WO2002066445A1 - Derives de la quinazoline - Google Patents

Derives de la quinazoline Download PDF

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Publication number
WO2002066445A1
WO2002066445A1 PCT/JP2002/001575 JP0201575W WO02066445A1 WO 2002066445 A1 WO2002066445 A1 WO 2002066445A1 JP 0201575 W JP0201575 W JP 0201575W WO 02066445 A1 WO02066445 A1 WO 02066445A1
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group
hydrogen atom
alkyl
alkyl group
alkoxy
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PCT/JP2002/001575
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English (en)
French (fr)
Japanese (ja)
Inventor
Yasunori Kitano
Eiji Kawahara
Tsuyoshi Suzuki
Daisuke Abe
Masahiro Nakajou
Naoko Ueda
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Mitsubishi Pharma Corporation
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Priority to AT02700688T priority Critical patent/ATE475652T1/de
Priority to KR1020037011020A priority patent/KR100861486B1/ko
Priority to EP02700688A priority patent/EP1369418B1/en
Priority to JP2002565961A priority patent/JP4285996B2/ja
Priority to DE60237145T priority patent/DE60237145D1/de
Priority to CA002442742A priority patent/CA2442742A1/en
Priority to US10/468,788 priority patent/US7294629B2/en
Publication of WO2002066445A1 publication Critical patent/WO2002066445A1/ja
Priority to US11/819,679 priority patent/US20070265260A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel quinazoline derivatives. More specifically, the present invention relates to quinazoline derivatives having tyrosine-specific protein kinase (hereinafter, tyrosine kinase) inhibitory activity.
  • tyrosine kinase tyrosine-specific protein kinase
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the quinazoline derivative and a pharmaceutically acceptable carrier, a tyrosine kinase inhibitor containing the quinazoline derivative, an anticancer agent, tyrosine such as arteriosclerosis-based disease and psoriasis.
  • the present invention relates to a therapeutic and / or Z-prophylactic agent for a disease caused by enhanced kinase activity.
  • drugs that directly inhibit DNA synthesis or directly inhibit cell division are widely used. These drugs act as cytotoxic agents and may be effective against rapidly dividing cancer cells.However, in many cases, their cytotoxicity is not limited to cancer cells, so they are also highly toxic to normal cells. As a result, as a result, the side effects of chemotherapy using such drugs have become a problem.
  • a method of increasing the selectivity of suppressing proliferation of cancer cells there is known a method of increasing the selectivity of suppressing proliferation of cancer cells.
  • Tyrosine kinases are enzymes that phosphorylate tyrosine residues in proteins, and are well known to play important and central functions in cell differentiation, proliferation, and intracellular signaling. At the same time, disruption in the control of tyrosine kinase activity leads to cell differentiation and proliferation and abnormalities in intracellular signaling mechanisms, and is thought to be directly involved in the development of many diseases. For example, atherosclerosis C1 ⁇ 2. J. Physiol., 1991 »260 (4-part 1), C721-C730; Biochem. Biophys. Res. Co. n., 1993, 192 (3), 13 19-1326. , Psoriasis [/. Invest.
  • tyrosine Kinase activity has also been found to be detected more frequently in tumor cells than in normal cells [Cell, 1987, 50, 823].
  • HER2 also called ErbB2 or Neu
  • growth factor potato receptor tyrosine kinase such as EGF receptor
  • receptor tyrosine kinase has been found to be greatly involved in cancer formation. And has been found to have enhanced receptor tyrosine kinase activity in human cancer [Cancer Res., 1991, 51, 4430-4435; Cancer Res., 199 2, 52, 3636—3641. Cancer Chemother. Pharmacol., 1993, 32, 1-19.
  • these receptor tyrosine kinases are overexpressed in many tumors, including brain, lung, stomach, intestine, overturning, head and neck, esophagus, bladder, kidney, prostate, ovary, breast, child, thyroid, etc. Bull., 1991, 47, 87; Expert Opin. Invest, Drugs, 1994, 3 (6), 577-595; JP-A-5-208911].
  • the involvement of the EGF receptor has also been shown in angiogenesis closely related to cancer metastasis. Biol. Che., 1995, 912, 895-898; Cancer Res., 1995, 55, 3772-3776].
  • drugs that inhibit tyrosine kinase are useful not only as preventive or therapeutic drugs for the above-mentioned diseases but also as anticancer drugs having a new mechanism of action and having few side effects applicable to many cancer types.
  • Various tyrosine kinase inhibitors have been studied so far, and are disclosed in JP-A-6-73025, JP-A-5-208911, Japanese Patent No. 2994165, It is disclosed in Japanese Unexamined Patent Publication (Kokai) No. 1-25050857 or also in a recent paper by Diane H. Boschelli [Drugs of the Future 199924 (E), 515-537;], but has not yet been put to practical use.
  • EGF receptor The EGF receptor, HER2, ErbB3, and ErbB4 all belong to the ErbB family, and these receptors form a heterocomplex and are involved in intracellular signaling. Interaction is observed L7. Clin. Oncol. 2001 19 (18s), 32s ⁇ 40s].
  • co-expression of EGF receptor and HER2 further accelerates canceration by EGF receptor alone Cell 198758, 287-292].
  • co-expression of EGF receptor and HER2 in breast cancer, oral cancer, lung cancer and the like results in a poor prognosis' iClin. Cancer Res. 19995, 4164-4174].
  • breast cancer In some cases, co-expression of EGF receptor and HER2 has been reported to be associated with endocrine therapy resistance [;: Steroid Biochem. 198934, 123-131]. .
  • An object of the present invention was to find an agent that inhibits EGF receptor tyrosine kinase and an agent that inhibits both EGF receptor tyrosine kinase and HER2 tyrosine kinase.
  • Dual inhibitors of EGF receptor and HER2 not only have broad advantages in indications than drugs that act only on a single kinase, but also have a stronger therapeutic effect due to the synergistic effect of dual inhibition. Is excellent.
  • the compound of the present invention has a long-lasting enzyme inhibitory action, and can obtain a superior therapeutic effect as compared with a reversible inhibitor that has been reported hitherto. Disclosure of the invention
  • the present inventors have made intensive studies to solve the above problems, and as a result, have found that a quinazoline derivative having a specific structure has a strong tyrosine kinase inhibitory activity and a cancer cell growth inhibitory effect, and have reached the present invention.
  • the gist of the present invention is:
  • R 1 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a dinitro group, a CiCg alkyl group, a CiCs alkoxy group, one S (O) f 13 (where, ⁇ represents an integer of 0 to 2, and R 13 is Represents an alkyl group. ), -NR 14 R 15 (wherein, R 14 and R 15 are each independently a hydrogen atom, Ji-Ji 5 alkyl group, C 1 -C 5 al force Noiru group or C ⁇ Ji 5 alkylsulfonyl group ), C. ⁇ C 5 alkenyl group or C. It represents a ⁇ C 5 alkynyl group, One of R 2 and R 3 is
  • R 27 represents a Moruho. Reno Good Ci Cs alkyl group optionally substituted by a group.
  • R 4 are each independently a hydrogen atom, a halogen atom, or a halogen atom, a morpholino group
  • R 7 represents a halogen atom, a morpholino group, a 4-C 5 alkyl group which may be replaced by a 4-C Cs alkylpyrazine 11-yl ′ or a di (Ci Cs alkyl) amino).
  • R 17, R 18 each independently represent a hydrogen atom or a Ci Cs alkyl group, u and j are 0 or 1 V represents an integer of 1 to 5, R 19 is a hydrogen atom, a hydroxy group, a cyano group, an amino group, (05 alkoxy group, morpholino group, 41 CiCs alkylpiperazine-1 1 ⁇
  • the text refers to di (Ci Cs alkyl) amino.
  • V represents an integer of 2 to 5.
  • R 2 is a) a hydrogen atom, b) a C 1 -C 5 alkylsulfonyl group, C) Cj
  • r and t each independently represent an integer of 1 to 3, k represents 0 or 1, W represents a hydrogen atom, a hydroxy group, a CiCs alkoxy group, Alkanooxy group, carboxyl group, cyano group, di (C Cs alkyl) amino group, monoreholino group, pyrrolidine-111, piperidine-111, 4-Ci-Cs-alkylpiperazine-1-1 Or CONR 21 R 22 (wherein, R 21 and R 22 each independently represent a hydrogen atom or a Ci Cs alkyl group).
  • B for.
  • n represents an integer of 1 or 2
  • R 1 represents a halogen atom, a cyano group, a Ci Cs alkyl group, a C 1 -C 5 alkoxy group, — S (0) f R 13 (where f is represents an integer of 0 to 2, 1 13 represents one to Ji 5 Arukiru group), one NR 14 R 1 '5 (wherein, R 14 and R 15 are each independently a hydrogen atom, €, 05 It represents an alkyl group, Ci Cs alkanol I group or C Cs alkyl sulfonyl Le group), or an C 2 -C 5 ⁇ / Rekiniru group, "
  • R 27 S 0 2 NH- (wherein, R 27 represents a substituted C ⁇ 0 5 optionally alkyl morpholino group), (R 28 S0 2> 2 N- (wherein, R 28 is morpholino Represents a C Cs alkyl group which may be substituted with a group), Ci Cs alkoxy group, Me CO CH 2 CO—, Me S CH 2 CH 2 CO—, NCCH 2 CO
  • X one C (O) - or S 0 2 - represents, with each R 4, R 5 and R 6 are independently a hydrogen atom, a halogen atom, statement halogen atom, a morpholino group, 4 one Represents a C 1 -C 5 alkyl group which may be substituted by Ci-C 5 alkylpirazin-1-yl or di (Ci Cg alkyl) amino.
  • R 8 and R 9 each independently represent a) a hydrogen atom, b) a Ci Cg alkyl group optionally substituted with an alkoxy group, m represents an integer of 0 to 3, R 11 , R 12 each independently represent a hydrogen atom or a Ci Cs alkyl group, Y represents a hydrogen atom, a hydroxy group, a Ci Cs alkoxy group, a Ct Cs alkanoyloxy group, a N (R le ) — (CO ) u- (CR 17 R 18) V- (CO) j - R 19 ( wherein, R 16 is a hydrogen atom, or a Shiano groups or C 1 -C S good C 1 ⁇ optionally substituted with an alkoxy group Represents a C S alkyl group, R 17 and R ia each independently represent a hydrogen atom or —C.
  • p and q each independently represents an integer of 2 or 3, Z one O-, in a carbonyl group or NR 2 ° (wherein, R 2. Is hydrogen, C 1 -C S a sulfonyl group , A C carbonyl group, a C i -C 5 alkoxycarbol group, or a cyano group or Represents a Ci Cs alkyl group which may be substituted with an alkoxy group. ;).
  • W is hydrogen atom, hydroxy group, CCS alkoxy, CL ⁇ C s Arukanoi Ruokishi group, carboxyl Group, shear / group, di (Ci Cs alkyl) amino group, morpholino group, or CONR 21 R 22 (wherein R 21 and R 22 are each independently a hydrogen atom or a C 1 -C 5 alkyl group
  • n represents an integer of 0 to 3
  • R 1 represents a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, a Ci Cs alkyl group, a C ⁇ Cs alkoxy group, a S (O) f R 13 (wherein, f represents an integer from 0 to 2, 1 13 represents 0 1 ⁇ Ji 5 Arukiru group.), -NR 14 R 35 (wherein, R 14 and R 15 are each independently, a hydrogen atom, Ci ⁇ C s alkyl group, C i Cs Arukanoiru group or C 1 -C 5 alkylsulfonyl - Le group table to), C 2 ⁇ C 5 alkenyl -. group or C 2 -C 6 alkynyl Represents a group,
  • X represents 1 C (O) — or 1 SO z —
  • R 4 , R 5 and R s each independently represent a hydrogen atom, a halogen atom, or a halogen atom, a morpholino group, C x -C 5 Arukirupi Bae Rajin one 1-I le or di (C 1 ⁇ C 5 alkyl) optionally substituted with Amino C, represents a -C 5 alkyl group.
  • R 7 represents a halogen atom, a morpholino group, or a 4- to 5- alkylpyrazine-11-yl or a C ⁇ -C 5 alkyl group which may be substituted by di (Ci Cg alkyl) amino) )
  • R 3 is'
  • Y is a hydrogen atom, arsenic Dorokishi group, C 1 -C 5 alkoxy group, C ⁇ Cs Arukanoiru Okishi group one N is 16) - (CO) u- ( CR 17 R 18) V- (CO) j - R 19 (where '
  • R 1 B represents a hydrogen atom, or a C i -C 5 alkyl group which may be substituted with a cyano group or a Ct Cs alkoxy group
  • R 17 and R 18 each independently represent a hydrogen atom or a C 1 -C 5 alkyl group.
  • u and j is 0 or 1
  • V represents an integer of 1 to 5
  • R 19 represents a hydrogen atom, hydroxy group, Shiano group, an amino group, Ji ⁇ . C 5 alkoxy group , morpholino group
  • 4 one C Cs Arukirupi Bae Rajin - represents a one I le, or di (C 3 -C 5 alkyl) amino group.
  • ⁇
  • r and t each independently represent an integer of 1 to 3, k represents 0 or 1, W represents a hydrogen atom, a hydroxy group, a C Cs alkoxy group, a C Cs alkanoyloxy group, a carboxyl group Group, cyano group, di (C Cs alkyl group) amino group, monorefolino group, pyrrolidine-1-yl, piperidin-1-yl, 4-C CsT lucirpiperazine-11-yl or one CONR 21 R 22 (wherein, R 21 and R 22 each independently represent a hydrogen atom or a CiCs alkyl group.).
  • R 21 and R 22 each independently represent a hydrogen atom or a CiCs alkyl group.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (10) and a pharmaceutically acceptable carrier.
  • a tyrosine-specific protein kinase inhibitor comprising, as an active ingredient, the compound according to any one of (1) to (10).
  • a method for treating and / or preventing a disease caused by enhanced activity of a tyrosine-specific protein kinase comprising the compound according to any one of (1) to (10) as an active ingredient.
  • FIG. 1 shows an XRD pattern of the compound la′l / 2H 20 A type crystal.
  • Figure 2 shows the XRD pattern of the compound la'2TsOH type A crystal.
  • the compound of the present invention is a quinazoline derivative represented by the general formula (I).
  • Examples of the halogen atom defined for each substituent of the general formula (I) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the alkyl group include a methyl group, an ethyl group, and n-propyl.
  • Examples of the alkanoyl group include a honolemil group, an acetyl group, a propionyl group, a butyryl group, an isopallyl group, and a paleryl group.
  • the quinazoline derivative of the present invention can be prepared by a known method using a corresponding acid or base. Is converted to salt.
  • Salts include, for example, inorganic salts such as hydrochloride, sulfate, carbonate, and phosphate, or formate, acetate, propionate, lactate, oxalate, fumarate, maleate, and the like. Salts with organic acids such as acid, citrate, tartrate, benzoate, phthalate, methanesulfonate, p-toluenesulfonate, isethionate, glucuronate, dalconate, etc.
  • inorganic salts such as hydrochloride, sulfate, carbonate, and phosphate, or formate, acetate, propionate, lactate, oxalate, fumarate, maleate, and the like.
  • Salts with organic acids such as acid, citrate, tartrate, benzoate, phthalate, methanesulfonate, p-toluenesulfonate, isethionate, glucuronate, dal
  • salts with alkali metals such as sodium salts and potassium salts
  • salts with alkaline earth metals such as magnesium salts and calcium salts
  • ammonium salts pharmacologically acceptable organic amines (tetramethylamine, Salts with triethylamine, benzinoleamine, phenetinoleamine, monoethanolamine, diethanolamine, tris (hydroxyxylamine), lysine, arginine and the like.
  • the quinazoline derivative of the present invention can have various steric structures.
  • its absolute configuration may be any of the (S) -form, the (R) -form, or the racemic form.
  • the optical isomers or diastereoisomers in pure form, any mixtures of these isomers, racemates and the like are all included in the scope of the present invention.
  • the quinazoline derivative represented by the formula (I) can exist in a solvated form such as a hydrate and an unsolvated form, and the present invention relates to all quinazoline derivatives having anticancer activity. Includes solvated forms of this type.
  • Tables 1 to 9 show preferred specific examples of the compound of the present invention.
  • Me represents a methyl group
  • Et represents an ethyl group
  • Pr represents a propyl group.
  • R 31 is bonded to either the 6-position or the 7-position of the quinazoline ring, and —NH 2 and one NC ⁇ are the other ones. And other symbols are as defined above. ],
  • Examples of the compound () include tetrahydrofuran (hereinafter referred to as THF), ether solvents such as methyl ether, hydrocarbon solvents such as toluene and heptane, dimethylformamide (hereinafter referred to as DMF), and dimethyl sulfoxide (hereinafter referred to as DMF).
  • THF tetrahydrofuran
  • ether solvents such as methyl ether
  • hydrocarbon solvents such as toluene and heptane
  • DMF dimethylformamide
  • DMF dimethyl sulfoxide
  • DMSO methyl methacrylate
  • a non-protonic polar solvent such as acetonitrile or the like
  • a protic polar solvent such as methanol, tert-butanol, water, or a mixed solvent thereof
  • 0 to 10 equivalents of triethylamine and getylamine Pyridine, 4- (N, N-dimethylamino) pyridine (hereinafter referred to as DMAP), or a nitrogen-containing base or an inorganic base such as sodium carbonate or potassium hydrogencarbonate, or the presence or absence of the corresponding sulfone.
  • Compound (I) can be produced by a coexisting condensation reaction.
  • the vinylsulfonamide compound is treated by treating the loethylsulfur halide with the compound ( ⁇ ) in the presence of an excess of a base such as triethylamine or with a base, and the compound () and -ketene are converted into toluene, acetonitrile or the like. By reacting in a solvent, an acetyl acetoamide can be produced.
  • Compound ( ⁇ ) is prepared by converting the corresponding nitro compound (1 '') into an ethereal solvent such as THF and getyl ether, a hydrocarbon solvent such as toluene and heptane, and a non-protonic polar solvent such as DMF and acetonitrile.
  • an ethereal solvent such as THF and getyl ether
  • a hydrocarbon solvent such as toluene and heptane
  • a non-protonic polar solvent such as DMF and acetonitrile
  • ⁇ represents an amino group, a nitro group, an alkoxy group, or an amide group such as a sulfonamide or an acrylamide
  • Q represents elimination of a halogen atom, trifluoromethanesulfonyl (OTf) or the like.
  • M is a hydrogen atom, L i, M g Br, Sn R 3 , B (OR) 2; L i, Mg B r, SnR 3, AIR have B (oR) in 2, Z r C p 2 C 1 ( wherein, R represents a hydrogen atom or a lower alkyl group, C p is cyclopentadienyl GETS two Le group ).
  • Compound (H ') and compound (DI) or compound ( ⁇ ') are ether-based such as THF, Solvents, hydrocarbon solvents such as toluene, non-protonic polar solvents such as DMF, dimethyl sulfoxide, and acetonitrile; protonic polar solvents such as methanol, tert-butanol, and water; 10 equivalents of nitrogen-containing bases such as triethylamine, getylamine and pyridine or inorganic bases such as sodium carbonate, potassium carbonate and cesium fluoride, 0.001 to 0.5 equivalents of Pd (PPh 3 ) Pd (0Ac) 2 , PdCl 2 Reaction with + 2D C C to +200 C TC for 5 minutes to 48 hours in the presence or absence of palladium complex such as (PPh 3 ) 2 and 0.001 to 0.5 equivalent of copper compound such as Cul
  • M Li can be prepared by acting odor Chemical chill magnesium etc. Gurinya reactants, .M g X (X is (Representing a halogen atom)], and can be prepared by, for example, reacting with a trialkyltin chloride compound, zinc chloride or a trialkoxyboron compound.
  • can be, from ( ⁇ ') ( ⁇ ' ⁇ 2) from ([pi ') ([rho' is sulfonamide de represents an amino-de-group such as acrylamide) method of converting the compound described above () ( A condensation reaction to I) can be used.
  • R 2 one of R. 3 is represented by an alkoxy group compound is also a compound ( ⁇ ') ( ⁇ ' represents a ⁇ alkoxy group) And compound (1 ⁇ ⁇ ) or compound ( ⁇ ') (Scheme 2).
  • R 3 is
  • ether solvents such as THF, getyl ether, hydrocarbon solvents such as toluene, halogenated hydrocarbons such as dichloromethane, DMF, Non pro ton polar solvent such as Asetonitoriru, methanol, tert- butanol, pro tons polar solvent or a mixed solvent thereof such as water, from 0.0001 to 0.5 equivalent amount of Pd / BaS0 4 Pt0 2, Pd / C or the like methods and for example 0 by catalytic hydrogenation reduction to catalyze;.! ⁇ 5 equivalents of LiAlH 4, (i one Bu) 2 AlH, a method of performing arsenide Dorometaru reaction using diborane, followed by hydrolysis Can also be manufactured.
  • a solvent such as THF or getyl ether
  • a hydrocarbon solvent such as toluene
  • a non-protic solvent such as DMF or acetonitrile.
  • X 1 and X 2 are the same or one of them represents a bromine atom or a chlorine atom.
  • an appropriate solvent such as dichloromethane and carbon tetrachloride, for example, 0.1 to 10 equivalents of carbon tetrabromide and triphenylphosphine-2, respectively.
  • R 24 represents a hydrogen atom or a trialkylsilyl group
  • M t is.
  • L i, Mg B r or C e C 1 represents 2 or the like of the metal atom (Dan)
  • R 27 is a hydrogen atom
  • R 25, R 26 are each R lfi - (CR 17 R 1B ) V - (CO) one R 19 (wherein j, each symbol is as defined above Or R 2S and R 26 are taken together to form a ring,
  • Alcohol compounds can be converted to acid anhydrides such as acetic anhydride, acylating agents such as acid anhydrides, etc. or alkylating agents such as alkyl halide alkyl methanesulfonates such as dichloromethane, toluene, and acetonitrile.
  • acid anhydrides such as acetic anhydride
  • acylating agents such as acid anhydrides, etc.
  • alkylating agents such as alkyl halide alkyl methanesulfonates such as dichloromethane, toluene, and acetonitrile.
  • alkylating agents such as alkyl halide alkyl methanesulfonates such as dichloromethane, toluene, and acetonitrile.
  • alkylating agents such as alkyl halide alkyl methanesulfonates such as dichloromethane, toluene, and acetonitrile.
  • the alkoxide generated in the system is directly captured by an acylating agent such as an acid anhydride or an acid chloride or an alkylating agent without isolating the alcohol form.
  • an acylating agent such as an acid anhydride or an acid chloride or an alkylating agent without isolating the alcohol form.
  • the alcohol compound is dissolved in a suitable solvent such as acetonitrile, toluene, THF, etc. at a temperature of from 130 to 120 at 0.000 10.5 equivalents of a suitable Lewis acid, for example, Sc (OTf) 3
  • An acylated product can also be produced by reacting an acid anhydride and an acid chloride in the presence of BF 3 and OE 2 .
  • a detrimethylsilyl treatment by a conventional method may be performed before or after the acylation step or the etherification step, if necessary.
  • the acylated compound is prepared in an appropriate solvent such as THF, dichloromethane, toluene, and acetonitrile in the presence of 0.001 to 0.5 equivalents of a copper compound such as CuCl, Cu1 or copper powder.
  • a copper compound such as CuCl, Cu1 or copper powder.
  • Non-protonic poles such as hydrocarbon solvents, DMF, dimethyl sulfoxide, and acetonitrile 0 to 10 equivalents of nitrogen-containing bases such as triethylamine, getylamine, pyridine, DMAP, or sodium carbonate in a protic polar solvent such as methanol, tert-butanol, and water, or a mixed solvent thereof in a neutral solvent
  • a protic polar solvent such as methanol, tert-butanol, and water
  • a mixed solvent thereof in a neutral solvent
  • the quinazoline derivative of the present invention is a therapeutic and / or prophylactic agent for a disease caused by enhanced tyrosine kinase activity, ie, an anticancer agent, a disease based on arteriosclerosis (eg, ischemic heart disease, acute coronary syndrome, etc.). And treatment for psoriasis and. It can be used as a chemical.
  • the compound of the present invention represented by the above general formula (I) is usually administered systemically or locally, in an oral or parenteral form. Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, and the like. It is usually administered orally, once to several times daily, in the range of 1 mg to 5 g at a time, per adult, or 1 to 5 g per dose, per adult, in the range of ling to 5 g per dose. It is given parenterally once to several times a day, or is continuously administered intravenously for 1 to 24 hours a day.
  • the dose when administering the compound of the present invention, it is used as a solid composition, a liquid composition and other compositions for oral administration, an injection, an external preparation, a patch, a suppository and the like for parenteral administration.
  • the compounds can be administered alone or as part of a pharmaceutically acceptable composition containing a pharmaceutically acceptable excipient.
  • One or more of the compounds represented by the general formula (I) can be administered simultaneously or sequentially.
  • Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like. Capsules include hard capsules and soft capsules.
  • the one or more active substances include at least one inert diluent, such as ratatose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, poly, and the like. Bielpyrrolidone, mixed with magnesium aluminate metasilicate.
  • the composition is formulated according to the usual practice, with additives other than inert diluents, e.g. lubricants such as talc, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, disintegrants such as cellulose calcium dalcholate. And a solubilizing agent such as glutamate or aspartic acid.
  • Tablets or pills may be coated with gastric or enteric film such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary, or in two or more layers. It may be coated. More gelatin Capsules of such resorbable materials are also included.
  • gastric or enteric film such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc., if necessary, or in two or more layers. It may be coated. More gelatin Capsules of such resorbable materials are also included.
  • Liquid compositions for oral administration include pharmaceutically acceptable solutions, suspensions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as water. Or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl honolem Amide, cottonseed oil, america hodimo oil, sorghum germ oil, olive oil, castor oil, and fatty acid esters of sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, or mixtures of these substances, etc. Good. In addition to such inert diluents, the compositions may also contain adjuvants such as wetting agents, suspending agents, sweeten
  • Suspensions contain, in addition to the active compound, suspending agents such as ethoxyl isostearyl alcohol, polyoxyethylene sorbitol sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and It may contain tragacanth or a mixture of these substances. .
  • suspending agents such as ethoxyl isostearyl alcohol, polyoxyethylene sorbitol sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and It may contain tragacanth or a mixture of these substances.
  • compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.
  • the composition may contain, in addition to the inert diluent, a buffering agent that isotonic with a stabilizer such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid.
  • a buffering agent such as sodium bisulfite, for example, sodium chloride, sodium citrate, or citric acid.
  • the method for producing the spray is described in, for example, US Pat. Nos. 2,686,691 and 3,095,355.
  • compositions for parenteral administration include physiologically acceptable sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • the non-aqueous solution and suspension include propylene glycol, polyethylene dalicol, olive oil, ethanol, and polysorbate 80. like this
  • the compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid).
  • These are sterilized by, for example, filtration through a filter for retaining bacteria, blending of a bactericide or irradiation. They can also be used to produce a sterile solid composition, for example, dissolved in sterile water or a sterile injection solvent before use of the freeze-dried product.
  • compositions for non-administrative administration include one or more active substances, including topical solutions, soft solutions, liniments, suppositories, pessaries and the like, formulated in a conventional manner. .
  • reaction operation was carried out at ambient temperature, ie 18-25t :, under an inert gas such as nitrogen atmosphere;
  • the structure of the target product of the general formula (I) is a proton (' ⁇ or 1 H) nuclear magnetic resonance (NMR) method (3030 or 27 ⁇ , 300 MHz unless otherwise specified) and / or or was confirmed by mass spectrum method: Hi NMR was measured among unless otherwise specified deuterated dimethyl sulfoxide (DMSO-d Medical DMSO-d 6) or a heavy black port e ⁇ arm (CDC1 3, CDC1 3), Chemical shift values are expressed as delta values ( ⁇ ) with respect to tetramethylsilane (TMS), and peak multiplicity is shown as follows: s, singlet; d, doublet; t, triplet; q, Quadruple; m, multiplet ;. br, broad peak
  • the desired product can be obtained by washing the product with acetonitrile (1.2 heated with water and then filtered) (7-black mouth-6-nitro-4-quinazolininole)-(3-black mouth-4-funoleolopheninole) ) Amine (54.6 g, 67%) was obtained.
  • the filtrate was separated, and the organic layer was washed with water (500 mL), 1% aqueous ammonia (250 mL x 2), water (250 m), saturated edible water (500 mL) in that order, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure.
  • a yellow solid (61.4 g) mainly containing 2-cyano-5-bromonitrobenzene was obtained. This was dissolved in ethyl acetate (270 mL), platinum oxide monohydrate (330 mg, 1.35 mmol) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred under a hydrogen atmosphere for 41.5 hours.
  • the amino compound 2a (6.08 g, 13,4 ol) obtained by the method of Synthesis Example 2, acrylic acid (1.38 raL, 20.1 mraol), triethylamine (2.8 mL, 20.1 mmol) and EDC (3, A solution of 86 g (20.1 nunol) in DMF (100 mL) was stirred at room temperature for one hour. Acrylic acid (0.46 mL, 6.71 nunol), triethylamine (0.93 mL, 6.71 mmol) and EDC (1.29 g, 6.71 mmol) were added to the reaction mixture, and the mixture was further stirred. The reaction solution was poured into aqueous sodium hydrogen carbonate (300 mL), and the mixture was filtered. The residue was washed with water and water-ethanol and dried. The crude product was heated and stirred with water-ethanol and then cooled to room temperature. The precipitate was collected by filtration and dried to obtain the desired compound la (3.41 g, 50%).
  • acetylene compound 4 used as a starting material was synthesized according to the method of Synthesis Example 1 except for the cases shown in the following Synthesis Examples. In some cases, the product was converted to the corresponding hydrochloride (4N hydrochloric acid-ethyl acetate). The yield and 1 HN MR spectrum data are shown in the table.
  • Acetic acid 1,1-bis (ethoxymethyl) -2-propynyl ester (15.00 g, 70 mmol) and 1-methylbiperazine (8.41 g, 84 mmol), copper (I) chloride (350 mg triethylamine (9.7 mL, 70 lustrol) ), was dissolved in THF (0.99 mL), 2 hours pressurized heat refluxing. after completion of the reaction, the f Bu0Me added to the reaction mixture, after neutralized extract was extracted with 3N hydrochloric acid.
  • the extract was neutralized with a 6 N aqueous sodium hydroxide solution, extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate and 4N hydrochloric acid-ethyl acetate (17.0 mL) was added. The precipitated crystals were filtered and dried under reduced pressure to obtain Compound 4r (7.44 g, 79%) as pale yellow crystals.
  • the crude product was subjected to silica gel phenol chromatography (clonor honolem-methanoinole-trietinoleamine), and the crude product obtained was recrystallized from water-ethanol to obtain the desired compound la a (127 mg, 16%).
  • Trifenylphosphine (118 fflg, 0.46 ramol) and palladium acetate (II) (51 mg, 0.23 mol) were added, and the mixture was stirred at 80 ⁇ : for 3 hours. After the reaction solution was brought to room temperature, the solvent was distilled off under reduced pressure. Add sodium bicarbonate water to the residue, Extracted with ethyl acetate. The organic layer was washed with water (X3) and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a nitro form 3ab.
  • the XRD pattern of this crystal is shown in FIG. 1, and this crystal is referred to as a type A crystal.
  • the characteristic peaks shown in Fig. 1 are as follows.
  • Elemental analysis (calculated) (as C 27 H 28 C1FN 60 ⁇ 1 / 2H Z 0) C, 62.85; H, 5.66; N, 16.29; (analytical) C, 62.68; H, 5.58; N, 16.14 .
  • Fig. 2 The XRD data of this crystal is shown in Fig. 2, and this crystal is assumed to be an A-type crystal.
  • the characteristic peaks shown in Fig. 2 are as follows. Characteristic peak (20, ⁇ 0.2 °)
  • Example 31 Isopropyl alcohol (5.0 mL) was added to the crude crystals (148 mg) obtained by the method of Example 1, and the mixture was heated to an internal temperature of about 80 with stirring. After the solid was completely dissolved, the solution was cooled to room temperature while stirring. The precipitate was collected by filtration, and the precipitate was washed with isopropyl alcohol and dried under reduced pressure at 60 ° C. for 6 hours to give the title compound as pale yellow crystals (133 mg, 90%). The XRD pattern of this crystal showed an A-type crystal.
  • Example 31 Acetonitrile (6.5 mL) was added to the crude crystals (147 mg) obtained by the method of Example 1, and the mixture was heated to an internal temperature of about 70 with stirring. After the solid was completely dissolved, the solution was cooled to room temperature with stirring. The precipitate was collected by filtration, and the precipitate was washed with acetate and trityl, and dried under reduced pressure for 60 ⁇ for 6 hours to give the title compound as pale yellow crystals (113 rag, 77%). The XRD pattern of this crystal showed an A-type crystal.
  • Ethanol 2.5 mL was added to the crude crystals (158 rag) obtained by the method of Example 31, and the mixture was heated with stirring at an internal temperature of about SO. After the solid was completely dissolved, ethyl acetate (8.0) was added dropwise while stirring the solution, and then cooled to room temperature. The precipitate was collected by filtration, and the precipitate was washed with ethanol: ethyl acetate (1: 5) and dried under reduced pressure at 603 ⁇ 4 for 6 hours to give the title compound as pale-yellow crystals (125 mg, 7950). XRD pattern showed Form A crystals.
  • the XRD pattern of this crystal is measured, and this crystal form is designated as A-type crystal.
  • Example 53 la-3HCl-4H 2 0
  • a -type crystals Preparation of (5) * crude crystal obtained by the method of Example 32 (0.400 g) in water (2.0 mL) was added, ⁇ oil The bath was heated to 70 ° C. After the solid was completely dissolved, the solution was added dropwise to acetone (30 mL). The precipitate was collected by filtration and dried at 80 under reduced pressure for 7 hours to give the title compound (0.313 g) as colorless crystals. The XRD pattern of this crystal showed an A-type crystal.
  • the desired 6-trilate 6c (quantitative) was obtained in the same manner as in Synthesis Example 13-2) using 4- (3-methoxyphenylamino) -7-methoxyquinazolin-6-ol. .
  • Acetic acid 4-cyclomouth-7-ethoxy-6-quinazolinyl ester (10 g, 40.3 mmol) was added to isopropanol (250 mL) and 3-chloromouth-4 -fluoroaniline (5.86 g, 40.3 mmol), and the oil was added. The mixture was stirred at a bath temperature of 90 for 2 hours. After cooling, the product was collected by filtration, dried, and added to methanol (120 mL). After adding 28% ammonia water (12 mL) and stirring at room temperature, water (200 mL) was added.
  • Example 58 The reaction was carried out in the same manner as in Example 56 using '6-triflate 6b and 4- (1,1-dimethyl-2-probyl) piperazine (see Synthesis Example 9). After the reaction solution was concentrated under reduced pressure, it was partitioned between chloroform and aqueous sodium bicarbonate, and the organic layer was concentrated under reduced pressure. After the crude product was suspended in acetonitrile and stirred, the solid obtained by filtration was purified by silica gel column chromatography to obtain the desired compound lbc (yield 73 ° / o).
  • the compound lbc was converted into the desired compound lbe in the same manner as in Example 59 using iseptyl iodide (yield 48%).
  • Example 66> A pyridine (7 inL) solution of the amino compound 2c (700 mg, 1.46 mmol) obtained by the method of Example 3 was cooled to 0 to 5 and then methanesulfonyl chloride (125 ⁇ 1., 1.61 mmol) was dripped slowly. While the reactor was kept in an ice bath, the temperature was raised naturally, and the reaction solution was poured into sodium bicarbonate water. The precipitated solid was collected by filtration and washed with cold water.
  • the resulting crude product was subjected to silica gel column chromatography (chloroform-methanol), and the resulting compound was washed with acetonitrile. The product was collected and dried under reduced pressure to obtain the desired compound lea (552 mg, 68%).
  • the amino compound 2a (452 mg, 1.00 minol), tetronic acid (126 mg, 1.50 mmol), baking soda (423 mg, 5.00 ul) and HATU (701 mg, 1.84 mmol) obtained by the method of Synthesis Example 2
  • the DMF (1.0 mL) solution was stirred at room temperature for 20 hours.
  • the reaction mixture was poured into aqueous sodium hydrogen carbonate (Q00 aL) and extracted with ethyl acetate (50 mL x 2).
  • the obtained organic layer was washed with a saturated saline solution (50 mL ⁇ 2), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was subjected to silica gel column chromatography (methylene chloride-methanol), and further washed with ethyl acetate to obtain the desired coupling compound lag (71 mg, 143 ⁇ 4). .
  • the target compound using 3-methoxylin as a phosphorus.Converted to lak (40% yield).
  • Acetic acid 4-mouth-7-ethoxy-6-quinazolinyl ester 400 mg, 1.50 mraol was added to isopropanol (10 mL)-dichloromethane (2 nL), and the mixture was stirred and stirred for 4-(3-aminophenyl).
  • -2-Methyl-3-butyne-l-onore 290 mg, 1.65 mmol was added.
  • hexane 50 mL was added, followed by concentration.
  • Example 25 After cooling a solution of the acrylamide lz (300 mg, 1.46 rnmol) in dichloromethane (4.5 mL) obtained by the method of Example 5 to ⁇ - ⁇ , trifluoroacetic acid (TFA) (4.5 mL) was added. Was. After stirring for 1.5 hours as it was, the solvent was distilled off under reduced pressure. The residue was washed with getyl ether and collected by filtration to obtain the desired compound lap ⁇ nTFA (50 mg).
  • TFA trifluoroacetic acid
  • Example 1 3 Compound 2t (Example 20) is described in Example 1. [Using 4- (4-morpholino) -2-butinoic acid instead of acrylic acid]
  • A431 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) under 37, 5% CO 2, and the cells were cultured at 10 mM N-2-Hydroxitytyl piperazino-N, -2-Ethanth ⁇ Honic acid (H epes) buffer (pH 7.4), contains 0.25 M saccharose, 0.1 mM EDTA After homogenization in the solution, centrifugation was performed at 3,000 G for 5 minutes, and the supernatant was further centrifuged at 100,000 OG for 30 minutes to obtain an A431 cell membrane fraction. The sample was used as a partially purified EGF receptor.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • tyrosine kinase inhibition rate is determined by the following equation.
  • Inhibition rate (%) 100- ⁇ (A-C) I (B-C) ⁇ X 100
  • IC S was calculated from the inhibition rate obtained by changing the concentration of the test substance. Value (50% inhibition concentration) calculated 0 TJP02 / 01575
  • the NIH3T3 mouse fibroblast cell line transformed with the mutant C -eribB2 constitutively activated by replacing the valine at position 595 with glutamic acid (Hokkaido Univ. (Provided).
  • A4 cell This cell line is 37 by 10% FBS added DMEM / F12 mixed medium (hereinafter complete nedium), were cultured and maintained in a plastic dish in 53 ⁇ 4C0 2, 95% Ai.
  • the growth inhibition test for various human cancer cell lines was performed by the XTT method.
  • the detailed method is as follows.
  • the cells suspended in RPMI1640 medium supplemented with 10% FBS are seeded on a 96-well plate at 5,000 / 100 ⁇ / 1 well.
  • the drug is 100 ⁇ m in 3 times common ratio
  • the IC 50 value (concentration that inhibits cell proliferation by 50 %) was calculated from the dose inhibition curve and used as an index of the inhibitory activity.
  • Balb / c female nude mouse (Balb / cAJcl-nu mouse, CLEA Japan, 5 weeks old at the time of arrival) was subcutaneously subcutaneously subcutaneously transplanted with human epidermoid carcinoma cell A431 suspended in PBS at .5x106 / 100.
  • Compound la did not induce addition of revertant colonies more than twice the solvent control value in any of the strains.
  • Compound 1A on the other hand, induced a clear increase in the number of revertant colonies in TA2637 and TA2637, with or without metabolic activation, more than twice the vehicle control value.
  • compound la was mutagenic and compound 1A was mutagenic positive.
  • the compound (I) of the present invention has a strong tyrosine kinase inhibitory activity (cancer cell proliferation inhibitory action), and thus can be used as an anti-cancer agent and a therapeutic and / or preventive agent for arteriosclerosis-based diseases and psoriasis.
  • cancer cell proliferation inhibitory action can be used as an anti-cancer agent and a therapeutic and / or preventive agent for arteriosclerosis-based diseases and psoriasis.

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US8202879B2 (en) 2005-02-23 2012-06-19 Shionogi & Co., Ltd. Quinazoline derivatives having tyrosine kinase inhibitory activity
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10152477A (ja) * 1996-10-17 1998-06-09 Pfizer Inc アミノキナゾリン誘導体

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3134236B2 (ja) 1992-01-30 2001-02-13 株式会社林原生物化学研究所 α−グリコシル−Ｌ−アスコルビン酸高含有物の製造方法とその製造のための分離システム
JP2994165B2 (ja) 1992-06-26 1999-12-27 ゼネカ・リミテッド キナゾリン誘導体、その製造法および該キナゾリン誘導体を含有する抗癌作用を得るための医薬調剤
GEP20012442B (en) 1996-04-12 2001-05-25 Warner Lambert Co Irreversible Inhibitors of Tyrosine Kinases
ZA986732B (en) * 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
US6251912B1 (en) * 1997-08-01 2001-06-26 American Cyanamid Company Substituted quinazoline derivatives
UA73990C2 (en) * 2000-06-22 2005-10-17 Pfizer Prod Inc Substituted bicyclic derivatives for the treatment of abnormal cells growth
EP1690856A4 (en) * 2003-11-28 2007-09-05 Aveo Pharmaceuticals Inc CHINAZOLINE DERIVATIVE AND METHOD FOR THE PRODUCTION THEREOF

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10152477A (ja) * 1996-10-17 1998-06-09 Pfizer Inc アミノキナゾリン誘導体

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8343982B2 (en) 2002-03-30 2013-01-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds pharmaceutical compositions containing these compounds, their use and process for preparing the same
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US7569577B2 (en) 2003-09-16 2009-08-04 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
US7838530B2 (en) 2003-09-25 2010-11-23 Astrazeneca Ab Quinazoline derivatives as antiproliferative agents
US7625908B2 (en) 2003-11-13 2009-12-01 Astrazeneca Ab Quinazoline derivatives
WO2005051924A1 (ja) * 2003-11-28 2005-06-09 Mitsubishi Pharma Corporation キナゾリン誘導体及びその製造方法
US7632840B2 (en) 2004-02-03 2009-12-15 Astrazeneca Ab Quinazoline compounds for the treatment of hyperproliferative disorders
WO2006025490A1 (ja) * 2004-09-01 2006-03-09 Mitsubishi Pharma Corporation 分子シャペロン機能調節剤
WO2006106721A1 (ja) * 2005-03-30 2006-10-12 Shionogi & Co., Ltd. チロシンキナーゼ阻害作用を有するピリミジン誘導体
JP4993205B2 (ja) * 2005-03-30 2012-08-08 塩野義製薬株式会社 チロシンキナーゼ阻害作用を有するピリミジン誘導体
WO2007103233A3 (en) * 2006-03-03 2008-11-27 Aveo Pharmaceuticals Inc Processes for synthesizing 7-alkynyl-4-aminoquinazolines and a related intermediate
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
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
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8772298B2 (en) 2008-02-07 2014-07-08 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
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
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
JP2013522249A (ja) * 2010-03-16 2013-06-13 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング モルホリニルキナゾリン
US9090588B2 (en) 2011-03-04 2015-07-28 Newgen Therapeutics, Inc. Alkyne substituted quinazoline compound and methods of use
US11524956B2 (en) 2011-03-04 2022-12-13 Newgen Therapeutics, Inc. Alkyne substituted quinazoline compound and methods of use
US9187459B2 (en) 2011-05-17 2015-11-17 Newgen Therapeutics, Inc. Quinazoline-7-ether compounds and methods of use
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TWI309647B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2009-05-11
US20040116422A1 (en) 2004-06-17
KR100861486B1 (ko) 2008-10-02
EP1369418A1 (en) 2003-12-10
US7294629B2 (en) 2007-11-13
DE60237145D1 (de) 2010-09-09
EP1369418B1 (en) 2010-07-28
CN1264824C (zh) 2006-07-19
US20070265260A1 (en) 2007-11-15
ATE475652T1 (de) 2010-08-15
KR20030086269A (ko) 2003-11-07
JPWO2002066445A1 (ja) 2004-06-17
CN1492860A (zh) 2004-04-28

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