[go: up one dir, main page]

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

Alkynl and azido-substituted 4-anilinoquinazolines Download PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
amine
quinazolin
ethynylphenyl
ethynyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime, expires
Application number
US12/038,530
Inventor
Rodney Caughren Schnur
Lee Daniel Arnold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Inc
OSI Pharmaceuticals LLC
Original Assignee
Pfizer Inc
OSI Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=24622307&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=USRE41065(E1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from PCT/IB1995/000436 external-priority patent/WO1996030347A1/en
Application filed by Pfizer Inc, OSI Pharmaceuticals LLC filed Critical Pfizer Inc
Priority to US12/038,530 priority Critical patent/USRE41065E1/en
Application granted granted Critical
Publication of USRE41065E1 publication Critical patent/USRE41065E1/en
Assigned to OSI Pharmaceuticals, LLC reassignment OSI Pharmaceuticals, LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: OSI PHARMACEUTICALS, INC.
Adjusted expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

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

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.
US12/038,530 1995-06-06 2008-02-27 Alkynl and azido-substituted 4-anilinoquinazolines Expired - Lifetime USRE41065E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/038,530 USRE41065E1 (en) 1995-06-06 2008-02-27 Alkynl and azido-substituted 4-anilinoquinazolines

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/IB1995/000436 WO1996030347A1 (en) 1995-03-30 1995-06-06 Quinazoline derivatives
US08/653,786 US5747498A (en) 1996-05-28 1996-05-28 Alkynyl and azido-substituted 4-anilinoquinazolines
US12/038,530 USRE41065E1 (en) 1995-06-06 2008-02-27 Alkynl and azido-substituted 4-anilinoquinazolines

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/653,786 Reissue US5747498A (en) 1995-06-06 1996-05-28 Alkynyl and azido-substituted 4-anilinoquinazolines

Publications (1)

Publication Number Publication Date
USRE41065E1 true USRE41065E1 (en) 2009-12-29

Family

ID=24622307

Family Applications (2)

Application Number Title Priority Date Filing Date
US08/653,786 Ceased US5747498A (en) 1995-06-06 1996-05-28 Alkynyl and azido-substituted 4-anilinoquinazolines
US12/038,530 Expired - Lifetime USRE41065E1 (en) 1995-06-06 2008-02-27 Alkynl and azido-substituted 4-anilinoquinazolines

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US08/653,786 Ceased US5747498A (en) 1995-06-06 1996-05-28 Alkynyl and azido-substituted 4-anilinoquinazolines

Country Status (1)

Country Link
US (2) US5747498A (en)

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
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
WO2012068483A1 (en) 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment 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 (669)

* 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
ATE237596T1 (en) 1996-02-13 2003-05-15 Astrazeneca Ab CHINAZOLINE DERIVATIVES AND THEIR USE AS VEGF INHIBITORS
PT885198E (en) 1996-03-05 2002-06-28 Astrazeneca Ab 4-ANYLINOQUINAZOLINE 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
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
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
US6878716B1 (en) 1998-06-02 2005-04-12 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptor and uses thereof
US6686366B1 (en) 1998-06-02 2004-02-03 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A3 receptor and uses thereof
NZ508314A (en) 1998-06-02 2004-03-26 Osi Pharm Inc Pyrrolo[2,3d]pyrimidine compositions and their use
RS50273B (en) * 1998-08-18 2009-07-15 The Regents Of The Univeristy Of California, Epidermal growth factor receptor antagonists for treating hypersecretion of mucus in the lungs
AU4925199A (en) 1998-08-27 2000-03-21 Pfizer Products Inc. Quinolin-2-one derivatives useful as anticancer agents
WO2000012499A1 (en) 1998-08-27 2000-03-09 Pfizer Products Inc. Alkynyl-substituted 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
JP2002534468A (en) 1999-01-13 2002-10-15 バイエル コーポレイション ω-Carboxyaryl-substituted diphenylureas as p38 kinase inhibitors
UA71945C2 (en) 1999-01-27 2005-01-17 Pfizer Prod Inc Substituted bicyclic derivatives being used as anticancer agents
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
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
RS49836B (en) * 1999-03-31 2008-08-07 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
US6545004B1 (en) 1999-10-27 2003-04-08 Cytokinetics, Inc. Methods and compositions utilizing quinazolinones
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
DK1244647T3 (en) 1999-11-05 2006-09-25 Astrazeneca Ab Quinzoline derivatives as VIGF 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
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
US6680322B2 (en) 1999-12-02 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors 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
CA2403721C (en) * 2000-03-20 2009-06-09 Pfizer Products, Inc. Combined treatment with keratinocyte growth factor and epidermal growth factor inhibitor
CN1240688C (en) * 2000-04-07 2006-02-08 阿斯特拉曾尼卡有限公司 Quinazoline compounds
AU2001292137A1 (en) * 2000-10-13 2002-04-22 Astrazeneca Ab Quinazoline derivatives
AU2002217999A1 (en) 2000-11-01 2002-05-15 Cor Therapeutics, Inc. Process for the production of 4-quinazolinylpiperazin-1-carboxylic acid phenylamides
ES2290199T3 (en) * 2000-11-22 2008-02-16 Novartis Ag MIXTURE THAT INCLUDES AN AGENT THAT REDUCES THE ACTIVITY OF FCVE AND AN AGENT THAT REDUCES THE ACTIVITY OF FCE.
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
EP1395577A1 (en) * 2000-12-19 2004-03-10 Pfizer Products Inc. Crystal forms of 6- (4-chloro-phenyl)-hydroxy-(-3-methyl-3h-imidaol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1h-quinolin-2-one, 2,3-dihydroxybutanedioate salts and method of production
GEP20084484B (en) * 2001-01-05 2008-09-25 Pfizer Antibodies to insulin-like growth factor i receptor
EP3406249A1 (en) 2001-02-19 2018-11-28 Novartis AG Treatment of breast tumors with a rapamycin derivative in combination with an aromatase inhibitor
JP2002293773A (en) * 2001-03-30 2002-10-09 Sumika Fine Chemicals Co Ltd Method for producing quinazoline derivative
DE60219617T2 (en) 2001-05-16 2008-01-03 Novartis Ag COMBINATION OF N-5- 4- (4-METHYL-PIPERAZINO-METHYL) -BENZOYLAMIDO -2-METHYLPHENYL -4- (3-PYRIDIL) -2-PYRIMIDINE AMINE WITH A BIPHOSPHONATE
AU2002345792A1 (en) 2001-06-21 2003-01-08 Pfizer Inc. Thienopyridine and thienopyrimidine anticancer agents
WO2003000188A2 (en) * 2001-06-21 2003-01-03 Ariad Pharmaceuticals, Inc. Novel quinazolines and uses thereof
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
EP1435959A2 (en) * 2001-10-09 2004-07-14 University of Cincinnati Inhibitors of the egf receptor for the treatment of thyroid cancer
GB0126433D0 (en) * 2001-11-03 2002-01-02 Astrazeneca Ab Compounds
MXPA04004219A (en) * 2001-11-03 2004-09-10 Astrazeneca Ab Quinazoline derivatives as antitumor agents.
AR039067A1 (en) * 2001-11-09 2005-02-09 Pfizer Prod Inc ANTIBODIES FOR CD40
CA2467717A1 (en) * 2001-11-19 2003-05-30 Interleukin Genetics, Inc. Functional polymorphisms of the interleukin-1 locus affecting transcription and susceptibility to inflammatory and infectious diseases
WO2003043995A1 (en) * 2001-11-20 2003-05-30 Cytokinetics, Inc. Process for the racemization of chiral quinazolinones
GB0128510D0 (en) * 2001-11-28 2002-01-23 Novartis Ag Organic compounds
DK1450811T3 (en) * 2001-11-30 2010-02-15 Osi Pharm Inc Compounds specific for adenosine A1 and A3 receptors and uses thereof
US20030229067A1 (en) * 2001-12-20 2003-12-11 Arlindo Castelhano Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use
KR20040068317A (en) 2001-12-20 2004-07-30 오에스아이 파마슈티컬스, 인코포레이티드 Pyrimidine a2b selective antagonist compounds, their synthesis and use
KR20040085151A (en) 2002-01-17 2004-10-07 뉴로젠 코포레이션 Substituted quinazolin-4-ylamine analogues as modulators of capsaicin
EP1481971B1 (en) * 2002-02-06 2011-11-16 Ube Industries, Ltd. Process for producing 4-aminoquinazoline compound
EP2324825A1 (en) 2002-02-11 2011-05-25 Bayer Healthcare LLC Aryl ureas with angiogenesis inhibiting activity
CA2475879A1 (en) * 2002-02-15 2003-08-28 Cytokinetics, Inc. Synthesis of quinazolinones
TW200813014A (en) * 2002-03-28 2008-03-16 Astrazeneca Ab Quinazoline derivatives
US7078409B2 (en) 2002-03-28 2006-07-18 Beta Pharma, Inc. Fused quinazoline derivatives useful 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
PL371188A1 (en) * 2002-03-30 2005-06-13 Boehringer Ingelheim Pharma Gmbh & Co.Kg 4-(n-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors
JP2005530785A (en) * 2002-05-09 2005-10-13 サイトキネティクス・インコーポレーテッド Compounds, compositions and methods
NZ537076A (en) * 2002-05-09 2007-06-29 Cytokinetics Inc Pyrimidinone compounds, compositions and methods
DK1505959T3 (en) 2002-05-16 2009-02-23 Novartis Ag Use of EDG receptor binding agents in cancer
AU2003265242A1 (en) * 2002-05-23 2003-12-22 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
WO2003106426A1 (en) * 2002-06-14 2003-12-24 Cytokinetics, Inc. Compounds, compositions, and methods
AU2003249212C1 (en) 2002-07-15 2011-10-27 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
US7211580B2 (en) * 2002-07-23 2007-05-01 Cytokinetics, Incorporated Compounds, compositions, and methods
US20040048853A1 (en) * 2002-08-21 2004-03-11 Gustave Bergnes Compounds, compositions, and methods
EP1558083A4 (en) * 2002-09-30 2008-04-16 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
SI1585743T1 (en) * 2002-12-19 2007-08-31 Pfizer 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
EP1603570B9 (en) 2003-02-26 2013-10-23 Sugen, Inc. Aminoheteroaryl compounds as protein kinase inhibitors
UY28213A1 (en) 2003-02-28 2004-09-30 Bayer Pharmaceuticals Corp NEW CYANOPIRIDINE DERIVATIVES USEFUL IN THE TREATMENT OF CANCER AND OTHER DISORDERS.
AU2004226586B2 (en) * 2003-04-03 2008-12-11 Pfizer Inc. Dosage forms comprising AG013736
GB0309009D0 (en) * 2003-04-22 2003-05-28 Astrazeneca Ab Quinazoline derivatives
US7470724B2 (en) * 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
US7407965B2 (en) * 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
CN101410120A (en) * 2003-04-25 2009-04-15 吉里德科学公司 Anti-inflammatory phosphonate compounds
EP1620109A2 (en) * 2003-04-25 2006-02-01 Gilead Sciences, Inc. Kinase inhibitor phosphonate conjugates
US20050261237A1 (en) * 2003-04-25 2005-11-24 Boojamra Constantine G Nucleoside phosphonate analogs
US7452901B2 (en) * 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
US7300924B2 (en) * 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
SG182849A1 (en) 2003-04-25 2012-08-30 Gilead Sciences Inc Antiviral phosphonate analogs
US20090247488A1 (en) * 2003-04-25 2009-10-01 Carina Cannizzaro Anti-inflammatory phosphonate compounds
WO2004096287A2 (en) * 2003-04-25 2004-11-11 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
WO2005002626A2 (en) 2003-04-25 2005-01-13 Gilead Sciences, Inc. Therapeutic phosphonate compounds
US7432261B2 (en) * 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
GB0309850D0 (en) * 2003-04-30 2003-06-04 Astrazeneca Ab Quinazoline derivatives
KR20060025141A (en) * 2003-05-15 2006-03-20 아르퀼 인코포레이티드 Inhibitors of P38 and methods of using the same
EP2644195A1 (en) 2003-05-19 2013-10-02 Irm Llc Immunosuppressant Compounds and Compositions
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
JP4860474B2 (en) 2003-05-20 2012-01-25 バイエル、ファーマシューテイカルズ、コーポレイション Diarylureas for diseases mediated by PDGFR
PL1680426T3 (en) * 2003-06-10 2008-02-29 Hoffmann La Roche 1.3.4-triaza-phenalene and 1,3,4,6-tetraazaphenalene derivatives
US8309562B2 (en) * 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
JP5129957B2 (en) * 2003-07-03 2013-01-30 ミリアド ジェネティクス， インコーポレイテッド 4-Arylamino-quinazolines as caspase activators and inducers of apoptosis
ES2523837T3 (en) 2003-07-18 2014-12-01 Amgen Inc. Specific binding agents to hepatocyte growth factor
JP4777887B2 (en) 2003-07-23 2011-09-21 バイエル、ファーマシューテイカルズ、コーポレイション Fluoro-substituted omegacarboxyaryl diphenylureas for the treatment and prevention of diseases and conditions
WO2005012290A1 (en) * 2003-07-29 2005-02-10 Astrazeneca Ab Piperidyl-quinazoline derivatives as tyrosine kinase inhibitors
GB0317665D0 (en) * 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
JP4569876B2 (en) * 2003-07-30 2010-10-27 宇部興産株式会社 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
BRPI0414011A (en) * 2003-08-29 2006-10-24 Pfizer naphthalencarboxamides and their derivatives useful as new antiangiogenic agents
MXPA06002296A (en) * 2003-08-29 2006-05-22 Pfizer Thienopyridine-phenylacet amides and their derivatives useful as new anti-angiogenic 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
MXPA06002964A (en) * 2003-09-16 2006-06-14 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors.
GB0321648D0 (en) * 2003-09-16 2003-10-15 Astrazeneca Ab Quinazoline derivatives
MXPA06002963A (en) * 2003-09-16 2006-06-14 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors.
AU2004272345A1 (en) * 2003-09-16 2005-03-24 Astrazeneca Ab Quinazoline derivatives
DE602004004811T2 (en) * 2003-09-19 2007-11-22 Astrazeneca Ab quinazoline derivatives
ATE352550T1 (en) * 2003-09-19 2007-02-15 Astrazeneca Ab CHINAZOLINE DERIVATIVES
AU2004276055A1 (en) * 2003-09-25 2005-04-07 Astrazeneca Ab Quinazoline derivatives
GB0322409D0 (en) * 2003-09-25 2003-10-29 Astrazeneca Ab 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
US7427624B2 (en) * 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
US7432273B2 (en) * 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
JP2007510652A (en) * 2003-11-03 2007-04-26 サイトキネティクス・インコーポレーテッド Pyrimidin-4-one compounds, compositions and methods
EP1680420A4 (en) * 2003-11-07 2008-09-24 Cytokinetics Inc Compounds, compositions, and methods
GB0326459D0 (en) * 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
US7671072B2 (en) * 2003-11-26 2010-03-02 Pfizer Inc. Aminopyrazole derivatives as GSK-3 inhibitors
US7439254B2 (en) * 2003-12-08 2008-10-21 Cytokinetics, Inc. Compounds, compositions, and methods
US20070281907A1 (en) * 2003-12-22 2007-12-06 Watkins William J Kinase Inhibitor Phosphonate Conjugates
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
WO2005075439A1 (en) * 2004-02-03 2005-08-18 Astrazeneca Ab Quinazoline derivatives
WO2005094830A1 (en) * 2004-03-30 2005-10-13 Pfizer Products Inc. Combinations of signal transduction inhibitors
CN1964970B (en) 2004-04-07 2011-08-03 诺瓦提斯公司 Inhibitors of iap
BRPI0510604B8 (en) * 2004-05-06 2021-05-25 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amide compound, its use and pharmaceutical composition comprising it 4-phenylamino-quinazolin-6-yl-amide compound, its use and pharmaceutical composition comprising it
ES2553264T3 (en) * 2004-05-27 2015-12-07 The Regents Of The University Of Colorado Methods for predicting the clinical outcome for epidermal growth factor receptor inhibitors for 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
CA2571421A1 (en) 2004-06-24 2006-01-05 Nicholas Valiante Compounds for immunopotentiation
US20100226931A1 (en) * 2004-06-24 2010-09-09 Nicholas Valiante Compounds for immunopotentiation
EP1802341A1 (en) * 2004-07-16 2007-07-04 Pfizer Products Inc. Combination treatment for non-hematologic malignancies using an anti-igf-1r antibody
PL1778251T3 (en) 2004-07-27 2011-09-30 Gilead Sciences Inc Nucleoside phosphonate conjugates as anti hiv agents
PL1784396T3 (en) * 2004-08-26 2011-05-31 Pfizer Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
MX2007001986A (en) * 2004-08-26 2007-05-10 Pfizer Aminoheteroaryl compounds as protein tyrosine kinase inhibitors.
ME01788B (en) * 2004-08-26 2011-02-28 Pfizer Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
EP2258704A1 (en) * 2004-10-19 2010-12-08 ArQule, Inc. Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 map kinase
JP2008518024A (en) * 2004-10-26 2008-05-29 ギリアード サイエンシーズ， インコーポレイテッド Phosphonate derivatives of mycophenolic acid
US20060107555A1 (en) * 2004-11-09 2006-05-25 Curtis Marc D Universal snow plow adapter
JP2008521900A (en) 2004-11-30 2008-06-26 アムジエン・インコーポレーテツド Quinolines and quinazoline analogues and their use as medicaments for the treatment of cancer
WO2006064196A1 (en) 2004-12-14 2006-06-22 Astrazeneca Ab Pyrazolopyrimidine compounds as antitumor agents
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
US20090155247A1 (en) * 2005-02-18 2009-06-18 Ashkenazi Avi J Methods of Using Death Receptor Agonists and EGFR Inhibitors
US20060188498A1 (en) * 2005-02-18 2006-08-24 Genentech, Inc. Methods of using death receptor agonists and EGFR inhibitors
CA2599210A1 (en) * 2005-02-26 2006-08-31 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
GB0504474D0 (en) * 2005-03-04 2005-04-13 Astrazeneca Ab Chemical compounds
US20080182865A1 (en) * 2005-03-11 2008-07-31 Witta Samir E Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
BRPI0608039A2 (en) * 2005-03-11 2009-06-16 Univ Colorado cancer cells sensitive to histone deacetylase inhibitors
US20060216288A1 (en) * 2005-03-22 2006-09-28 Amgen Inc Combinations for the treatment of cancer
JP4324636B2 (en) 2005-03-31 2009-09-02 アジェンシス，インコーポレイテッド Antibodies and related molecules that bind to 161P2F10B protein
CA2604735A1 (en) * 2005-04-12 2006-10-19 Elan Pharma International Limited Nanoparticulate quinazoline derivative formulations
GB0508717D0 (en) * 2005-04-29 2005-06-08 Astrazeneca Ab Chemical compounds
GB0508715D0 (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
ATE488513T1 (en) * 2005-09-20 2010-12-15 Astrazeneca Ab 4-(1H-INDAZOLE-5-YLAMINO)QUINAZOLINE COMPOUNDS AS ERBB RECEPTOR TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF CANCER
ES2374450T3 (en) 2005-09-20 2012-02-16 OSI Pharmaceuticals, LLC ANTI-BANGEOUS RESPONSE BIOLOGICAL MARKERS FOR KINNER INHIBITORS OF THE GROWTH FACTOR RECEIVER 1 SIMILAR TO INSULIN.
EP1940825A1 (en) * 2005-09-20 2008-07-09 Astra Zeneca AB Quinazoline derivatives as anticancer agents
US9006224B2 (en) 2005-11-21 2015-04-14 Novartis Ag Neuroendocrine tumor treatment
US7960545B2 (en) * 2005-11-23 2011-06-14 Natco Pharma Limited Process for the prepartion of erlotinib
US20090029968A1 (en) * 2005-12-02 2009-01-29 Bernard Christophe Barlaam Quinazoline derivatives used as inhibitors of erbb tyrosine kinase
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
AU2007240548A1 (en) 2006-04-05 2007-11-01 Novartis Ag Combinations of therapeutic agents for treating cancer
US20090233905A1 (en) 2006-04-05 2009-09-17 Gregory Peter Burke Combinations comprising bcr-abl/c-kit/pdgf-r tk inhibitors for treating cancer
AR060358A1 (en) * 2006-04-06 2008-06-11 Novartis Vaccines & Diagnostic QUINAZOLINS FOR THE INHIBITION OF PDK 1
WO2007123892A2 (en) * 2006-04-17 2007-11-01 Arqule Inc. Raf inhibitors and their uses
EP2010521A1 (en) 2006-04-19 2009-01-07 Novartis Ag Indazole compounds and methods for inhibition of cdc7
EP2026800A1 (en) 2006-05-09 2009-02-25 Novartis AG Combination comprising an iron chelator and an anti-neoplastic agent and use thereof
FR2903387B1 (en) * 2006-07-05 2008-08-29 Alcatel Sa ACTUATOR FOR SYSTEMS FOR GUIDING SPACE EQUIPMENTS WITH VARIABLE ROTATION RATIOS
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
PE20121506A1 (en) 2006-07-14 2012-11-26 Amgen Inc TRIAZOLOPYRIDINE COMPOUNDS AS C-MET INHIBITORS
CA2659307A1 (en) * 2006-07-28 2008-01-31 Synthon B.V. Crystalline erlotinib
US7547781B2 (en) * 2006-09-11 2009-06-16 Curis, Inc. Quinazoline based EGFR inhibitors containing a zinc binding moiety
US8604044B2 (en) * 2006-09-11 2013-12-10 Curis, Inc. Quinazoline based EGFR inhibitors containing a zinc binding moiety
WO2008033747A2 (en) * 2006-09-11 2008-03-20 Curis, Inc. Multi-functional small molecules as anti-proliferative agents
WO2008033748A2 (en) * 2006-09-11 2008-03-20 Curis, Inc. Quinazoline based egfr inhibitors containing a zinc binding moiety
WO2008033782A2 (en) 2006-09-12 2008-03-20 Genentech, Inc. Methods and compositions for the diagnosis and treatment of lung cancer using pdgfra, kit or kdr 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
CN101516885A (en) 2006-09-29 2009-08-26 诺瓦提斯公司 Pyrazolopyrimidines as PI3K lipid kinase inhibitors
US8372856B2 (en) * 2006-10-27 2013-02-12 Synthon Bv Hydrates of erlotinib hydrochloride
BRPI0718029A2 (en) 2006-11-06 2013-11-26 Supergen Inc IMIDAZO (1,2-B) PYRIDAZINE AND PIRAZOLE (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
US8343950B2 (en) * 2006-12-15 2013-01-01 Concert Pharmaceuticals, Inc. Quinazoline derivatives and methods of treatment
CA2672438A1 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
WO2008086014A2 (en) 2007-01-09 2008-07-17 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
EP2120900A2 (en) 2007-02-15 2009-11-25 Novartis AG Combination of lbh589 with other therapeutic agents for treating cancer
AU2008219166B2 (en) 2007-02-16 2013-05-16 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-Met inhibitors
PT2170844T (en) * 2007-02-21 2016-08-05 Natco Pharma Ltd Novel polymorphs of erlotinib hydrochloride and method of preparation
NZ579997A (en) * 2007-04-04 2012-08-31 Cipla Ltd PROCESS FOR PREPARATION OF N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
AU2008236995A1 (en) * 2007-04-10 2008-10-16 Myrexis, Inc. Dosages and methods for the treatment of cancer
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
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
MX2009013815A (en) * 2007-06-22 2010-03-01 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
WO2009009778A1 (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
WO2009024989A2 (en) 2007-08-17 2009-02-26 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
PL2188313T3 (en) 2007-08-21 2018-04-30 Amgen, Inc. Human c-fms antigen binding proteins
US20090124642A1 (en) * 2007-08-23 2009-05-14 Augusto Canavesi Crystalline forms of Erlotinib HCI and formulations thereof
TW200927732A (en) * 2007-08-23 2009-07-01 Plus Chemicals S A Crystalline forms of erlotinib HCl and formulations thereof
EP2185574B1 (en) 2007-09-07 2013-05-08 Agensys, Inc. Antibodies and related molecules that bind to 24p4c12 proteins
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
JP5474792B2 (en) * 2007-09-10 2014-04-16 キュリス，インコーポレイテッド Tartrate salt of a quinazoline-based EGFR inhibitor containing a zinc binding moiety or a complex thereof
US8119616B2 (en) * 2007-09-10 2012-02-21 Curis, Inc. Formulation of quinazoline based EGFR inhibitors containing a zinc binding moiety
WO2009049305A2 (en) * 2007-10-12 2009-04-16 Arqule, Inc. 5- (2-hydroxyphenyl) tetrazoles as hsp90 inhibitors against cancer
CN101861159A (en) * 2007-10-19 2010-10-13 马尔药品公司 Improved Antitumor Therapy
EP2220054A2 (en) 2007-10-29 2010-08-25 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
US20110053991A1 (en) * 2007-11-19 2011-03-03 Gore Lia Treatment of Histone Deacetylase Mediated Disorders
KR20100093129A (en) 2007-12-20 2010-08-24 노파르티스 아게 Thiazole derivatives used as pi 3 kinase inhibitors
CN101918374A (en) * 2008-01-18 2010-12-15 纳特科制药有限公司 6.7-dialkoxy ouinazoline 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
WO2009095480A1 (en) * 2008-01-30 2009-08-06 Pharma Mar, S.A. Improved antitumoral treatments
MY150290A (en) * 2008-02-07 2013-12-31 Boehringer Ingelheim Int Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production
EP2262522A1 (en) * 2008-03-07 2010-12-22 Pharma Mar, S.A. Improved antitumoral treatments
ES2524259T3 (en) 2008-03-24 2014-12-04 Novartis Ag Aryl sulfonamide matrix metalloproteinase inhibitors
EP2628726A1 (en) 2008-03-26 2013-08-21 Novartis AG Hydroxamate-based inhibitors of deacetylases b
CN102083801A (en) * 2008-03-28 2011-06-01 康瑟特制药公司 Quinazoline derivatives and methods of treatment
US8088782B2 (en) * 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
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
CA2730226A1 (en) * 2008-07-07 2010-01-14 Plus Chemicals Sa Crystalline forms of erlotinib base and erlotinib hcl
US20100093667A1 (en) 2008-07-08 2010-04-15 Gilead Sciences, Inc. Salts of hiv inhibitor compounds
JP5539351B2 (en) * 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclohexyloxy-substituted heterocycles, medicaments containing these compounds, and methods for producing 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
JP5836125B2 (en) 2008-10-16 2015-12-24 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション Fully human antibodies against high molecular weight melanoma-related antigens and uses thereof
US20110223241A1 (en) * 2008-10-16 2011-09-15 Celator Pharmaceuticals, Inc. Combination methods and compositions
US8710104B2 (en) * 2008-11-07 2014-04-29 Triact Therapeutics, Inc. Catecholic butanes and use thereof for 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
KR20110112352A (en) 2008-12-18 2011-10-12 노파르티스 아게 Novel of 1- (4-BL-[(E) -4-cyclohexyl-3-trifluoromethyl-benzyloxyimino] -ethyl｝ -2-ethyl-benzyl) -azetidine-3-carboxylic acid One polymorph form
CN102256941A (en) 2008-12-18 2011-11-23 诺瓦提斯公司 New salts
JP5627597B2 (en) 2008-12-18 2014-11-19 ノバルティス アーゲー 1- [4- [1- (4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino) -ethyl] -2-ethyl-benzyl] -azetidine-3-carboxylic acid hemifumarate
CN110818633A (en) 2009-01-16 2020-02-21 埃克塞里艾克西斯公司 Malate and crystal form thereof
WO2010083617A1 (en) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines as protein kinase inhibitors
JP2012516345A (en) 2009-01-29 2012-07-19 ノバルティス アーゲー Substituted benzimidazoles for astrocytoma treatment
CN102307875A (en) * 2009-02-09 2012-01-04 苏伯俭股份有限公司 Pyrrolopyrimidinyl axl kinase inhibitors
EP2400985A2 (en) 2009-02-25 2012-01-04 OSI Pharmaceuticals, LLC Combination of an either an anti-igf-1r antibody or an igf binding protein and a small molecule igf-1r kinase inhibitor
JP2012519170A (en) 2009-02-26 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー INSITU method for monitoring 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
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
EP2401613A2 (en) 2009-02-27 2012-01-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
TW201035088A (en) 2009-02-27 2010-10-01 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
CN102356092B (en) 2009-03-20 2014-11-05 霍夫曼-拉罗奇有限公司 Bispecific anti-HER antibodies
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
US8530492B2 (en) 2009-04-17 2013-09-10 Nektar Therapeutics Oligomer-protein tyrosine kinase inhibitor conjugates
AU2010264698C1 (en) 2009-06-26 2013-05-16 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
CA2770873A1 (en) 2009-08-12 2011-02-17 Novartis Ag Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation
SG10201404886PA (en) 2009-08-17 2014-10-30 Intellikine Llc Heterocyclic compounds and uses thereof
BR112012008061A2 (en) 2009-08-20 2016-03-01 Novartis Ag heterocyclic oxime compounds
BR112012008075A2 (en) 2009-08-26 2016-03-01 Novartis Ag tetrasubstituted heteroaryl compounds and their use as mdm2 and / or mdm4 modulators
PH12012500823A1 (en) 2009-11-04 2013-01-07 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
CA2780875A1 (en) 2009-11-13 2011-05-19 Pangaea Biotech, S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
PT3351558T (en) 2009-11-13 2020-04-09 Daiichi Sankyo Europe Gmbh Material and methods for treating or preventing her-3 associated diseases
US20110130711A1 (en) * 2009-11-19 2011-06-02 Follica, Inc. Hair growth treatment
JP6220126B2 (en) 2009-11-23 2017-10-25 セルリアン・ファーマ・インコーポレイテッド Polymers based on cyclodextrins 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
CA2781218A1 (en) 2009-12-08 2011-06-16 Novartis Ag Heterocyclic sulfonamide derivatives
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (en) 2009-12-22 2015-09-29 Novartis Ag ISOQUINOLINONES AND REPLACED QUINAZOLINONES
EP2348020A1 (en) 2009-12-23 2011-07-27 Esteve Química, S.A. Preparation process of erlotinib
AR079984A1 (en) 2010-01-12 2012-03-07 Hoffmann La Roche TRICYCLIC HETEROCICLIC COMPOUNDS, COMPOSITIONS AND ITS USE IN THE TREATMENT OF DISEASES MEDIATED BY THE INHIBITION OF JAK1
WO2011090940A1 (en) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
HRP20161742T4 (en) 2010-02-12 2024-07-05 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
RU2587619C2 (en) 2010-02-18 2016-06-20 Дженентек, Инк. Neuregulin antagonists and use thereof in treating malignant growth
JP2013527748A (en) 2010-03-03 2013-07-04 オーエスアイ・ファーマシューティカルズ，エルエルシー Biological markers useful for predicting anticancer responses to insulin-like growth factor 1 receptor kinase inhibitors
AU2011223655A1 (en) 2010-03-03 2012-06-28 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
WO2011113802A2 (en) 2010-03-17 2011-09-22 F. Hoffmann-La Roche Ag Imidazopyridine compounds, compositions and methods of use
US20110237686A1 (en) 2010-03-26 2011-09-29 Cerulean Pharma Inc Formulations and methods of use
EP2558864A1 (en) 2010-04-16 2013-02-20 Genentech, Inc. Fox03a as predictive biomarker for pi3k/akt kinase pathway inhibitor efficacy
JP2013526590A (en) 2010-05-21 2013-06-24 シェンヅェン サルブリス ファーマシューティカルズ カンパニー リミテッド Fused ring quinazoline derivatives and uses thereof
ES2695899T3 (en) 2010-06-16 2019-01-11 Univ Pittsburgh Commonwealth Sys Higher Education Antibodies against endoplasmin and its 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
CA2806273A1 (en) 2010-07-23 2012-03-08 Generics (Uk) Limited 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
WO2012031027A1 (en) 2010-08-31 2012-03-08 Genentech, Inc. Biomarkers and methods of treatment
WO2012035039A1 (en) 2010-09-15 2012-03-22 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
EP2627648A1 (en) 2010-09-16 2013-08-21 Novartis AG 17aHYDROXYLASE/C17,20-LYASE INHIBITORS
RU2013126041A (en) 2010-11-19 2014-12-27 Ф.Хоффманн-Ля Рош Аг 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
EA201390917A1 (en) 2010-12-21 2013-12-30 Новартис Аг DIGETEROARYLIC CONNECTIONS 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
ES2611885T3 (en) 2011-01-31 2017-05-11 Novartis Ag Novel Heterocyclic Derivatives
EP2673277A1 (en) 2011-02-10 2013-12-18 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
JP5808826B2 (en) 2011-02-23 2015-11-10 インテリカイン， エルエルシー Heterocyclic compounds and uses thereof
EA023998B1 (en) 2011-03-04 2016-08-31 Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед Amino-quinolines as kinase inhibitors
KR20220031732A (en) 2011-03-04 2022-03-11 뉴젠 세러퓨틱스 인코포레이티드 Alkyne substituted quinazoline compound and methods of use
WO2012129145A1 (en) 2011-03-18 2012-09-27 OSI Pharmaceuticals, LLC Nscle combination therapy
WO2012129344A1 (en) 2011-03-23 2012-09-27 Amgen Inc. Fused tricyclic dual 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.
MX2013011329A (en) 2011-04-01 2014-03-12 Genentech Inc Combinations of akt inhibitor compounds and erlotinib, 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
US20140178368A1 (en) 2011-04-19 2014-06-26 Leslie Lynne SHARP Combinations of anti-4-1bb antibodies and adcc-inducing antibodies for the treatment of cancer
EP2702173A1 (en) 2011-04-25 2014-03-05 OSI Pharmaceuticals, LLC Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment
KR20140025492A (en) 2011-04-28 2014-03-04 노파르티스 아게 17α-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
CN102918029B (en) 2011-05-17 2015-06-17 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
CA2838029A1 (en) 2011-06-09 2012-12-13 Novartis Ag Heterocyclic sulfonamide derivatives
EP2721008B1 (en) 2011-06-20 2015-04-29 Novartis AG Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors
WO2012175487A1 (en) 2011-06-20 2012-12-27 Novartis Ag Cyclohexyl isoquinolinone compounds
MX2013015001A (en) 2011-06-27 2014-03-31 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
EP3409278B8 (en) 2011-07-21 2020-11-04 Sumitomo Dainippon Pharma Oncology, Inc. Heterocyclic protein kinase inhibitors
KR20140047160A (en) 2011-08-12 2014-04-21 에프. 호프만-라 로슈 아게 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
WO2013025853A1 (en) 2011-08-17 2013-02-21 Genentech, Inc. Neuregulin antibodies and uses thereof
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
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
EP2751285B2 (en) 2011-08-31 2020-04-01 Genentech, Inc. Method for sensitivity testing of a tumour for a egfr kinase inhibitor
CA2848809A1 (en) 2011-09-15 2013-03-21 Novartis Ag 6-substituted 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyradines as c-met tyrosine kinase
JP2014526538A (en) 2011-09-20 2014-10-06 エフ．ホフマン−ラ ロシュ アーゲー Imidazopyridine compounds, compositions and methods of use
MX2014003698A (en) 2011-09-30 2014-07-28 Genentech Inc Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to egfr kinase inhibitor in tumours or tumour cells.
ES2654160T3 (en) 2011-10-04 2018-02-12 Igem Therapeutics Limited Anti-HMW-MAA IgE antibodies
CA2853256C (en) 2011-10-28 2019-05-14 Novartis Ag Novel purine derivatives and their use in the treatment of disease
CA2856149A1 (en) 2011-11-08 2013-05-16 Pfizer Inc. Methods of treating inflammatory disorders using anti-m-csf antibodies
CN104080787B (en) 2011-11-29 2016-09-14 诺华股份有限公司 Pyrazolo pyrrolidine compound
EP2785864A2 (en) 2011-11-30 2014-10-08 F. Hoffmann-La Roche AG Erbb3 mutations in cancer
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
EP2794594A1 (en) 2011-12-22 2014-10-29 Novartis AG Quinoline derivatives
IN2014CN04174A (en) 2011-12-22 2015-09-04 Novartis Ag
JP2015503516A (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
AU2012355613A1 (en) 2011-12-23 2014-07-17 Novartis Ag Compounds for inhibiting the interaction of BCL2 with binding partners
CA2859867A1 (en) 2011-12-23 2013-06-27 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
EA201491260A1 (en) 2011-12-23 2014-11-28 Новартис Аг COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE INTERACTION OF BCL2 WITH PARTNERS ON THE LINKAGE
EA201491264A1 (en) 2011-12-23 2014-11-28 Новартис Аг COMPOUNDS FOR INHIBITING THE INTERACTION OF BCL-2 WITH PARTNERS ON BINDING
UY34591A (en) 2012-01-26 2013-09-02 Novartis Ag IMIDAZOPIRROLIDINONA COMPOUNDS
KR20140117644A (en) 2012-01-31 2014-10-07 스미스클라인 비이참 (코르크) 리미티드 Method of treating cancer
AR090263A1 (en) 2012-03-08 2014-10-29 Hoffmann La Roche COMBINED ANTIBODY THERAPY AGAINST HUMAN CSF-1R AND USES OF THE SAME
EP2831115A1 (en) 2012-03-27 2015-02-04 F. Hoffmann-La Roche AG Diagnosis and treatments relating to her3 inhibitors
AU2013243097A1 (en) 2012-04-03 2014-10-09 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
JP6381523B2 (en) 2012-05-16 2018-08-29 ノバルティス アーゲー Administration regimen of PI-3 kinase inhibitor
WO2013175417A1 (en) 2012-05-24 2013-11-28 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
JP6427097B2 (en) 2012-06-15 2018-11-21 ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドＴｈｅ Ｂｒｉｇｈａｍ ａｎｄ Ｗｏｍｅｎ’ｓ Ｈｏｓｐｉｔａｌ， Ｉｎｃ． Compositions for treating cancer and methods for producing said compositions
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
US9738643B2 (en) 2012-08-06 2017-08-22 Duke University Substituted indazoles 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
US9394257B2 (en) 2012-10-16 2016-07-19 Tolero Pharmaceuticals, Inc. PKM2 modulators and methods for their use
CA2888803A1 (en) 2012-11-05 2014-05-08 Jooeun Bae Xbp1, cd138, and cs1 peptides, pharmaceutical compositions that include the peptides, and methods of using such 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
ES2651331T3 (en) 2013-01-10 2018-01-25 Glaxosmithkline Intellectual Property (No. 2) Limited Fatty acid synthase inhibitors
EP2948453B1 (en) 2013-01-22 2017-08-02 Novartis AG Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction
EP2948451B1 (en) 2013-01-22 2017-07-12 Novartis AG Substituted purinone compounds
WO2014128612A1 (en) 2013-02-20 2014-08-28 Novartis Ag Quinazolin-4-one derivatives
CN111139256A (en) 2013-02-20 2020-05-12 诺华股份有限公司 Cancer treatment using humanized anti-EGFRvIII chimeric antigen receptors
JP6301374B2 (en) 2013-02-21 2018-03-28 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Quinazolines as kinase inhibitors
EP2958592A1 (en) 2013-02-22 2015-12-30 F. Hoffmann-La Roche AG Methods of treating cancer and preventing drug resistance
AU2014223548A1 (en) 2013-02-26 2015-10-15 Triact Therapeutics, Inc. Cancer therapy
US9925240B2 (en) 2013-03-06 2018-03-27 Genentech, Inc. Methods of treating and preventing cancer drug resistance
RU2015143517A (en) 2013-03-13 2017-04-19 Дженентек, Инк. Pyrazole-containing compounds and their use
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
MX2015011899A (en) 2013-03-15 2016-05-05 Genentech Inc Methods of treating cancer and preventing cancer drug resistance.
EP2968340A4 (en) 2013-03-15 2016-08-10 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
JP6268276B2 (en) 2013-04-04 2018-01-24 ヤンセン ファーマシューティカ エヌ．ベー． Novel N (2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) -4-quinazolinamine derivatives and N- (2,3-dihydro-1H-indoles as PERK inhibitors -5-yl) -4-quinazolineamine derivatives
JP2016519684A (en) 2013-04-08 2016-07-07 デニス エム ブラウン Methods and compositions for improving the efficacy of suboptimally administered medication and / or reducing side effects
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
EP3027623A4 (en) * 2013-08-02 2017-03-01 Ignyta, 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
US9227969B2 (en) 2013-08-14 2016-01-05 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
TW201605896A (en) 2013-08-30 2016-02-16 安美基股份有限公司 GITR antigen binding proteins
KR20160049003A (en) 2013-09-05 2016-05-04 제넨테크, 인크. Antiproliferative compounds
CA2923667A1 (en) 2013-09-09 2015-03-12 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
TW201605857A (en) 2013-10-03 2016-02-16 赫孚孟拉羅股份公司 Therapeutic inhibitors of CDK8 and uses thereof
WO2015051302A1 (en) 2013-10-04 2015-04-09 Aptose Biosciences Inc. Compositions and methods for treating cancers
US20150147333A1 (en) 2013-10-18 2015-05-28 Genentech, Inc. Anti-rspo antibodies and methods of use
TW201605450A (en) 2013-12-03 2016-02-16 諾華公司 Combination of Mdm2 inhibitor and BRAF inhibitor and their use
PT3076969T (en) 2013-12-06 2021-11-23 Novartis Ag Dosage regimen for an alpha-isoform 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
MX2016007965A (en) 2013-12-17 2016-10-28 Genentech Inc Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists.
RS59659B2 (en) 2013-12-17 2023-08-31 Hoffmann La Roche PD-1 AXIS BINDING ANTAGONISTS AND TAXANE-ASSISTED CANCER TREATMENTS
WO2015128837A1 (en) 2014-02-26 2015-09-03 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
EP3122728A4 (en) 2014-03-28 2017-10-25 Calitor Sciences, LLC Substituted heteroaryl compounds and methods of use
WO2015153514A1 (en) 2014-03-31 2015-10-08 Genentech, Inc. Combination therapy comprising anti-angiogenesis agents and ox40 binding agonists
BR112016022658A2 (en) 2014-03-31 2017-10-17 Genentech Inc 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
MX2016014531A (en) 2014-05-07 2017-05-01 Remedica 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
EP3177320B1 (en) 2014-07-31 2021-01-06 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
AU2015294889B2 (en) 2014-07-31 2018-03-15 Novartis Ag Combination therapy
CN107074823B (en) 2014-09-05 2021-05-04 基因泰克公司 Therapeutic compounds and their uses
CN107073125A (en) 2014-09-19 2017-08-18 基因泰克公司 CBP/EP300 and BET inhibitor is used for the purposes for the treatment of cancer
WO2016057924A1 (en) 2014-10-10 2016-04-14 Genentech, Inc. Pyrrolidine amide compounds as histone demethylase inhibitors
CA2966507A1 (en) 2014-11-03 2016-05-12 Genentech, Inc. Methods and biomarkers for predicting efficacy and evaluation of an ox40 agonist treatment
AU2015343337A1 (en) 2014-11-03 2017-06-15 Genentech, Inc. Assays for detecting T cell immune subsets and methods of use thereof
SG11201703376QA (en) 2014-11-06 2017-05-30 Genentech Inc Combination therapy comprising ox40 binding agonists and tigit inhibitors
MA40943A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
MA40940A (en) 2014-11-10 2017-09-19 Constellation Pharmaceuticals Inc SUBSTITUTED PYRROLOPYRIDINES USED AS BROMODOMA INHIBITORS
WO2016077375A1 (en) 2014-11-10 2016-05-19 Genentech, Inc. Bromodomain inhibitors and uses thereof
WO2016081384A1 (en) 2014-11-17 2016-05-26 Genentech, Inc. Combination therapy comprising ox40 binding agonists and pd-1 axis binding antagonists
EP3632915A1 (en) 2014-11-27 2020-04-08 Genentech, Inc. 4,5,6,7-tetrahydro-1 h-pyrazolo[4,3-c]pyridin-3-amine compounds as cbp and/or ep300 inhibitors
WO2016097918A1 (en) 2014-12-18 2016-06-23 Pfizer Inc. Pyrimidine and triazine derivatives and their use as axl inhibitors
BR112017010788A2 (en) 2014-12-23 2017-12-26 Genentech Inc methods of identifying a cancer patient and identifying a cancer patient who may benefit from administration of a vegf antagonist, method of treating a cancer patient, and method for determining ovarian cancer stage
KR20170095893A (en) 2014-12-24 2017-08-23 제넨테크, 인크. Therapeutic, diagnostic, and prognostic methods for cancer of the bladder
EP3240908A2 (en) 2014-12-30 2017-11-08 F. Hoffmann-La Roche AG Methods and compositions for prognosis and treatment of cancers
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
JP6659703B2 (en) 2015-01-09 2020-03-04 ジェネンテック， インコーポレイテッド Pyridazinone derivatives and their use in the treatment of cancer
JP6889661B2 (en) 2015-01-09 2021-06-18 ジェネンテック， インコーポレイテッド 4,5-Dihydroimidazole derivative and its use as a histone dimethylase (KDM2B) inhibitor
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
EP3250571B1 (en) 2015-01-29 2022-11-30 Genentech, Inc. Therapeutic compounds and uses thereof
CN107438593B (en) 2015-01-30 2020-10-30 基因泰克公司 Therapeutic compounds and uses thereof
AU2016214923A1 (en) * 2015-02-03 2017-08-24 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
JP6955445B2 (en) 2015-04-07 2021-10-27 ジェネンテック， インコーポレイテッド Antigen binding complex with agonistic activity and how to use it
CN107995863A (en) 2015-04-20 2018-05-04 特雷罗药物股份有限公司 Prediction of response to avocidide by mitochondrial analysis
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
EP3294770B2 (en) 2015-05-12 2024-03-20 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
KR102608921B1 (en) 2015-05-18 2023-12-01 스미토모 파마 온콜로지, 인크. Albocidip prodrug with increased bioavailability
EP3708681A1 (en) 2015-05-29 2020-09-16 F. Hoffmann-La Roche AG Therapeutic and diagnostic methods for cancer
MX2017014740A (en) 2015-06-08 2018-08-15 Genentech Inc Methods of treating cancer using anti-ox40 antibodies.
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
AU2016280070B2 (en) 2015-06-17 2022-09-15 Genentech, Inc. Methods of treating locally advanced or metastatic breast cancers using PD-1 axis binding antagonists and taxanes
KR20180034538A (en) 2015-08-03 2018-04-04 톨레로 파마수티컬스, 인크. Concurrent therapy for the treatment of cancer
US20180230431A1 (en) 2015-08-07 2018-08-16 Glaxosmithkline Intellectual Property Development Limited Combination Therapy
JP6946270B2 (en) 2015-08-26 2021-10-06 ファンダシオン デル セクトル プーブリコ エスタタル セントロ ナショナル デ インベスティゲーショネス オンコロジカス カルロス ３（エフ エス ピー クニオ） Condensed tricyclic compound as a protein kinase inhibitor
EP3347097B1 (en) 2015-09-11 2021-02-24 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine derivatives as modulators of the kinases jak, flt3 and aurora
DK3353210T3 (en) 2015-09-25 2025-01-06 Hoffmann La Roche Anti-TIGIT antibodies and methods of use
KR20180073674A (en) 2015-11-02 2018-07-02 노파르티스 아게 Therapy for phosphatidylinositol 3-kinase inhibitors
JP2019505476A (en) 2015-12-01 2019-02-28 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ Combination treatment and method
AU2016369528B2 (en) 2015-12-16 2021-04-22 Genentech, Inc. Process for the preparation of tricyclic PI3K inhibitor compounds and methods for using the same for the treatment of cancer
CN108368179B (en) 2016-01-08 2022-08-23 豪夫迈·罗氏有限公司 Methods of treating CEA positive cancers using PD-1 axis binding antagonists and anti-CEA/anti-CD 3 bispecific antibodies
EP3423596B1 (en) 2016-02-29 2022-09-28 Genentech, Inc. Therapeutic and diagnostic methods for cancer
MX2018010851A (en) 2016-03-08 2019-02-07 Janssen Biotech Inc Gitr antibodies, methods, and uses.
WO2017180864A1 (en) 2016-04-14 2017-10-19 Genentech, Inc. Anti-rspo3 antibodies and methods of use
KR20180134347A (en) 2016-04-15 2018-12-18 제넨테크, 인크. Diagnosis and Treatment of Cancer
CN109154027A (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
MX2018012492A (en) 2016-04-15 2019-06-06 Genentech Inc Methods for monitoring and treating cancer.
WO2017184956A1 (en) 2016-04-22 2017-10-26 Duke University Compounds and methods for targeting hsp90
JP7160688B2 (en) 2016-05-24 2022-10-25 ジェネンテック， インコーポレイテッド Heterocyclic inhibitors of CBP/EP300 and their use in treating cancer
JP7014736B2 (en) 2016-05-24 2022-02-01 ジェネンテック， インコーポレイテッド Pyrazolopyridine derivatives for the treatment of cancer
EP3469099A1 (en) 2016-06-08 2019-04-17 F. Hoffmann-La Roche AG Diagnostic and therapeutic methods for cancer
US11649289B2 (en) 2016-08-04 2023-05-16 Glaxosmithkline Intellectual Property Development Limited 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
CN109476748B (en) 2016-08-08 2023-05-23 豪夫迈·罗氏有限公司 Methods for treatment and diagnosis of cancer
EP3503914A1 (en) 2016-08-23 2019-07-03 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
EP3519441B1 (en) 2016-09-27 2022-03-30 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules
WO2018060833A1 (en) 2016-09-27 2018-04-05 Novartis Ag Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib
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
AU2017339517B2 (en) 2016-10-06 2024-03-14 Foundation Medicine, Inc. Therapeutic and diagnostic methods for cancer
WO2018081648A2 (en) 2016-10-29 2018-05-03 Genentech, Inc. 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
RS62456B1 (en) 2016-12-22 2021-11-30 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
AU2018228873A1 (en) 2017-03-01 2019-08-29 Genentech, Inc. Diagnostic and therapeutic methods for cancer
MX2019012187A (en) 2017-04-13 2019-11-25 Hoffmann La Roche 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
CN111492245A (en) 2017-07-21 2020-08-04 基因泰克公司 Methods of treatment and diagnosis of cancer
PL3661937T3 (en) 2017-08-01 2021-12-20 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
CA3070297A1 (en) 2017-08-11 2019-02-14 Genentech, Inc. Anti-cd8 antibodies and uses thereof
MX2020002502A (en) 2017-09-08 2020-07-20 Amgen Inc Inhibitors of kras g12c and methods of using the same.
CA3073073A1 (en) 2017-09-08 2019-03-14 F. Hoffmann-La Roche Ag Diagnostic and therapeutic methods for cancer
WO2019055579A1 (en) 2017-09-12 2019-03-21 Tolero Pharmaceuticals, Inc. Treatment regimen for cancers that are insensitive to bcl-2 inhibitors using the mcl-1 inhibitor alvocidib
RU2020114641A (en) 2017-09-26 2021-10-27 Серо Терапьютикс, Инк. CHIMERIC INTERNALIZING RECEPTOR MOLECULES AND METHODS OF APPLICATION
WO2019075367A1 (en) 2017-10-13 2019-04-18 Tolero Pharmaceuticals, Inc. Pkm2 activators in combination with reactive oxygen species for treatment of cancer
WO2019083960A1 (en) 2017-10-24 2019-05-02 Oncopep, Inc. Peptide vaccines and hdac inhibitors for treating multiple myeloma
US12059463B2 (en) 2017-10-24 2024-08-13 Oncopep, Inc. Peptide vaccines and pembrolizumab for treating breast cancer
WO2019084395A1 (en) 2017-10-27 2019-05-02 University Of Virginia Patent Foundation Compounds and methods for regulating, limiting, or inhibiting avil expression
CA3077664A1 (en) 2017-11-06 2019-05-09 Genentech, Inc. Diagnostic and therapeutic methods for cancer
JP7254076B2 (en) 2017-11-19 2023-04-07 サンシャイン・レイク・ファーマ・カンパニー・リミテッド Substituted heteroaryl compounds and methods of use
EP3740468A4 (en) 2018-01-20 2021-10-06 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of 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
AU2019225249A1 (en) 2018-02-26 2020-09-17 Genentech, Inc. Dosing for treatment with anti-tigit and anti-PD-L1 antagonist antibodies
MX2020010241A (en) 2018-03-28 2020-10-16 Cero Therapeutics Inc Cellular immunotherapy compositions and uses thereof.
WO2019191334A1 (en) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Chimeric tim4 receptors and uses thereof
KR20210024441A (en) 2018-03-28 2021-03-05 세로 테라퓨틱스, 인코포레이티드 Expression vectors for chimeric phagocytic receptors, genetically modified host cells, and uses thereof
US11045484B2 (en) 2018-05-04 2021-06-29 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
MA52564A (en) 2018-05-10 2021-03-17 Amgen Inc KRAS G12C INHIBITORS FOR CANCER TREATMENT
CA3100200A1 (en) 2018-05-21 2019-11-28 Nanostring Technologies, Inc. Molecular gene signatures and methods of using same
EP3802535B1 (en) 2018-06-01 2022-12-14 Amgen, Inc Kras g12c inhibitors and methods of using the same
AU2019284472B2 (en) 2018-06-11 2024-05-30 Amgen Inc. KRAS G12C inhibitors for treating cancer
CA3100390A1 (en) 2018-06-12 2020-03-12 Amgen Inc. Kras g12c inhibitors encompassing piperazine ring and use thereof in the treatment of cancer
CN112585166A (en) 2018-06-23 2021-03-30 豪夫迈·罗氏有限公司 Methods of treating lung cancer with PD-1 axis binding antagonists, platinating agents, and topoisomerase II inhibitors
MX2021000558A (en) 2018-07-18 2021-04-13 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
MX2021000977A (en) 2018-07-26 2021-04-12 Sumitomo Pharma Oncology Inc Methods for treating diseases associated with abnormal acvr1 expression and acvr1 inhibitors for use in the same.
WO2020051099A1 (en) 2018-09-03 2020-03-12 Genentech, Inc. Carboxamide and sulfonamide derivatives useful as tead modulators
KR20210063330A (en) 2018-09-19 2021-06-01 제넨테크, 인크. Methods of treatment and diagnosis for bladder cancer
MX2021003213A (en) 2018-09-21 2021-05-12 Genentech Inc Diagnostic methods for triple-negative breast cancer.
BR112021006407A8 (en) 2018-10-04 2022-12-06 Inst Nat Sante Rech Med use of egfr inhibitors for keratoderms
MX2021004348A (en) 2018-10-18 2021-05-28 Genentech Inc Diagnostic and therapeutic methods for sarcomatoid kidney 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
JP7454572B2 (en) 2018-11-19 2024-03-22 アムジエン・インコーポレーテツド KRAS G12C inhibitor and its use
KR20210099066A (en) 2018-12-04 2021-08-11 스미토모 다이니폰 파마 온콜로지, 인크. CDK9 inhibitors and polymorphs thereof for use as agents for the 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
WO2020131627A1 (en) 2018-12-19 2020-06-25 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
ES2997190T3 (en) 2018-12-20 2025-02-14 Amgen Inc Heteroaryl amides useful as kif18a inhibitors
KR20210106474A (en) 2018-12-20 2021-08-30 암젠 인크 KIF18A inhibitor
JP2022514268A (en) 2018-12-20 2022-02-10 アムジエン・インコーポレーテツド KIF18A inhibitor
JP2022513967A (en) 2018-12-20 2022-02-09 アムジエン・インコーポレーテツド Heteroarylamide useful as a KIF18A inhibitor
CA3128064A1 (en) 2019-02-01 2020-08-06 Glaxosmithkline Intellectual Property Development Limited Combination treatments for cancer comprising belantamab mafodotin and an anti ox40 antibody and uses and methods thereof
JP2022519649A (en) 2019-02-08 2022-03-24 ジェネンテック， インコーポレイテッド How to diagnose and treat cancer
KR20210146290A (en) 2019-02-12 2021-12-03 스미토모 다이니폰 파마 온콜로지, 인크. Formulations comprising heterocyclic protein kinase inhibitors
WO2020165672A1 (en) 2019-02-15 2020-08-20 Shivalik Rasayan Limited Process for preparation of highly pure fingolimod hydrochloride
CA3130695A1 (en) 2019-02-27 2020-09-03 Genentech, Inc. Dosing for treatment with anti-tigit and anti-cd20 or anti-cd38 antibodies
WO2020172712A1 (en) 2019-02-27 2020-09-03 Epiaxis Therapeutics Pty Ltd Methods and agents for assessing t-cell function and predicting response to therapy
KR20210146287A (en) 2019-03-01 2021-12-03 레볼루션 메디슨즈, 인크. Bicyclic heteroaryl compounds and uses thereof
JP2022522778A (en) 2019-03-01 2022-04-20 レボリューション メディシンズ インコーポレイテッド Bicyclic heterocyclyl compounds and their use
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
EP3941463A1 (en) 2019-03-22 2022-01-26 Sumitomo Dainippon 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
WO2020226986A2 (en) 2019-05-03 2020-11-12 Genentech, Inc. 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
MX2021014126A (en) 2019-05-21 2022-01-04 Amgen Inc FORMS IN SOLID STATE.
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
MX2022001295A (en) 2019-08-02 2022-02-22 Amgen Inc Kif18a inhibitors.
JP7640521B2 (en) 2019-08-02 2025-03-05 アムジエン・インコーポレーテツド Heteroaryl amides useful as KIF18A inhibitors - Patents.com
CN114391012A (en) 2019-08-02 2022-04-22 美国安进公司 Pyridine derivatives as KIF18A inhibitors
JP2022542319A (en) 2019-08-02 2022-09-30 アムジエン・インコーポレーテツド KIF18A inhibitor
US20230192853A1 (en) 2019-09-04 2023-06-22 Genentech, Inc. Cd8 binding agents and uses thereof
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
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
PE20221110A1 (en) 2019-09-27 2022-07-11 Genentech Inc DOSE ADMINISTRATION 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
CA3155857A1 (en) 2019-10-24 2021-04-29 Amgen Inc. PYRIDOPYRIMIDINE DERIVATIVES USEFUL AS KRAS G12C AND KRAS G12D INHIBITORS IN THE TREATMENT OF CANCER
US20230024096A1 (en) 2019-10-29 2023-01-26 Hoffmann-La Roche Inc. Bifunctional compounds for the treatment of cancer
CN114867735A (en) 2019-11-04 2022-08-05 锐新医药公司 RAS inhibitors
EP4054720A1 (en) 2019-11-04 2022-09-14 Revolution Medicines, Inc. Ras inhibitors
JP2022553858A (en) 2019-11-04 2022-12-26 レボリューション メディシンズ インコーポレイテッド RAS inhibitor
KR20220092580A (en) 2019-11-06 2022-07-01 제넨테크, 인크. Diagnosis and treatment methods for the treatment of blood cancer
WO2021092115A1 (en) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
CR20220207A (en) 2019-11-13 2022-06-06 Genentech Inc Therapeutic compounds and methods of use
TW202132271A (en) 2019-11-14 2021-09-01 美商安進公司 Improved synthesis of kras g12c inhibitor compound
AU2020381492A1 (en) 2019-11-14 2022-05-26 Amgen Inc. Improved synthesis of KRAS G12C inhibitor compound
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
JP2023505100A (en) 2019-11-27 2023-02-08 レボリューション メディシンズ インコーポレイテッド Covalent RAS inhibitors and uses thereof
BR112022011357A2 (en) 2019-12-13 2022-08-23 Genentech Inc ISOLATED ANTIBODIES, ONE OR MORE ISOLATED NUCLEIC ACIDS, ONE OR MORE VECTORS, ONE OR MORE HOST CELLS, COMPOSITION, KIT, ANTIBODY USE, METHODS TO PRODUCE THE ANTIBODY AND METHOD TO TREAT OR DELAY PROGRESSION OF A LY6G6D POSITIVE CANCER
TW202136276A (en) 2019-12-20 2021-10-01 美商艾瑞斯卡公司 Tricyclic pyridones and pyrimidones
JP2023509701A (en) 2020-01-07 2023-03-09 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 SHP2 inhibitor dosing and methods of treating cancer
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
CN115038466A (en) 2020-01-28 2022-09-09 葛兰素史密斯克莱知识产权发展有限公司 Combination therapy and uses and methods thereof
WO2021177980A1 (en) 2020-03-06 2021-09-10 Genentech, Inc. Combination therapy for cancer comprising pd-1 axis binding antagonist and il6 antagonist
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
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
EP4127724A1 (en) 2020-04-03 2023-02-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
EP4143345A1 (en) 2020-04-28 2023-03-08 Genentech, Inc. Methods and compositions for non-small cell lung cancer immunotherapy
IL299039A (en) 2020-06-16 2023-02-01 Genentech Inc Methods and compositions for treating triple-negative breast cancer
JP2023530351A (en) 2020-06-18 2023-07-14 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 Methods of delaying, preventing and treating acquired resistance to RAS inhibitors
AU2021293507A1 (en) 2020-06-18 2023-02-02 F. Hoffmann-La Roche Ag Treatment with anti-TIGIT antibodies and PD-1 axis binding antagonists
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
US20230285576A1 (en) 2020-08-05 2023-09-14 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
WO2022036265A1 (en) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Chimeric tim receptors and uses thereof
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
WO2022047259A1 (en) 2020-08-28 2022-03-03 California Institute Of Technology Synthetic mammalian signaling circuits for robust cell population control
CN116209438A (en) 2020-09-03 2023-06-02 锐新医药公司 Treatment of malignant diseases with SHP2 mutations using SOS1 inhibitors
EP4214209A1 (en) 2020-09-15 2023-07-26 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022066805A1 (en) 2020-09-23 2022-03-31 Erasca, Inc. Tricyclic pyridones and pyrimidones
KR20230082632A (en) 2020-10-05 2023-06-08 제넨테크, 인크. 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
US20230107642A1 (en) 2020-12-18 2023-04-06 Erasca, Inc. Tricyclic pyridones and pyrimidones
TW202241885A (en) 2020-12-22 2022-11-01 大陸商上海齊魯銳格醫藥研發有限公司 Sos1 inhibitors and uses thereof
KR20230146052A (en) 2021-02-12 2023-10-18 에프. 호프만-라 로슈 아게 Bicyclic tetrahydroazepine derivatives for cancer treatment
CN117203223A (en) 2021-02-26 2023-12-08 凯洛尼亚疗法有限公司 Lymphocyte targeting lentiviral vectors
JP2024517847A (en) 2021-05-05 2024-04-23 レボリューション メディシンズ インコーポレイテッド RAS inhibitors
AR125787A1 (en) 2021-05-05 2023-08-16 Revolution Medicines Inc RAS INHIBITORS
CN117500811A (en) 2021-05-05 2024-02-02 锐新医药公司 Covalent RAS inhibitors and uses thereof
JP2024520457A (en) 2021-05-25 2024-05-24 エラスカ・インコーポレイテッド Sulfur-containing heteroaromatic tricyclic KRAS inhibitors
TW202317126A (en) 2021-06-15 2023-05-01 美商建南德克公司 Egfr inhibitor and perk activator in combination therapy
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
JP2024529474A (en) 2021-07-28 2024-08-06 セロ・セラピューティクス・インコーポレイテッド Chimeric Tim4 receptor and uses thereof
WO2023018699A1 (en) 2021-08-10 2023-02-16 Erasca, Inc. Selective kras inhibitors
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
TW202340212A (en) 2021-11-24 2023-10-16 美商建南德克公司 Therapeutic compounds and methods of use
TW202332429A (en) 2021-11-24 2023-08-16 美商建南德克公司 Therapeutic compounds and methods of use
EP4448526A1 (en) 2021-12-17 2024-10-23 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
CN119136806A (en) 2022-03-08 2024-12-13 锐新医药公司 Methods for treating immune-refractory lung cancer
CN119487067A (en) 2022-04-01 2025-02-18 基因泰克公司 Administration of treatment with anti-FCRH 5/anti-CD 3 bispecific antibodies
EP4522653A1 (en) 2022-05-11 2025-03-19 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
IL317449A (en) 2022-06-07 2025-02-01 Genentech Inc Method for determining the efficacy of a lung cancer treatment comprising an anti-pd-l1 antagonist and an anti-tigit antagonist antibody
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
TW202417042A (en) 2022-07-13 2024-05-01 美商建南德克公司 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
AU2023317584A1 (en) 2022-08-02 2025-02-13 Luca Science Inc. Methods of improving cellular therapy with organelle complexes
IL316935A (en) 2022-08-11 2025-01-01 Hoffmann La Roche Bicyclic tetrahydrothiazepine derivatives
CN119698413A (en) 2022-08-11 2025-03-25 豪夫迈·罗氏有限公司 Bicyclic tetrahydrothiazepine derivatives
TW202417439A (en) 2022-08-11 2024-05-01 瑞士商赫孚孟拉羅股份公司 Bicyclic tetrahydrothiazepine derivatives
AR130167A1 (en) 2022-08-11 2024-11-13 Hoffmann La Roche BICYCLIC TETRAHYDROAZEPINE DERIVATIVES
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
WO2024085242A2 (en) 2022-10-21 2024-04-25 Kawasaki Institute Of Industrial Promotion Non-fouling or super stealth vesicle
WO2024091991A1 (en) 2022-10-25 2024-05-02 Genentech, Inc. Therapeutic and diagnostic methods for multiple myeloma
TW202434206A (en) 2023-02-17 2024-09-01 美商伊瑞斯卡公司 Kras inhibitors
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
US20240352038A1 (en) 2023-04-14 2024-10-24 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
TW202446388A (en) 2023-04-14 2024-12-01 美商銳新醫藥公司 Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
WO2024233341A1 (en) 2023-05-05 2024-11-14 Genentech, Inc. Dosing for treatment with anti-fcrh5/anti-cd3 bispecific antibodies
WO2024254455A1 (en) 2023-06-08 2024-12-12 Genentech, Inc. Macrophage signatures for diagnostic and therapeutic methods for lymphoma
WO2025024257A1 (en) 2023-07-21 2025-01-30 Genentech, Inc. Diagnostic and therapeutic methods for cancer
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a 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

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. *

Cited By (19)

* 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
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
WO2012068483A1 (en) 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment based on hypoxic status
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
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
US9321759B2 (en) 2011-03-17 2016-04-26 The Trustees Of The University Of Pennsylvania Methods and use of bifunctional enzyme-building clamp-shaped molecules
US9546179B2 (en) 2011-12-20 2017-01-17 Wei Qian Heterocycle amido alkyloxy substituted quinazoline derivative and use thereof
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
US11285212B2 (en) 2013-03-01 2022-03-29 California Institute Of Technology Targeted nanoparticles
US10240207B2 (en) 2014-03-24 2019-03-26 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with HGF expression
US10717825B2 (en) 2015-07-01 2020-07-21 California Instite of Technology Cationic mucic acid polymer-based delivery system
US11041050B2 (en) 2015-07-01 2021-06-22 California Institute Of Technology Cationic mucic acid polymer-based delivery systems
US10710968B2 (en) 2016-01-13 2020-07-14 Hadasit Medical Research Services And Development Ltd. Radiolabeled erlotinib analogs and uses thereof
US11708335B2 (en) 2017-12-18 2023-07-25 Sterngreene, Inc. Pyrimidine compounds useful as tyrosine kinase inhibitors
WO2019178433A1 (en) 2018-03-15 2019-09-19 Abbvie Inc. Abbv-621 in combination with anti-cancer agents for the treatment of pancreatic cancer
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

Also Published As

Publication number Publication date
US5747498A (en) 1998-05-05

Similar Documents

Publication Publication Date Title
USRE41065E1 (en) Alkynl and azido-substituted 4-anilinoquinazolines
EP0817775B1 (en) Quinazoline derivatives
US6395733B1 (en) Heterocyclic ring-fused pyrimidine derivatives
EP0831829B1 (en) Heterocyclic ring-fused pyrimidine derivatives
US6225318B1 (en) 4-aminoquinazolone derivatives
US6015814A (en) Quinazoline derivative
NZ245662A (en) Quinazoline derivatives, preparation and pharmaceutical compositions thereof
EP0837063A1 (en) 4-Aminoquinazoline derivatives
US8080558B2 (en) 4-(tetrazol-5-yl)-quinazoline derivatives as anti-cancer agent
AU778961B2 (en) Intermediates for the preparation of 4-(substituted phenylamino)quinazoline derivatives

Legal Events

Date Code Title Description
AS Assignment

Owner name: OSI PHARMACEUTICALS, LLC, ILLINOIS

Free format text: CHANGE OF NAME;ASSIGNOR:OSI PHARMACEUTICALS, INC.;REEL/FRAME:040608/0830

Effective date: 20110331