WO2004048366A1 - 2-oxoindoline derivatives - Google Patents

2-oxoindoline derivatives 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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French (fr)
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/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
    • C07D401/14—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

Abstract

It is intended to provide vascular endothelial growth factor inhibitors useful as drugs, in particular, remedies for diseases in which angiogenesis participates, for example, solid cancer and diabetic retinopathy. Namely, 2-oxoindoline derivatives represented by the following general formula wherein a quinoline ring is directly bonded at the 2-position to the 3-position of an indoline ring and a double bond is isomerized have a favorable VEGF inhbitory effect, an angiogenesis inhibitory effect and an antitumor effect. Thus, these compounds are useful in regulating cancer, in particular, solid cancer and tumor such as angioma, and as preventives/remedies for diseases such as rheumatoid arthritis, psoriasis, scleriasis and carcinomatous ascitic/pleural effusion as well as preventives/remedies for retinal diseases such as diabetic retinopathy and ophthalmic diseases such as angiogenic glaucoma. wherein the substituents R1, R2, R3 and G are each as defined in claim 1.

Description

明細書  Specification
2-ォキソインドリン誘導体 技術分野  2-oxoindoline derivatives
本発明は、 血管内皮細胞增殖因子 (VEGF： Vascular Endothelial Growth Factor)阻害 活性並びに癌増殖抑制活性を有し、血管新生の関与する癌や糖尿病性網膜症などの疾患 の治療薬として有用な 2-ォキソインドリン誘導体に関する。 背景技術  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. Oxoindoline derivatives. Background art
幾つかの疾病では、その症状や病因と密接に闋連した病的血管新生を伴うことが知ら れている。 中でも代表的な疾病は癌、 特に固形癌で、 癌組織が直径 1〜2 mmを越え て増殖するためには、既存血管から新生血管が延びて癌組織まで到達することが必要で あリ (J. Natl. Cancer Inst, 82， 4 (1990)) 、 また血管が癌組織に到達すると癌組織の增 殖が爆発的に加速される。また、糖尿病性網膜症では網膜に病的血管新生を伴い、それ が原因でしばしば失明することがある。更に慢性関節リューマチ、乾癬、血管腫、強皮 症、血管新生緑内障などの疾病においても病的血管新生を伴い、それが主な症状の一つ となっている （N. Engl. J. Med., 320， 121 1 (1989)) 。 従って血管新生を阻害する物質 は固形癌や前述の疾病の治療に利用できる可能性がある。  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. Diseases such as rheumatoid arthritis, psoriasis, hemangiomas, scleroderma, and neovascular glaucoma also involve pathological angiogenesis, which 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.
血管内皮細胞は血管の最も内側の層を形成している細胞である。血管新生は血管内皮 細胞が成長因子や生理活性物質または物理的損傷などの刺激を受けて、増殖することに よって行われる。直接または間接的に血管内皮細胞の増殖を刺激する成長因子はいくつ か知られているが、血管内皮細胞に極めて特異的に作用する点で他の成長因子と区別さ れる因子として、 血管内皮細胞増殖因子 (VEGF)が知られている。 即ち、 VEGFのレセ プタ一は、血管内皮細胞以外ではごく限られた細胞でしか発現しておらず、血管内皮選 択的であることが報告されている (J. Clin. Invest., 89， 244-253 (1992)) 。  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と癌との関係を示唆する以下のような報告がある。 多くの癌細胞は VEGFを 分泌する (Biochem. Biophys. Res. Commun., 194, 1234 (1993)) 。 癌組織切片を抗 VEGF抗体で染色すると癌組織およびその周辺の新生血管が強く染色される （上 Exp. Med., 174， 1275(1991)、 Cancer Res., 53, 4727 (1993)) 。 VEGFレセプターの一つが 遺伝的に不活化されたマウスでは移植された癌の増殖が抑制される （Nature, 367, 576 (1994))。抗 VEGF中和抗体が担癌マウスに対して抗腫瘍活性を示す（Nature, 362, 841 (1993)、 Biochem. Biophys. Res. Commun., 194, 1234 (1993)) 。 以上の事実から、 癌 細胞が分泌する VEGFは腫瘍血管新生に中心的な役割を果たすと考えられる。 また、 VEGFは血管透過性の亢進にも関与していることが知られておリ、癌性腹水■胸水貯留 を引き起こす要因のひとつと考えられている。 The following reports suggest a relationship between VEGF and cancer. Many cancer cells secrete VEGF (Biochem. Biophys. Res. Commun., 194, 1234 (1993)). When a cancer tissue section is stained with an anti-VEGF antibody, the cancer tissue and its surrounding new blood vessels are strongly stained (Exp. Med., 174, 1275 (1991), Cancer Res., 53, 4727 (1993)). One of the VEGF receptors In a genetically inactivated mouse, the growth of the transplanted cancer is suppressed (Nature, 367, 576 (1994)). Anti-VEGF neutralizing antibodies show antitumor activity against tumor-bearing mice (Nature, 362, 841 (1993), Biochem. Biophys. Res. Commun., 194, 1234 (1993)). These facts suggest that 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のレセプターは、ヒトでは Flt-1と KDR/Flk-1の 2種類が知られている（FASEB 丄， 13, 9-22 (1999)) 。 これら 2種類の遺伝子破壊の結果から Rt-1は内皮細胞の正常な 分化や形態形成に、 Flk-1は内皮細胞の形成と増殖に関わっていることが示されている Two types of VEGF receptors 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.
(Nature, 376， 66-70 (1995)、 Nature, 376, 62-66 (1995)) 、 日本薬理学雑誌， 107, 1 19-131 (1996)) 。 VEGFは Flk-1 レセプターに結合し、 チロシンキナーゼを介するシ グナル伝達機構を経て、 血管内皮細胞の増殖を促進すると考えられている （Proc. Natl. Acad. Sci. USA, 88， 9026-9030 (1991)) 。 さらに in vitroにおいて VEGFは内皮細胞に 対して直接的な血管新生誘導活性を有していることが示されている （丄 Cell. Physiol, 149, 50-59 (1991))。 (Nature, 376, 66-70 (1995), Nature, 376, 62-66 (1995)), Japanese Pharmacological Journal, 107, 119-131 (1996)). 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 (丄 Cell. Physiol, 149, 50-59 (1991)).
従って、 VEGFと VEGFレセプター （殊に Flk-1 ) の結合を阻害あるいは VEGFシグ ナル伝達を阻害する、 VEGF阻害剤は血管新生や癌性腹水等を抑制し、癌、特に固形癌 の治療に有用であることが期待されている。  Therefore, 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阻害薬としては、 従来、 抗 VEGFヒ卜モノクローナル抗体 （特開平 9-316099 号公報） やいくつかのポリペプチド （特開平 9-255700、 同 9-154588号公報） が報告 されていた。 最近になって、 下式で示される SU6668(Cancer Res., 60, 4152-4160 (2000))や PTK787/ZK222584(Cancer Res., 60， 2178-2189 (2000))などの VEGF阻害作 用を示す経口投与可能な低分子化合物が報告されている。  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.
Figure imgf000004_0001
Figure imgf000004_0001
また、チロシンキナーゼ阻害剤並びに血管新生阻害剤として有用な化合物として、キ ナゾリン置換ォキシインドール誘導体 （W097/42187及び WO99/10349号公報） 、 或 いはピロロトリアジン置換インドリン- 2-オン誘導体 （WO00/71 129号公報） の開示が ある。 しかし、 具体的な薬理データの開示は無い。 Further, as compounds useful as tyrosine kinase inhibitors and angiogenesis inhibitors, quinazoline-substituted oxyindole derivatives (W097 / 42187 and WO99 / 10349), Or pyrrolotriazine-substituted indoline-2-one derivatives (WO00 / 71129). However, no specific pharmacological data is disclosed.
—方、 2-ォキソィンドリン誘導体としては、 3-キノリン -2(1 H)-ィリデンィンドリン -2- オンの合成方法の報告がある (Annali di Chimica (Rome), 57(6), 688-97 (1967)、 Chemical & Pharmaceutical Bulletin, 18(9), 1822-30 (1970) 、 Chemical & Pharmaceutical Bulletin, 19(8)， 1669-80 (1971)参照） 。 しかし、 その医薬用途について は何等開示がない。 発明の開示  On the other hand, as a 2-oxoindrin derivative, there is a report on a method for synthesizing 3-quinolin-2 (1H) -ylidenindrin-2-one (Annali di Chimica (Rome), 57 (6), 688) -97 (1967), Chemical & Pharmaceutical Bulletin, 18 (9), 1822-30 (1970), Chemical & Pharmaceutical Bulletin, 19 (8), 1669-80 (1971)). However, there is no disclosure of its pharmaceutical uses. Disclosure of the invention
血管新生の関与する癌、特に固形癌や糖尿病性網膜症などの疾患の治療薬として有用 な血管内皮細胞増殖因子 (VEGF)阻害剤、 殊に経口投与可能な薬剤の創製が今なお切望 されている。  There is still a strong need for the creation of vascular endothelial cell growth factor (VEGF) inhibitors, especially orally administrable drugs, that are useful as therapeutics for cancers involving angiogenesis, especially solid cancers and diseases such as diabetic retinopathy. I have.
本発明者等は、 VEGF阻害作用に基づき血管新生を阻害する化合物につき、鋭意研究 した結果、キノリン環の 2位とィンドリノン環の 3位が直接結合し、二重結合が異性化 した、 3-キノリン -2(1 H)-ィリデンィンドリン -2-オン誘導体が、 良好な VEGF阻害作用 を有し、 VEGFの関与する血管新生を伴う疾患の予防若しくは治療剤として有用である ことを見出し、 先に出願を行った （PCT/JP02/05014；国際公開 02/94809号パンフレ ッ卜)。 更に、 本発明者等は当該骨格を有する化合物を種々検討し、 良好な V E G F阻 害作用並びに癌増殖抑制作用を有する特定の化合物を見出し本発明を完成した。  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.
即ち、 本発明は、 下表の式 A乃至 Fで示される 2-ォキソインドリン誘導体又はその 塩に関する。 また、 本発明は、 下表の式 A乃至 Fで示される 2-ォキソインドリン誘導 体又はその塩と製薬学的に許容される担体からなる医薬組成物、殊に、血管内皮細胞増 殖因子阻害剤、 血管新生阻害剤、 若しくは抗癌剤である医薬組成物にも関する。 That is, 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 The present invention also relates to a pharmaceutical composition which is an angiogenesis inhibitor or an anticancer agent.
表 1 table 1
Figure imgf000006_0001
Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0002
(表中、 ALKは C1-6アルキル基を、 R は H又は C1-6アルキル基をそれぞれ示す。 ） 本発明化合物中、 好ましい化合物としては、 以下に列記する 2-ォキソインドリン誘 導体又はその塩が挙げられる。  (In the table, ALK represents a C1-6 alkyl group, and R represents an H or a C1-6 alkyl group.) Among the compounds of the present invention, preferred compounds include the following 2-oxoindoline derivatives or salts thereof. No.
3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキソインドリ ン -6-カルバルデヒド 0- (ピリジン- 2-ィルメチル)ォキシム又はその塩、  3- [6-[(4-methylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylidene 2-oxoindolin-6-carbaldehyde 0- (pyridine-2-ylmethyl) oxime or a salt thereof,
3-[6-[(4-ェチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキソインドリ ン -6-カルバルデヒド 0- (ピリジン- 2-ィルメチル)ォキシム又はその塩、  3- [6-[(4-Ethylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylidentate 2-oxoindolin-6-carbaldehyde 0- (pyridine-2-ylmethyl) oxime or a salt thereof,
3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキソインドリ ン -6-カルバルデヒド 0-(1 , 3-チアゾール -4-ィルメチル)ォキシム又はその塩、  3- [6-[(4-methylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylident 2-oxoindolin-6-carbaldehyde 0- (1,3-thiazol-4-ylmethyl) oxym Or a salt thereof,
3-[6-[(4-ェチルビペラジン- 1-ィノレ)メチル]キノリン -2(1 H)-ィリデント 2-ォキソインドリ ン -6-カルバルデヒド 0-(1 , 3-チアゾール -4-ィルメチル)ォキシム又はその塩、  3- [6-[(4-Ethylbiperazine-1-ynole) methyl] quinoline-2 (1H) -ylidene 2-oxoindolin-6-carbaldehyde 0- (1,3-thiazol-4-ylmethyl) oxime or Its salt,
3-[2-(2-ォキソ -6-{ [(ピリジン- 2-ィルメ トキシ）ィミノ]メチル }インドリン -3-ィリデ ン) -1 ,2-ジヒドロキノリン -6-ィル]プロピオン酸又はその塩、 3- [2- (2-oxo-6-{[(pyridine-2-ylmethoxy) imino] methyl} indoline-3-ylide -1), 2-Dihydroquinoline-6-yl] propionic acid or a salt thereof,
3- (1 ,5-ナフチリジン- 2(1 H)-ィリデン) -2-ォキソィンドリン -6-カルバルデヒド 0- (ピリ ジン- 2-ィルメチル)ォキシム又はその塩、  3- (1,5-naphthyridine-2 (1H) -ylidene) -2-oxoindolin-6-carbaldehyde 0- (pyridin-2-ylmethyl) oxime or a salt thereof,
4- {1-[3-(2-{6- [(メ トキシィミノ）メチルト 2-ォキソ -1 ,2-ジヒドロ- 3H-インドール- 3-ィリデ ン }-1，2-ジヒドロキノリン -6 -ィル)プロピル]ピぺリジン- 4-ィル }酪酸ェチル又はその塩、 3-{1-[3-(2-{6-〖(メ トキシィミノ）メチル] -2-ォキソ -1 ,2-ジヒドロ- 3H-ィンドール- 3-ィリデ ン}-1，2-ジヒドロキノリン- 6 -ィル)プロピル]ピぺリジン- 4-ィル }プロピオン酸又はその  4- {1- [3- (2- {6-[(Methoxyimino) methylto 2-oxo-1,2-dihydro-3H-indole-3-ylidene} -1,2-dihydroquinoline-6-di L) propyl] piperidin-4-yl} ethyl butyrate or a salt thereof, 3- {1- [3- (2- {6-{(methoxyimino) methyl] -2-oxo-1,2-dihydro -3H-indole-3-ylidene} -1,2-dihydroquinoline-6-yl) propyl] piperidin-4-yl} propionic acid or
3-{1-[3-(2-{6- [(メ 卜キシィミノ）メチル] -2-ォキソ -1 ,2-ジヒドロ- 3H-ィンドール- 3-ィリデ ン }-1，2-ジヒドロキノリン- 6-ィル）プロピル]ピぺリジン- 4-ィル }プロピオン酸メチル又 はその塩、 及び 3- {1- [3- (2- {6-[(Methoxyximino) methyl] -2-oxo-1,2-dihydro-3H-indole-3-ylidene} -1,2-dihydroquinoline- 6-yl) propyl] piperidin-4-yl} methyl propionate or a salt thereof, and
3-[6-{3-[4-(3-メ トキシ -3-ォキソプロピル）ピペリジン- 1-ィル]プロピル }キノリン -2(1 H)- ィリデン ]-5-メチル -2-ォキソインドリン -6-カルボン酸メチル又はその塩。  3- [6- {3- [4- (3-Methoxy-3-oxopropyl) piperidin-1-yl] propyl} quinoline-2 (1H) -ylidene] -5-methyl-2-oxoindoline-6 -Methyl carboxylate or a salt thereof.
本発明において、 C1-6アルキル基としては、， 炭素数 1〜 6個の直鎖状又は分枝状の アルキル基であり、 好ましくは炭素数 1乃至 4個のアルキル基であり、 更に好ましくはメ チル及びェチル基である。  In the present invention, 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.
本発明化合物は、キノリン環 1位の窒素原子〜ィンドリノン環 1位の窒素原子に連な る共役系において理論的に可能な複数の互変異性体あるいは立体異性体を有しておリ、 本発明にはこれらの異性体を分離したもの、 あるいは混合物が包含される。  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.
本発明化合物は置換基の種類によっては、更に幾何異性体や互変異性体が存在する場 合があるが、本発明にはこれらの異性体を分離したもの、あるいは混合物が包含される。 また、本発明化合物は、塩を形成する場合がある。 ここに、塩としては製薬学的に許 容される塩であり、 酸付加塩としては、 具体的には塩酸、 臭化水素酸、 ヨウ化水素酸、 硫酸、 硝酸、 リン酸等の無機酸、 ギ酸、 酢酸、 プロピオン酸、 シユウ酸、 マロン酸、 コ ハク酸、 フマル酸、 マレイン酸、 乳酸、 リンゴ酸、 酒石酸、 クェン酸、 メタンスルホン 酸、 タンスルホン酸、ァスパラギン酸、 グルタミン酸等の有機酸との酸付加塩等が挙 げられ、 塩基との塩としては、 ナトリウム、 カリウム、 マグネシウム、 カルシウム、 アル ミニゥム等の金属を含む無機塩基、 あるいはメチルァミン、 ェチルァミン、 エタノールァ ミン、リジン、オル二チン等の有機塩基との塩やアンモニゥム塩等が挙げられる。さらに、 本発明は、本発明化合物及びその塩の各種の水和物や溶媒和物及び結晶多形の物質をも 包含する。 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. Here, the salt is a pharmaceutically acceptable salt, and 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 Examples of 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. further, The present invention also includes various hydrates, solvates, and polymorphs of the compound of the present invention and salts thereof.
また、本発明化合物には、蕖理学的に許容されるプロドラッグも含まれる。薬理学的 に許容されるプロドラッグとは、加溶媒分解により又は生理学的条件下で本発明の置換 基、 例えば C02H等に変換される基を有する化合物である。 プロドラッグを形成する 基としては、 Prog. Med., 5， 2157-2161 (1985)や 「医薬品の開発」 （廣川書店、 1990 年） 第 7巻 分子設計 163-198に記載の基が挙げられる。 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. .
(製造法） (Manufacturing method)
本発明化合物は文献記載の方法、例えば、 Chem. Pharm. Bull., 18(9), 1822-30 (19 70)、 J. Am. Chem. Soc, 122(7), 1360-70 (2000)等に記載された方法と同様の方法 を用いて、 あるいは当業者に公知の方法を適用して容易に製造することができる。 なお、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護 基、すなわち容易に当該官能基に転化可能な基に置き換えておくことが製造技術上効果 的な場合がある。 しかるのち、必要に応じて保護基を除去し、所望の化合物を得ること ができる。 このような官能基としては例えばアミノ基、水酸基、 カルボキシル基等を挙 げることができ、 それらの保護基としては例えばグリ一ン (Greene)及びゥッッ (Wuts) 著、 rprotective Groups in Organic Synthesisj 第 3版に記載の保護基を挙げること ができ、 これらを反応条件に応じて適宜用いればよい。  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. Depending on the type of functional group, 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.
以下に代表的な製造方法を説明する。 Hereinafter, a typical manufacturing method will be described.
Figure imgf000009_0001
Figure imgf000009_0001
(I)  (I)
(式中、 R4は、 ジエトキシメチル、 P-トルエンスルホニル、 トリメチルシリルェチル スルホニル等の保護基を、 しは、ハロゲン、スルホネート等の当該反応に適用可能な脱 離基を示す。 以下同様。 ） (In the formula, 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. )
第 1製法 First manufacturing method
本発明化合物 （I) は、 常法により、 キノリン N—才キシド化合物 （II) にインドリ ノン類（V) を反応させることにより製造できる。反応は、例えば、 Ann. Chim.(Rome), 57(6), 188-97 (1967)、 Khim. Geterotsikl. Soedin., 10， 1371-3 (1970)、 Chem. Pharm. Bull., 18(9), 1822-30 (1970)、 及び Chem. Pharm. Bull., 19(8)， 1669-80 (1971)記載の方 法を適宜適用して行うことができ、反応に不活性な溶媒（例えばクロ口ホルム、ァセト 二トリル等） 中、 反応対応量の化合物 （II) 及び （V) 又はいずれか一方を過剰量用い、 活性化剤として適当なァシル化剤（塩化べンゾィル、無水酢酸等）、スルホ二ル化剤（塩 化 P-トルエンスルホニル等） 、 アルキル化剤 （ヨウ化メタン等） 或いはシリル化剤 （ク 口ロトリメチルシラン等）を使用して常温乃至加温下好ましくは溶媒の還流温度下にて 行うのが有利である。無水酢酸を用いる場合は溶媒として用いるのが有利であり、常温 乃至加温下にて行うことが好ましい。 第 2製法 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). For example, 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) or a silylating agent (such as octatrimethylsilane) at room temperature or under heating, preferably at room temperature. It is advantageous to work at the reflux temperature. When acetic anhydride is used, it is advantageous to use it as a solvent, and it is preferable to use acetic anhydride at normal temperature to heating. Second manufacturing method
第 1工程において、 J. Am. Chem. Soc" 122(7)， 1360-70 (2000)等に記載された方法 に準じて、 反応に不活性な溶媒 （例えばトルエン、 テトラヒドロフラン (THF)等） 中、 反応対応量の化合物 （IV) 及び （VI) 又はいずれか一方を過剰量用い、 常温乃至加温下 で、 塩基 （例えばナトリウム tert-ブトキシド等） 存在下、 パラジウム錯体 （例えば酢 酸パラジウム、塩化パラジウム、 ジベンジリデンァセトン二パラジウム等） で処理する ことより化合物 （III) を製造することができる。必要に応じパラジウム錯体のリガンド In the first step, a solvent inert to the reaction (for example, toluene, tetrahydrofuran (THF), etc.) according to the method described in J. Am. Chem. Soc "122 (7), 1360-70 (2000), 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
(例えば BINAP、 DPPF、 Xantphos等） を添加すると反応が有利に進む場合もある。 次に、 第 2工程において、 W097/42187号公報等に記載された方法に沿って化合物In some cases, the addition of (eg, BINAP, DPPF, Xantphos, etc.) favors the reaction. Next, in the second step, the compound was prepared according to a method described in W097 / 42187 and the like.
(III) を塩酸等の酸存在下、 或いは、 Tetrahedron, 56(7), 979-988(2000)等に記載され た方法に沿って還元剤 （例えばトリブチルチンヒドリ ド等）存在下、脱保護することに より化合物 （I) を製造できる。 (III) is deprotected in the presence of an acid such as hydrochloric acid, or in the presence of a reducing agent (for example, tributyltin hydride) according to the method described in Tetrahedron, 56 (7), 979-988 (2000). By doing so, compound (I) can be produced.
第 3製法 Third manufacturing method
Figure imgf000010_0001
Figure imgf000010_0001
(式中、 halはハロゲンを、 R5は低級アルキルを示す。 以下同様） (In the formula, hal represents halogen, R 5 represents lower alkyl. The same applies hereinafter.)
第 1工程は、 公知の反応条件 （例えば、 丄 Med. Chem.，42， 5120-5130 (1999)等） に 準じて容易に行うことができる。 反応に不活性な溶媒 （例えば N，N-ジメチルホル厶ァ ミ ド (DMF)、 ジメチルスルホキシド (DMSO)、 THF等） 中、 反応対応量の化合物 （VIII) 及び （IX) 又はいずれか一方を過剰量用い、 常温乃至加温下で、 塩基 （例えば水素化ナ トリウム （NaH) 、 ナトリウム tert-ブトキシド等） 又は酸 （例えば酢酸） 存在下、 反 応させることにより化合物 （X) を製造することができる。 次に、 第 2工程において、 化合物（X)の二トロ基を常法の還元反応、例えば丄 Med. Chem., 42, 5120-5130(1999) 等記載の方法に準じて還元することにより化合物 （I) を製造できる。 必要に応じ、 加 温あるいは加圧すると反応が有利に進む場合もある。 この間、 化合物 （X) において常 法の条件を適応して置換基変換をすることも可能である。例えば、 R1, R2がアルデヒド、 ケトン等の場合、 縮合反応等によリオキシム化合物等に変換することができる。 その他の製造法 The first step can be easily performed according to known reaction conditions (eg, Med. Chem., 42, 5120-5130 (1999) and the like). In 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. Next, in the second step, 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
本発明化合物は上記製法の他、種々の公知の置換基の修飾反応によっても製造する事 ができる。 例えば、 B. M. Trost編： COMPREHENSIVE ORGANMC SYNTHESIS (Pergamon Press)(1991), R. C. Larock著： COMPREHENSIVE ORGANIC  The compound of the present invention can be produced by various known substituent modification reactions in addition to the above-mentioned production methods. For example, B. M. Trost: COMPREHENSIVE ORGANMC SYNTHESIS (Pergamon Press) (1991), R. C. Larock: COMPREHENSIVE ORGANIC
TRANSFORMATIONS (VCH Publishers)(1989), J. March 著： ADVANCED ORGANIC CHEMISTRY (John WILEY & SON)(1992)或いは日本化学会編「実験化学講座」第 4版 (丸善)等の文献又はその引用文献記載の条件を参考にして容易に製造することができ る。 以下に主な製造法を記載する。 TRANSFORMATIONS (VCH Publishers) (1989), J. March: ADVANCED ORGANIC CHEMISTRY (John WILEY & SON) (1992) It can be easily manufactured by referring to the conditions described above. The main production methods are described below.
アミノアルキル基を含む置換基を有する化合物は、 （1 ) ハロゲン置換アルキル基、 或いは、エポキシドを有する化合物より、常法のアミノ化反応により、 ( 2 ) アルデヒ ド、 若しくは、 ケトンを有する化合物より、 常法の還元的ァミノ化反応 （例えば、 Tetrahedron Lett., 31 , 5595-5598 (1990)等を参考可能） により、 （ 3 )保護されたァミ ノアルキル基を有する化合物より、 脱保護反応 （例えば、 tert-ブトキシカルポニル基 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. By 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
(Boc) の場合、 塩酸或いはトリフルォロ酢酸 （TFA) 等との処理、 フタルイミド基の 場合、 ヒドラジン或いはメチルァミンによる処理等）によって容易に製造する事ができ る。 In the case of (Boc), it can be easily produced by treatment with hydrochloric acid or trifluoroacetic acid (TFA), and in the case of a phthalimide group, treatment with hydrazine or methylamine.
還元的ァミノ化反応において、 一方が、 ケトンもしくは 2級ァミン、或いは、 ケトン と 2級アミンなどの組み合わせで反応が進行しにくい場合、 例えば、 丄 Org. Chem., 55(8), 2552 (1990)に記載された方法と同様の方法によリ製造するのが好ましい。  In the reductive amination reaction, when one of them is difficult to proceed with ketone or secondary amine or a combination of ketone and secondary amine, for example, 丄 Org. Chem., 55 (8), 2552 (1990 ) Is preferably produced by a method similar to that described in (1).
カルボキシル基を有する化合物は、エステル基を有する化合物よリ常法の加水分解反 応によって製造することができる。  A compound having a carboxyl group can be produced from a compound having an ester group by a conventional hydrolysis reaction.
ォキシムを含む置換基を有する化合物は、アルデヒド、或いは、ケトンを有する化合 物からヒドロキシルアミン類を用いる常法の脱水縮合反応等によリ製造することがで きる。  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.
N-ォキシド化合物は周知の酸化反応、 すなわち、 反応に不活性な溶媒中 （例えば、 クロ口ホルム又はジクロロメタン等） m-クロ口過安息香酸、 過酸化水素等の酸化剤と の反応によって製造することができる。同様の酸化条件によって、スルフィ ドをスルホ キシド、 或いは、 スルホンへ変換することも可能である。 N-ヒドロキシアミ ド結合を 有する前駆化合物よリ脱ヒドロキシ化反応を行い所望の化合物を得る場合、常法の還元 条件 （例えば、酢酸中金属鉄との反応、加水素分解反応等） を経る事により容易に行う ことができる。ヘテロ芳香環の導入はその前駆体となる置換基を導入後、常法の縮合反 応によるへテロ環へと変換する方法により容易に行うことが可能である。 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. When 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.
(原料化合物の合成） (Synthesis of starting compounds)
本発明化合物の原料化合物の一部は新規化合物であリ、これらの化合物は公知の原料 化合物と同様にして、あるいは当業者に公知の方法を用いて容易に合成できる。代表的 な合成法を以下に示す。  Some of the 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.
合成法 1 (酸化） 参考文献： Synthesis, 87-90 (1997) 等 Synthesis method 1 (oxidation) Reference: Synthesis, 87-90 (1997), etc.
Figure imgf000012_0001
Figure imgf000012_0001
合成法 2 参考文献：丄 Heterocyclic Chem., 15, 1425-1430 (1978)等 Synthetic method 2 Reference: 丄 Heterocyclic Chem., 15, 1425-1430 (1978), etc.
Figure imgf000012_0002
Figure imgf000012_0002
キノリン酢酸誘導体 （IX) は、 常法により、 化合物 （II) を適当なァシル化剤、 スル ホニル化剤、 アルキル化剤、或いは、 シリル化剤存在下、 ァセト酢酸ェチルエステル又 はマロン酸ジエステル等と処理することにより製造できる。  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.
合成法 3 (ハロゲン化） 参考文献：丄 Am. Chem. Soc, 77， 1054-1055 (1955)、 Tetrahedron, 54， 13655-13680 (1998) 等 Synthesis method 3 (halogenation) References: 丄 Am. Chem. Soc, 77, 1054-1055 (1955), Tetrahedron, 54, 13655-13680 (1998), etc.
Figure imgf000012_0003
Figure imgf000012_0003
その他の原料化合物の合成法 Method for synthesizing other starting compounds
キノリン環上に置換基を有する化合物は、例えば、 Heterocycles, 54, 105-108 (2001), 丄 Med. Chem., 26, 580-585 (1983) 記載の方法、 或いは、 Org. Synth. Col. Vol. 3， 272 (1955), Syn. Commun., 15, 125 (1995) 等を適用して 4-クロ口キノリン誘導体を製造 後、常法によリクロロ基を還元条件などを経て除去する方法等を適応することによって も製造できる。 Compounds having a substituent on the quinoline ring can be prepared, for example, by the method described in Heterocycles, 54, 105-108 (2001), 丄 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.
インドリノン環の合成は、 Synthesis, 51-53 (1993) 或いは Eur. J. Med. Chem" 15， 330-332 (1980) 等に記載された条件を適応することにより容易に製造できる。  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).
インドリノン環上への置換基導入は、そのハロゲン誘導体との鈴木一宮浦反応、フリ 一デルクラフツ反応、 及び、 導入した -ハロケトン類を用いた縮合反応を経るヘテロ 芳香環への変換反応等を適応することにより行う事ができる。例えば、 J. Med. Chem., 42, 5120-5130 (1999), Synthesis, 873-874 (1989), J. Org. Chem., 17, 1252-1255 (1952) 等に記載の方法を適用することが可能である。 また、 導入したヘテロ芳香環上 の 1級ァミンは、 例えば、 丄 Med. Chem., 39, 834-841 (1996) 記載の方法を適用する ことにより除去可能である。  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).
更に、 必要に応じて、 アミノ化、 イミノ化、 ァシル化、 アルキル化、 アミド化、 スル ホンアミド化、 エステル化、 ウレァ化、 ハロゲン化、 ニトロ化、 酸化、 還元、 保護、 脱 保護等の種々の公知の置換基の修飾反応に付すことにより、所望の原料化合物を製造す る事ができる。 これらの反応は、例えば、前記日本化学会編「実験化学講座」第 4版 (丸 善)等の文献記載の条件を参考にして行うことができる。  Further, if necessary, amination, iminoization, acylation, alkylation, amidation, sulfonamidation, esterification, ureation, halogenation, nitration, oxidation, reduction, protection, deprotection, etc. By subjecting the substituent to a known substituent modification reaction, a desired starting compound can be produced. These reactions can be performed, for example, by referring to the conditions described in the literature such as the above-mentioned “Chemical Chemistry Lecture”, 4th edition (Maruzen), edited by The Chemical Society of Japan.
このようにして製造された本発明化合物の単離 '精製は、抽出、濃縮、留去、結晶化、 濾過、 再結晶、 各種クロマトグラフィー等の通常の化学操作を適応して行われる。 各種の異性体は異性体間の物理化学的な性質の差を利用して常法によリ単離できる。 例えば、 ラセミ化合物は一般的な光学分割法により [例えば、 一般的な光学活性酸 （酒 石酸等） とのジァステレオマー塩に導き、光学分割する方法等] 光学的に純粋な異性体 に導くことができる。また、 ジァステレオマーの混合物は、例えば分別結晶化又はクロ マトグラフィ一等により分離できる。また、光学活性な化合物は適当な光学活性な原料 を用いることにより製造することもできる。 本発明化合物又はその塩と製薬学的に許容される担体からなる医薬組成物は、当分野 において通常用いられている薬剤用担体、賦形剤等を用いて通常使用されている方法に よって調製することができる。 投与は錠剤、 丸剤、 カプセル剤、 顆粒剤、 散剤、 液剤、 吸入剤等による経口投与、 又は、 静注、 筋注等の注射剤、 坐剤、 点眼剤、 眼軟膏、 経皮 用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤等による非経口投与のいず れの形態であってもよい。 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. For example, 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]. Can be. In addition, 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. For 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.
経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。 このよ うな固体組成物においては、ひとつ又はそれ以上の活性物質が、少なくともひとつの不 活性な希釈剤、例えば乳糖、 マンニトール、 ブドウ糖、 ヒドロキシプロピルセルロース 、微結晶セルロース、デンプン、 ポリビニルピロリ ドン、 メタケイ酸アルミン酸マグネ シゥム等と混合される。組成物は、 常法に従って、不活性な希釈剤以外の添加剤、例え ばステアリン酸マタネシゥムのような潤滑剤や繊維素グリコール酸カルシウムのよう な崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要によリシ ョ糖、ゼラチン、 ヒドロキシプロピルセルロース、 ヒドロキシプロピルメチルセルロー スフタレートなどの糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよし、。 経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、 シロ ップ剤、 エリキシル剤等を含み、 一般的に用いられる不活性な希釈剤、 例えば精製水、 エタノールを含む。この組成物は不活性な希釈剤以外に湿潤剤、懸濁剤のような補助剤 、 甘味剤、 風味剤、 芳香剤、 防腐剤を含有していてもよい。  As a solid composition for oral administration, tablets, powders, granules and the like are used. In such a solid composition, 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. If necessary, 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.
非経口投与のための注射剤としては、無菌の水性又は非水性の溶液剤、懸濁剤、乳濁 剤を含有する。水性の溶液剤、懸濁剤としては、例えば注射用蒸留水及び生理食塩液が 含まれる。非水溶性の溶液剤、懸濁剤としては、例えばプロピレングリコール、 ポリエ チレングリコール、ォリーブ油のような植物油、エタノールのようなアルコール類、ポ リソルベート 8 0 (商品名） 等がある。 このような組成物は、 さらに防腐剤、 湿潤剤、 乳化剤、分散剤、安定化剤、溶解補助剤のような補助剤を含んでもよい。 これらは例え ばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される 。これらはまた無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶 解して使用することもできる。  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. Examples of the 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.
本発明化合物の投与量は、通常、経口投与の場合、 1日当たり約 0. 0 0 1から 5 0 m g Z k g、 好ましくは 0. 0 "！〜 1 O m g Z k gが、静脈投与される場合、 1 日当た リ、約 0. 0 0 0 1から 5 m g Z k gがそれぞれ適当であり、 これを 1 日 1回乃至複数 回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜 決定される。 産業上の利用可能性 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. Industrial applicability
本発明化合物は、 VEGF阻害作用を有し、 VEGFが関与する疾患や病態の治療■改善 に有用である。 特に VEGFに起因する血管新生の抑制剤として、 癌、 特に固形癌、 血 管腫などの腫瘍の増殖抑制に、慢性関節リューマチ、乾癬、強皮症などの疾病の予防 - 治療に、 また、糖尿病性網膜症等の網膜疾患や血管新生緑内障などの眼疾患の予防 台 療に有用である。  INDUSTRIAL APPLICABILITY 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. In particular, as an inhibitor of 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 It is useful for the preventive treatment of retinal diseases such as retinopathy and ocular diseases such as neovascular glaucoma.
後記試験例に示す様に、本発明化合物は、 VEGFのチロシンキナーゼを介するシグナ ル伝達を良好に阻害し、 VEGF刺激による血管内皮細胞増殖に対し良好な抑制活性を有 していた。 更に、 本発明化合物は、 COLO205 (ヒト大腸癌） 担癌ヌードマウスを用い た癌増殖抑制試験において、低用量の経口投与においても強力な癌増殖を抑制すること が確認され、 経口投与可能な血管新生阻害剤並びに抗癌剤として有用である。  As shown in Test Examples described later, 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.
また、本発明化合物は、 VEGFに起因する血管透過性の亢進を抑制し、癌性腹水■胸 水貯留の改善剤としても有用である。  Further, 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.
本発明化合物の効果は以下の試験例によって確認された。  The effect of the compound of the present invention was confirmed by the following test examples.
試験例 1 KDRキナーゼ阻害試験  Test example 1 KDR kinase inhibition test
1 ) KDRキナーゼドメインの発現  1) Expression of KDR kinase domain
KDR細胞内領域 （アミノ酸 790〜1168)を PCR 法により、 Human umbilical vein endothelial cells (HUVEC) から調製した cDNAから増幅した。 FLAG™(Sigma-Aldrich Co.の商標） 配列 (DYKDDDDK)を C末部に導入した遺伝子を pFASTBAC1 (G旧 COBRL 社製)の BamHIおよび Notl部位へクローニングした。 リコンビナントバキュ口ウィル スは Bacto-To-Bac expression system(G旧 COBRL社製)のマニュアルに従い調製した。 蛋白の発現のため Sf-9細胞にリコンビナントバキュ口ウィルスを感染させ、 72時間後 の細胞を回収した。  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 ™ (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.
2 ) KDRキナーゼドメインの精製  2) Purification of KDR kinase domain
KDR キナーゼドメインを発現した Sf-9 細胞を緩衝液 (20mM Tris, 150mM NaCI, 1 mM PMSF(phenylmethanesulfonyl fluoride), 10 ji g/ml aprotinin)中で超音波破砕し、 10，000rpm、 4 °C、 30分間の遠心後の上清を得た。 同上清中の KDRキナーゼドメィン を M2-agarose(Sigma社製)に結合後、 0.1 mg/mlの Flagぺプチドで溶出した。 精製し た KDR キナーゼドメインは透析によって保存用緩衝液 （20mM Tris, 150mM NaCI, 10% glycerol)に置換後、 -80°Cにて保存した。 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.
3 ) HTRFによる in vit o KDR キナーゼアツセィ 3) In vitro o KDR kinase assay by HTRF
Homogeneous, time-resolved fluorescence (HTRF)はチロシンキナーゼ活性測定に 適応可能であり、 その理論は Clin. Chem. 41 , 1391-1397 (1995) に報告されている。 試験化合物をジメチルスルホキシド (DMSO)にて最終濃度の 50倍濃度に調製した。 1 ϋ I の 化 合 物 溶 液 を well へ 添 加 後 、 反 応 緩衝 液（50mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) pH7.5, 1mM gCI2, 4mM MnCI2 0.1 % BSA(bovine serum albmin))で希釈した 100ngの精製 KDRキナーゼドメィンを 25〃 I添加した。 100mMにて- 20°Cで保存しておいた ATP溶液を反応緩衝液にて 2〃 M に希釈し、 25 I を wellへ添加することによりキナーゼ反応を開始した。 室温にて 20分間の反応後に 10〃 Iの 0.5M EDTAを添加することにより反応を停止した。 続い て検出抗体希釈緩衝液 (50mM HEPES pH7.5， 0.1 % BSA, 0.5M KF)で希釈した 6.5ng の Cryptate標識抗リン酸化チ口シン抗体 (PT66)(Cis Bio International社製）と 100ngの XL665標識抗 FLAG™(M2) 抗体 (Cis Bio International社製)を 50/ 1で添加し、 室温で 2時間ィンキュベーションした。 リン酸化量の検出は Discovery(Packard社製)を用い て測定した。 DMSOを添加した時の Discoveryでの測定値の Ratioを 100%とし、 ATP を添加しない場合の Ratioを 0%とし、 試験化合物が 50%抑制する濃度を化合物阻害 活性の 50値として算出した。 Homogeneous, time-resolved fluorescence (HTRF) is applicable to the measurement of tyrosine kinase activity, the theory of which is reported in Clin. Chem. 41, 1391-1397 (1995). The test compound was adjusted to 50 times the final concentration with dimethyl sulfoxide (DMSO). 1 After adding the compound solution of 1 I to the well, the reaction buffer (50 mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) pH7.5, 1 mM gCI 2 , 4 mM MnCI 2 0.1 25 〃I of 100 ng of purified KDR kinase domain diluted with% BSA (bovine serum albmin) was added. The ATP solution stored at −20 ° C. at 100 mM was diluted to 2 μM 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. Subsequently, 6.5 ng of Cryptate-labeled anti-phosphorylated ticin antibody (PT66) (Cis Bio International) diluted with a detection antibody dilution buffer (50 mM HEPES pH 7.5, 0.1% BSA, 0.5 M KF) and 100 ng of XL665-labeled anti-FLAG ™ (M2) antibody (Cis Bio International) was added at 50/1, and the mixture was incubated at room temperature for 2 hours. 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.
結果：結果を下表に示す。 本発明化合物は、 KDRキナーゼによるリン酸化を良好に 阻害した。 よって、本発明化合物は、 VEGFのチロシンキナーゼを介するシグナル伝達 を良好に阻害し、 VEGF阻害剤として有用であることが確認された。  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.
表 2
Figure imgf000016_0001
試験例 2 ヒ卜大腸癌担癌ヌードマウスを用いた in vivo癌増殖抑制試験 Table 2
Figure imgf000016_0001
Test Example 2 In vivo tumor growth inhibition test using human colon cancer-bearing nude mice
試験方法： ヒト大腸癌である COLO205細胞の 3〜4 x 106個を雌性 Balb/cヌードマ ウスの背側部皮下に投与した。 試験化合物は、 腫瘍容量が 50〜150mm3に達した時か ら 14日間 1 日 1回経口投与した。 また、 対照群には 0.5% メチルセルロース水溶液を 経口投与した。腫瘍径の測定はノギスを用い、最終投与の翌日に測定した。 尚、腫瘍容 量は以下の計算式を用い、 算出した。 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.
腫瘍容量 = (短径 2 X長径） ノ 2 Tumor volume = (minor axis 2 X major axis) no 2
結果：本試験において、本発明の実施例化合物 1、 2、 3、 4、 7、 8及び 9の化合物は、 3若しくは 10mg/kg/dayの経口投与において、 コントロールに対して有意な癌増殖抑 制活性を有することが確認された。  Results: In this test, the compounds of Examples 1, 2, 3, 4, 7, 8, and 9 of the present invention showed significant inhibition of cancer growth at 3 or 10 mg / kg / day orally after administration. It was confirmed to have antistatic activity.
よって、本発明化合物は、良好な V E G F阻害作用並びに癌増殖抑制作用を有し、血 管新生阻害剤並びに抗癌剤として有用であることが示された。殊に低用量の経口投与に おいても良好な癌増殖抑制作用を有することから、経口投与可能な抗癌剤として有用で める。 発明を実施するための最良の形態  Therefore, it was shown that 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. In particular, 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. BEST MODE FOR CARRYING OUT THE INVENTION
以下、本発明化合物の製造例を実施例に、本発明化合物の製造参考例、原料化合物の: 製造例並びに製造参考例を参考例に示す。  Hereinafter, Production Examples of the compound of the present invention will be described in Examples, and Reference Production Examples of the compound of the present invention, Production Examples and Reference Examples of the starting compounds will be shown in Reference Examples.
また、 参考例及び後記表中に記載される物理化学的性状の略号は、 F+:FAB-MS ( +H)+; F-: FAB-MS (M-H)-; F: FAB-MS (M)+; N1 :1H-NMR(DMSO-d6)TMS内部標準)の 特徴的ピーク (5 ppm;並びに N2:1H-NMR(CDCI3，TMS 内部標準)の特徴的ピーク S ppm を、 それぞれ示す。 Abbreviations of physicochemical properties described in Reference Examples and Tables below are: F +: FAB-MS (+ H) + ; F-: FAB-MS (MH)-; F: FAB-MS (M) +; N1: 1 H-NMR (DMSO-d 6) TMS internal standard) characteristic peak (5 ppm; N2: 1 H-NMR (CDCI 3 , TMS internal standard) characteristic peak S ppm Show.
参考例 1 ： 4-ブロモ -2-メチル -5-ニトロベンザルデヒドの THF溶液に、 メ トキシルァ ミン塩酸塩を加え 50°Cにて 8時間撹拌した。 反応液より生成物を精製し、 無色油状の 4-ブロモ -2-メチル -5-ニトロベンザルデヒド O-メチルォキシムを得た。 F-:272，274。 参考例 2： 6-(2-プロモェトキシ)キノリンの酢酸ェチル溶液に、 70% m-ク口口過安息 香酸を加え攪拌した。 生成した沈殿物を濾取し、 淡黄色固体の 6-(2-ブロモエトキシ） キノリン N-ォキシドを得た。 F+:268, 270。  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.
参考例 3 : 3-キノリン -6-ィルプロパン- 1-オールのジクロロメタン /DMSO混合溶液に、 氷冷下にて TEAと三酸化ィォゥピリジン錯体を加え撹拌後精製し、茶色油状の 3-キノ リ ン -6-ィルプロパナールを得た N2:2.87-2.93(2H,m),3.15(2H,t),7.39(1 H,dd), 7.57(1 H,dd)>7.61 (1 H,s)!8.05(1 H,d)l8.08-8.12(1 H,m),8.87( H,dd),9.86(1 H,t)o 参考例 4： 4-ク口口- 2-メ トキシ -5-二トロ安息香酸のエタノール溶液に濃硫酸を加え、 還流下撹拌後精製し、無色固体の 4-ク口口- 2-メ トキシ -5-ニトロ安息香酸ェチルを得た。 Reference Example 3: To a mixed solution of 3-quinoline-6-ylpropan-1-ol in dichloromethane / DMSO, TEA and iodopyridine trioxide complex were added under ice-cooling, and the mixture was purified by stirring. 6-ylpropanal N2: 2.87-2.93 (2H, m), 3.15 (2H, t), 7.39 (1H, dd), 7.57 (1H, dd) > 7.61 (1H, s) ! 8.05 ( 1 H, d) l 8.08-8.12 (1 H, m), 8.87 (H, dd), 9.86 (1 H, t) o Reference Example 4: 4-Hokuguchi-2-Methoxy-5-nitrobenzoic acid was added to an ethanol solution of concentrated sulfuric acid, and the mixture was purified by stirring under reflux and purified as a colorless solid. This gave ethyl-5-nitrobenzoate.
F+:260o F +: 260 o
参考例 5 : 60%NaHの DMSO懸濁液に、マロン酸ジメチルをゆつくリと滴下した後、 100°Cにて撹袢した。 室温まで冷却した後、 N-(2，5-ジクロロ- 4-ニトロフエニル)ァセ卜 アミドを加え、 同温にて、 次いで 100°Cにて撹拌した。生成物を精製後、 酢酸ェチルよ リ結晶化し、 無色固体の [5- (ァセチルァミノ）-4-ク口口- 2-二トロフエニル】マ口ン酸ジメ チルを得た。 F:344。  Reference Example 5: After dimethyl malonate was added dropwise to a suspension of 60% NaH in DMSO, the mixture was stirred at 100 ° C. After cooling to room temperature, N- (2,5-dichloro-4-nitrophenyl) acetamide was added, and the mixture was stirred at the same temperature and then at 100 ° C. After purification of the product, the product was recrystallized from ethyl acetate to obtain a colorless solid of [5- (acetylamino) -4-kuguchi-2--2-nitrophenyl] dimethyl dimethyl. F: 344.
参考例 6： [5- (ァセチルァミノ） -4-ク口口- 2-二トロフエニル]マロン酸ジメチルの DMSO溶液に、 無水塩化リチウム及び水を加え、 100°Cにて撹拌した。放冷後、 反応 液を酢酸ェチルと飽和食塩水の混合液にあけ、酢酸ェチルにて抽出した。有機層を洗 浄後、 濃縮し、 得られた粗結晶をメタノールから再結晶して、 無色固体の [5- (ァセチ ルァミノ） -4-クロ口- 2-ニトロフエニル]酢酸メチルを得た。 F:286。  Reference Example 6: Anhydrous lithium chloride and water were added to a DMSO solution of [5- (acetylamino) -4-kuguchi-2--2-nitrophenyl] malonate, and the mixture was stirred at 100 ° C. After cooling, the reaction solution was poured into a mixture of ethyl acetate and saturated saline, and extracted with ethyl acetate. The organic layer was washed, concentrated, and the resulting crude crystals were recrystallized from methanol to give methyl [5- (acetylamino) -4-chloro-2--2-nitrophenyl] acetate as a colorless solid. F: 286.
参考例 7： (4-ホルミル -2-二トロフエニル)マ口ン酸ジェチルの 6M塩酸溶液を還流下 撹拌した。 反応液を氷冷後、 生じた沈殿をろ取し、 洗浄して、 茶色固体の (4-ホルミル -2-二トロフエニル)酢酸を得た。 F+:210。  Reference Example 7: A 6M hydrochloric acid solution of getyl (4-formyl-2-ditrophenyl) mamate was stirred under reflux. After the reaction solution was cooled with ice, the resulting precipitate was collected by filtration and washed to obtain brown solid of (4-formyl-2-ditrophenyl) acetic acid. F +: 210.
参考例 8： [5- (ァセチルァミノ）-4-ク口口- 2-二トロフエニル]酢酸メチルの酢酸溶液に、 還元鉄を加え、 100°Cにて撹拌した。 放冷後、 反応液をセライ卜ろ過し、 DMF にて洗 浄した。 ろ液を濃縮後、 水を加え、 生じた沈殿をろ取し、 水洗して、 無色固体の N-(6- クロ口- 2-ォキソインドリン -5-ィル)ァセ卜アミ ドを得た。 F+:225。  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.
参考例 9： 3-[6-(2-プロモェトキシ）キノ リン -2(1 H)-ィリデン]インドリン -2-オン (1.86g)をァセトニトリル (100ml)に懸濁し、モルホリン (2.11 g)を加え、 80°Cにて 4時間 攪拌した。放冷後、反応液に飽和炭酸水素ナトリウム水溶液と飽和食塩水を加え、 クロ 口ホルムにて抽出した。有機層を無水硫酸ナトリウムにて乾燥、溶媒を留去した。残さ をシリカゲルカラムクロマトグラフィー (以下 SCC と略記する) (メタノール-酢酸ェチ ル -28%アンモニア水にて溶出）にて精製し、得られた固体をエタノールから再結晶し、 赤色固体の 3-[6-(2-モルホリン -4-ィルェトキシ)キノリン -2(1 H)-ィリデン]ィンドリン -2-オン 960mgを得た。 N1 :2.51 (4H,t), 2.78(2H,t), 3.59(4H,t), 4.16(2H,t), 10.53(1 H，s), 14.46(1 H,s) ； F+:390。 参考例 10： 2-(2-ォキソインドリン -3-ィリデン )-1，2-ジヒドロキノリン- 6-カルバルデ ヒド (0.5g)、2-モルホリン -4-ィルェチルァミン (0.91 mL)のジクロロエタン (35mL)溶液に、 酢酸 (0.99mL)を加え、 室温下 2時間撹拌した。 反応液に、 水素化トリァセトキシホウ 素ナ卜リゥム (1.1g)を加え、 室温下 13時間撹拌した。 反応液に飽和炭酸水素ナ卜リウ 厶水溶液を加え、ジクロロェタンにて抽出した。有機層を、水、飽和食塩水にて洗浄し、 無水硫酸マグネシウムにて乾燥後、 溶媒を留去した。残渣を SCC (クロ口ホルムにて溶 出)にて精製後、 得られた固体をろ取、 酢酸ェチルにて洗浄し、 橙色固体の 3-(6-{[(2-モ ルホリン -4-ィルェチル)ァミノ]メチル }キノリン -2(1 H)-ィリデン)インドリン -2-オン 168mgを得た。 N1 : 3.55 (4H, t)， 3.78 (2H, s), 10.56 (1 H, s) ； F+: 403。 Reference Example 9: 3- [6- (2-Promoethoxy) quinoline-2 (1H) -ylidene] indolin-2-one (1.86 g) was suspended in acetonitrile (100 ml), and morpholine (2.11 g) was added. The mixture was stirred at 80 ° C for 4 hours. After cooling, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hereinafter abbreviated as SCC) (eluted with methanol-ethyl acetate-28% aqueous ammonia), and the obtained solid was recrystallized from ethanol to give a red solid 960 mg of [6- (2-morpholine-4-ylethoxy) quinoline-2 (1H) -ylidene] indrin-2-one was obtained. N1: 2.51 (4H, t), 2.78 (2H, t), 3.59 (4H, t), 4.16 (2H, t), 10.53 (1 H, s), 14.46 (1 H, s); F +: 390. Reference Example 10: A solution of 2- (2-oxoindoline-3-ylidene) -1,2-dihydroquinoline-6-carbaldehyde (0.5 g) and 2-morpholine-4-ylethylamine (0.91 mL) in dichloroethane (35 mL) was added. Then, acetic acid (0.99 mL) was added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added sodium triacetoxyborohydride (1.1 g), and the mixture was stirred at room temperature for 13 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloroethane. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by SCC (eluted with chloroform), the resulting solid was collected by filtration, washed with ethyl acetate, and the orange solid 3- (6-{[(2-morpholine-4- 168 mg of [ylethyl) amino] methyl} quinoline-2 (1H) -ylidene) indolin-2-one were obtained. N1: 3.55 (4H, t), 3.78 (2H, s), 10.56 (1 H, s); F +: 403.
参考例 11 ： 2-(2-ォキソインドリン -3-ィリデン )-1，2-ジヒドロキノリン -6-カルバルデ ヒド (0.6g)、 N-(2-メ トキシェチル) -N-メチルァミン (0.89mL)のジクロロェタン (3mL)溶 液に、 チタンテトライソプロポキシド (0.68mL)を加え、 室温下 1 時間撹拌した。 氷冷 後、 反応液に、 水素化トリァセトキシホウ素ナトリウム (1.32g)を加え、 室温下 1.5 時 間撹拌した。反応液に飽和炭酸水素ナトリゥム水溶液を加え、ジクロロエタンにて抽出 した。 有機層を、水、飽和食塩水にて洗浄し、 無水硫酸マグネシウムにて乾燥後、 溶媒 を留去した。 残渣を SCC (クロ口ホルムにて溶出)にて精製後、 得られた固体をろ取、 酢酸ェチルにて洗浄し、 赤色固体の 3-(6-{[N-(2-メ トキシェチル) -N-メチルァミノ]メチ ル}キノリン- 2(1 H)-イリデン）インドリン- 2-オン 1 14mg を得た。 N1 : 2.19 (2H, s)， 2.25-2.60 (4H, m)， 3.53 (2H, s)， 10.57 (1 H， s), 14.38 (1 H, s) ； F+: 361。  Reference Example 11: 2- (2-oxoindoline-3-ylidene) -1,2-dihydroquinoline-6-carbaldehyde (0.6 g), dichloroethane of N- (2-methoxethyl) -N-methylamine (0.89 mL) (3 mL) Titanium tetraisopropoxide (0.68 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After cooling on ice, sodium triacetoxyborohydride (1.32 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloroethane. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by SCC (eluted with chloroform), the resulting solid was collected by filtration, washed with ethyl acetate, and the red solid 3- (6-{[N- (2-methoxethyl)- There were obtained 114 mg of N-methylamino] methyl} quinolin-2 (1H) -ylidene) indolin-2-one. N1: 2.19 (2H, s), 2.25-2.60 (4H, m), 3.53 (2H, s), 10.57 (1 H, s), 14.38 (1 H, s); F +: 361.
参考例 12： 6-メ トキシインドリン -2-オン (200mg)の無水酢酸 (10mL)溶液に、 キノリ ン 1-ォキシド (214mg)を加え、 50°Cに t 5時間撹拌した。 放冷後、 氷水にあけ、 酢酸 ェチルにて抽出した。有機層を飽和炭酸水素ナトリゥ厶水溶液、水及び飽和食塩水にて 洗浄し、 無水硫酸マグネシウムにて乾燥後、 溶媒を留去した。 残渣を SCC (クロ口ホル 厶にて溶出)にて精製後、 ジェチルエーテルより結晶化した。 得られた結晶をろ取し、 クロ口ホルムにて洗浄し、 赤色固体の 6-メ トキシ -3-キノリン- 2(1 Η)-イリデンインドリ ン -2-オン 30mgを得た。 F-:279。  Reference Example 12: To a solution of 6-methoxyindoline-2-one (200 mg) in acetic anhydride (10 mL) was added quinolin 1-oxide (214 mg), and the mixture was stirred at 50 ° C for 5 hours. After cooling, the mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by SCC (eluted with chloroform) and crystallized from getyl ether. The obtained crystals were collected by filtration, and washed with a filter form to obtain 30 mg of a red solid, 6-methoxy-3-quinolin-2 (1Η) -ylidenindolin-2-one. F-: 279.
参考例 13： 4-(2-ォキソ -3-キノリン -2(1 H)-ィリデンィンドリン -5-ィル)酪酸ェチル (350mg)を 6M塩酸 (15mL)に懸濁し、還流下 5時間撹拌した。放冷後、生じた沈殿をろ 取し、 水洗し、 橙色固体の 4-(2-ォキソ -3-キノリン -2(1 H)-ィリデンィンドリン -5-ィル） 酪酸 97mgを得た。 F+:347。 Reference Example 13: 4- (2-Oxo-3-quinoline-2 (1H) -ylideneindrin-5-yl) ethyl ester (350 mg) was suspended in 6 M hydrochloric acid (15 mL) and refluxed. Stirred for hours. After allowing to cool, the resulting precipitate is collected by filtration, washed with water, and orange solid 4- (2-oxo-3-quinoline-2 (1H) -ylidenindrin-5-yl) 97 mg of butyric acid was obtained. F +: 347.
参考例 14： 3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデン ]-2-ォ キソインドリン -6-カルバルデヒド 0-メチルォキシ厶 (1.20g)の THF(15mL)溶液にホル マリン (5mL)及び濃塩酸 (0.1mL)を加え、 24時間室温にて撹袢した。 1M 水酸化ナトリ ゥム水溶液を加え、 クロ口ホルム-イソプロパノール (3:1 V/V)混合溶媒にて抽出し、 飽 和食塩水で洗浄した。無水硫酸ナトリウムを用いて乾燥後、濃縮し、残渣をメタノール (20mL)に懸濁し、 28% アンモニア水溶液 (2mL)を加え、 14時間室温で撹拌した。 水を 加え、 クロ口ホルム-イソプロパノール (3:1 V/V)混合溶媒にて抽出し、 飽和食塩水で洗 浄した。 無水硫酸ナトリウムを用いて乾燥後、 濃縮し、 残渣を SCC (メタノール-クロ 口ホルムにて溶出)にて精製し、 橙色固体の 3-[6-[(4-メチルビペラジン- 1-ィル)メチル] キノリン -2(1 H)-ィリデン] -2-ォキソィンドリン -6-カルバルデヒ ド 881mg を得た。 F+:401。  Reference Example 14: 3- [6-[(4-methylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylidene] -2-oxoindoline-6-carbaldehyde 0-methyloxam (1.20 g ) In THF (15 mL) was added with formalin (5 mL) and concentrated hydrochloric acid (0.1 mL), and the mixture was stirred at room temperature for 24 hours. A 1 M aqueous solution of sodium hydroxide was added, and the mixture was extracted with a mixed solvent of formaldehyde-isopropanol (3: 1 V / V) and washed with saturated saline. After drying using anhydrous sodium sulfate, the mixture was concentrated, the residue was suspended in methanol (20 mL), a 28% aqueous ammonia solution (2 mL) was added, and the mixture was stirred at room temperature for 14 hours. Water was added, and the mixture was extracted with a mixed solvent of formaldehyde-isopropanol (3: 1 V / V), and washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated, and the residue was purified by SCC (eluted with methanol-chloroform) to give orange-colored 3- [6-[(4-methylbiperazin-1-yl) methyl ] Quinoline-2 (1H) -ylidene] -2-oxoindolin-6-carbaldehyde 881 mg was obtained. F +: 401.
実施例 1 : 3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキ ソインドリン -6-カルバルデヒド (400mg)のメタノール (20mL)溶液に 2- [(ァミノォキシ) メチル]ピリジン (248mg)および濃塩酸 (1滴)を加え 50°Cで 2時間撹拌した。放冷後、濃 縮し得られた残渣を SCC (メタノ一ル-クロロホルムにて溶出）にて精製後、 DMF(20mL) 溶液とし、 4M 塩化水素/酢酸ェチル溶液 (2mL)を加え室温で 20分間撹拌した。 濃縮し た後、残渣を水-エタノールょリ再結晶し赤色固体の 3-[6-[(4-メチルピペラジン- 1-ィル) メチル】キノリン -2(1 H)-ィリデン ]-2-ォキソインドリン -6-カルバルデヒド 0- (ピリジン -2-ィルメチル)ォキシム 三塩酸塩 320mgを得た。  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. After concentration, the residue was recrystallized from water-ethanol to give a red solid, 3- [6-[(4-methylpiperazin-1-yl) methyl] quinoline-2 (1H) -ylidene] -2- 320 mg of oxoindoline-6-carbaldehyde 0- (pyridine-2-ylmethyl) oxime trihydrochloride was obtained.
上記の参考例若しくは実施例と同様にして後記表 3〜4に記載の参考例化合物並びに表 5 記載の実施例化合物を得た。 後記表 3~5に、 各化合物の構造式と物理化学的性状をそれぞ れ示す。  In the same manner as in the above Reference Examples or Examples, Reference Example compounds described in Tables 3 and 4 below and Example compounds described in Table 5 were obtained. Tables 3 to 5 below show the structural formulas and physicochemical properties of each compound, respectively.
表中の略号は、 Rex：参考例； Ex：実施例； Str：構造； Sy：製造法 (当該化合 物をこの前記参考例若しくは実施例と同様の方法によリ製造した事を示す。）； Dat： 物理化学的性状； Me：メチル；及び Et：ェチル； をそれぞれ示す。 61 The abbreviations in the table are: Rex: Reference Example; Ex: Example; Str: Structure; Sy: Production method (indicating that the compound was produced by the same method as in the above Reference Example or Example). Dat: physicochemical properties; Me: methyl; and Et: ethyl. 61
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Claims

請求の範囲 The scope of the claims
1 . 下表の式 A乃至 Fで示される 2-ォキソインドリン誘導体又はその塩 c 1. 2-oxoindoline derivatives represented by the formulas A to F in the following table or their salts c
Figure imgf000024_0001
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000024_0002
中、 ALKは C1-6アルキル基を、 R は H又は C1-6アルキル基をそれぞれ示す。 ）  In the formula, ALK represents a C1-6 alkyl group, and R represents H or a C1-6 alkyl group. )
2 . 3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデン ]-2-ォキソ インドリン -6-カルバルデヒド O- (ピリジン- 2-ィルメチル)ォキシ厶又はその塩。 2.3- [6-[(4-Methylbiperazine-1-yl) methyl] quinoline-2 (1H) -ylidene] -2-oxoindoline-6-carbaldehyde O- (pyridine-2-ylmethyl) oxy Or salt thereof.
3 . 3-[6-[(4-ェチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデン ]-2-ォキソ インドリン- 6-カルバルデヒド 0- (ピリジン- 2-ィルメチル)ォキシム又はその塩。  3. 3- [6-[(4-Ethylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylidene] -2-oxoindoline-6-carbaldehyde 0- (pyridine-2-ylmethyl) oxime Or a salt thereof.
4 . 3-[6-[(4-メチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキソ インドリン -6-カルバルデヒド 0-(1，3-チアゾール -4-ィルメチル)ォキシム又はその塩。  4. 3- [6-[(4-Methylbiperazine-1-yl) methyl] quinoline-2 (1H) -ylidentate 2-oxoindoline-6-carbaldehyde 0- (1,3-thiazol-4-ylmethyl) ) Oxime or a salt thereof.
5 . 3-[6-[(4-ェチルビペラジン- 1-ィル)メチル]キノリン -2(1 H)-ィリデント 2-ォキソ インドリン- 6-カルバルデヒド 0-(1，3-チアゾール -4-ィルメチル)ォキシム又はその塩。  5. 3- [6-[(4-Ethylbiperazin-1-yl) methyl] quinoline-2 (1H) -ylidentate 2-oxoindoline-6-carbaldehyde 0- (1,3-thiazol-4-ylmethyl) ) Oxime or a salt thereof.
6 . 3-[2-(2-ォキソ -6-{ [(ピリジン- 2-ィルメ トキシ)ィミノ]メチル }インドリン- 3-イリ デン) -1，2-ジヒドロキノリン- 6-ィル]プロピオン酸又はその塩。 6. 3- [2- (2-oxo-6-{[(pyridine-2-ylmethoxy) imino] methyl} indoline-3-ylidene) -1,2-dihydroquinoline-6-yl] propionic acid Or a salt thereof.
7 . 3-(1，5-ナフチリジン- 2(1 H)-ィリデン )-2-ォキソインドリン -6-カルバルデヒド 0- (ピリジン- 2-ィルメチル)ォキシム又はその塩。 7. 3- (1,5-Naphthyridin-2 (1H) -ylidene) -2-oxoindoline-6-carbaldehyde 0- (pyridine-2-ylmethyl) oxime or a salt thereof.
8 . 4-{1-[3-(2-{6- [(メ 卜キシィミノ）メチル] -2-ォキソ -1 ,2-ジヒドロ- 3H-ィンドール -3-ィリデン }-1，2-ジヒドロキノリン -6-ィル)プロピル]ピペリジン- 4-ィル }酪酸ェチル又 はその塩。  8. 4- {1- [3- (2- {6-[(Methoxyximino) methyl] -2-oxo-1,2-dihydro-3H-indole-3-ylidene} -1,2-dihydroquinoline -6-yl) propyl] piperidine-4-yl} ethyl butyrate or a salt thereof.
9 . 3-{1-[3-(2-{6- [(メ トキシィミノ）メチル] -2-ォキソ -1，2-ジヒドロ- 3H-ィンドール -3-ィリデン }-1，2-ジヒドロキノリン -6-ィル)プロピル]ピぺリジン- 4-ィル }プロピオン酸 又はその塩。  9. 3- {1- [3- (2- {6-[(Methoxyimino) methyl] -2-oxo-1,2-dihydro-3H-indole-3-ylidene} -1,2-dihydroquinoline- 6-yl) propyl] piperidin-4-yl} propionic acid or a salt thereof.
1 0 . 3-{1-[3-(2-{6- [(メ トキシィミノ）メチル ]-2-ォキソ -1，2-ジヒドロ- 3H-ィンド一 ル- 3-ィリデント 1，2-ジヒドロキノリン -6-ィル)プロピル]ピペリジン- 4-ィル }プロピオン 酸メチル又はその塩。  10. 3- {1- [3- (2- {6-[(Methoxyimino) methyl] -2-oxo-1,2-dihydro-3H-indole-3-yrident 1,2-dihydroquinoline -6-yl) propyl] piperidine-4-yl} methyl propionate or a salt thereof.
1 1 . 3-[6-{3-[4-(3-メ トキシ -3-ォキソプロピル）ピぺリジン- 1-ィル]プロピル }キノ リン -2(1 H)-ィリデント 5-メチル -2-才キソインドリン -6-力ルポン酸メチル又はその塩。  1.1. 3- [6- {3- [4- (3-Methoxy-3-oxopropyl) pyridin-1-yl] propyl} quinoline-2 (1H) -yrident 5-methyl-2 -Kisoindoline -6-Methyl ruponate or a salt thereof.
1 2 . 請求の範囲 1記載の 2-ォキソインドリン誘導体又はその塩と製薬学的に許 容される担体からなる医薬組成物。  12. A pharmaceutical composition comprising the 2-oxoindoline derivative or a salt thereof according to claim 1 and a pharmaceutically acceptable carrier.
1 3 . 血管内皮細胞増殖因子阻害剤である請求の範囲 1 2記載の医薬組成物。  13. The pharmaceutical composition according to claim 12, which is a vascular endothelial cell growth factor inhibitor.
1 4. 血管新生阻害剤である請求の範囲 1 2記載の医薬組成物。  14. The pharmaceutical composition according to claim 12, which is an angiogenesis inhibitor.
1 5 . 抗癌剤である請求の範囲 1 2記載の医薬組成物。  15. The pharmaceutical composition according to claim 12, which is an anticancer agent.
PCT/JP2003/014736 2002-11-22 2003-11-19 2-oxoindoline derivatives WO2004048366A1 (en)

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