, methanesulfonyl and C1-C4 alkoxy;
or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
R2 is hydrogen or C1-C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5;
n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1-C6 alkyl, —NR6R6, and C1-C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5; and,
R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1-C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R6.
2. The compound according to claim 1 wherein R2 is hydrogen and R4 is -(ethynyl)-R11.
3. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a pharmaceutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
4. The compound of claim 1 wherein each R1 is independently selected from hydrogen, hydroxy, hydroxyamino, nitro, carbamoyl, ureido, R5 optionally substituted with halo, —OR6, carboxy, or —C(O)NH2; —OR5 optionally substituted with halo, —OR6, —OC(O)R6, —NR6R6, or A; —NR6R6, —C(O)NR6R6, —SR5, phenyl-(C2-C4)-alkoxy wherein said phenyl moiety is optionally substituted with 1 or 2 substituents independently selected from halo, R5 or —OR5.
5. The compound according to claim 1 wherein R2 is hydrogen and R4 is azido.
6. The compound of claim 1 wherein R3 is halo and R1 is hydrogen or —OR5.
7. The compound of claim 6 wherein R1 is methoxy.
8. The compound of claim 1 selected from the group consisting of:
(6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine;
[3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine;
(3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine;
(6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine;
(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine;
(6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;
(3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine;
(3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine;
(6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine;
(3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine;
(3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine;
(3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine;
(3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine;
(7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine;
(3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine;
(6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
(7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine;
[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine;
(3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
(3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
(4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine;
(3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine;
(6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine
(6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;
(6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine;
[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine;
[6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine;
[6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
[6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
[6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol;
[6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
[7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
[7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol;
2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol;
2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol;
[6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine;
(3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine;
(3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine;
(6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
(6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
(6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
(6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine;
[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine;
(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;
[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; and
2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol. that is [6,7-bis( 2 -methoxyethoxy)quinazolin- 4 -yl]-( 3 -ethynylphenyl)-amine.
9. The compound of claim 1 selected from the group consisting of
(6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;
(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine;
(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine;
(6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine;
(6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine;
(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine;
(6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine;
(6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; and
(6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine.
10. The compound of claim 1 selected from the group consisting of:
(6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
(3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine;
[6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;
[6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine;
(6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine;
(3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine; and,
(6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine.
11. A pharmaceutical composition for the treatment of a hyperproliferative disorder in a mammal which comprises a therapeutically-effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
12. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of claim 1.
13. The method of claim 12 wherein said hyperproliferative disorder is cancer.
14. The method of claim 13 wherein said cancer is brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, gynecological or thyroid cancer.
15. The method of claim 12 wherein the hyperproliferative disease is noncancerous.
16. The method of claim 15 wherein said disorder is a benign hyperplasia of the skin or prostate.
17. A process for preparing a compound of the formula
Figure USRE041065-20091229-C00008
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
m is 1, 2, or 3;
each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1-C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
or each R1 is independently selected from R9 and (C1-C4)-alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, —OR6, —NR6R6, —C(O)R7, —NHOR5, —OC(O)R6, cyano, A and —YR5; R5is C1-C4 alkyl; R6 is independently hydrogen or R5; R7 is R5, —OR6 or —NR6R6; A is selected from piperidino, morpholino, pyrrolidino, 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1-C4 alkylene)(CO2H), phenoxy, phenyl, phenylsulfanyl, C2-C4 alkenyl, and -(C1-C4 alkylene)C(O)NR6R6; and Y is S, SO, or SO2; wherein the alkyl moieties in R5, —OR6 and —NR6R6 are optionally substituted by one to three substituents independently selected from halo and R9, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R9 groups may comprise a single R1 group;
or each R1 is independently selected from —NHSO2R5, phthalimido-(C1-C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-(C2-C4)-alkanoylamino wherein R10 is selected from halo, —OR6, C2-C4 alkanoyloxy, —C(O)R7, and —NR6R6; and wherein the foregoing R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1-C4 alkyl, cyano, methanesulfonyl and C1-C4 alkoxy;
or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
R2 is hydrogen or C1-C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5;
n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1-C6 alkyl, —NR6R6, and C1-C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1-C4 alkoxy, —NR6R6, and —SO2R5; and,
R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1-C6 alkyl optionally substituted by hydroxy, —OR6, or —NR6R6;
 which comprises
a) treating a compound of the formula
Figure USRE041065-20091229-C00009
 wherein R1 and m are as defined above, with CCl4 and (C6-C10aryl)3P, optionally supported on an inert polymer, wherein the aryl moieties of said (C6-C10aryl)3P are optionally substituted by C1-C6 alkyl; and
b) treating the product of step a) with a compound of the formula
Figure USRE041065-20091229-C00010
 wherein R2, R3 and n are as defined above, and J is Y or R4, wherein R4 is as defined above and wherein Y is NH2, Br, I or trifluoromethanesulfonyloxy, with the proviso that when J is Y then the product of step b) must further be treated with an alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an azide where Y is NH2.
18. The process of claim 17 wherein each aryl group is selected from phenyl, naphth-1-yl and naphth-2-yl.
19. The process of claim 17 wherein each Ar in (C6-C10aryl)3P is phenyl.
20. The process of claim 17 wherein said (C6-C10aryl)3P is supported on an inert polymer.
21. The process of claim 20 wherein said inert polymer is a divinylbenzene-cross-linked polymer of styrene.
22. The composition of claim 3 wherein said hyperproliferative disorder is cancer.
23. The composition of claim 22 wherein said cancer is selected from the group consisting of renal, liver, kidney, colorectal, brain, lung, skin, bladder, gastric, pancreatic, breast, head, neck, oesophageal, vulval, gynecological, and thyroid cancer.
24. The composition of claim 3 wherein said hyperproliferative disorder is benign.
25. The composition of claim 24 wherein said hyperproliferative disorder is benign hyperplasia of the skin or prostate.
26. The composition of claim 25 wherein said hyperproliferative disorder is A pharmaceutical composition for the treatment of psoriasis in a mammal which comprises a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
27. A method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a pharmaceutically effective amount of the compound of claim 1.
28. The method of claim 27 wherein said hyperproliferative disorder is cancer.
29. The method of claim 28 wherein said cancer is selected from the group consisting of renal, liver, kidney, colorectal, brain, lung, skin, bladder, gastric, pancreatic, breast, head, neck, oesophageal, vulval, gynecological, and thyroid cancer.
30. The method of claim 27 wherein said hyperproliferative disorder is benign.
31. The method of claim 30 wherein said hyperproliferative disorder is benign hyperplasia of the skin or prostate.
32. The method of claim 31 wherein said hyperproliferative disorder is A method of treating psoriasis in a mammal which comprises administering to said mammal a therapeutically effective amount of the compound of claim 1.
33. A pharmaceutical composition for the treatment of psoriasis in a mammal which comprises a therapeutically effective amount of the compound of claim 8 and a pharmaceutically acceptable carrier.
34. A compound that is a pharmaceutically acceptable salt of [6,7-bis( 2 -methoxyethoxy)quinazolin- 4 -yl]-( 3 -ethynylphenyl)-amine.
35. A compound that is a hydrochloride salt of [6,7-bis( 2 -methoxyethoxy)quinazolin- 4 -yl]-( 3 -ethynylphenyl)-amine.
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090226443A1 (en) * 2008-03-06 2009-09-10 Genentech, Inc. Combination therapy with c-met and egfr antagonists
WO2011133520A1 (en) 2010-04-19 2011-10-27 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a hsp90 inhibitory compounds and a egfr inhibitor
WO2012068483A1 (en) 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment based on hypoxic status
WO2012068487A1 (en) 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment with oxygen sensitive agents based on hypoxic status
WO2012125913A1 (en) 2011-03-17 2012-09-20 The Trustees Of The University Of Pennsylvania Methods and use of bifunctional enzyme-building clamp-shaped molecules
WO2013091507A1 (en) 2011-12-20 2013-06-27 Qian Wei Heterocycle amido alkyloxy substituted quinazoline derivative and use thereof
WO2013170182A1 (en) 2012-05-11 2013-11-14 Synta Pharmaceuticals Corp. Treating cancer with an hsp90 inhibitory compound
WO2014118737A1 (en) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Erlotinib salts
US9295676B2 (en) 2011-03-17 2016-03-29 The Trustees Of The University Of Pennsylvania Mutation mimicking compounds that bind to the kinase domain of EGFR
US10240207B2 (en) 2014-03-24 2019-03-26 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with HGF expression
WO2019178433A1 (en) 2018-03-15 2019-09-19 Abbvie Inc. Abbv-621 in combination with anti-cancer agents for the treatment of pancreatic cancer
US10710968B2 (en) 2016-01-13 2020-07-14 Hadasit Medical Research Services And Development Ltd. Radiolabeled erlotinib analogs and uses thereof
US10717825B2 (en) 2015-07-01 2020-07-21 California Instite of Technology Cationic mucic acid polymer-based delivery system
US11285212B2 (en) 2013-03-01 2022-03-29 California Institute Of Technology Targeted nanoparticles
US11708335B2 (en) 2017-12-18 2023-07-25 Sterngreene, Inc. Pyrimidine compounds useful as tyrosine kinase inhibitors
US11998616B2 (en) 2018-06-13 2024-06-04 California Institute Of Technology Nanoparticles for crossing the blood brain barrier and methods of treatment using the same

Families Citing this family (689)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
GB9424233D0 (en) * 1994-11-30 1995-01-18 Zeneca Ltd Quinazoline derivatives
CN1125817C (en) 1996-02-13 2003-10-29 曾尼卡有限公司 Quinazoline derivatives as VEGF inhibitors
JP4464466B2 (en) 1996-03-05 2010-05-19 アストラゼネカ・ユーケイ・リミテッド 4-anilinoquinazoline derivatives
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
US6225318B1 (en) 1996-10-17 2001-05-01 Pfizer Inc 4-aminoquinazolone derivatives
MEP42008A (en) * 1998-04-29 2011-02-10 Osi Farmaceuticals Inc N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
US6706721B1 (en) * 1998-04-29 2004-03-16 Osi Pharmaceuticals, Inc. N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
NZ508314A (en) 1998-06-02 2004-03-26 Osi Pharm Inc Pyrrolo[2,3d]pyrimidine compositions and their use
EP1119349B1 (en) * 1998-08-18 2008-07-02 The Regents Of The University Of California Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs
ES2259237T3 (en) * 1998-08-27 2006-09-16 Pfizer Products Inc. DERIVATIVES OF QUINOLIN-2-ONA ALQUINILS SUBSTITUTED USEFUL AS ANTI-TARGET AGENTS.
EP1107962B1 (en) 1998-08-27 2005-02-23 Pfizer Products Inc. Quinolin-2-one derivatives useful as anticancer agents
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2000041698A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS
JP3270834B2 (en) 1999-01-27 2002-04-02 ファイザー・プロダクツ・インク Heteroaromatic bicyclic derivatives useful as anticancer agents
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
DE19911509A1 (en) * 1999-03-15 2000-09-21 Boehringer Ingelheim Pharma Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
US6258820B1 (en) * 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
YU13200A (en) * 1999-03-31 2002-10-18 Pfizer Products Inc. Process and intermediates for preparing anti-cancer compounds
US6126917A (en) * 1999-06-01 2000-10-03 Hadasit Medical Research Services And Development Ltd. Epidermal growth factor receptor binding compounds for positron emission tomography
US6432979B1 (en) 1999-08-12 2002-08-13 American Cyanamid Company Method of treating or inhibiting colonic polyps and colorectal cancer
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
IL149034A0 (en) 1999-11-05 2002-11-10 Astrazeneca Ab Quinazoline derivatives as vegf inhibitors
UA74803C2 (en) * 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use
US7087613B2 (en) * 1999-11-11 2006-08-08 Osi Pharmaceuticals, Inc. Treating abnormal cell growth with a stable polymorph of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
US6664252B2 (en) 1999-12-02 2003-12-16 Osi Pharmaceuticals, Inc. 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
US7160890B2 (en) * 1999-12-02 2007-01-09 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
GB0002952D0 (en) * 2000-02-09 2000-03-29 Pharma Mar Sa Process for producing kahalalide F compounds
US20060063752A1 (en) * 2000-03-14 2006-03-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
MY124799A (en) * 2000-03-20 2006-07-31 Pfizer Prod Inc Combined treatment with keratinocyte growth factor and epidermal growth factor inhibitor
AU779695B2 (en) * 2000-04-07 2005-02-10 Astrazeneca Ab Quinazoline compounds
EP1326860A1 (en) * 2000-10-13 2003-07-16 AstraZeneca AB Quinazoline derivatives
ATE502928T1 (en) 2000-11-01 2011-04-15 Millennium Pharm Inc NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
WO2002041882A2 (en) * 2000-11-22 2002-05-30 Novartis Ag Combination comprising an agent decreasing vegf activity and an agent decreasing egf activity
US6673802B2 (en) 2000-12-01 2004-01-06 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
US6680324B2 (en) * 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
AUPR213700A0 (en) 2000-12-18 2001-01-25 Biota Scientific Management Pty Ltd Antiviral agents
MXPA03005525A (en) 2000-12-19 2003-10-06 Pfizer Prod Inc Crystal forms of 6-[(4 -chloro-phenyl) -hydroxy- (-3-methyl-3h-imidaol -4-yl)-methyl] -4-(3-ethynyl -phenyl)-1 -methyl-1h -qu inolin-2 -one, 2,3-dihydroxybutanedioate salts and method of production.
EA012079B3 (en) * 2001-01-05 2018-07-31 Пфайзер Инк. MONOCLONAL ANTIBODY TO RECEPTOR OF INSULIN-LIKE GROWTH FACTOR I (IGF-I) AND METHODS OF ITS APPLICATION
CN104083365A (en) 2001-02-19 2014-10-08 诺华股份有限公司 Cancer treatment
JP2002293773A (en) * 2001-03-30 2002-10-09 Sumika Fine Chemicals Co Ltd Method for producing quinazoline derivative
US20040167134A1 (en) 2001-05-16 2004-08-26 Christian Bruns Combination comprising n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine and a chemotherapeutic agent
US7132427B2 (en) * 2001-06-21 2006-11-07 Ariad Pharmaceuticals, Inc. Quinazolines and uses thereof
WO2003000194A2 (en) 2001-06-21 2003-01-03 Pfizer Inc. Thienopyridine and thienopyrimidine anticancer agents
US6740757B2 (en) 2001-08-29 2004-05-25 Pfizer Inc Enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3h-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1h-quinolin-2-one and salts thereof, useful in the treatment of cancer
WO2003030908A2 (en) * 2001-10-09 2003-04-17 The University Of Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
ATE423104T1 (en) * 2001-11-03 2009-03-15 Astrazeneca Ab QUINAZOLINE DERIVATIVES AS ANTI-TUMOR AGENT
GB0126433D0 (en) * 2001-11-03 2002-01-02 Astrazeneca Ab Compounds
AR039067A1 (en) * 2001-11-09 2005-02-09 Pfizer Prod Inc ANTIBODIES FOR CD40
KR101059898B1 (en) * 2001-11-19 2011-08-29 인터레우킨 제네틱스, 인코포레이티드 Functional polymorphisms of the interleukin-1 locus affecting transcription and susceptibility to inflammatory and infectious diseases
US6753428B2 (en) * 2001-11-20 2004-06-22 Cytokinetics, Inc. Process for the racemization of chiral quinazolinones
GB0128510D0 (en) * 2001-11-28 2002-01-23 Novartis Ag Organic compounds
EP2050751A1 (en) * 2001-11-30 2009-04-22 OSI Pharmaceuticals, Inc. Compounds specific to adenosine A1 and A3 receptors and uses thereof
CN1816551A (en) * 2001-12-20 2006-08-09 Osi药物公司 Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use
EA007468B1 (en) 2001-12-20 2006-10-27 Оси Фармасьютикалз, Инк. Pyrimidine a2b selective antagonist compounds, their synthesis and use
CA2473796A1 (en) 2002-01-17 2003-07-31 Neurogen Corporation Substituted quinazolin-4-ylamine analogues
JP4389205B2 (en) * 2002-02-06 2009-12-24 宇部興産株式会社 Preparation of 4-aminoquinazoline compounds
WO2003068228A1 (en) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Aryl ureas with angiogenesis inhibiting activity
AU2003213092A1 (en) * 2002-02-15 2003-09-09 Smithkline Beecham Corporation Syntheses of quinazolinones
US7078409B2 (en) 2002-03-28 2006-07-18 Beta Pharma, Inc. Fused quinazoline derivatives useful as tyrosine kinase inhibitors
TW200813014A (en) * 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives
IL164167A0 (en) * 2002-03-30 2005-12-18 Boehringer Ingelheim Pharma 4-(N-phenylamino)-quinazolines/ quinolines as tyrosine kinase inhibitors
US6924285B2 (en) * 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
KR20050036911A (en) * 2002-05-09 2005-04-20 싸이토키네틱스, 인코포레이티드 Compounds, methods and compositions
WO2003097053A1 (en) 2002-05-09 2003-11-27 Cytokinetics, Inc. Compounds, compositions, and methods
PT1505959E (en) 2002-05-16 2009-02-05 Novartis Ag Use of edg receptor binding agents in cancer
JP2005536475A (en) * 2002-05-23 2005-12-02 サイトキネティクス・インコーポレーテッド Compounds, compositions and methods
WO2003106426A1 (en) * 2002-06-14 2003-12-24 Cytokinetics, Inc. Compounds, compositions, and methods
UA77303C2 (en) * 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
EP1521747B1 (en) 2002-07-15 2018-09-05 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
EP1537089A4 (en) * 2002-07-23 2008-04-16 Cytokinetics Inc Compounds compositions and methods
AU2003262747A1 (en) * 2002-08-21 2004-03-11 Cytokinetics, Inc. Compounds, compositions, and methods
AU2003277079A1 (en) * 2002-09-30 2004-05-04 Cytokinetics, Inc. Compounds, compositions, and methods
GB0304367D0 (en) * 2003-02-26 2003-04-02 Pharma Mar Sau Methods for treating psoriasis
US20040186160A1 (en) * 2002-12-13 2004-09-23 Sugen, Inc. Hexahydro-cyclohepta-pyrrole oxindole as potent kinase inhibitors
CA2510850A1 (en) * 2002-12-19 2004-07-08 Pfizer Inc. 2-(1h-indazol-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophthalmic diseases
US7148231B2 (en) † 2003-02-17 2006-12-12 Hoffmann-La Roche Inc. [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph
JP4695588B2 (en) 2003-02-26 2011-06-08 スージェン， インク． Amino heteroaryl compounds as protein kinase inhibitors
US7557129B2 (en) 2003-02-28 2009-07-07 Bayer Healthcare Llc Cyanopyridine derivatives useful in the treatment of cancer and other disorders
EP1613320A1 (en) * 2003-04-03 2006-01-11 Pfizer Inc. Dosage forms comprising ag013736
GB0309009D0 (en) * 2003-04-22 2003-05-28 Astrazeneca Ab Quinazoline derivatives
US7452901B2 (en) * 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
CN101410120A (en) * 2003-04-25 2009-04-15 吉里德科学公司 Anti-inflammatory phosphonate compounds
KR20060022647A (en) * 2003-04-25 2006-03-10 길리애드 사이언시즈, 인코포레이티드 Kinase Inhibition Phosphonate Analogs
US7429565B2 (en) 2003-04-25 2008-09-30 Gilead Sciences, Inc. Antiviral phosphonate analogs
WO2005002626A2 (en) 2003-04-25 2005-01-13 Gilead Sciences, Inc. Therapeutic phosphonate compounds
WO2004096285A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Anti-infective phosphonate conjugates
WO2004096287A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
US7432261B2 (en) * 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US7470724B2 (en) * 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
GB0309850D0 (en) * 2003-04-30 2003-06-04 Astrazeneca Ab Quinazoline derivatives
US7902192B2 (en) * 2003-05-15 2011-03-08 Arqule, Inc. Inhibitors of P38 and methods of using the same
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
BRPI0410439A (en) 2003-05-19 2006-06-06 Irm Llc immunosuppressive compounds and compositions
DE602004007382T2 (en) 2003-05-20 2008-04-17 Bayer Pharmaceuticals Corp., West Haven DIARYL UREAS FOR PDGFR MEDIATED DISEASES
MXPA05013145A (en) * 2003-06-10 2006-03-17 Hoffmann La Roche 1.3.4-triaza-phenalene and 1,3,4,6-tetraazaphenalene derivatives.
US7618975B2 (en) * 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8309562B2 (en) * 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
BRPI0412885A (en) 2003-07-18 2006-10-03 Amgen Inc polypeptides, specific binding agents, nucleic acid molecules and isolated cell lines, host cells, compositions and antigen binding domain or antibody and methods of treating cancer and solid tumor in a patient, detecting growth factor level hepatocyte (hgf) in a sample, obtaining antibody and inhibiting hgf binding to met and decreasing or preventing the binding of any of the hepatocyte growth factor (hgf) -specific binding agents
NZ544920A (en) 2003-07-23 2009-11-27 Bayer Healthcare Llc 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide and metabolites for the treatment and prevention of diseases and conditions
GB0317665D0 (en) * 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
CA2533345A1 (en) * 2003-07-29 2005-02-10 Astrazeneca Ab Piperidyl-quinazoline derivatives as tyrosine kinase inhibitors
EP1650196B1 (en) * 2003-07-30 2011-03-30 Ube Industries, Ltd. Process for producing 6,7-bis(2-methoxyethoxy)-quinazolin-4-one
HN2004000285A (en) 2003-08-04 2006-04-27 Pfizer Prod Inc ANTIBODIES DIRECTED TO c-MET
ES2314444T3 (en) * 2003-08-29 2009-03-16 Pfizer Inc. TIENOPIRIDINE-PHENYLACETAMIN AND ITS USEFUL DERIVATIVES AS NEW ANTIANGIOGEN AGENTS.
BRPI0414011A (en) * 2003-08-29 2006-10-24 Pfizer naphthalencarboxamides and their derivatives useful as new antiangiogenic agents
GB0321066D0 (en) * 2003-09-09 2003-10-08 Pharma Mar Sau New antitumoral compounds
AR045563A1 (en) * 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
EP1664030A1 (en) * 2003-09-16 2006-06-07 AstraZeneca AB Quinazoline derivatives
GB0321648D0 (en) * 2003-09-16 2003-10-15 Astrazeneca Ab Quinazoline derivatives
EP1664028A1 (en) * 2003-09-16 2006-06-07 AstraZeneca AB Quinazoline derivatives as tyrosine kinase inhibitors
HRP20080329T3 (en) * 2003-09-16 2008-08-31 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
PL1667992T3 (en) * 2003-09-19 2007-05-31 Astrazeneca Ab Quinazoline derivatives
ATE353888T1 (en) * 2003-09-19 2007-03-15 Astrazeneca Ab CHINAZOLINE DERIVATIVES
GB0322409D0 (en) * 2003-09-25 2003-10-29 Astrazeneca Ab Quinazoline derivatives
US20070043010A1 (en) * 2003-09-25 2007-02-22 Astrazeneca Uk Limited Quinazoline derivatives
SI2392564T1 (en) * 2003-09-26 2014-02-28 Exelixis, Inc. c-Met modulators and methods of use
US7456189B2 (en) * 2003-09-30 2008-11-25 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation
WO2005044308A1 (en) * 2003-10-24 2005-05-19 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
US7427624B2 (en) * 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
EP1682534A2 (en) * 2003-11-03 2006-07-26 Cytokinetics, Inc. Pyrimidin-4-one compounds, compositions, and methods
WO2005046588A2 (en) * 2003-11-07 2005-05-26 Cytokinetics, Inc. Compounds, compositions, and methods
GB0326459D0 (en) * 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
DE602004028150D1 (en) * 2003-11-26 2010-08-26 Pfizer Prod Inc AMINOPYRAZOL DERIVATIVES AS GSK-3 INHIBITORS
WO2005061460A1 (en) * 2003-12-08 2005-07-07 Cytokinetics, Inc. Compounds, compositions, and methods
BRPI0418031A (en) * 2003-12-22 2007-04-17 Gilead Sciences Inc phosphonate-substituted kinase inhibitors
US20050153990A1 (en) * 2003-12-22 2005-07-14 Watkins William J. Phosphonate substituted kinase inhibitors
NZ547907A (en) * 2003-12-22 2010-07-30 Gilead Sciences Inc 4'-Substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity
US20080113874A1 (en) * 2004-01-23 2008-05-15 The Regents Of The University Of Colorado Gefitinib sensitivity-related gene expression and products and methods related thereto
US7632840B2 (en) * 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
BRPI0509580A (en) * 2004-03-30 2007-11-27 Pfizer Prod Inc signal transduction inhibitor combinations
CN1964970B (en) 2004-04-07 2011-08-03 诺瓦提斯公司 Inhibitors of IAP
MXPA06012756A (en) * 2004-05-06 2007-01-16 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amides.
JP5422120B2 (en) * 2004-05-27 2014-02-19 ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド，ア ボディー コーポレイト Methods for predicting clinical outcome for epidermal growth factor receptor inhibitors by cancer patients
WO2005116035A1 (en) * 2004-05-27 2005-12-08 Pfizer Products Inc. Pyrrolopyrimidine derivatives useful in cancer treatment
CA2567832A1 (en) * 2004-06-04 2005-12-15 Astrazeneca Ab Quinazoline derivatives as erbb receptor tyrosine kinases
EP2277595A3 (en) 2004-06-24 2011-09-28 Novartis Vaccines and Diagnostics, Inc. Compounds for immunopotentiation
US20100226931A1 (en) * 2004-06-24 2010-09-09 Nicholas Valiante Compounds for immunopotentiation
WO2006008639A1 (en) * 2004-07-16 2006-01-26 Pfizer Products Inc. Combination treatment for non-hematologic malignancies using an anti-igf-1r antibody
ES2720618T3 (en) 2004-07-27 2019-07-23 Gilead Sciences Inc Phosphonate analogs of HIV inhibitor compounds
ME01788B (en) * 2004-08-26 2011-02-28 Pfizer Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
GEP20094845B (en) * 2004-08-26 2009-11-25 Pfizer Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
CA2578075A1 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Aminoheteroaryl compounds as protein tyrosine kinase inhibitors
US8178672B2 (en) * 2004-10-19 2012-05-15 Arqule, Inc. Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 MAP kinase
CA2585353A1 (en) * 2004-10-26 2006-05-04 Gilead Sciences, Inc. Phosphonate derivatives of mycophenolic acid
US20060107555A1 (en) * 2004-11-09 2006-05-25 Curtis Marc D Universal snow plow adapter
MX2007006230A (en) 2004-11-30 2007-07-25 Amgen Inc Quinolines and quinazoline analogs and their use as medicaments for treating cancer.
DE602005026865D1 (en) 2004-12-14 2011-04-21 Astrazeneca Ab PYRAZOLOPYRIMIDINE COMPOUNDS AS ANTITUM-MEANS
US8258145B2 (en) * 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
CA2592900A1 (en) 2005-01-03 2006-07-13 Myriad Genetics Inc. Nitrogen containing bicyclic compounds and therapeutical use thereof
US7625911B2 (en) * 2005-01-12 2009-12-01 Mai De Ltd. Amorphous form of erlotinib hydrochloride and its solid amorphous dispersion
US20060188498A1 (en) * 2005-02-18 2006-08-24 Genentech, Inc. Methods of using death receptor agonists and EGFR inhibitors
US20090155247A1 (en) * 2005-02-18 2009-06-18 Ashkenazi Avi J Methods of Using Death Receptor Agonists and EGFR Inhibitors
UY29398A1 (en) * 2005-02-26 2006-10-02 Astrazeneca Ab DERIVATIVES OF QUINAZOLINAS, PHARMACEUTICALLY ACCEPTABLE SUSSALES, COMPOSITIONS THAT CONTAIN THEM, PREPARATION PROCEDURES AND APPLICATIONS.
GB0504474D0 (en) * 2005-03-04 2005-04-13 Astrazeneca Ab Chemical compounds
US20080234265A1 (en) * 2005-03-11 2008-09-25 The Regents Of The University Of Colorado Histone Deacetylase Inhibitors Sensitize Cancer Cells to Epidermal Growth Factor Inhibitors
US20080182865A1 (en) * 2005-03-11 2008-07-31 Witta Samir E Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
US20060216288A1 (en) * 2005-03-22 2006-09-28 Amgen Inc Combinations for the treatment of cancer
EP2444099A1 (en) 2005-03-31 2012-04-25 Agensys, Inc. Antibodies and related molecules that bind to 161P2F10B proteins
EA014611B1 (en) * 2005-04-12 2010-12-30 Элан Фарма Интернэшнл Лтд. Nanoparticulate quinazoline derivative formulations
GB0508715D0 (en) * 2005-04-29 2005-06-08 Astrazeneca Ab Chemical compounds
GB0508717D0 (en) * 2005-04-29 2005-06-08 Astrazeneca Ab Chemical compounds
US20070099856A1 (en) * 2005-05-13 2007-05-03 Gumerlock Paul H Combined treatment with docetaxel and an epidermal growth factor receptor kinase inhibitor using an intermittent dosing regimen
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
AU2006288716A1 (en) * 2005-09-06 2007-03-15 T.K. Signal Ltd. Polyalkylene glycol derivatives of 4- (phenylamino)quinazolines useful as irreversible inhibitors of epidermal growth factor receptor tyrosine kinase
CA2623125A1 (en) 2005-09-20 2007-03-29 Osi Pharmaceuticals, Inc. Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
EP1928861B1 (en) * 2005-09-20 2010-11-17 AstraZeneca AB 4- (ih-indazol-5-yl-amino)-quinazoline compounds as erbb receptor tyrosine kinase inhibitors for the treatment of cancer
US20090239861A1 (en) * 2005-09-20 2009-09-24 Robert Hugh Bradbury Quinazoline derivatives as anticancer agents
PT2275103E (en) 2005-11-21 2014-07-24 Novartis Ag Mtor inhibitors in the treatment of endocrine tumors
US7960545B2 (en) * 2005-11-23 2011-06-14 Natco Pharma Limited Process for the prepartion of erlotinib
DE602006009304D1 (en) * 2005-12-02 2009-10-29 Astrazeneca Ab CHINAZOLEINDERIVATE
WO2007063291A1 (en) * 2005-12-02 2007-06-07 Astrazeneca Ab 4-anilino-substituted quinazoline derivatives as tyrosine kinase inhibitors
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي PI-3 Kinase inhibitors and methods of their use
PE20070978A1 (en) * 2006-02-14 2007-11-15 Novartis Ag HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks)
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
KR20140019032A (en) 2006-04-05 2014-02-13 노파르티스 아게 Combinations of therapeutic agents for treating cancer
KR20080109068A (en) 2006-04-05 2008-12-16 노파르티스 아게 Combination comprising RC-AL / C-VIT / PDV-R TV inhibitors to treat cancer
TW200808739A (en) * 2006-04-06 2008-02-16 Novartis Vaccines & Diagnostic Quinazolines for PDK1 inhibition
EP2013218A2 (en) * 2006-04-17 2009-01-14 Arqule, Inc. Raf inhibitors and their uses
CN101472915A (en) 2006-04-19 2009-07-01 诺瓦提斯公司 Indazole compounds and methods for inhibition of CDC7
BRPI0711385A2 (en) 2006-05-09 2011-11-08 Novartis Ag combination comprising an iron chelator and an antineoplastic agent and its use
FR2903387B1 (en) * 2006-07-05 2008-08-29 Alcatel Sa ACTUATOR FOR SYSTEMS FOR GUIDING SPACE EQUIPMENTS WITH VARIABLE ROTATION RATIOS
PE20121506A1 (en) 2006-07-14 2012-11-26 Amgen Inc TRIAZOLOPYRIDINE COMPOUNDS AS C-MET INHIBITORS
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
CN101547910A (en) * 2006-07-28 2009-09-30 合成纤维有限公司 Crystalline Erlotinib
US7547781B2 (en) * 2006-09-11 2009-06-16 Curis, Inc. Quinazoline based EGFR inhibitors containing a zinc binding moiety
CA2662587C (en) * 2006-09-11 2013-08-06 Curis, Inc. Quinazoline based egfr inhibitors
CA2662617C (en) * 2006-09-11 2014-11-18 Changgeng Qian Quinazoline based egfr inhibitors containing a zinc binding moiety
AU2007296744A1 (en) * 2006-09-11 2008-03-20 Curis, Inc. Multi-functional small molecules as anti-proliferative agents
EP2845912A1 (en) 2006-09-12 2015-03-11 Genentech, Inc. Methods and compositions for the diagnosis and treatment of lung cancer using KIT gene as genetic marker
AU2007305423A1 (en) * 2006-09-28 2008-04-10 Follica, Inc. Methods, kits, and compositions for generating new hair follicles and growing hair
KR20090073121A (en) 2006-09-29 2009-07-02 노파르티스 아게 Pyrazolopyrimidines as PI3 'Lipid Kinase Inhibitors
US8372856B2 (en) * 2006-10-27 2013-02-12 Synthon Bv Hydrates of erlotinib hydrochloride
AU2007316417B2 (en) 2006-11-06 2013-08-22 Tolero Pharmaceuticals, Inc. Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors
EP1921070A1 (en) * 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
US20100260674A1 (en) * 2006-12-15 2010-10-14 Concert Pharmaceuticals, Inc. Quinazoline derivatives and methods of treatment
WO2008076949A2 (en) * 2006-12-15 2008-06-26 Concert Pharmaceuticals Inc. Quinazoline derivatives and methods of treatment
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
EP2118069B1 (en) 2007-01-09 2014-01-01 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
US7998949B2 (en) * 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
BRPI0807812A2 (en) 2007-02-15 2020-06-23 Novartis Ag COMBINATIONS OF LBH589 WITH OTHER THERAPEUTIC AGENTS TO TREAT CANCER
US8314087B2 (en) 2007-02-16 2012-11-20 Amgen Inc. Nitrogen-containing heterocyclyl ketones and methods of use
PT2170844T (en) * 2007-02-21 2016-08-05 Natco Pharma Ltd Novel polymorphs of erlotinib hydrochloride and method of preparation
KR101441930B1 (en) * 2007-04-04 2014-09-19 시플라 리미티드 Process for the preparation of erlotinib and its pharmaceutically acceptable salts
WO2008124824A1 (en) * 2007-04-10 2008-10-16 Myriad Genetics, Inc. Dosages and methods for the treatment of cancer
DE102007024470A1 (en) * 2007-05-24 2008-11-27 Bayer Schering Pharma Aktiengesellschaft New sulfoximine-substituted quinoline and/or quinazoline derivatives are erythropoietin-producing hepatoma amplified sequence-receptor kinase inhibitors useful to prepare medicaments to e.g. treat endometriosis and stenosis
JP2010527951A (en) * 2007-05-24 2010-08-19 バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト Novel sulfoximine substituted quinoline and quinazoline derivatives as kinase inhibitors
BRPI0813355A2 (en) * 2007-06-22 2014-12-30 Arqule Inc QUINAZOLINONE COMPOUNDS AND METHODS OF USE THEREOF
WO2009007984A2 (en) * 2007-07-11 2009-01-15 Hetero Drugs Limited An improved process for erlotinib hydrochloride
CA2692977A1 (en) * 2007-07-12 2009-01-15 Tragara Pharmaceuticals, Inc. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders
WO2009023876A1 (en) * 2007-08-16 2009-02-19 Myriad Genetics, Inc. Method of treating non-small cell lung cancer
EP2176241B1 (en) 2007-08-17 2015-12-23 Hetero Drugs Limited A novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b
EA023555B1 (en) 2007-08-21 2016-06-30 Амген Инк. HUMAN c-fms ANTIGEN BINDING PROTEINS
US20090131665A1 (en) * 2007-08-23 2009-05-21 Ales Gavenda Process for the preparation of crystalline forms A, B and pure crystalline form a of erlotinib HCI
US20090124642A1 (en) * 2007-08-23 2009-05-14 Augusto Canavesi Crystalline forms of Erlotinib HCI and formulations thereof
DE102008012435A1 (en) * 2008-02-29 2009-09-03 Schebo Biotech Ag New quinazoline compounds are tyrosin-kinase inhibitors e.g. to treat cancer, hematologic or solid tumors, non-Hodgkin tumors or T-cell lymphoma; and for the modulation of the cell cycle, cell differentiation, apoptosis or angiogenesis
HRP20130649T1 (en) 2007-09-07 2013-08-31 Agensys, Inc. Antibodies and related molecules that bind to 24p4c12 proteins
WO2009035718A1 (en) 2007-09-10 2009-03-19 Curis, Inc. Tartrate salts or complexes of quinazoline based egfr inhibitors containing a zinc binding moiety
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
EP2217580B1 (en) * 2007-10-12 2011-12-21 ArQule, Inc. Substituted tetrazole compounds and uses thereof
KR20100099128A (en) * 2007-10-19 2010-09-10 파르마 마르 에스.에이. Improved antitumoral treatments
CA2703767A1 (en) 2007-10-29 2009-05-07 Natco Pharma Limited Novel 4-(tetrazol-5-yl)-quinazoline derivatives as anti cancer agents
EP2060565A1 (en) 2007-11-16 2009-05-20 4Sc Ag Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
WO2009067543A2 (en) * 2007-11-19 2009-05-28 The Regents Of The University Of Colorado Treatment of histone deacetylase mediated disorders
EP2240475B1 (en) 2007-12-20 2013-09-25 Novartis AG Thiazole derivatives used as pi 3 kinase inhibitors
PT2229369T (en) * 2008-01-18 2016-11-24 Natco Pharma Ltd 6,7-dialkoxy-quinazoline derivatives useful for treatment of cancer-related disorders
TWI472339B (en) 2008-01-30 2015-02-11 Genentech Inc Composition comprising antibody that binds to domain ii of her2 and acidic variants thereof
AU2009209541A1 (en) * 2008-01-30 2009-08-06 Pharma Mar, S.A. Improved antitumoral treatments
CA2711582A1 (en) 2008-02-07 2009-08-13 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles, formulations containing said compounds, use thereof and processes for the preparation thereof
CN101965192A (en) * 2008-03-07 2011-02-02 法马马有限公司 Antitumoral treatments
KR101673621B1 (en) 2008-03-24 2016-11-07 노파르티스 아게 Arylsulfonamide-based matrix metalloprotease inhibitors
JP5330498B2 (en) 2008-03-26 2013-10-30 ノバルティス アーゲー Hydroxamate-based inhibitors of deacetylase B
WO2009121042A1 (en) * 2008-03-28 2009-10-01 Concert Pharmaceuticals, Inc. Quinazoline derivatives and methods of treatment
CA2723989C (en) 2008-05-13 2017-04-25 Astrazeneca Ab Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
CN101584696A (en) 2008-05-21 2009-11-25 上海艾力斯医药科技有限公司 Composition containing quinazoline derivatives, preparation method and use
EP2307386A1 (en) * 2008-07-07 2011-04-13 Plus Chemicals S.A. Crystalline forms of erlotinib base and erlotinib hcl
KR101642527B1 (en) 2008-07-08 2016-07-25 길리애드 사이언시즈, 인코포레이티드 Salts of hiv inhibitor compounds
US8648191B2 (en) * 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
CN101653606B (en) * 2008-08-19 2013-02-13 鼎泓国际投资（香港）有限公司 Pharmaceutical composition containing protein kinase B inhibitor and epidermal growth factor receptor tyrosine kinase inhibitor and application thereof
KR101132937B1 (en) 2008-10-01 2012-04-06 주식회사종근당 ?-3-ethynylphenyl-6,7-bis2-methoxyethoxy-4-quinazolinamine napsylate
WO2010040212A1 (en) * 2008-10-08 2010-04-15 Apotex Pharmachem Inc. Processes for the preparation of erlotinib hydrochloride
CN101723906B (en) * 2008-10-10 2011-09-28 山西仁源堂药业有限公司 Compound, medical composition containing same as well as preparation method and application
EP2334701A4 (en) 2008-10-16 2014-01-08 Univ Pittsburgh FULLY HUMAN ANTIBODIES DIRECTED AGAINST ANTIGEN ASSOCIATED WITH HIGH MOLECULAR WEIGHT MELANOMA AND USES THEREOF
WO2010043050A1 (en) 2008-10-16 2010-04-22 Celator Pharmaceuticals Corporation Combinations of a liposomal water-soluble camptothecin with cetuximab or bevacizumab
CA2742986C (en) * 2008-11-07 2015-03-31 Triact Therapeutics, Inc. Use of catecholic butane derivatives in cancer therapy
US20100222371A1 (en) * 2008-11-20 2010-09-02 Children's Medical Center Corporation Prevention of surgical adhesions
AU2009322158A1 (en) * 2008-12-05 2010-06-10 Arqule, Inc. RAF inhibitors and their uses
EP2676953B1 (en) 2008-12-18 2017-03-22 Novartis AG Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3 -trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid for use in the treatment of lymphocyte mediated diseases
MX2011006622A (en) 2008-12-18 2011-07-12 Novartis Ag New salts.
RU2011129230A (en) 2008-12-18 2013-01-27 Новартис Аг NEW POLYMORPHIC FORM 1- [4- [1- (4-Cyclohexyl-3-trifluoromethylbenzyloxylimino) Ethyl] -2-Ethylbenzyl] Azetidine-3-Carboxylic Acid
MX2011007620A (en) 2009-01-16 2011-11-04 Exelixis Inc N (4 - {[6,7-BIS (METILOXI) QUINOLIN-4-IL] OXI} PHENYL) -N '- (4-FLUOROPHENYL) CYCLOPROPANE-1,1-DICARBOXAMIDE, AND ITS CRYSTALLINE FORMS THE CANCER TREATMENT.
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
US20110281917A1 (en) 2009-01-29 2011-11-17 Darrin Stuart Substituted Benzimidazoles for the Treatment of Astrocytomas
US20100204221A1 (en) * 2009-02-09 2010-08-12 Hariprasad Vankayalapati Pyrrolopyrimidinyl axl kinase inhibitors
WO2010099139A2 (en) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Combination anti-cancer therapy
EP2400990A2 (en) 2009-02-26 2012-01-04 OSI Pharmaceuticals, LLC In situ methods for monitoring the emt status of tumor cells in vivo
US8642834B2 (en) 2009-02-27 2014-02-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
US8465912B2 (en) 2009-02-27 2013-06-18 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010098866A1 (en) 2009-02-27 2010-09-02 Supergen, Inc. Cyclopentathiophene/cyclohexathiophene dna methyltransferase inhibitors
WO2010107968A1 (en) 2009-03-18 2010-09-23 Osi Pharmaceuticals, Inc. Combination cancer therapy comprising administration of an egfr inhibitor and an igf-1r inhibitor
AR075896A1 (en) 2009-03-20 2011-05-04 Genentech Inc ANTI-HER ANTIBODIES (EPIDERMAL GROWTH FACTOR)
EP2236139A1 (en) 2009-03-31 2010-10-06 F. Hoffmann-La Roche AG Combination therapy of erlotinib with an anti-IGF-1R antibody, which does not inhibit binding of insulin to the insulin receptor
CN102746242A (en) * 2009-04-16 2012-10-24 欧美嘉股份有限公司 Synthesis method of 6, 7-substituent-4-aniline quinazoline
WO2010120386A1 (en) 2009-04-17 2010-10-21 Nektar Therapeutics Oligomer-protein tyrosine kinase inhibitor conjugates
HRP20140593T1 (en) 2009-06-26 2014-08-01 Novartis Ag 1, 3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
US9050341B2 (en) 2009-07-14 2015-06-09 Natco Pharma Limited Methods of treating drug resistant and other tumors by administering 6,7-dialkoxy quinazoline derivatives
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
UA108618C2 (en) 2009-08-07 2015-05-25 APPLICATION OF C-MET-MODULATORS IN COMBINATION WITH THEMOSOLOMID AND / OR RADIATION THERAPY FOR CANCER TREATMENT
WO2011018454A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
IN2012DN01961A (en) 2009-08-17 2015-08-21 Intellikine Llc
MX2012002179A (en) 2009-08-20 2012-03-16 Novartis Ag Heterocyclic oxime compounds.
MX2012002420A (en) 2009-08-26 2012-06-27 Novartis Ag Tetra-substituted heteroaryl compounds and their use as mdm2 and/or mdm4 modulators.
CA2779935A1 (en) 2009-11-04 2011-05-12 Novartis Ag Heterocyclic sulfonamide derivatives useful as mek inhibitors
EP2499118A2 (en) 2009-11-12 2012-09-19 Ranbaxy Laboratories Limited Processes for the preparation of erlotinib hydrochloride form a and erlotinib hydrochloride form b
TW201121570A (en) 2009-11-12 2011-07-01 Genentech Inc A method of promoting dendritic spine density
ES2781299T3 (en) 2009-11-13 2020-09-01 Daiichi Sankyo Europe Gmbh Materials and methods to treat or prevent diseases associated with HER-3
WO2011058164A1 (en) 2009-11-13 2011-05-19 Pangaea Biotech, S.A. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
US20110130711A1 (en) * 2009-11-19 2011-06-02 Follica, Inc. Hair growth treatment
MX2012005987A (en) 2009-11-23 2012-06-25 Cerulean Pharma Inc Cyclodextrin-based polymers for therapeutic delivery.
WO2011068403A2 (en) 2009-12-02 2011-06-09 Ultimorphix Technologies B.V. Novel n-{3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamjne salts
CN102648188A (en) 2009-12-08 2012-08-22 诺瓦提斯公司 Heterocyclic sulfonamide derivatives
CU24130B1 (en) 2009-12-22 2015-09-29 Novartis Ag ISOQUINOLINONES AND REPLACED QUINAZOLINONES
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
EP2348020A1 (en) 2009-12-23 2011-07-27 Esteve Química, S.A. Preparation process of erlotinib
EP2523957A1 (en) 2010-01-12 2012-11-21 F. Hoffmann-La Roche AG Tricyclic heterocyclic compounds, compositions and methods of use thereof
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
WO2011098971A1 (en) 2010-02-12 2011-08-18 Pfizer Inc. Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one
CA2784211C (en) 2010-02-18 2019-12-24 Genentech, Inc. Neuregulin antagonists and use thereof in treating cancer
US20110275644A1 (en) 2010-03-03 2011-11-10 Buck Elizabeth A Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
EP2542893A2 (en) 2010-03-03 2013-01-09 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
KR20130001272A (en) 2010-03-17 2013-01-03 에프. 호프만-라 로슈 아게 Imidazopyridine compounds, compositions and methods of use
WO2011119995A2 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations and methods of use
JP2013528787A (en) 2010-04-16 2013-07-11 ジェネンテック， インコーポレイテッド FOX03A as a predictive biomarker of the effects of PI3K / AKT kinase pathway inhibitors
BR112012028964A2 (en) 2010-05-21 2016-07-26 Shanghai Inst Pharm Industry polycyclic quinazolines, their method of preparation and their uses
ES2611479T3 (en) 2010-06-16 2017-05-09 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Endoplasmin antibodies and their use
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
CN102311438A (en) * 2010-06-30 2012-01-11 和记黄埔医药（上海）有限公司 Quinazoline compound
UA112517C2 (en) 2010-07-06 2016-09-26 Новартіс Аг TETRAHYDROPYRIDOPYRIMIDINE DERIVATIVES
NZ628796A (en) 2010-07-23 2016-02-26 Generics Uk Ltd Pure erlotinib
AR082418A1 (en) 2010-08-02 2012-12-05 Novartis Ag CRYSTAL FORMS OF 1- (4-METHYL-5- [2- (2,2,2-TRIFLUORO-1,1-DIMETHYL-Ethyl) -PIRIDIN-4-IL] -TIAZOL-2-IL) -AMIDE OF 2 -AMIDA OF THE ACID (S) -PIRROLIDIN-1,2-DICARBOXILICO
CA2815154A1 (en) 2010-08-06 2012-02-09 U3 Pharma Gmbh Use of her3 binding agents in prostate treatment
CN101914068A (en) * 2010-08-14 2010-12-15 浙江华海药业股份有限公司 Novel crystal form of erlotinib alkali and preparation method thereof
RU2013114360A (en) 2010-08-31 2014-10-10 Дженентек, Инк. BIOMARKERS AND TREATMENT METHODS
RU2013114352A (en) 2010-09-15 2014-10-20 Ф. Хоффманн-Ля Рош Аг AZABENZENESIAZOLES, COMPOSITIONS AND METHODS OF APPLICATION
WO2012035078A1 (en) 2010-09-16 2012-03-22 Novartis Ag 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
CA2817785A1 (en) 2010-11-19 2012-05-24 Toby Blench Pyrazolopyridines and pyrazolopyridines and their use as tyk2 inhibitors
EP2643351A1 (en) 2010-11-24 2013-10-02 Glaxo Group Limited Multispecific antigen binding proteins targeting hgf
CN102557977B (en) * 2010-12-20 2014-07-30 浙江海正药业股份有限公司 Synthesis intermediate of erlotinib and preparation method thereof
EP2655340B1 (en) 2010-12-21 2015-01-21 Novartis AG Bi-heteroaryl compounds as vps34 inhibitors
EP2468883A1 (en) 2010-12-22 2012-06-27 Pangaea Biotech S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
WO2012085176A1 (en) 2010-12-23 2012-06-28 F. Hoffmann-La Roche Ag Tricyclic pyrazinone compounds, compositions and methods of use thereof as janus kinase inhibitors
US9134297B2 (en) 2011-01-11 2015-09-15 Icahn School Of Medicine At Mount Sinai Method and compositions for treating cancer and related methods
WO2012104776A1 (en) 2011-01-31 2012-08-09 Novartis Ag Novel heterocyclic derivatives
WO2012107500A1 (en) 2011-02-10 2012-08-16 Novartis Ag [1, 2, 4] triazolo [4, 3 -b] pyridazine compounds as inhibitors of the c-met tyrosine kinase
US20120214830A1 (en) 2011-02-22 2012-08-23 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma
EP2492688A1 (en) 2011-02-23 2012-08-29 Pangaea Biotech, S.A. Molecular biomarkers for predicting response to antitumor treatment in lung cancer
WO2012116237A2 (en) 2011-02-23 2012-08-30 Intellikine, Llc Heterocyclic compounds and uses thereof
ES2609578T3 (en) 2011-03-04 2017-04-21 Glaxosmithkline Intellectual Property Development Limited Amino-quinolines as kinase inhibitors
WO2012122058A2 (en) 2011-03-04 2012-09-13 Newgen Therapeutics, Inc. Alkyne substituted quinazoline compound and methods of use
WO2012129145A1 (en) 2011-03-18 2012-09-27 OSI Pharmaceuticals, LLC Nscle combination therapy
ES2620521T3 (en) 2011-03-23 2017-06-28 Amgen Inc. Dual condensed tricyclic inhibitors of CDK 4/6 and FLT3
ITPD20110091A1 (en) 2011-03-24 2012-09-25 Univ Padova USEFUL INHIBITORS FOR RELATED PATHOLOGIES: PHARMACOFORIC MODELS, IDENTIFIED COMPOUNDS BY THESE MODELS, METHODS FOR THEIR PREPARATION, THEIR FORMULATION AND THEIR THERAPEUTIC USE.
KR20140025434A (en) * 2011-04-01 2014-03-04 제넨테크, 인크. Combinations of akt inhibitor compounds and chemotherapeutic agents, and methods of use
WO2012142164A1 (en) 2011-04-12 2012-10-18 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Human monoclonal antibodies that bind insulin-like growth factor (igf) i and ii
CA3019531A1 (en) 2011-04-19 2012-10-26 Pfizer Inc. Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer
WO2012149014A1 (en) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment
CA2834224A1 (en) 2011-04-28 2012-11-01 Novartis Ag 17.alpha.-hydroxylase/c17,20-lyase inhibitors
WO2012150606A2 (en) 2011-05-03 2012-11-08 Cadila Healthcare Limited A process for preparing stable polymophic form of erlotinib hydrochloride
WO2012155339A1 (en) 2011-05-17 2012-11-22 江苏康缘药业股份有限公司 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof
CN102796109B (en) * 2011-05-23 2015-10-07 复旦大学 4-Aminoquinazolines compounds and its production and use
EP2718276A1 (en) 2011-06-09 2014-04-16 Novartis AG Heterocyclic sulfonamide derivatives
US8859535B2 (en) 2011-06-20 2014-10-14 Novartis Ag Hydroxy substituted isoquinolinone derivatives
EP2721007B1 (en) 2011-06-20 2015-04-29 Novartis AG Cyclohexyl isoquinolinone compounds
CA2840315A1 (en) 2011-06-27 2013-01-03 Novartis Ag Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives
US8575339B2 (en) * 2011-07-05 2013-11-05 Xueheng Cheng Derivatives of erlotinib
WO2013007765A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Fused tricyclic compounds for use as inhibitors of janus kinases
WO2013007768A1 (en) 2011-07-13 2013-01-17 F. Hoffmann-La Roche Ag Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors
US9416132B2 (en) 2011-07-21 2016-08-16 Tolero Pharmaceuticals, Inc. Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
JP5855253B2 (en) 2011-08-12 2016-02-09 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Indazole compounds, compositions and methods of use
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
US12194002B2 (en) 2011-08-17 2025-01-14 Dennis Brown Compositions and methods to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dibromodulcitol
CN103890007A (en) 2011-08-17 2014-06-25 霍夫曼-拉罗奇有限公司 Neuregulin antibodies and uses thereof
TWI547494B (en) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 Aminoquinazolines as kinase inhibitors
US20130084286A1 (en) 2011-08-31 2013-04-04 Thomas E. Januario Diagnostic markers
US9062045B2 (en) 2011-09-15 2015-06-23 Novartis Ag Triazolopyridine compounds
EP2758397A1 (en) 2011-09-20 2014-07-30 F.Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
SG11201400996SA (en) 2011-09-30 2014-04-28 Genentech Inc Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to egfr kinase inhibitor in tumours or tumour cells
WO2013050725A1 (en) 2011-10-04 2013-04-11 King's College London Ige anti -hmw-maa antibody
KR20140090218A (en) 2011-10-28 2014-07-16 노파르티스 아게 Novel purine derivatives and their use in the treatment of disease
CN104271599A (en) 2011-11-08 2015-01-07 辉瑞公司 Methods of treating inflammatory disorders using anti-M-CSF antibodies
EP2785717B1 (en) 2011-11-29 2016-01-13 Novartis AG Pyrazolopyrrolidine compounds
WO2013081645A2 (en) 2011-11-30 2013-06-06 Genentech, Inc. Erbb3 mutations in cancer
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
PL2794600T3 (en) 2011-12-22 2018-06-29 Novartis Ag 2,3-Dihydro-benzo[1,4]oxazine derivatives and related compounds as phosphoinositide-3 kinase (PI3K) inhibitors for the treatment of e.g. rheumatoid arthritis
US20150148377A1 (en) 2011-12-22 2015-05-28 Novartis Ag Quinoline Derivatives
AU2012355619A1 (en) 2011-12-23 2014-07-17 Novartis Ag Compounds for inhibiting the interaction of BCL2 with binding partners
JP2015503519A (en) 2011-12-23 2015-02-02 ノバルティス アーゲー Compound for inhibiting interaction between BCL2 and binding partner
CA2859862A1 (en) 2011-12-23 2013-06-27 Novartis Ag Compounds for inhibiting the interaction of bcl2 with binding partners
JP2015503518A (en) 2011-12-23 2015-02-02 ノバルティス アーゲー Compound for inhibiting interaction between BCL2 and binding partner
EP2794589A1 (en) 2011-12-23 2014-10-29 Novartis AG Compounds for inhibiting the interaction of bcl2 with binding partners
US20130178520A1 (en) 2011-12-23 2013-07-11 Duke University Methods of treatment using arylcyclopropylamine compounds
UY34591A (en) 2012-01-26 2013-09-02 Novartis Ag IMIDAZOPIRROLIDINONA COMPOUNDS
CN104204226A (en) 2012-01-31 2014-12-10 史密斯克莱.比奇曼（科克）有限公司 ways to treat cancer
AR090263A1 (en) 2012-03-08 2014-10-29 Hoffmann La Roche COMBINED ANTIBODY THERAPY AGAINST HUMAN CSF-1R AND USES OF THE SAME
JP2015514710A (en) 2012-03-27 2015-05-21 ジェネンテック， インコーポレイテッド Diagnosis and treatment of HER3 inhibitors
MX371119B (en) 2012-04-03 2020-01-17 Novartis Ag Combination products with tyrosine kinase inhibitors and their use.
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
CN102659692B (en) 2012-05-04 2014-04-09 郑州泰基鸿诺药物科技有限公司 Double-linked Erlotinib and preparation method thereof
CN104349779A (en) 2012-05-16 2015-02-11 诺华股份有限公司 Dosage regimen for a pi-3 kinase inhibitor
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
CN103420924B (en) * 2012-05-25 2016-08-31 浙江九洲药业股份有限公司 A kind of preparation method of Erlotinib hydrochloride crystal form A
BR112014031421A2 (en) 2012-06-15 2017-06-27 Brigham & Womens Hospital Inc cancer treatment compositions and methods for producing them
WO2013190089A1 (en) 2012-06-21 2013-12-27 Pangaea Biotech, S.L. Molecular biomarkers for predicting outcome in lung cancer
CN102887835A (en) * 2012-07-24 2013-01-23 连云港盛和生物科技有限公司 Method for synthesizing 2-amino-4,5-bis-(2-methoxyethoxy)cyanophenyl
CN102827086A (en) * 2012-08-03 2012-12-19 浙江理工大学 Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline
WO2014025395A1 (en) 2012-08-06 2014-02-13 Duke University Compounds and methods for targeting hsp90
EP2890696A1 (en) 2012-08-29 2015-07-08 Amgen, Inc. Quinazolinone compounds and derivatives thereof
WO2014037961A1 (en) 2012-09-04 2014-03-13 Shilpa Medicare Limited Crystalline erlotinib hydrochloride process
TWI592417B (en) 2012-09-13 2017-07-21 葛蘭素史克智慧財產發展有限公司 Aminoquinazoline kinase inhibitor prodrug
WO2014062838A2 (en) 2012-10-16 2014-04-24 Tolero Pharmaceuticals, Inc. Pkm2 modulators and methods for their use
CN110787285B (en) 2012-11-05 2025-06-13 达纳-法伯癌症研究所股份有限公司 XBP1, CD138 and CS1 peptides, pharmaceutical compositions comprising the peptides, and methods of using the peptides and compositions
TW201422625A (en) 2012-11-26 2014-06-16 Novartis Ag Solid form of dihydro-pyrido-oxazine derivative
US9260426B2 (en) 2012-12-14 2016-02-16 Arrien Pharmaceuticals Llc Substituted 1H-pyrrolo [2, 3-b] pyridine and 1H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors
EP2943484B1 (en) 2013-01-10 2017-10-25 Glaxosmithkline Intellectual Property (No. 2) Limited Fatty acid synthase inhibitors
EP2948451B1 (en) 2013-01-22 2017-07-12 Novartis AG Substituted purinone compounds
WO2014115080A1 (en) 2013-01-22 2014-07-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
HUE046961T2 (en) 2013-02-20 2020-04-28 Univ Pennsylvania Treatment of cancer using a chimeric antigen receptor against humanized EGFRVIII
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
AR094707A1 (en) 2013-02-21 2015-08-19 Glaxosmithkline Ip Dev Ltd COMPOUND OF QUINAZOLIN-4-AMINA, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE FOR THE TREATMENT OF A DISEASE MEDIATED BY THE RIP2 KINASE
JP2016509045A (en) 2013-02-22 2016-03-24 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト How to treat cancer and prevent drug resistance
AU2014223548A1 (en) 2013-02-26 2015-10-15 Triact Therapeutics, Inc. Cancer therapy
JP2016510751A (en) 2013-03-06 2016-04-11 ジェネンテック， インコーポレイテッド Methods of treating and preventing anticancer drug resistance
BR112015022545A2 (en) 2013-03-13 2017-07-18 Constellation Pharmaceuticals Inc pyrazole compounds and the uses thereof
EP2968540A2 (en) 2013-03-14 2016-01-20 Genentech, Inc. Combinations of a mek inhibitor compound with an her3/egfr inhibitor compound and methods of use
CA2905993C (en) 2013-03-14 2022-12-06 Tolero Pharmaceuticals, Inc. Substituted 4-amino-pyrimidinyl-2-amino-phenyl derivatives and pharmaceutical compositions thereof for use as jak2 and alk2 inhibitors
EP2968565A2 (en) 2013-03-14 2016-01-20 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
CN105339001A (en) 2013-03-15 2016-02-17 基因泰克公司 Ways to treat cancer and prevent cancer resistance
WO2014151147A1 (en) 2013-03-15 2014-09-25 Intellikine, Llc Combination of kinase inhibitors and uses thereof
EP2976085A1 (en) 2013-03-21 2016-01-27 INSERM - Institut National de la Santé et de la Recherche Médicale Method and pharmaceutical composition for use in the treatment of chronic liver diseases associated with a low hepcidin expression
WO2014155268A2 (en) 2013-03-25 2014-10-02 Novartis Ag Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity
ES2638317T3 (en) 2013-04-04 2017-10-19 Janssen Pharmaceutica Nv New derivatives of N- (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -4-quinazolinamine and N- (2,3-dihydro-1H-indole-5-yl) -4-quinazolinamine as PERK inhibitors
WO2014168986A1 (en) 2013-04-08 2014-10-16 Brown Dennis M Therapeutic benefit of suboptimally administered chemical compounds
US9206188B2 (en) 2013-04-18 2015-12-08 Arrien Pharmaceuticals Llc Substituted pyrrolo[2,3-b]pyridines as ITK and JAK inhibitors
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
CN103333124B (en) * 2013-05-28 2015-03-25 埃斯特维华义制药有限公司 Preparation method of hydrochloric acid erlotinib crystal form F
UY35675A (en) 2013-07-24 2015-02-27 Novartis Ag SUBSTITUTED DERIVATIVES OF QUINAZOLIN-4-ONA
TW201536291A (en) * 2013-08-02 2015-10-01 Cephalon Inc Methods of treating various cancers using an AXL/cMET inhibitor alone or in combination with other agents
WO2015022664A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
WO2015022663A1 (en) 2013-08-14 2015-02-19 Novartis Ag Compounds and compositions as inhibitors of mek
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
TW201605896A (en) 2013-08-30 2016-02-16 安美基股份有限公司 GITR antigen binding proteins
CA2922925A1 (en) 2013-09-05 2015-03-12 Genentech, Inc. Antiproliferative compounds
US9381246B2 (en) 2013-09-09 2016-07-05 Triact Therapeutics, Inc. Cancer therapy
JP6494633B2 (en) 2013-09-22 2019-04-03 キャリター・サイエンシーズ・リミテッド・ライアビリティ・カンパニーＣａｌｉｔｏｒ Ｓｃｉｅｎｃｅｓ， Ｌｌｃ Aminopyrimidine compounds substituted and methods of use
AR097894A1 (en) 2013-10-03 2016-04-20 Hoffmann La Roche CDK8 THERAPEUTIC INHIBITORS OR USE OF THE SAME
DK3052102T3 (en) 2013-10-04 2020-03-09 Aptose Biosciences Inc CANCER TREATMENT COMPOSITIONS
MX2016004802A (en) 2013-10-18 2016-07-18 Genentech Inc Anti-rsp02 and/or anti-rsp03 antibodies and their uses.
TW201605450A (en) 2013-12-03 2016-02-16 諾華公司 Combination of Mdm2 inhibitor and BRAF inhibitor and their use
MX378409B (en) 2013-12-06 2025-03-10 Novartis Ag DOSAGE REGIMEN FOR AN ALPHA-ISOMORPHIC SELECTIVE PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR.
CN103709110B (en) * 2013-12-13 2016-05-04 浙江普洛康裕制药有限公司 A kind of preparation method of erlotinid hydrochloride key intermediate
CN112353943A (en) 2013-12-17 2021-02-12 豪夫迈·罗氏有限公司 Methods of treating cancer with PD-1 axis binding antagonists and taxanes
JP2017501167A (en) 2013-12-17 2017-01-12 ジェネンテック， インコーポレイテッド Combination therapy comprising OX40 binding agonist and PD-1 axis binding antagonist
US20160361309A1 (en) 2014-02-26 2016-12-15 Glaxosmithkline Intellectual Property (No.2) Limited Methods of treating cancer patients responding to ezh2 inhibitor gsk126
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
WO2015145388A2 (en) 2014-03-27 2015-10-01 Novartis Ag Methods of treating colorectal cancers harboring upstream wnt pathway mutations
WO2015148869A1 (en) 2014-03-28 2015-10-01 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
CA2943834A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
CN106103486B (en) 2014-03-31 2020-04-21 豪夫迈·罗氏有限公司 Anti-OX40 antibodies and methods of use
AU2015241198A1 (en) 2014-04-03 2016-11-17 Invictus Oncology Pvt. Ltd. Supramolecular combinatorial therapeutics
CN103980207B (en) * 2014-04-04 2016-03-09 亿腾药业（泰州）有限公司 A kind of synthetic method of erlotinib hydrochloride B type crystal
US20170027940A1 (en) 2014-04-10 2017-02-02 Stichting Het Nederlands Kanker Instituut Method for treating cancer
WO2015169932A1 (en) 2014-05-07 2015-11-12 Pharos Generics Ltd Polymorph purity, monitoring and associated compositions
KR101592258B1 (en) 2014-06-20 2016-02-05 보령제약 주식회사 formulation and method of preparing the same
CN104193689B (en) * 2014-07-23 2017-02-08 大连理工大学 Method for synthesizing erlotinib hydrochloride
WO2016011658A1 (en) 2014-07-25 2016-01-28 Novartis Ag Combination therapy
EP3473271B1 (en) 2014-07-31 2022-07-20 The Government of the United States of America as represented by the Secretary of the Department of Health and Human Services Human monoclonal antibodies against epha4 and their use
MX373272B (en) 2014-07-31 2020-04-16 Novartis Ag Combination therapy
CN107074823B (en) 2014-09-05 2021-05-04 基因泰克公司 Therapeutic compounds and their uses
JP2017529358A (en) 2014-09-19 2017-10-05 ジェネンテック， インコーポレイテッド Use of CBP / EP300 inhibitors and BET inhibitors for the treatment of cancer
JP6783230B2 (en) 2014-10-10 2020-11-11 ジェネンテック， インコーポレイテッド Pyrrolidone amide compounds as inhibitors of histone demethylase
KR20170086540A (en) 2014-11-03 2017-07-26 제넨테크, 인크. Assays for detecting t cell immune subsets and methods of use thereof
RU2017119231A (en) 2014-11-03 2018-12-06 Дженентек, Инк. METHODS AND BIOMARKERS FOR PREDICTING EFFICIENCY AND EVALUATING TREATMENT WITH OX40 AGONIST
RU2017119428A (en) 2014-11-06 2018-12-06 Дженентек, Инк. COMBINED THERAPY, INCLUDING THE USE OF OX40-CONNECTING AGONISTS AND TIGIT INHIBITORS
WO2016077375A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Bromodomain inhibitors and uses thereof
MA40940A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
KR20170096112A (en) 2014-11-17 2017-08-23 제넨테크, 인크. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
US9763922B2 (en) 2014-11-27 2017-09-19 Genentech, Inc. Therapeutic compounds and uses thereof
JP6621477B2 (en) 2014-12-18 2019-12-18 ファイザー・インク Pyrimidine and triazine derivatives and their use as AXL inhibitors
KR20170094165A (en) 2014-12-23 2017-08-17 제넨테크, 인크. Compositions and methods for treating and diagnosing chemotherapy-resistant cancers
WO2016105503A1 (en) 2014-12-24 2016-06-30 Genentech, Inc. Therapeutic, diagnostic and prognostic methods for cancer of the bladder
CN107208138A (en) 2014-12-30 2017-09-26 豪夫迈·罗氏有限公司 Methods and compositions for cancer prognosis and treatment
CN107406414B (en) 2015-01-09 2022-04-19 基因泰克公司 (piperidin-3-yl) (naphthalen-2-yl) methanone derivatives as inhibitors of histone demethylase KDM2B for the treatment of cancer
CN107406429B (en) 2015-01-09 2021-07-06 基因泰克公司 Pyridazinone derivatives and their use in the treatment of cancer
CN107406418B (en) 2015-01-09 2021-10-29 基因泰克公司 4,5-Dihydroimidazole derivatives and their use as histone demethylase (KDM2B) inhibitors
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
WO2016123391A1 (en) 2015-01-29 2016-08-04 Genentech, Inc. Therapeutic compounds and uses thereof
JP6636031B2 (en) 2015-01-30 2020-01-29 ジェネンテック， インコーポレイテッド Therapeutic compounds and uses thereof
US20180050993A1 (en) * 2015-02-03 2018-02-22 Trillium Therapeutics Inc. Novel fluorinated derivatives as egfr inhibitors useful for treating cancers
MA41598A (en) 2015-02-25 2018-01-02 Constellation Pharmaceuticals Inc PYRIDAZINE THERAPEUTIC COMPOUNDS AND THEIR USES
CA2981183A1 (en) 2015-04-07 2016-10-13 Greg Lazar Antigen binding complex having agonistic activity and methods of use
WO2016172214A1 (en) 2015-04-20 2016-10-27 Tolero Pharmaceuticals, Inc. Predicting response to alvocidib by mitochondrial profiling
EP3288957A4 (en) 2015-05-01 2019-01-23 Cocrystal Pharma, Inc. NUCLEOSIDE ANALOGUES FOR USE IN THE TREATMENT OF FLAVIVIRIDAE AND CANCER FAMILY VIRUS INFECTIONS
IL295002A (en) 2015-05-12 2022-09-01 Genentech Inc Therapeutic and diagnostic methods for cancer comprising a pd-l1 binding antagonist
DK3527574T3 (en) 2015-05-18 2022-06-27 Sumitomo Pharma Oncology Inc ALVOCIDIB PRODUCTS THAT HAVE INCREASED BIO-AVAILABILITY
HK1248773A1 (en) 2015-05-29 2018-10-19 豪夫迈‧罗氏有限公司 Therapeutic and diagnostic methods for cancer
EP3303397A1 (en) 2015-06-08 2018-04-11 H. Hoffnabb-La Roche Ag Methods of treating cancer using anti-ox40 antibodies and pd-1 axis binding antagonists
MX2017014740A (en) 2015-06-08 2018-08-15 Genentech Inc Methods of treating cancer using anti-ox40 antibodies.
HK1251493A1 (en) 2015-06-17 2019-02-01 豪夫迈‧罗氏有限公司 Methods of treating locally advanced or metastatic breast cancers using pd-1 axis binding antagonists and taxanes
AU2016301315C1 (en) 2015-08-03 2022-07-07 Sumitomo Pharma Oncology, Inc. Combination therapies for treatment of cancer
US20180230431A1 (en) 2015-08-07 2018-08-16 Glaxosmithkline Intellectual Property Development Limited Combination Therapy
AU2016313263B2 (en) 2015-08-26 2021-02-04 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Condensed tricyclic compounds as protein kinase inhibitors
US9938257B2 (en) 2015-09-11 2018-04-10 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
HRP20241752T1 (en) 2015-09-25 2025-02-28 F. Hoffmann - La Roche Ag ANTI-TIGIT ANTIBODIES AND METHODS OF USE
CA3002954A1 (en) 2015-11-02 2017-05-11 Novartis Ag Dosage regimen for a phosphatidylinositol 3-kinase inhibitor
EP4015537A1 (en) 2015-12-01 2022-06-22 GlaxoSmithKline Intellectual Property Development Limited Combination treatments and uses and methods thereof
PL3978500T3 (en) 2015-12-16 2024-03-11 Genentech, Inc. Process for the preparation of tricyclic pi3k inhibitor compounds
EP3400246B1 (en) 2016-01-08 2020-10-21 H. Hoffnabb-La Roche Ag Methods of treating cea-positive cancers using pd-1 axis binding antagonists and anti-cea/anti-cd3 bispecific antibodies
JP6821693B2 (en) 2016-02-29 2021-01-27 ジェネンテック， インコーポレイテッド Treatment and diagnosis for cancer
CA3016894A1 (en) 2016-03-08 2017-09-14 Janssen Biotech, Inc. Gitr antibodies, methods, and uses
US20170319688A1 (en) 2016-04-14 2017-11-09 Genentech, Inc. Anti-rspo3 antibodies and methods of use
WO2017181079A2 (en) 2016-04-15 2017-10-19 Genentech, Inc. Methods for monitoring and treating cancer
CA3018406A1 (en) 2016-04-15 2017-10-19 Genentech, Inc. Diagnostic and therapeutic methods for cancer
CN109154613A (en) 2016-04-15 2019-01-04 豪夫迈·罗氏有限公司 For monitoring and the method for the treatment of cancer
US11261187B2 (en) 2016-04-22 2022-03-01 Duke University Compounds and methods for targeting HSP90
EP3464286B1 (en) 2016-05-24 2021-08-18 Genentech, Inc. Pyrazolopyridine derivatives for the treatment of cancer
EP4067347B1 (en) 2016-05-24 2024-06-19 Genentech, Inc. Heterocyclic inhibitors of cbp/ep300 for the treatment of cancer
WO2017214373A1 (en) 2016-06-08 2017-12-14 Genentech, Inc. Diagnostic and therapeutic methods for cancer
AU2017294772B2 (en) 2016-07-14 2024-05-02 Scholar Rock, Inc. TGFB antibodies, methods, and uses
EP3494140A1 (en) 2016-08-04 2019-06-12 GlaxoSmithKline Intellectual Property Development Ltd Anti-icos and anti-pd-1 antibody combination therapy
CN109963871A (en) 2016-08-05 2019-07-02 豪夫迈·罗氏有限公司 Multivalent and multiepitopic antibodies with agonistic activity and methods of use
WO2018029124A1 (en) 2016-08-08 2018-02-15 F. Hoffmann-La Roche Ag Therapeutic and diagnostic methods for cancer
US20190209669A1 (en) 2016-08-23 2019-07-11 Oncopep, Inc. Peptide vaccines and durvalumab for treating breast cancer
WO2018039203A1 (en) 2016-08-23 2018-03-01 Oncopep, Inc. Peptide vaccines and durvalumab for treating multiple myeloma
WO2018060833A1 (en) 2016-09-27 2018-04-05 Novartis Ag Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib
WO2018064076A1 (en) 2016-09-27 2018-04-05 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
US10207998B2 (en) 2016-09-29 2019-02-19 Duke University Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
CA3038712A1 (en) 2016-10-06 2018-04-12 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP3532091A2 (en) 2016-10-29 2019-09-04 H. Hoffnabb-La Roche Ag Anti-mic antibidies and methods of use
WO2018094275A1 (en) 2016-11-18 2018-05-24 Tolero Pharmaceuticals, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
CA3047557A1 (en) 2016-12-19 2018-06-28 Tolero Pharmaceuticals, Inc. Profiling peptides and methods for sensitivity profiling
SG11201906223TA (en) 2016-12-22 2019-08-27 Amgen Inc Benzisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as kras g12c inhibitors for treating lung, pancreatic or colorectal cancer
EP3589754B1 (en) 2017-03-01 2023-06-28 F. Hoffmann-La Roche AG Diagnostic and therapeutic methods for cancer
WO2018189220A1 (en) 2017-04-13 2018-10-18 F. Hoffmann-La Roche Ag An interleukin-2 immunoconjugate, a cd40 agonist, and optionally a pd-1 axis binding antagonist for use in methods of treating cancer
JOP20190272A1 (en) 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
TWI823859B (en) 2017-07-21 2023-12-01 美商建南德克公司 Therapeutic and diagnostic methods for cancer
WO2019027920A1 (en) 2017-08-01 2019-02-07 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections
EP3665197A2 (en) 2017-08-11 2020-06-17 H. Hoffnabb-La Roche Ag Anti-cd8 antibodies and uses thereof
MX2020002553A (en) 2017-09-08 2020-07-22 Hoffmann La Roche DIAGNOSTIC AND THERAPEUTIC METHODS FOR CANCER.
UY37870A (en) 2017-09-08 2019-03-29 Amgen Inc KRAS G12C INHIBITORS AND METHODS TO USE THEM FIELD OF THE INVENTION
JP7196160B2 (en) 2017-09-12 2022-12-26 スミトモ ファーマ オンコロジー， インコーポレイテッド Treatment Regimens for Cancers Insensitive to BCL-2 Inhibitors Using the MCL-1 Inhibitor Albocidib
DK3688032T3 (en) 2017-09-26 2025-12-15 Cero Therapeutics Holdings Inc CHIMERIC ENGULFMENT RECEPTOR MOLECULES AND METHODS OF USE
US20200237766A1 (en) 2017-10-13 2020-07-30 Tolero Pharmaceuticals, Inc. Pkm2 activators in combination with reactive oxygen species for treatment of cancer
WO2019083962A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. Peptide vaccines and pembrolizumab for treating breast cancer
WO2019083960A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. Peptide vaccines and hdac inhibitors for treating multiple myeloma
EP3710001B1 (en) 2017-10-27 2025-06-18 University Of Virginia Patent Foundation Compounds and methods for regulating, limiting, or inhibiting avil expression
PL3707510T3 (en) 2017-11-06 2024-09-30 F. Hoffmann-La Roche Ag Diagnostic and therapeutic methods for cancer
EP3710006A4 (en) 2017-11-19 2021-09-01 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use
AU2019207535B2 (en) 2018-01-15 2021-12-23 Epiaxis Therapeutics Pty Ltd Agents and methods for predicting response to therapy
EP3740468B1 (en) 2018-01-20 2025-12-31 Sunshine Lake Pharma Co., Ltd. SUBSTITUTED AMINOPYRIMIDEN COMPOUNDS AND METHOD FOR USE
WO2019147552A1 (en) 2018-01-25 2019-08-01 The Cleveland Clinic Foundation Compounds for treating ilk-mediated diseases
CN108358798A (en) * 2018-02-12 2018-08-03 黑龙江鑫创生物科技开发有限公司 A kind of method of micro passage reaction synthesis Tarceva intermediate
CA3092108A1 (en) 2018-02-26 2019-08-29 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
US20210024607A1 (en) 2018-03-28 2021-01-28 Cero Therapeutics, Inc. Expression vectors for chimeric engulfment receptors, genetically modified host cells, and uses thereof
US12291557B2 (en) 2018-03-28 2025-05-06 Cero Therapeutics Holdings, Inc. Chimeric TIM4 receptors and uses thereof
KR20210024443A (en) 2018-03-28 2021-03-05 세로 테라퓨틱스, 인코포레이티드 Cellular immunotherapy composition and use thereof
CA3099118A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
MA52501A (en) 2018-05-04 2021-03-10 Amgen Inc KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE
MX2020011907A (en) 2018-05-10 2021-01-29 Amgen Inc Kras g12c inhibitors for the treatment of cancer.
CA3100200A1 (en) 2018-05-21 2019-11-28 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
AU2019278998B2 (en) 2018-06-01 2023-11-09 Amgen Inc. KRAS G12C inhibitors and methods of using the same
JP7357644B2 (en) 2018-06-11 2023-10-06 アムジエン・インコーポレーテツド KRAS G12C inhibitors for treating cancer
AU2019336588B2 (en) 2018-06-12 2022-07-28 Amgen Inc. KRAS G12C inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer
MY205645A (en) 2018-06-23 2024-11-02 Genentech Inc Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor
AU2019305637A1 (en) 2018-07-18 2021-03-11 Genentech, Inc. Methods of treating lung cancer with a PD-1 axis binding antagonist, an antimetabolite, and a platinum agent
EP3826988A4 (en) 2018-07-24 2023-03-22 Hygia Pharmaceuticals, LLC COMPOUNDS, DERIVATIVES AND ANALOGS AGAINST CANCER
JP2021530554A (en) 2018-07-26 2021-11-11 スミトモ ダイニッポン ファーマ オンコロジー， インコーポレイテッド Methods and ACVR1 Inhibitors for Treatment of Diseases with Abnormal ACVR1 Expression
TW202024023A (en) 2018-09-03 2020-07-01 瑞士商赫孚孟拉羅股份公司 Therapeutic compounds and methods of use
AU2019342099A1 (en) 2018-09-19 2021-04-08 Genentech, Inc. Therapeutic and diagnostic methods for bladder cancer
JP7475336B2 (en) 2018-09-21 2024-04-26 ジェネンテック， インコーポレイテッド Diagnostic methods for triple-negative breast cancer
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas
WO2020077409A1 (en) 2018-10-17 2020-04-23 The University Of Queensland Epigenetic biomarker and uses therefor
KR20210079311A (en) 2018-10-18 2021-06-29 제넨테크, 인크. Diagnosis and treatment methods for sarcoma renal cancer
JP7516029B2 (en) 2018-11-16 2024-07-16 アムジエン・インコーポレーテツド Improved synthesis of key intermediates for KRAS G12C inhibitor compounds
JP7377679B2 (en) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド Combination therapy comprising a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancer
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020117988A1 (en) 2018-12-04 2020-06-11 Tolero Pharmaceuticals, Inc. Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
JP2022515197A (en) 2018-12-19 2022-02-17 アレイ バイオファーマ インコーポレイテッド 7-((3,5-dimethoxyphenyl) amino) quinoxaline derivative as an FGFR inhibitor for treating cancer
US12180207B2 (en) 2018-12-19 2024-12-31 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of FGFR tyrosine kinases
US12441736B2 (en) 2018-12-20 2025-10-14 Amgen Inc. KIF18A inhibitors
JOP20210154B1 (en) 2018-12-20 2023-09-17 Amgen Inc KIF18A inhibitors
ES2996960T3 (en) 2018-12-20 2025-02-13 Amgen Inc Heteroaryl amides useful as kif18a inhibitors
EP3897855B1 (en) 2018-12-20 2023-06-07 Amgen Inc. Kif18a inhibitors
BR112021014911A2 (en) 2019-02-01 2021-11-23 Glaxosmithkline Ip Dev Ltd Belantamab mafodotin in combination with pembrolizumab for cancer treatment
EP3921443A1 (en) 2019-02-08 2021-12-15 F. Hoffmann-La Roche AG Diagnostic and therapeutic methods for cancer
EP3924351B1 (en) 2019-02-12 2025-05-21 Sumitomo Pharma America, Inc. Crystalline form of the hydrochloride salt of 2-((1r,4r)-4-((3-(3-(trifluoromethyl)phenyl) imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexyl)propan-2-ol
WO2020165672A1 (en) 2019-02-15 2020-08-20 Shivalik Rasayan Limited Process for preparation of highly pure fingolimod hydrochloride
JP7520389B2 (en) 2019-02-27 2024-07-23 エピアクシス セラピューティクス プロプライエタリー リミテッド Methods and agents for assessing T cell function and predicting response to therapy - Patents.com
KR20210133237A (en) 2019-02-27 2021-11-05 제넨테크, 인크. Dosing for treatment with anti-TIGIT and anti-CD20 or anti-CD38 antibodies
US20230148450A9 (en) 2019-03-01 2023-05-11 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
SG11202109662YA (en) 2019-03-15 2021-10-28 Univ California Compositions and methods for treating cancer
WO2020191326A1 (en) 2019-03-20 2020-09-24 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of acute myeloid leukemia (aml) with venetoclax failure
US11712433B2 (en) 2019-03-22 2023-08-01 Sumitomo Pharma Oncology, Inc. Compositions comprising PKM2 modulators and methods of treatment using the same
WO2020223233A1 (en) 2019-04-30 2020-11-05 Genentech, Inc. Prognostic and therapeutic methods for colorectal cancer
TWI879768B (en) 2019-05-03 2025-04-11 美商建南德克公司 Methods of treating cancer with an anti-pd-l1 antibody
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
CR20210665A (en) 2019-05-21 2022-01-25 Amgen Inc Solid state forms
US20230295313A1 (en) 2019-06-26 2023-09-21 Glaxosmithkline Intellectual Property Development Limited Il1rap binding proteins
CN112300279A (en) 2019-07-26 2021-02-02 上海复宏汉霖生物技术股份有限公司 Methods and compositions directed to anti-CD 73 antibodies and variants
CN114302880B (en) 2019-08-02 2025-07-15 美国安进公司 KIF18A inhibitors
WO2021026099A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
CN114391012B (en) 2019-08-02 2025-10-31 美国安进公司 Pyridine derivatives as KIF18A inhibitors
US20220281843A1 (en) 2019-08-02 2022-09-08 Amgen Inc. Kif18a inhibitors
WO2021046159A1 (en) 2019-09-04 2021-03-11 Genentech, Inc. Cd8 binding agents and uses thereof
WO2021043961A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy
WO2021046293A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and tremelimumab
AU2020351734A1 (en) 2019-09-27 2022-04-14 Genentech, Inc. Dosing for treatment with anti-TIGIT and anti-PD-L1 antagonist antibodies
EP4038097A1 (en) 2019-10-03 2022-08-10 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
EP4684786A2 (en) 2019-10-24 2026-01-28 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
JP2023511472A (en) 2019-10-29 2023-03-20 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bifunctional compounds for the treatment of cancer
US11739074B2 (en) 2019-11-04 2023-08-29 Revolution Medicines, Inc. Ras inhibitors
CN120988055A (en) 2019-11-04 2025-11-21 锐新医药公司 RAS inhibitors
CA3160142A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
JP2022553803A (en) 2019-11-06 2022-12-26 ジェネンテック， インコーポレイテッド Diagnostic and therapeutic methods for the treatment of blood cancers
JP7812056B2 (en) 2019-11-08 2026-02-09 レヴォリューション・メディスンズ，インコーポレイテッド Bicyclic heteroaryl compounds and uses thereof
MX2022005775A (en) 2019-11-13 2022-06-09 Genentech Inc Therapeutic compounds and methods of use.
CN110894189B (en) * 2019-11-14 2021-07-06 山东罗欣药业集团股份有限公司 Preparation method of erlotinib hydrochloride
TWI882037B (en) 2019-11-14 2025-05-01 美商安進公司 Improved synthesis of kras g12c inhibitor compound
AU2020383535A1 (en) 2019-11-14 2022-05-05 Amgen Inc. Improved synthesis of KRAS G12C inhibitor compound
CN114980976A (en) 2019-11-27 2022-08-30 锐新医药公司 Covalent RAS inhibitors and uses thereof
KR20220113790A (en) 2019-12-13 2022-08-16 제넨테크, 인크. Anti-LY6G6D Antibodies and Methods of Use
AU2020408562A1 (en) 2019-12-20 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
BR112022010086A2 (en) 2020-01-07 2022-09-06 Revolution Medicines Inc SHP2 INHIBITOR DOSAGE AND CANCER TREATMENT METHODS
WO2021194481A1 (en) 2020-03-24 2021-09-30 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
WO2021154761A1 (en) 2020-01-27 2021-08-05 Genentech, Inc. Methods for treatment of cancer with an anti-tigit antagonist antibody
BR112022014562A2 (en) 2020-01-28 2022-09-13 Glaxosmithkline Ip Dev Ltd COMBINATION TREATMENTS, USES AND METHODS THEREOF
WO2021168202A1 (en) * 2020-02-19 2021-08-26 United States Government As Represented By The Department Of Veterans Affairs Egfr inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
WO2021233534A1 (en) 2020-05-20 2021-11-25 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
WO2021185844A1 (en) 2020-03-16 2021-09-23 Pvac Medical Technologies Ltd Use of substance and pharmaceutical composition thereof, and medical treatments or uses thereof
CN115698717A (en) 2020-04-03 2023-02-03 基因泰克公司 Cancer treatment and diagnosis methods
WO2021211776A1 (en) 2020-04-15 2021-10-21 California Institute Of Technology Thermal control of t-cell immunotherapy through molecular and physical actuation
WO2021222167A1 (en) 2020-04-28 2021-11-04 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
MX2022015877A (en) 2020-06-16 2023-01-24 Genentech Inc Methods and compositions for treating triple-negative breast cancer.
MX2022015881A (en) 2020-06-18 2023-01-24 Genentech Inc Treatment with anti-tigit antibodies and pd-1 axis binding antagonists.
TW202214253A (en) 2020-06-18 2022-04-16 美商銳新醫藥公司 Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
US11787775B2 (en) 2020-07-24 2023-10-17 Genentech, Inc. Therapeutic compounds and methods of use
EP4189121A1 (en) 2020-08-03 2023-06-07 Genentech, Inc. Diagnostic and therapeutic methods for lymphoma
WO2022029220A1 (en) 2020-08-05 2022-02-10 Ellipses Pharma Ltd Treatment of cancer using a cyclodextrin-containing polymer-topoisomerase inhibitor conjugate and a parp inhibitor
EP4196612A1 (en) 2020-08-12 2023-06-21 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2022036287A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Anti-cd72 chimeric receptors and uses thereof
WO2022036285A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Compositions and methods for treating cancer with chimeric tim receptors in combination with inhibitors of poly (adp-ribose) polymerase
WO2022036265A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Chimeric tim receptors and uses thereof
WO2022047259A1 (en) 2020-08-28 2022-03-03 California Institute Of Technology Synthetic mammalian signaling circuits for robust cell population control
AU2021344830A1 (en) 2020-09-03 2023-04-06 Revolution Medicines, Inc. Use of SOS1 inhibitors to treat malignancies with SHP2 mutations
MX2023003060A (en) 2020-09-15 2023-04-05 Revolution Medicines Inc Indole derivatives as ras inhibitors in the treatment of cancer.
MX2023003338A (en) 2020-09-23 2023-06-14 Erasca Inc Tricyclic pyridones and pyrimidones.
TWI836278B (en) 2020-10-05 2024-03-21 美商建南德克公司 Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
TW202237638A (en) 2020-12-09 2022-10-01 日商武田藥品工業股份有限公司 Compositions of guanylyl cyclase c (gcc) antigen binding agents and methods of use thereof
WO2022133345A1 (en) 2020-12-18 2022-06-23 Erasca, Inc. Tricyclic pyridones and pyrimidones
EP4267250A1 (en) 2020-12-22 2023-11-01 Qilu Regor Therapeutics Inc. Sos1 inhibitors and uses thereof
JP2024506339A (en) 2021-02-12 2024-02-13 エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト Bicyclic tetrahydroazepine derivatives for the treatment of cancer
EP4298114A1 (en) 2021-02-26 2024-01-03 Kelonia Therapeutics, Inc. Lymphocyte targeted lentiviral vectors
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
TW202309053A (en) 2021-05-05 2023-03-01 美商銳新醫藥公司 Ras inhibitors
IL308193A (en) 2021-05-05 2024-01-01 Revolution Medicines Inc Ras inhibitors
AU2022280025A1 (en) 2021-05-25 2023-12-07 Erasca, Inc. Sulfur-containing heteroaromatic tricyclic kras inhibitors
CN117479943A (en) 2021-06-15 2024-01-30 基因泰克公司 EGFR inhibitors and PERK activators in combination therapy and their use in the treatment of cancer
US20240293558A1 (en) 2021-06-16 2024-09-05 Erasca, Inc. Kras inhibitor conjugates
KR20240119868A (en) 2021-07-28 2024-08-06 세로 테라퓨틱스, 인코포레이티드 Chimeric TIM4 receptor and its uses
WO2023018699A1 (en) 2021-08-10 2023-02-16 Erasca, Inc. Selective kras inhibitors
JP2024535380A (en) 2021-09-23 2024-09-30 エラスカ・インコーポレイテッド Polymorphic forms of EGFR inhibitors
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
WO2023097195A1 (en) 2021-11-24 2023-06-01 Genentech, Inc. Therapeutic indazole compounds and methods of use in the treatment of cancer
TW202340212A (en) 2021-11-24 2023-10-16 美商建南德克公司 Therapeutic compounds and methods of use
US20250282782A1 (en) 2021-12-17 2025-09-11 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4490146B1 (en) 2022-03-07 2026-02-18 Amgen Inc. A process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile
CN119136806A (en) 2022-03-08 2024-12-13 锐新医药公司 Methods for treating immune-refractory lung cancer
WO2023191816A1 (en) 2022-04-01 2023-10-05 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2023219613A1 (en) 2022-05-11 2023-11-16 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN119856056A (en) 2022-06-07 2025-04-18 基因泰克公司 Methods for determining the efficacy of lung cancer treatment comprising anti-PD-L1 antagonists and anti-TIGHT antagonist antibodies
JP2025521232A (en) 2022-06-10 2025-07-08 レボリューション メディシンズ インコーポレイテッド Macrocyclic RAS inhibitors
CA3261147A1 (en) 2022-07-13 2024-01-18 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN119604530A (en) 2022-07-19 2025-03-11 基因泰克公司 Administration of Therapeutic Antibodies Using Anti-FCRH5/Anti-CD3 Bispecific Antibodies
WO2024030441A1 (en) 2022-08-02 2024-02-08 National University Corporation Hokkaido University Methods of improving cellular therapy with organelle complexes
EP4568746A1 (en) 2022-08-11 2025-06-18 F. Hoffmann-La Roche AG Bicyclic tetrahydrothiazepine derivatives
PE20250876A1 (en) 2022-08-11 2025-03-28 Hoffmann La Roche Bicyclic derivatives of tetrahydrothiazepine
CR20250042A (en) 2022-08-11 2025-03-25 Hoffmann La Roche Bicyclic tetrahydrothiazepine derivatives
EP4568960A1 (en) 2022-08-11 2025-06-18 F. Hoffmann-La Roche AG Bicyclic tetrahydroazepine derivatives
GEAP202516749A (en) 2022-10-14 2025-07-25 Black Diamond Therapeutics Inc Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
JP2025538859A (en) 2022-10-21 2025-12-02 公益財団法人川崎市産業振興財団 Non-adsorbing or super stealth vesicles
TW202426505A (en) 2022-10-25 2024-07-01 美商建南德克公司 Therapeutic and diagnostic methods for cancer
WO2024173842A1 (en) 2023-02-17 2024-08-22 Erasca, Inc. Kras inhibitors
EP4687905A1 (en) 2023-03-30 2026-02-11 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
EP4688790A1 (en) 2023-04-07 2026-02-11 Revolution Medicines, Inc. Macrocyclic ras inhibitors
KR20250172857A (en) 2023-04-14 2025-12-09 레볼루션 메디슨즈, 인크. Crystalline form of RAS inhibitor
KR20250169290A (en) 2023-04-14 2025-12-02 레볼루션 메디슨즈, 인크. Crystalline form of RAS inhibitor, composition containing same and method of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
AU2024270495A1 (en) 2023-05-05 2025-10-09 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
CN121285742A (en) 2023-06-08 2026-01-06 基因泰克公司 Macrophage characterization for diagnostic and therapeutic methods of lymphoma
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
WO2025034702A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 for use in the treatment of ras protein-related disease or disorder
WO2025049277A1 (en) 2023-08-25 2025-03-06 Genentech, Inc. Methods and compositions for treating non-small cell lung cancer comprising an anti-tigit antagonist antibody and a pd-1 axis binding antagonist
US20250154171A1 (en) 2023-10-12 2025-05-15 Revolution Medicines, Inc. Ras inhibitors
WO2025137507A1 (en) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Sos1 inhibitors and uses thereof
WO2025171296A1 (en) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Ras inhibitors
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors
WO2025255438A1 (en) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Ras inhibitors
WO2026015796A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015825A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Use of ras inhibitor for treating pancreatic cancer
WO2026015790A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026015801A1 (en) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Methods of treating a ras related disease or disorder
WO2026030464A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Dosage regimen for reducing cytokine release syndrome (crs) with anti-fcrh5/anti-cd3 bispecific antibodies in multiple myeloma therapy
WO2026030476A1 (en) 2024-07-30 2026-02-05 Genentech, Inc. Precision medicine for optimal dosage of combined therapies systems and methods of use thereof

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU466233A1 (en) 1973-06-08 1975-04-05 Всесоюзный научно-исследовательский химико-фармацевтический институт им. С.Орджоникидзе Method for producing 2-methyl-4-dialkylaminoalkylaminoquinazoline derivatives
US4138590A (en) 1977-01-13 1979-02-06 American Home Products Corporation Prostaglandin derivatives
DE2936705A1 (en) 1978-09-11 1980-03-20 Sankyo Co NEW 4-ANILINOQUINAZOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
EP0477700A1 (en) 1990-09-17 1992-04-01 Asahi Kasei Kogyo Kabushiki Kaisha 6'-C-alkyl- or alkynyl-neplanocin A, and its preparation process and use
WO1992020642A1 (en) 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
EP0520722A1 (en) 1991-06-28 1992-12-30 Zeneca Limited Therapeutic preparations containing quinazoline derivatives
WO1993004047A1 (en) 1991-08-16 1993-03-04 Merck & Co., Inc. Quinazoline derivatives as inhibitors of hiv reverse transcriptase
US5214144A (en) 1991-10-07 1993-05-25 Dowelanco Process for the preparation of 4-haloquinazolines
CA2086968A1 (en) 1992-01-20 1993-07-21 Andrew John Barker Quinazoline derivatives
US5256781A (en) 1991-10-24 1993-10-26 American Home Products Corporation Substituted quinazolines as angiotensin II antagonists
EP0602851A1 (en) 1992-12-10 1994-06-22 Zeneca Limited Quinazoline derivatives
EP0635507A1 (en) 1993-07-19 1995-01-25 Zeneca Limited Tricyclic derivatives and their use as anti-cancer agents
EP0635498A1 (en) 1993-07-19 1995-01-25 Zeneca Limited Quinazoline derivatives and their use as anti-cancer agents
WO1995015758A1 (en) 1993-12-10 1995-06-15 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase
US5427766A (en) 1993-11-15 1995-06-27 The Dow Chemical Company Radiolabeled steroids for use in radiochemical-guided surgery
US5436233A (en) 1992-07-15 1995-07-25 Ono Pharmaceutical Co., Ltd. 4-aminoquinazoline derivatives
WO1996015118A1 (en) 1994-11-12 1996-05-23 Zeneca Limited Aniline derivatives
WO1996028430A1 (en) 1995-03-14 1996-09-19 Novartis Ag Trisubstituted phenyl derivatives
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
WO1997030035A1 (en) 1996-02-13 1997-08-21 Zeneca Limited Quinazoline derivatives as vegf inhibitors
WO1997032856A1 (en) 1996-03-05 1997-09-12 Zeneca Limited 4-anilinoquinazoline derivatives
WO1998013354A1 (en) 1996-09-25 1998-04-02 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US5736534A (en) 1994-02-23 1998-04-07 Pfizer Inc. 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents
WO2004072049A1 (en) 2003-02-17 2004-08-26 F. Hoffmann-La Roche Ag Polymorph of {6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl}-(3e)
US6900221B1 (en) 1999-11-11 2005-05-31 Osi Pharmaceuticals, Inc. Stable polymorph on N-(3-ethynylphenyl)-6, 7-bis (2methoxyethoxy)-4-quinazolinamine hydrochloride, methods of production, and pharmaceutical uses thereof

Patent Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU466233A1 (en) 1973-06-08 1975-04-05 Всесоюзный научно-исследовательский химико-фармацевтический институт им. С.Орджоникидзе Method for producing 2-methyl-4-dialkylaminoalkylaminoquinazoline derivatives
US4138590A (en) 1977-01-13 1979-02-06 American Home Products Corporation Prostaglandin derivatives
DE2936705A1 (en) 1978-09-11 1980-03-20 Sankyo Co NEW 4-ANILINOQUINAZOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM
EP0477700A1 (en) 1990-09-17 1992-04-01 Asahi Kasei Kogyo Kabushiki Kaisha 6'-C-alkyl- or alkynyl-neplanocin A, and its preparation process and use
WO1992020642A1 (en) 1991-05-10 1992-11-26 Rhone-Poulenc Rorer International (Holdings) Inc. Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase
EP0520722A1 (en) 1991-06-28 1992-12-30 Zeneca Limited Therapeutic preparations containing quinazoline derivatives
EP0520722B1 (en) 1991-06-28 1996-12-27 Zeneca Limited Therapeutic preparations containing quinazoline derivatives
WO1993004047A1 (en) 1991-08-16 1993-03-04 Merck & Co., Inc. Quinazoline derivatives as inhibitors of hiv reverse transcriptase
US5214144A (en) 1991-10-07 1993-05-25 Dowelanco Process for the preparation of 4-haloquinazolines
US5256781A (en) 1991-10-24 1993-10-26 American Home Products Corporation Substituted quinazolines as angiotensin II antagonists
US5616582A (en) 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
CA2086968A1 (en) 1992-01-20 1993-07-21 Andrew John Barker Quinazoline derivatives
EP0566226A1 (en) 1992-01-20 1993-10-20 Zeneca Limited Quinazoline derivatives
CA2086968C (en) 1992-01-20 1998-06-23 Andrew John Barker Quinazoline derivatives
US5457105A (en) 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5439895A (en) 1992-07-15 1995-08-08 Ono Pharmaceutical Co., Ltd. 4-aminoquinazoline derivatives
US5436233A (en) 1992-07-15 1995-07-25 Ono Pharmaceutical Co., Ltd. 4-aminoquinazoline derivatives
EP0602851A1 (en) 1992-12-10 1994-06-22 Zeneca Limited Quinazoline derivatives
WO1995003283A1 (en) 1993-07-19 1995-02-02 Zeneca Limited Quinazoline derivatives and their use as anti-cancer agents
US5475001A (en) 1993-07-19 1995-12-12 Zeneca Limited Quinazoline derivatives
EP0635498A1 (en) 1993-07-19 1995-01-25 Zeneca Limited Quinazoline derivatives and their use as anti-cancer agents
EP0635507A1 (en) 1993-07-19 1995-01-25 Zeneca Limited Tricyclic derivatives and their use as anti-cancer agents
US5427766A (en) 1993-11-15 1995-06-27 The Dow Chemical Company Radiolabeled steroids for use in radiochemical-guided surgery
WO1995015758A1 (en) 1993-12-10 1995-06-15 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase
US5654307A (en) 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5736534A (en) 1994-02-23 1998-04-07 Pfizer Inc. 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents
WO1996015118A1 (en) 1994-11-12 1996-05-23 Zeneca Limited Aniline derivatives
WO1996028430A1 (en) 1995-03-14 1996-09-19 Novartis Ag Trisubstituted phenyl derivatives
WO1997030035A1 (en) 1996-02-13 1997-08-21 Zeneca Limited Quinazoline derivatives as vegf inhibitors
WO1997032856A1 (en) 1996-03-05 1997-09-12 Zeneca Limited 4-anilinoquinazoline derivatives
WO1998013354A1 (en) 1996-09-25 1998-04-02 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6900221B1 (en) 1999-11-11 2005-05-31 Osi Pharmaceuticals, Inc. Stable polymorph on N-(3-ethynylphenyl)-6, 7-bis (2methoxyethoxy)-4-quinazolinamine hydrochloride, methods of production, and pharmaceutical uses thereof
WO2004072049A1 (en) 2003-02-17 2004-08-26 F. Hoffmann-La Roche Ag Polymorph of {6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl}-(3e)

Non-Patent Citations (67)

* Cited by examiner, † Cited by third party
Title
Alexander Levitzki and Aviv Gazit, "Tyrosine Kinase Inhibition: An Approach to Drug Development," Science, vol. 267, Mar. 24, 1995, 1782-1788.
Armarego, W.L.F., "Fused Pyrimidines", Interscience Publishers, 1967, Part 1, Chapters 4, 5, pp. 69 thru 269.
Banker, G.S. et al, "Modern Pharmaceutices, 3ed", Marcel Dekker, New York. 1996, pp. 451 and 596. *
Barker et al., "Inhibition of EGF Receptor Tyrosine Kinase Activity by 4-Anilinoquinazolines", British Journal of Cancer, 69: 18 Abstract 6.6 (1994).
Barker, A.J., "Quinazoline Tyrosine Kinase-Inhibiting Anticancer Agents", 1993, DialogWeb, Abstract, 2 pages.
Batra, S.K. et al., "Epdiermal Growth Factor Ligand-independent, Unregulated, Cell-transforming Potential of a Naturally Occurring Human Mutant EGFRvlll Gene," Cell Growth & Differentiation, Oct. 1995, 6, 1251-1259.
Before the Registrar of Patents and Designs in Jerusalem in re: Teva Pharmaceutical Industries Vs. OSI Pharmaceuticals, Inc., Opponent's Statement of Arguments and Appendices, Aug. 5, 2007.
Bihl et all, "Proliferation of Human Non-Small Cell Lung Cancer Cell Lines: Role of Interleukin-6", Am. J. Respir. Cell Mol. Biol., 19(4):606-612 (1998).
Botros, S. et al., "Synthesis of Certain Nitroquinazoline Structurally Related to Some Chemotherapeutic Agents", Egypt. J. Pharm. Sci., 1972, 13(1), 1-21.
Buter, J. & Giaccone, G., "Medical Treatment of Non-Small-Cell Lung Cancer", Annals of Oncology, 16(2), ii229-ii232 (2005).
Capuzzo, F. et al., "Clinical experience with Gefitinib: An Update", Critical Reviews in Oncology/Hematology, 58, 31-45, (2006).
Cecil Textbook of Medicine, edited by Bennet, J.C., and Plum F., 20th edition, vol. 1, 1004-1010, 1996. *
Chemical Abstracts, American Chemical Society, Abstract 98:107246, 1983, 98(13), 4 pages.
Cohen et al., Current Opinion in Chemical Biology, 3, 459-465, 1999. *
Decision on Pre-Grant Opposition in re. Matter of Indian Patent Application No. 537/Del/1996, in the name of Pfizer Products Inc, and OSI Pharmaceuticals Inc., Jul. 4, 2007.
Dermer et al., Bio/Technology, 1994, 12:320. *
Easty et al., "Ten Human Carcinoma Cell Lines Derived from Squamous Carcinomas of the Head and Neck", Br. J. Cancer, 43:772-785 (1981).
Freshney et al., Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p4. *
Fry, D. W. et al., "A Specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase," Science, Aug. 19, 1994, 265, 1093-1095.
Golub et al., Science, 286, 531-537, 1999. *
Hansch, C. et al., "Aromatic constituent constants for structure-activity corellations," J. Med. Chem., 1973 16(11), 1207-1216.
Hickish, T.F. et al., "Clinical benefit from palliative chemotheraphy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors," British Journal of Cancer, 1998, 78(1), 28-33.
In the High Court of Delhi at New Delhi, C.C. No. 52 of 2008 in C.S. (O.S.) No. 89 of 2008, In Re. F. Hoffmann-La Roche Ltd. & Anr. v. Cipla Ltd., Evidence by way of Affidavit on Behalf of Professor Nick Thatcher, and Appendices A and B, Mar. 25, 2009.
In the High Court of Delhi at New Delhi, C.C. No. 52 of 2008 in C.S. (O.S.) No. 89 of 2008, In Re. F. Hoffmann-La Roche Ltd. & Anr.v. Cipla Ltd. , Evidence by way of Affidavit on Behalf of Professor Roger John Griffin, and Appendices A and B, Mar. 26, 2009.
In the High Court of Delhi at New Delhi, C.S. (O.S.) No. 89 of 2008 in re: F. Hoffman LA Roche Ltd. & Anr . . . Vs. CIPLA, Counterclaim of the Defendant Under 64 of the Patents Act for Revocation of Patent No. 196774 Titled "A novel [6,7 -bis (2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride, " Jan. 21, 2008.
In the High Court of Delhi at New Delhi, C.S. (O.S.) No. 89 of 2008 in re: F. Hoffman LA Roche Ltd. & Anr Vs. CIPLA, Written Statement on Behalf of the Defendant to the Injunction Application, Jan. 21, 2008.
In the High Court of Delhi at New Delhi, C.S. (O.S.) No. 89 of 2008, In Re. F. Hoffmann-La Roche Ltd. & Anr. v. Cipla Ltd., Index of Particulars dated Mar. 30, 2009.
In the High Court of Delhi at New Delhi, C.S. (O.S.) No. 89 of 2008, In Re. F. Hoffmann-La Roche Ltd. &Anr. v. Cipla Ltd., Affidavit of Shivprasad Laud, Mar. 28, 2009.
In the High Court of Delhi at New Delhi, FAO (OS) 188/2008, In Re.: F. Hoffmann-La Roche Ltd. & Anr. v. Cipla Ltd., Judgement dated Apr. 24, 2009, 57 pages.
In the High Court of Delhi at New Delhi, I.A. 642/2008 in CS (OS) 89/2008. Decision dated Mar. 19, 2008 In Re.: F. Hoffman-La Roche Ltd., & Anr. vs. Cipla Limited.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman LA Roche Ltd & Anr.Versus CIPLA Ltd., Written Submissions on Behalf of the Respondent, CIPLA Limited, and Annexures A-H, Aug. 27, 2008.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd. & Anr. v. Cipla Ltd., Affidavit of Undertaking, 31.04.08, Board Resolution of Mar. 23, 2008 , and Powers of Attorney, 11 pages.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd. and OSI Pharmaceuticals, Inc. v. CIPLA Ltd., Memo of Appeal Against the Order/Judgement dated Mar. 19, 2008, 42 pages, Apr. 11, 2008.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd. v. CIPLA Ltd., Affidavit on behalf of the Plaintiffs dated Jul. 26, 2008, and Declaration dated Jan. 31, 2008 by Dr. Hubert Witte, 3 pages.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd.& Anr. v. CIPLA Ltd., Points Not Argued by the Defendant, 2 pages, Feb. 13, 2008.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd.v. CIPLA Ltd. , Rejoinder Arguments on Behalf of the Plaintiffs to the Arguments of the Defendant at Interloculory Application, 13 pages, Jul. 26, 2008.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd.v. CIPLA Ltd. , Rejoinder to the Reply filed by the Respondent, 25 pages, May 22, 2008.
In the High Court of Delhi at New Delhi, in Re.: F. Hoffman-La Roche Ltd.v. CIPLA Ltd. , Written Statement to the Counterclaim of the Defendant, 89 pages, Aug. 18, 2008.
In the High Court of Delhi at New Delhi, Re: F. Hoffman La Roche Ltd.& Anr. vs. CIPLA Ltd. , Replication on Behalf of Defendant to the Written Statement of the Plaintiff to the Defendant's Counter Claim, Mar. 31, 2009.
In the High Court of Delhi, C.S. (O.S.) No. 89 of 2008 in re:F. Hoffman LA Roche Ltd. & Anr Vs. CIPLA, Written Arguments on Behalf of the Defendants, Feb. 5, 2008.
In the United States District Court for the District of Delaware, Civ. A. No. 09-185, In Re.: OSI Pharmaceuticals, Inc., Pfizer Inc., and Genentech, Inc. v. Teva Pharmaceuticals USA, Inc.: Complaint for patent infringement and related documents, Mar. 19, 2009, 92 pages.
In the United States District Court for the District of Delaware, Civ. A. No. 09-186, In Re.: OSI Pharmsceuticals, Inc., Pfizer Inc., and Genentech, Inc. v. Mylan Pharmaceuticals, Inc.: Complaint for patent infringement and related documents, Mar. 19, 2009, 92 pages.
In the United States Patent and Trademark Office, Application for Extension of Patent Term Under 35 U.S.C. 156, in re: U.S. Patent No. 5,747,498, dated Jan. 13, 2005, 22 pages.
Jong Ho Park et al., "Postoperative Adjuvant Therapy for Stage II Non-Small-Cell Lung Cancer," Ann Thorac Surg, 1999, 68, 1821-1826.
Kelloff, G.J. et al., "Epidermal Growth Factor Receptor Kinase Inhibitors as Potential Cancer Chemopreventives", Cancer Epidemiology, Biomarkers & Prevention, 5(8): 657-666 (1996).
Klohs, W.D. et al., "Inhibitors of Tyrosine Kinhase", Current Opinion in Oncology, 9(6), 562-568 (1997).
LeMahieu, R.A. et al., "(e)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenoic acids, a New Series of Antiallergy Agents", J. Med. Chem., 1983, 26(3), 420-425.
Mattson, K., "Docetaxel (Taxotere(R)) in the neo-adjuvant setting in non-small-cell lung cancer," Annals of Oncology, 1999, 10(Suppl. 5), S69-S72.
Mattson, K., "Docetaxel (Taxotere®) in the neo-adjuvant setting in non-small-cell lung cancer," Annals of Oncology, 1999, 10(Suppl. 5), S69-S72.
Moody, T.W., "Peptides and Growth Factors in Non-Small Cell Lung Cancer," Peptides, 1996, 17(3), 545-555.
Notification letter dated Feb. 6, 2009, from Teva Pharmaceuticals USA, Inc. to OSI Pharmaceuticals, Inc. and Pfizer, Inc. re: Notification Pursuant to � 505(j)(2)(B)(ii) of the Federal Food, Drug and Cosmetic Act.
Notification letter dated Feb. 6, 2009, from Teva Pharmaceuticals USA, Inc. to OSI Pharmaceuticals, Inc. and Pfizer, Inc. re: Notification Pursuant to § 505(j)(2)(B)(ii) of the Federal Food, Drug and Cosmetic Act.
Opposition filed by Natco Pharma on Apr. 5, 2007, in respect of Indian Patent Application No. 537 DEL/96.
Pollack, V.A. et al., "Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358, 774: Dynamics of receptor inhibition In Situ and antitumor effects in athymic mice," J. Pharmacol. Exp Ther., 1999, 291, 739-748.
Pollack, V.A. et al., "Therapy of human carcinoma in athymic mice by inhibition of EGF receptor-mediated signal transduction with CP-358774: Dynamics of receptor inhibition and anti-tumor effects," Proc. American Association for Cancer Research, Mar. 1997, vol. 38, p. 633, Abstract No. 4249.
Pollack, V.A. et al., "Therapy of human carcinomas in althymic mice by inhibition of EGF receptor-mediated signal transduction with CP-358774: Pharmacodynamics of receptor inhibition and anti-tumor effects", Proc. Am Assoc. Cancer Res., 38, 633 (1997).
Powell et al., British Journal of Dermatology, 141: 802-810, 1999. *
Proceedings of the American Association for Cancer Research, vol. 37, Mar. 1996, 390-391.
Reply Statement in support by the Applicant for Indian Patent Application No. 537/DEL/96 made by Pfizer Products Inc. and OSI Pharmaceuticals Inc., with enclosures, Jun. 4, 2007.
Structural Similarities with the Closest Prior Art-Annex B to CIPLA's written arguments dated Aug. 27, 2008.
Sun, C. et al., "Studies on Drugs for Coronary Diseases. II. Synthesis of Compounds Related to Changrolin, a New Antiarrhythmic Agent", 1981, DialogWeb, 2 pages Abstract, 565-570 (publication believed to be abstracted also enclosed).
The Merck Manual of Diagnosis and Therapy, 1999, Seventeenth Edition, Beers, M.H. et al., (eds.), Published by Merck Research Laboratories, Whitehouse Station, NJ., pp. 988-995.
Thornber, C. W., "Isosterism and Molecular Modification in Drug Design," 1979, Chem. Soc. Rev., 8, 563-580.
Traxler et al. Ex. Opin. Ther. Patents 7(6):571-588, 1997. *
Twombly, R. "FDA Oncology Committee Debates Iressa's Status Following Negative Trial Results", J. Nat'l. Cancer Institute, 97(7), 473 (2005).
Wiley Rein letter dated Feb. 23, 2009, and Detailed Legal and Factual Basis for Mylan's Paragraph IV Patent Certification regarding U.S. Patent Nos. 5,747,498, 6,900,221 and 7,087,61.
Wolft Manfred E. "Burger's Medicinal Chemistry, 5ed, Part 1", John Wiley & Sons, 1995, pp. 975-977. *

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