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WO2004048366A1 - Derives 2-oxoindoline - Google Patents

Derives 2-oxoindoline Download PDF

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Publication number
WO2004048366A1
WO2004048366A1 PCT/JP2003/014736 JP0314736W WO2004048366A1 WO 2004048366 A1 WO2004048366 A1 WO 2004048366A1 JP 0314736 W JP0314736 W JP 0314736W WO 2004048366 A1 WO2004048366 A1 WO 2004048366A1
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Prior art keywords
methyl
salt
oxoindoline
quinoline
ylidene
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PCT/JP2003/014736
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English (en)
Japanese (ja)
Inventor
Kiyohiro Samizu
Hiroyuki Hisamichi
Akira Matsuhisa
Yukitaka Ideyama
Sadao Kuromitsu
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Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU2003284572A priority Critical patent/AU2003284572A1/en
Publication of WO2004048366A1 publication Critical patent/WO2004048366A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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

Definitions

  • the present invention has a vascular endothelial cell growth factor (VEGF) inhibitory activity and a cancer growth inhibitory activity, and is useful as a therapeutic agent for diseases involving angiogenesis, such as cancer and diabetic retinopathy.
  • VEGF vascular endothelial cell growth factor
  • Some diseases are known to be associated with pathological angiogenesis that is closely linked to their symptoms and etiology.
  • a typical disease is cancer, particularly solid cancer.In order for cancer tissue to grow beyond 1-2 mm in diameter, it is necessary for new blood vessels to extend from existing blood vessels to reach the cancer tissue. J. Natl. Cancer Inst, 82, 4 (1990)), and when blood vessels reach cancerous tissue, the growth of cancerous tissue is explosively accelerated. Also, diabetic retinopathy is associated with pathological neovascularization of the retina, which often causes blindness.
  • angiogenesis is one of the main symptoms (N. Engl. J. Med. , 320, 121 1 (1989)). Therefore, substances that inhibit angiogenesis may be used for the treatment of solid cancers and the aforementioned diseases.
  • Vascular endothelial cells are cells that form the innermost layer of blood vessels. Angiogenesis is performed by proliferating vascular endothelial cells under stimulation from growth factors, physiologically active substances, or physical damage. Several growth factors that directly or indirectly stimulate the proliferation of vascular endothelial cells are known, but vascular endothelial cells are distinguished from other growth factors in that they act very specifically on vascular endothelial cells. Growth factors (VEGF) are known. That is, it has been reported that VEGF receptors are expressed only in very limited cells other than vascular endothelial cells and are selective for vascular endothelium (J. Clin. Invest., 89, 244-253 (1992)).
  • VEGF secreted by cancer cells plays a central role in tumor angiogenesis.
  • VEGF is also known to be involved in the enhancement of vascular permeability, and is considered to be one of the factors that cause cancerous ascites and pleural effusion.
  • VEGF receptors Two types are known in humans, Flt-1 and KDR / Flk-1 (FASEB III, 13, 9-22 (1999)). The results of these two gene disruptions indicate that Rt-1 is involved in normal endothelial cell differentiation and morphogenesis, and Flk-1 is involved in endothelial cell formation and proliferation.
  • VEGF is thought to bind to the Flk-1 receptor and promote the proliferation of vascular endothelial cells via a signal transmission mechanism via tyrosine kinase (Proc. Natl. Acad. Sci. USA, 88, 9026-9030 ( 1991)). Furthermore, it has been shown that VEGF has an angiogenesis-inducing activity directly on endothelial cells in vitro ( ⁇ Cell. Physiol, 149, 50-59 (1991)).
  • VEGF inhibitors which inhibit the binding of VEGF to VEGF receptors (especially Flk-1) or inhibit VEGF signal transmission, suppress angiogenesis and cancerous ascites, and are useful for the treatment of cancer, especially solid cancer. Is expected to be.
  • VEGF inhibitors As VEGF inhibitors, anti-VEGF human monoclonal antibodies (JP-A-9-316099) and some polypeptides (JP-A-9-255700, JP-A-9-154588) have been reported. Recently, VEGF inhibitors such as SU6668 (Cancer Res., 60, 4152-4160 (2000)) and PTK787 / ZK222584 (Cancer Res., 60, 2178-2189 (2000)) represented by The following orally administrable low molecular weight compounds have been reported.
  • quinazoline-substituted oxyindole derivatives W097 / 42187 and WO99 / 10349
  • pyrrolotriazine-substituted indoline-2-one derivatives WO00 / 71129
  • VEGF vascular endothelial cell growth factor
  • the present inventors have conducted intensive studies on compounds that inhibit angiogenesis based on VEGF inhibitory action.As a result, the 2-position of the quinoline ring and the 3-position of the indolinone ring were directly bonded, and the double bond was isomerized. Quinoline-2 (1H) -ylidenindrin-2-one derivatives have good VEGF inhibitory activity and are useful as preventive or therapeutic agents for diseases associated with angiogenesis involving VEGF An application was filed earlier (PCT / JP02 / 05014; International Publication No. 02/94809 pamphlet). Furthermore, the present inventors have studied various compounds having the skeleton, found a specific compound having a good VEGF inhibitory action and a cancer growth inhibitory action, and completed the present invention.
  • the present invention relates to 2-oxoindoline derivatives represented by the following formulas A to F or salts thereof.
  • the present invention also relates to a pharmaceutical composition comprising a 2-oxoindoline derivative represented by the following formulas A to F or a salt thereof and a pharmaceutically acceptable carrier, in particular, a vascular endothelial cell growth factor inhibitor.
  • a pharmaceutical composition which is an angiogenesis inhibitor or an anticancer agent.
  • ALK represents a C1-6 alkyl group
  • R represents an H or a C1-6 alkyl group.
  • preferred compounds include the following 2-oxoindoline derivatives or salts thereof. No.
  • the C1-6 alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, more preferably Methyl and ethyl groups.
  • the compound of the present invention has a plurality of tautomers or stereoisomers that are theoretically possible in a conjugated system linked from the nitrogen atom at position 1 of the quinoline ring to the nitrogen atom at position 1 of the indolinone ring.
  • the invention includes a separated form or a mixture of these isomers.
  • the compound of the present invention may further have a geometric isomer or a tautomer depending on the type of the substituent, and the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may form a salt.
  • the salt is a pharmaceutically acceptable salt
  • the acid addition salt is, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Organic acids such as, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, tansulfonic acid, aspartic acid, and glutamic acid
  • the salt with a base include inorganic bases containing metals such as sodium, potassium, magnesium, calcium, and aluminum, and methylamine, ethylamine, ethanolamine, lysine, orditin. And the like, salts with organic bases such as and the like, and ammonium salts.
  • the present invention also includes various hydrates, solvates, and polymorphs of the compound of the present invention and salts thereof.
  • the compounds of the present invention also include physiologically acceptable prodrugs.
  • the pharmacologically acceptable prodrug, substituents of the present invention by solvolysis or under physiological conditions, is a compound having a group which is converted into for example C0 2 H or the like.
  • Prodrug-forming groups include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Drugs” (Hirokawa Shoten, 1990), Volume 7, Molecular Design 163-198. .
  • the compound of the present invention can be prepared by methods described in the literature, for example, Chem. Pharm. Bull., 18 (9), 1822-30 (1970), J. Am. Chem. Soc, 122 (7), 1360-70 (2000) And the like, or by applying a method known to those skilled in the art.
  • it may be effective in production technology to replace the functional group with an appropriate protecting group at the stage of raw materials or intermediates, that is, a group that can be easily converted to the functional group. is there. Thereafter, the desired compound can be obtained by removing the protecting group, if necessary.
  • Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like.
  • Examples of such a protective group include, for example, rprotective Groups in Organic Synthesis, by Greene and Wuts. The protecting groups described in the third edition can be mentioned, and these may be appropriately used according to the reaction conditions.
  • R 4 represents a protecting group such as diethoxymethyl, P-toluenesulfonyl, and trimethylsilylethyl sulfonyl, and represents a leaving group applicable to the reaction such as halogen and sulfonate. The same applies hereinafter.
  • the compound (I) of the present invention can be produced by reacting an indolinone (V) with a quinoline N-amine oxide compound (II) according to a conventional method.
  • the reaction is carried out, for example, in Ann. Chim. (Rome), 57 (6), 188-97 (1967), Khim. Geterotsikl. Soedin., 10, 1371-3 (1970), Chem. Pharm. Bull., 18 ( 9), 1822-30 (1970), and the method described in Chem. Pharm. Bull., 19 (8), 1669-80 (1971).
  • an excess of either (II) and / or (V) or a corresponding amount of the compound (II) and / or (V) in an appropriate amount as an activator is used as an activator.
  • a sulfonylating agent such as P-toluenesulfonyl chloride
  • an alkylating agent such as methane iodide
  • a silylating agent such as octatrimethylsilane
  • a solvent inert to the reaction for example, toluene, tetrahydrofuran (THF), etc.
  • a palladium complex e.g., palladium acetate, e.g., palladium acetate, Compound (III) can be produced by treating with palladium chloride, dibenzylideneacetone dipalladium, etc. If necessary, a ligand of a palladium complex
  • the addition of favors the reaction.
  • the compound was prepared according to a method described in W097 / 42187 and the like.
  • the first step can be easily performed according to known reaction conditions (eg, Med. Chem., 42, 5120-5130 (1999) and the like).
  • a solvent inert to the reaction eg, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF, etc.
  • excess amounts of the compounds (VIII) and / or (IX) in a reaction equivalent amount are added.
  • the compound (X) can be produced by reacting the compound (X) in the presence of a base (eg, sodium hydride (NaH), sodium tert-butoxide, etc.) or an acid (eg, acetic acid) at room temperature or under heating. it can.
  • a base eg, sodium hydride (NaH), sodium tert-butoxide, etc.
  • an acid eg, acetic acid
  • the compound (X) is subjected to reduction according to a conventional reduction reaction, for example, according to the method described in Med. Chem., 42, 5120-5130 (1999), etc. (I) can be manufactured. If necessary, heating or pressurization may promote the reaction in an advantageous manner. During this time, it is also possible to convert the substituent of compound (X) by applying the usual conditions. For example, when R 1 and R 2 are aldehydes, ketones, etc., they can be converted to lyoxime compounds or the like by a condensation reaction or the like. Other manufacturing methods
  • the compound of the present invention can be produced by various known substituent modification reactions in addition to the above-mentioned production methods.
  • B. M. Trost COMPREHENSIVE ORGANMC SYNTHESIS (Pergamon Press) (1991)
  • R. C. Larock COMPREHENSIVE ORGANIC
  • Compounds having a substituent containing an aminoalkyl group can be obtained from (1) a compound having a halogen-substituted alkyl group or an epoxide by a conventional amination reaction, and (2) a compound having an aldehyde or a ketone.
  • a conventional reductive amination reaction for example, see Tetrahedron Lett., 31, 5595-5598 (1990), etc.
  • (3) a deprotection reaction from a compound having a protected aminoalkyl group for example, Tert-butoxycarponyl group
  • a compound having a carboxyl group can be produced from a compound having an ester group by a conventional hydrolysis reaction.
  • the compound having a substituent containing oxime can be produced from a compound having an aldehyde or ketone by a conventional dehydration condensation reaction using hydroxylamines or the like.
  • the N-oxide compound is produced by a well-known oxidation reaction, that is, a reaction with an oxidizing agent such as m-chloroperbenzoic acid or hydrogen peroxide in a solvent inert to the reaction (for example, chloroform or dichloromethane). be able to. Under the same oxidation conditions, it is also possible to convert sulfide to sulfoxide or sulfone.
  • a desired compound is obtained by performing a dehydroxylation reaction with a precursor compound having an N-hydroxyamide bond, a conventional reduction method is used. It can be easily carried out by passing through conditions (eg, reaction with metallic iron in acetic acid, hydrogenolysis reaction, etc.).
  • the introduction of a heteroaromatic ring can be easily carried out by a method of introducing a substituent serving as a precursor thereof and then converting it into a heterocyclic ring by a conventional condensation reaction.
  • starting compounds of the compound of the present invention are novel compounds, and these compounds can be easily synthesized in the same manner as known starting compounds or by using methods known to those skilled in the art. Representative synthetic methods are shown below.
  • the quinolineacetic acid derivative (IX) can be prepared by converting compound (II) with ethyl acetate or malonic acid diester in the presence of a suitable acylating agent, sulfonylating agent, alkylating agent or silylating agent according to a conventional method. It can be manufactured by processing.
  • Compounds having a substituent on the quinoline ring can be prepared, for example, by the method described in Heterocycles, 54, 105-108 (2001), ⁇ Med. Chem., 26, 580-585 (1983), or Org. Synth. Col. Vol. 3, 272 (1955), Syn. Commun., 15, 125 (1995), etc. to produce 4-chloro quinoline derivatives Thereafter, it can also be produced by adapting a method of removing the chloro group through a reducing condition or the like by a conventional method.
  • the indolinone ring can be easily prepared by applying the conditions described in Synthesis, 51-53 (1993) or Eur. J. Med. Chem "15, 330-332 (1980).
  • the introduction of substituents on the indolinone ring involves the Suzuki Ichinomiyaura reaction with the halogen derivative, the Friedel Crafts reaction, and the conversion reaction to the heteroaromatic ring through the condensation reaction using the introduced -haloketones. It can be done by doing. For example, the method described in J. Med. Chem., 42, 5120-5130 (1999), Synthesis, 873-874 (1989), J. Org. Chem., 17, 1252-1255 (1952), etc. is applied. It is possible. Further, the primary amine on the introduced heteroaromatic ring can be removed, for example, by applying the method described in Med. Chem., 39, 834-841 (1996).
  • Isolation and purification of the compound of the present invention thus produced is carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • Various isomers can be isolated by a conventional method using the difference in physicochemical properties between the isomers.
  • a racemic compound can be converted to an optically pure isomer by a general optical resolution method [for example, to a diastereomer salt with a general optically active acid (tartaric acid, etc.) and to perform optical resolution].
  • a mixture of diastereomers can be separated by, for example, fractional crystallization or chromatography.
  • the optically active compound can also be produced by using an appropriate optically active raw material.
  • a pharmaceutical composition comprising the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier is prepared by a method usually used using pharmaceutical carriers, excipients and the like usually used in the art. can do.
  • oral administration such as tablets, pills, capsules, granules, powders, solutions, inhalants, etc., or injections such as intravenous and intramuscular injections, suppositories, eye drops, eye ointments, transdermal It may be in any form of parenteral administration using a liquid preparation, ointment, transdermal patch, transmucosal solution, transmucosal patch, or the like.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate.
  • the composition contains, in a conventional manner, additives other than inert diluents, for example, lubricants such as matanedium stearate, disintegrants such as calcium cellulose glycolate, stabilizers, and solubilizers. May be.
  • tablets or pills may be coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as Contains purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.
  • the dose of the compound of the present invention is generally about 0.001 to 50 mg Z kg per day for oral administration, preferably 0.0 "! To 1 O mg Z kg when administered intravenously.
  • the appropriate daily dose is about 0.001 to 5 mg Z kg, which should be administered once or more times a day, depending on symptoms, age, sex, etc. Is determined as appropriate according to the individual case.
  • the compound of the present invention has a VEGF inhibitory effect, and is useful for improving the therapeutic effect of diseases and conditions associated with VEGF.
  • VEGF angiogenesis caused by VEGF
  • it can be used to suppress the growth of tumors such as cancer, especially solid tumors and hemangiomas, to prevent and treat diseases such as rheumatoid arthritis, psoriasis and scleroderma, and to diabetes
  • retinal diseases such as retinopathy and ocular diseases such as neovascular glaucoma.
  • the compound of the present invention well inhibited the signal transmission of VEGF via tyrosine kinase, and had a favorable inhibitory activity on the proliferation of vascular endothelial cells induced by VEGF. Furthermore, in a cancer growth inhibition test using COLO205 (human colorectal cancer) -bearing nude mice, it was confirmed that the compound of the present invention strongly inhibited cancer growth even at a low dose of oral administration. It is useful as a newborn inhibitor and an anticancer agent.
  • the compound of the present invention suppresses the increase in vascular permeability caused by VEGF, and is also useful as an agent for improving cancerous ascites / pleural effusion.
  • Test example 1 KDR kinase inhibition test
  • the KDR intracellular region (amino acids 790 to 1168) was amplified by PCR from cDNA prepared from Human umbilical vein endothelial cells (HUVEC).
  • the gene in which the FLAG TM (trademark of Sigma-Aldrich Co.) sequence (DYKDDDDK) was introduced at the C-terminus was cloned into the BamHI and Notl sites of pFASTBAC1 (formerly G-COBRL).
  • Recombinant vaccum virus was prepared according to the manual of Bacto-To-Bac expression system (G formerly made by COBRL). Sf-9 cells were infected with the recombinant baculovirus for protein expression, and the cells were collected 72 hours later.
  • Sf-9 cells expressing the KDR kinase domain were sonicated in a buffer solution (20 mM Tris, 150 mM NaCI, 1 mM PMSF (phenylmethanesulfonyl fluoride), 10 jig / ml aprotinin), and 10,000 rpm, 4 ° C, The supernatant was obtained after 30 minutes of centrifugation. After binding the KDR kinase domain in the supernatant to M2-agarose (manufactured by Sigma), it was eluted with 0.1 mg / ml of Flag peptide. Purified The KDR kinase domain was replaced with a storage buffer (20 mM Tris, 150 mM NaCI, 10% glycerol) by dialysis, and then stored at -80 ° C.
  • a storage buffer (20 mM Tris, 150 mM NaCI, 10% glycerol
  • HTRF Homogeneous, time-resolved fluorescence
  • the ATP solution stored at ⁇ 20 ° C. at 100 mM was diluted to 2 ⁇ M with a reaction buffer, and the kinase reaction was started by adding 25 I to the well. After 20 minutes of reaction at room temperature, the reaction was stopped by adding 10M 0.5M EDTA.
  • PT66 Cryptate-labeled anti-phosphorylated ticin antibody
  • a detection antibody dilution buffer 50 mM HEPES pH 7.5, 0.1% BSA, 0.5 M KF
  • XL665-labeled anti-FLAG TM (M2) antibody 100 ng
  • the amount of phosphorylation was detected using Discovery (Packard).
  • the ratio of the value measured by Discovery when DMSO was added was set to 100%, the ratio when ATP was not added was set to 0%, and the concentration at which the test compound inhibited by 50% was calculated as the 50 value of the compound inhibitory activity.
  • Results The results are shown in the table below.
  • the compounds of the present invention successfully inhibited phosphorylation by KDR kinase. Therefore, it was confirmed that the compound of the present invention successfully inhibited signal transduction of VEGF via tyrosine kinase, and was useful as a VEGF inhibitor.
  • Test method 3 to 4 ⁇ 10 6 COLO205 cells, which are human colorectal cancer, were subcutaneously administered to the dorsal side of female Balb / c nude mice. Test compounds or when the tumor volume reached 50 to 150 mm 3 Orally once daily for 14 days. A 0.5% aqueous solution of methylcellulose was orally administered to the control group. The diameter of the tumor was measured using a caliper, the day after the final administration. The tumor capacity was calculated using the following formula.
  • Tumor volume (minor axis 2 X major axis) no 2
  • the compound of the present invention has a favorable VEGF inhibitory activity and a cancer growth inhibitory activity, and is useful as an angiogenesis inhibitor and an anticancer agent.
  • it has a good cancer growth inhibitory effect even when administered orally at a low dose, and thus is useful as an orally administrable anticancer agent.
  • Reference Example 1 Methoxylamine hydrochloride was added to a THF solution of 4-bromo-2-methyl-5-nitrobenzaldehyde, and the mixture was stirred at 50 ° C for 8 hours. The product was purified from the reaction solution to obtain colorless oily 4-bromo-2-methyl-5-nitrobenzaldehyde O-methyloxime. F-: 272,274.
  • Reference Example 2 To a solution of 6- (2-bromoethoxy) quinoline in ethyl acetate was added 70% m-hydroxyperbenzoic acid, followed by stirring. The resulting precipitate was collected by filtration to obtain a pale yellow solid, 6- (2-bromoethoxy) quinoline N-oxide. F +: 268, 270.
  • REFERENCE EXAMPLE 8 Reduced iron was added to an acetic acid solution of methyl [5- (acetylamino) -4-kuguchi-2--2-nitrophenyl] acetate, and the mixture was stirred at 100 ° C. After cooling, the reaction solution was filtered through celite and washed with DMF. After concentrating the filtrate, water was added, and the resulting precipitate was collected by filtration and washed with water to obtain a colorless solid of N- (6-clomouth-2-oxoindoline-5-yl) acetamide. . F +: 225.
  • Example 1 3- [6-[(4-methylbiperazin-1-yl) methyl] quinoline-2 (1H) -yrident 2-oxoindoline-6-carbaldehyde (400 mg) in methanol (20 mL) 2-[(Aminoxy) methyl] pyridine (248 mg) and concentrated hydrochloric acid (1 drop) were added to the mixture, and the mixture was stirred at 50 ° C for 2 hours. After cooling, the concentrated residue was purified by SCC (eluted with methanol-chloroform), converted to a DMF (20 mL) solution, added with a 4 M hydrogen chloride / ethyl acetate solution (2 mL), and added at room temperature. Stirred for minutes.
  • SCC eluted with methanol-chloroform

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention vise à l'obtention d'inhibiteurs du facteur de croissance vasculaire endothéliale utiles en tant que médicaments, en particulier en tant que remèdes contre des maladies dans lesquelles intervient l'angiogenèse, par exemple, le cancer à tumeur solide et la rétinopathie diabétique. Les dérivés 2-oxoindoline sont représentés par la formule générale dans laquelle les substituants R1, R2, R3 et G sont chacun définis dans la revendication 1, formule dans laquelle un cycle quinoléine est lié directement, au niveau de la position 2, à la position 3 d'un cycle indoline et une double liaison est isomérisée, les dérivés présentent un effet inhibiteur de VEGF favorable, un effet inhibiteur de l'angiogenèse et un effet antitumeur. Ainsi, ces composés sont utiles pour maîtriser le cancer, en particulier le cancer à tumeur solide et une tumeur telle que l'angiome, ils sont également utiles en tant que préventifs/remèdes contres des maladies telles que la polyarthrite rhumatoïde, le psoriasis, une induration de la paupière et contre l'épanchement ascétique/pleural carcinomateux, ils sont également utiles en tant que préventifs/remèdes contre des maladies rétiniennes telles que la rétinopathie diabétique et des maladies ophtalmiques telles que le glaucome angiogénique.
PCT/JP2003/014736 2002-11-22 2003-11-19 Derives 2-oxoindoline WO2004048366A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003284572A AU2003284572A1 (en) 2002-11-22 2003-11-19 2-oxoindoline derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002339847 2002-11-22
JP2002-339847 2002-11-22

Publications (1)

Publication Number Publication Date
WO2004048366A1 true WO2004048366A1 (fr) 2004-06-10

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PCT/JP2003/014736 WO2004048366A1 (fr) 2002-11-22 2003-11-19 Derives 2-oxoindoline

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AU (1) AU2003284572A1 (fr)
WO (1) WO2004048366A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997042187A1 (fr) * 1996-05-06 1997-11-13 Zeneca Limited Derives d'oxindole
WO1999010349A1 (fr) * 1997-08-22 1999-03-04 Zeneca Limited Derives d'oxindolylquinazoline utiles comme inhibiteurs d'angiogenese
WO1999015500A1 (fr) * 1997-09-05 1999-04-01 Glaxo Group Limited Derives substitues d'oxindole en tant qu'inhibiteurs de la tyrosine kinase et de la serine/threonine kinase
WO1999048868A2 (fr) * 1998-03-26 1999-09-30 Sugen, Inc. Familles heterocycliques de composes destinees a la modulation de la tyrosine-kinase
WO1999061422A1 (fr) * 1998-05-29 1999-12-02 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2000008202A2 (fr) * 1998-08-04 2000-02-17 Sugen, Inc. Modulateurs 3-methylidenyl-2-indolinone de proteine kinase
JP2001089471A (ja) * 1999-07-21 2001-04-03 Japan Tobacco Inc カルボスチリル化合物及びその医薬用途
WO2001029025A2 (fr) * 1999-10-19 2001-04-26 Merck & Co., Inc. Inhibiteurs de tyrosine kinases
WO2001094312A2 (fr) * 2000-06-02 2001-12-13 Sugen, Inc. Derives d'indolinone comme inhibiteurs de phosphatase/proteine kinase

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997042187A1 (fr) * 1996-05-06 1997-11-13 Zeneca Limited Derives d'oxindole
WO1999010349A1 (fr) * 1997-08-22 1999-03-04 Zeneca Limited Derives d'oxindolylquinazoline utiles comme inhibiteurs d'angiogenese
WO1999015500A1 (fr) * 1997-09-05 1999-04-01 Glaxo Group Limited Derives substitues d'oxindole en tant qu'inhibiteurs de la tyrosine kinase et de la serine/threonine kinase
WO1999048868A2 (fr) * 1998-03-26 1999-09-30 Sugen, Inc. Familles heterocycliques de composes destinees a la modulation de la tyrosine-kinase
WO1999061422A1 (fr) * 1998-05-29 1999-12-02 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2000008202A2 (fr) * 1998-08-04 2000-02-17 Sugen, Inc. Modulateurs 3-methylidenyl-2-indolinone de proteine kinase
JP2001089471A (ja) * 1999-07-21 2001-04-03 Japan Tobacco Inc カルボスチリル化合物及びその医薬用途
WO2001029025A2 (fr) * 1999-10-19 2001-04-26 Merck & Co., Inc. Inhibiteurs de tyrosine kinases
WO2001094312A2 (fr) * 2000-06-02 2001-12-13 Sugen, Inc. Derives d'indolinone comme inhibiteurs de phosphatase/proteine kinase

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