WO2001001981A1 - Vegf receptor antagonists - Google Patents

Vegf receptor antagonists Download PDF

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Publication number
WO2001001981A1
WO2001001981A1 PCT/JP2000/004405 JP0004405W WO0101981A1 WO 2001001981 A1 WO2001001981 A1 WO 2001001981A1 JP 0004405 W JP0004405 W JP 0004405W WO 0101981 A1 WO0101981 A1 WO 0101981A1
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Prior art keywords
vegf
compound
formula
group
receptor antagonist
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PCT/JP2000/004405
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French (fr)
Japanese (ja)
Inventor
Hisaya Wada
Hajime Asanuma
Tetsuo Takayama
Masakazu Sato
Takehiro Yamagishi
Masabumi Shibuya
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Taisho Pharmaceutical Co., Ltd.
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Priority to AU55725/00A priority Critical patent/AU5572500A/en
Publication of WO2001001981A1 publication Critical patent/WO2001001981A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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 relates to a VEGF receptor antagonist that inhibits binding of VEGF, a specific growth factor of vascular endothelial cells, to a receptor.
  • VEGF vascular endothelial growth factor
  • F1t-1 fms-like tyrosine kinase
  • KDR kinase insert do main containing receptor
  • VEGF and its receptors are not only physiological angiogenesis, but also diabetic retinopathy, rheumatoid arthritis, solid tumors (Advances in Cancer Research, Vol. 67, pp. 281-316, 1995), etc. It also plays a central role in the pathological angiogenesis seen in these diseases, suggesting that it is deeply involved in the development of such diseases.
  • VEGF and its receptor are known to be involved not only in angiogenesis but also in vascular permeability enhancement.
  • VEGF-induced vascular hyperpermeability is associated with pathological changes such as cancerous ascites retention and cerebral edema during ischemia-reperfusion injury (J. Clin. Invest., Vol. 104, pp. 1613-1620, 1999). It has been suggested to be involved in the symptoms.
  • substances that inhibit the binding between VEGF and its receptor are useful for treating various diseases in which pathological angiogenesis by VEGF is involved and in pathological disorders in which vascular permeability enhancement by VEGF is involved. It is considered useful for improving symptoms. Disclosure of the invention
  • An object of the present invention is to provide a VEGF receptor antagonist for treating a disease associated with VEGF-induced angiogenesis and ameliorating a pathological condition involving VEGF-induced hypervascularization. It is.
  • the VEGF receptor antagonist of the present invention has the following formula (1)
  • R 1 is a hydrogen atom, CO 2 R 5 or OR 6 (where 15 and 16 are each a hydrogen atom or a trialkyl group).
  • R 2 is a hydrogen atom or a group represented by CO 2 R 7 (where R 7 is a hydrogen atom or a C 6 alkyl group), and R 3 is a hydrogen atom or a d-6 alkyl group.
  • R 4 is C 8 - a 25 ⁇ alkyl group, X is 0, S or NH, Y is 0 or NHC0.
  • R 1 is a hydrogen atom or C0 2 R 5 (where R 5 is a hydrogen atom or a C physician 6 alkyl group.) in a group represented, R 2 is hydrogen atom, R 3 is a hydrogen atom or a d-6 alkyl group, R 4 is C 8 25 alkyl group,
  • R 1 is a hydrogen atom or C0 2 R 5 (where R 5 is a hydrogen atom or a C physician 6 alkyl group.) in a group represented
  • R 2 is hydrogen atom
  • R 3 is a hydrogen atom or a d-6 alkyl group
  • R 4 is C 8 25 alkyl group
  • the compound in which X is NH and Y is 0 or a pharmaceutically acceptable salt thereof is a novel compound.
  • the present invention provides a VEG comprising the VEGF receptor antagonist.
  • the present invention provides a method for treating a disease associated with VEGF, which comprises administering the above VEGF receptor antagonist.
  • the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the treatment of a therapeutic agent for a disease associated with VEGF, and a therapeutic agent for a disease associated with VEGF.
  • the d alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-alkyl group.
  • a methyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-alkyl group.
  • the C 5 alkyl group means a linear or branched alkyl group having a carbon number of 8-25, for example Okuchiru group, 7-Mechiruokuchiru group, 7, 7-Jimechiruoku ethyl group, O click evening decyl , 17-methyloxydecyl group, 17,17-dimethyloxydecyl group, penosylcosyl group, 23-methyltetracosyl group, and 22,22-dimethyltricosyl group.
  • the pharmaceutically acceptable salts in the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid And the like, salts with organic acids such as trimethylamine and methylamine, and salts with metal ions such as sodium ion, potassium ion and calcium ion.
  • mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid
  • acetic acid such as acetic acid, oxalic acid
  • lactic acid tartaric acid
  • fumaric acid maleic acid
  • methanesulfonic acid benzenesulfonic acid
  • metal ions such as sodium ion, potassium ion and calcium ion.
  • some of the compounds according to the present invention have a polymorphism, and the present invention includes any of the crystal forms.
  • R 1 is preferably C 0 2 R 5 (R 5 is as defined above), and R 2 is preferably a hydrogen atom. Further R 1 is more preferably a C_ ⁇ 2 H. R 3 is preferably a hydrogen atom. R 4 is preferably an alkyl group having 14 to 22 carbon atoms, and more preferably R 4 is an alkyl group having 18 carbon atoms. Examples of the compounds according to the present invention include the following.
  • the compound of formula (5) is stirred in a suitable solvent at a temperature between 0 ° C and 100 ° C in the presence of a lower alkyl halide and a base, and R 1 and R 2 are hydrogen atoms. Or a compound of the formula (5) in which R 3 is an alkyl group or an alkoxycarbonyl group is obtained.
  • a suitable solvent such as N, N-dimethylformamide is used.
  • the reduction methods include reduction using a metal or metal salt such as iron or tin in the presence of an acid such as ammonium chloride, hydrochloric acid or acetic acid, catalytic reduction using a catalyst such as palladium-carbon, Raney nickel, platinum oxide, palladium- Reduction with ammonium formate in the presence of a carbon catalyst.
  • a metal or metal salt such as iron or tin
  • an acid such as ammonium chloride, hydrochloric acid or acetic acid
  • catalytic reduction using a catalyst such as palladium-carbon, Raney nickel, platinum oxide, palladium- Reduction with ammonium formate in the presence of a carbon catalyst.
  • the solvent include solvents inert to the reaction, such as methanol, ethanol, and isopropyl alcohol.
  • the compound of formula (6) obtained here can be treated at a temperature between 100 ° C and 200 ° C in the presence or absence of a solvent inert to the reaction of the ketoester of formula (7) with toluene or xylene. To give the compound of formula (1) according to the present invention.
  • the alkoxycarbonyl group in the formula (1) can be converted into a carboxyl group by hydrolyzing the ester by a usual method for hydrolyzing an ester.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used as the VEGF receptor antagonist, in particular, in the treatment of VEGF-related diseases and in the production thereof.
  • the VEGF receptor antagonist of the present invention inhibits VEGF-dependent vascular endothelial cell proliferation by inhibiting the binding of a ligand (VEGF) to VEGF receptor.
  • VEGF vascular permeability enhancement
  • the diseases and pathological symptoms related to VEGF include, for example, diabetic retinopathy and other retinopathies, rheumatoid arthritis, solid tumors, cerebral edema and injury related to ischemia-reperfusion injury, psoriasis, atheroma Sclerosis, post-lens fibroplasia, neovascular glaucoma, age-related macular degeneration, thyroid hyperplasia (including Graves' disease), chronic inflammation, pneumonia, Neff's syndrome, reduced tumor immune function, ascites retention, endocardial fluid Effusions (such as those associated with pericarditis) and pleural effusion.
  • diabetic retinopathy and other retinopathies include, for example, diabetic retinopathy and other retinopathies, rheumatoid arthritis, solid tumors, cerebral edema and injury related to ischemia-reperfusion injury, psoriasis, atheroma Sclerosis, post-l
  • Diabetic retinopathy is a disease in which various abnormalities in the retinal blood vessels caused by prolonged exposure to hyperglycemic conditions cause a variety of lesions in the retina and vitreous body, and abnormalities in the eyeball as the disease progresses It is known that angiogenesis and bleeding lead to blindness. On the other hand, it has been reported that there is a positive correlation between elevated intraocular VEGF levels and abnormal intraocular neovascularization in diabetic patients (New Engl. J. Med., Vol. 331, 1480--1487, 1994). Also, in monkey retinopathy model, angiogenesis is suppressed by suppressing intravenous administration of anti-VEGF neutralizing monoclonal antibody by inhibiting VEGF activity (Arch.
  • VEGF receptor antagonist is considered to be effective for diabetic retinopathy and other ischemic retinopathies.
  • Serum VEGF levels in patients with rheumatoid arthritis are significantly higher than in healthy individuals, and it has been reported that VEGF production is increased in localized lesions (JI Adjunct uno l., Vol. 152, pp. 4149-p. 4156, 1994), suggesting that VEGF is deeply involved in the formation of pathological conditions.
  • J. Immunol., Vol. 164, pp. 5922- 5927, 2000 J. Immunol., Vol. 164, pp. 5922- 5927, 2000.
  • VEGF is also thought to play an important role in the neovascularization of malignant tumors (Biochem. Biophys. Res. Commun., Vol. 161, pp. 851-858, 1989).
  • VEGF is used for brain tumors such as gliomas, malignant lymphomas, pituitary adenomas, meningiomas, melanomas, colorectal cancer, ovarian cancer, Teng cancer, esophageal cancer, rhabdomyosarcoma, leiomyosarcoma, lipopositive sarcoma and lung gland It is known that the production of many solid malignant tumors such as cancer is enhanced (Nature, Vol. 362, pp. 841-844, 1993, Biochem. Biophys. Res. 183, p. 1167-p. 1174, p.
  • vascular endothelial cells proliferates vascular endothelial cells by binding to tyrosine kinase-type receptors present specifically on vascular endothelial cells, It is thought to be involved in tumor growth or metastasis by inducing tumor angiogenesis (0ncogene, vol. 5, p. 519-p. 524, 1990; Science, vol. 255, p. 899- Pp. 991, 1992).
  • VEGF receptor antagonists have antitumor effects on various solid tumors.
  • VEGF is thought to be involved in the development of edema due to its vascular hyperpermeability, and in a mouse cerebral ischemia model, administration of a fusion protein of mouse VEGF receptor protein [mFlt (1-3)] and IgG Suppresses brain edema and damage (J. Clin. Invest., Vol. 104, pp. 1613-1 pp. 1620, 1999).
  • the VEGF receptor antagonist according to the present invention and the therapeutic agent for a disease associated with VEGF according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc. It can be manufactured by the method specified in the 12th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected depending on the condition, age, and purpose of treatment of the patient.
  • excipients eg, crystalline cellulose, starch, lactose, mannitol, etc.
  • binders eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.
  • lubricants eg, For example, magnesium stearate, talc, and the like, and disintegrants (eg, carboxymethyl cellulose calcium)
  • disintegrants eg, carboxymethyl cellulose calcium
  • the dose of the compound of the present invention is 1 to 2000 mg per day when treating an adult, and the compound is administered once or several times a day. This dosage may be adjusted as appropriate according to the patient's age, weight and condition. Manufacturing example
  • aqueous sodium hydroxide solution (2.80 g of sodium hydroxide, 50 ml of water) was added to a mixture of the compound 37 of 5.00 suspended in 50 ml of ethanol, and the mixture was stirred at 80 ° C for 3 hours.
  • the reaction solution was acidified by adding 5% hydrochloric acid, and the precipitate was collected by filtration, washed with water, and dried to obtain 4.28 g of compound 41 (melting point: 214 to 219 ° C) (the following reaction formula (24) )).
  • NIH3T3 cells (7 ⁇ 10 4 cells / well) in which Flt-1 was forcibly expressed were seeded on a 24-well collagen-coated plate, and Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum and 200 zg / ml Geneticin G418 was added. ), And cultured at 37 ° C for 24 hours in a 5% carbon dioxide atmosphere. Place the cells in buffer A [containing 10 mM HEPES ( ⁇ -2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) and 0.1% BSA (bovine serum a lbumin) in DMEM] at 4 ° C for 30 minutes Planned paste.
  • buffer A containing 10 mM HEPES ( ⁇ -2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) and 0.1% BSA (bovine serum a lbumin) in DMEM] at 4 ° C for 30 minutes Plann
  • the medium was exchanged for buffer B (containing 10 mM HEPES and 0.5% BSA in DMEM), and each of the test compounds shown in Table 7 was dissolved in dimethyl sulfoxide and diluted to the specified concentration with buffer B to prepare.
  • the prepared test solution and [ 125 I] -VEGF (final concentration: 25 pM) were added, and the binding reaction was performed at 4 ° C for 90 minutes.
  • the cells were washed three times with ice-cold buffer A. Subsequently, 0.5 ml of 0.5 M NaOH was added to each well, and the cells were thawed at room temperature for 30 minutes.
  • Binding inhibition rate (%) [ 125 1] of test compound added group — VEGF specific binding amount
  • the human colon cancer cell line Co 1-1 tumor passaged subcutaneously in a nude mouse was excised, cut into small pieces, and a 2 mm x 2 mm x 2 mm tumor mass was implanted subcutaneously into the right flank of nude mice with a needle. dayO).
  • a test solution prepared by dissolving a test compound (compound 19) in isotonic phosphate buffer (PH9) was administered to tumor-implanted nude mice for 28 days (from day 1 to day 28) daily, as shown in Table 9. The dose was administered intraperitoneally.
  • the tumor volume was calculated from the values of the major axis and minor axis of the tumor measured using calipers on day 30 according to the following formula.
  • Tumor volume (mm 3 ) 0.5 X [major axis (mm)] x [minor axis (mm)] 2
  • T / C ( %) The tumor growth inhibitory effect of the test compound was expressed as T / C ( %) By the following equation. Table 9 shows the results.
  • the VEGF receptor antagonist of the present invention is considered to inhibit angiogenesis by inhibiting VEGF-dependent vascular endothelial cell proliferation, and to suppress VEGF-induced increase in vascular permeability.
  • the VEGF receptor antagonist of the present invention is expected to be used as a therapeutic agent for diseases involving angiogenesis induced by VEGF, such as diabetic retinopathy, rheumatoid arthritis, and solid tumors.
  • the VEGF receptor antagonist of the present invention is expected to have an effect of suppressing pathological symptoms associated with VEGF-induced vascular hyperpermeability such as cerebral edema during ischemia-reperfusion injury.

Abstract

VEGF receptor antagonists containing as the active ingredient comopunds of general formula (1) or medicinally acceptable salts thereof: wherein R1 is hydrogen, CO¿2?R?5, or OR6¿ (wherein R?5 and R6¿ are each hydrogen or C¿1?-C6 alkyl); R?2¿ is hydrogen or CO¿2R?7 (wherein R7 is hydrogen or C¿1?-C6 alkyl); R?3¿ is hydrogen or C¿1?-C6 alkyl; R?4 is C¿8-C25 alkyl; X is O, S or NH; and Y is O or NHCO.

Description

明細書  Specification
VEGF受容体拮抗剤 技術分野  VEGF receptor antagonist Technical field
本発明は、 血管内皮細胞の特異的増殖因子である VEGFの受容体への結合を 阻害する V E G F受容体拮抗剤に関する。  The present invention relates to a VEGF receptor antagonist that inhibits binding of VEGF, a specific growth factor of vascular endothelial cells, to a receptor.
本出願は、 日本国への特許出願 （特願平 1 1— 188269および特願平 1 1 — 188270) に基づくものであり、 当該日本出願の記載内容は本明細書の一 部として取り込まれるものとする。 背景技術  This application is based on patent applications to Japan (Japanese Patent Application No. 11-188269 and Japanese Patent Application No. 11-188270), and the description of the Japanese application is incorporated as a part of this specification. And Background art
VEGF (vascular endothelial growth factor) は血管内皮細胞に極めて特 異性の高い増殖因子であり、 VEGFとその受容体は発生発育や胎盤形成などの 生理的な血管新生において中心的な役割を果たしている。 VEGFの受容体とし ては、 F 1 t— 1 (fms-like tyrosine kinase) 及び KDR (kinase insert do main containing receptor) が報告されている (Advances in Cancer ResearchN 第 67巻、 第 281頁—第 316頁、 1995年） 。 VEGF (vascular endothelial growth factor) is a highly specific growth factor for vascular endothelial cells, and VEGF and its receptor play a central role in physiological angiogenesis such as development and development, and placental formation. F1t-1 (fms-like tyrosine kinase) and KDR (kinase insert do main containing receptor) have been reported as VEGF receptors (Advances in Cancer Research N 67: 281: 281). 316, 1995).
VEGFとその受容体は、 生理的な血管新生のみならず、 糖尿病性網膜症、 慢 性関節リウマチ、 固形腫瘍 （Advances in Cancer Research, 第 67卷、 第 281 頁—第 316頁、 1995年） などの疾患に見られる病的な血管新生にも中心的 な役割を果たしており、 そのような疾患の進展に深く関与していることが示唆さ れている。 また、 VEGFとその受容体は、 血管新生だけではなく、 血管透過性 亢進にも関与していることが知られている。 VEGFによる血管透過性亢進は、 癌性腹水貯留ゃ虚血再灌流障害時の脳浮腫 （J.Clin. Invest.、 第 104卷、 第 1 613頁一第 1620頁、 1999年） などの病的症状に関与していることが示 唆されている。  VEGF and its receptors are not only physiological angiogenesis, but also diabetic retinopathy, rheumatoid arthritis, solid tumors (Advances in Cancer Research, Vol. 67, pp. 281-316, 1995), etc. It also plays a central role in the pathological angiogenesis seen in these diseases, suggesting that it is deeply involved in the development of such diseases. VEGF and its receptor are known to be involved not only in angiogenesis but also in vascular permeability enhancement. VEGF-induced vascular hyperpermeability is associated with pathological changes such as cancerous ascites retention and cerebral edema during ischemia-reperfusion injury (J. Clin. Invest., Vol. 104, pp. 1613-1620, 1999). It has been suggested to be involved in the symptoms.
したがって、 VEGFとその受容体との結合を阻害する物質は、 VEGFによ る病的な血管新生が関与している種々の疾患の治療及び VEGFによる血管透過 性亢進が関与している病的な症状の改善に有用であると考えられる。 発明の開示 Therefore, substances that inhibit the binding between VEGF and its receptor are useful for treating various diseases in which pathological angiogenesis by VEGF is involved and in pathological disorders in which vascular permeability enhancement by VEGF is involved. It is considered useful for improving symptoms. Disclosure of the invention
本発明の目的は、 VEGFによって誘導される血管新生が関与する疾患の治療 及び VEGFによって誘導される血管透過性亢進が関与する病的症状の改善のた めの VEGF受容体拮抗剤を提供することである。  An object of the present invention is to provide a VEGF receptor antagonist for treating a disease associated with VEGF-induced angiogenesis and ameliorating a pathological condition involving VEGF-induced hypervascularization. It is.
本発明の VEGF受容体拮抗剤は、 下記式 （1)  The VEGF receptor antagonist of the present invention has the following formula (1)
Figure imgf000004_0001
Figure imgf000004_0001
(1) で表される化合物又はその医薬上許容される塩を有効成分として含むことを特徴 としている。 It is characterized by containing the compound represented by (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
式 （1) において、 R1は水素原子、 C02R5又は OR6 (ここで、 15及び16 はそれそれ水素原子又は〇卜6アルキル基である。 ） で表される基であり、 R2は 水素原子又は CO 2R7 (ここで、 R 7は水素原子又は C卜 6アルキル基である。 ） で表される基であり、 R3は水素原子又は d- 6アルキル基であり、 R4は C8-25ァ ルキル基であり、 Xは 0、 S又は NHであり、 Yは 0又は NHC0である。 In the formula (1), R 1 is a hydrogen atom, CO 2 R 5 or OR 6 (where 15 and 16 are each a hydrogen atom or a trialkyl group). , R 2 is a hydrogen atom or a group represented by CO 2 R 7 (where R 7 is a hydrogen atom or a C 6 alkyl group), and R 3 is a hydrogen atom or a d-6 alkyl group. There, R 4 is C 8 - a 25 § alkyl group, X is 0, S or NH, Y is 0 or NHC0.
上記式 （1) で表される化合物は、 その一部が写真フィルム用のカラー力ブラ —の用途で用いられることが知られている （Reinhold Groeger らヽ Veroeffentl ichungen Wissenschaftlichen Photo-Laborator ι en Wolfen、 第 10卷、 第 30 9頁〜第 315頁、 1965年） が、 式 （ 1 ) で表される化合物のうち、 R1は 水素原子又は C02R5 (ここで、 R 5は水素原子又は Cい 6アルキル基である。 ） で表される基であり、 R2は水素原子であり、 R 3は水素原子又は d- 6アルキル 基であり、 R4は C8 25アルキル基であり、 Xは NHであり、 Yは 0である化合 物又はその医薬上許容される塩は、 新規な化合物である。 It is known that a part of the compound represented by the above formula (1) is used for a color power blur for photographic film (Reinhold Groeger et al. Veroeffentl ichungen Wissenschaftlichen Photo-Laborator ι en Wolfen, (Vol. 10, 309 to 315, 1965) shows that among the compounds represented by the formula (1), R 1 is a hydrogen atom or C0 2 R 5 (where R 5 is a hydrogen atom or a C physician 6 alkyl group.) in a group represented, R 2 is hydrogen atom, R 3 is a hydrogen atom or a d-6 alkyl group, R 4 is C 8 25 alkyl group, The compound in which X is NH and Y is 0 or a pharmaceutically acceptable salt thereof is a novel compound.
さらに、 本発明は、 上記 VEGF受容体拮抗剤を含むことを特徴とする VEG Fが関与する疾患の治療薬を提供する。 Furthermore, the present invention provides a VEG comprising the VEGF receptor antagonist. Provide a therapeutic agent for a disease involving F.
さらに、 本発明は、 上記 VEGF受容体拮抗剤を投与することを特徴とする V E G Fが関与する疾患の治療方法を提供する。  Further, the present invention provides a method for treating a disease associated with VEGF, which comprises administering the above VEGF receptor antagonist.
さらに、 本発明は、 VEGFが関与する疾患の治療薬の治療のための式 （ 1) で表される化合物又はその医薬上許容される塩の使用、 および VEGFが関与す る疾患の治療用薬剤を製造するための式 （ 1) で表される化合物又はその医薬上 許容される塩の使用を提供する。 発明を実施するための最良の形態  Further, the present invention provides a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the treatment of a therapeutic agent for a disease associated with VEGF, and a therapeutic agent for a disease associated with VEGF. To provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the production of BEST MODE FOR CARRYING OUT THE INVENTION
本発明において、 d アルキル基とは炭素原子数 1〜 6の直鎖状又は分岐鎖状 のアルキル基を意味し、 例えばメチル基、 ェチル基、 プロピル基、 イソプロピル 基、 ブチル基、 イソブチル基、 t—ブチル基、 ペンチル基、 イソペンチル基、 1 —ェチルプロピル基、 へキシル基、 イソへキシル基、 1—ェチルブチル基などが 挙げられる。  In the present invention, the d alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-alkyl group. —Butyl group, pentyl group, isopentyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 1-ethylbutyl group and the like.
C 5アルキル基とは、 炭素原子数 8〜 25の直鎖状又は分岐鎖状のアルキル 基を意味し、 例えばォクチル基、 7—メチルォクチル基、 7， 7—ジメチルォク チル基、 ォク夕デシル基、 17—メチルォク夕デシル基、 17， 17—ジメチル ォク夕デシル基、 ペン夕コシル基、 23—メチルテトラコシル基、 22， 22- ジメチルトリコシル基などが挙げられる。 The C 5 alkyl group means a linear or branched alkyl group having a carbon number of 8-25, for example Okuchiru group, 7-Mechiruokuchiru group, 7, 7-Jimechiruoku ethyl group, O click evening decyl , 17-methyloxydecyl group, 17,17-dimethyloxydecyl group, penosylcosyl group, 23-methyltetracosyl group, and 22,22-dimethyltricosyl group.
また、 本発明において医薬上許容される塩としては、 例えば硫酸、 塩酸、 燐酸 などの鉱酸との塩、 酢酸、 シユウ酸、 乳酸、 酒石酸、 フマール酸、 マレイン酸、 メタンスルホン酸、 ベンゼンスルホン酸などの有機酸との塩、 トリメチルァミン、 メチルァミンなどのァミンとの塩、 ナトリウムイオン、 カリウムイオン、 カルシ ゥムイオンなどの金属イオンとの塩などが挙げられる。  The pharmaceutically acceptable salts in the present invention include, for example, salts with mineral acids such as sulfuric acid, hydrochloric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid And the like, salts with organic acids such as trimethylamine and methylamine, and salts with metal ions such as sodium ion, potassium ion and calcium ion.
また、 本発明に係る化合物には、 結晶多形を有するものが存在するが、 本発明 はそのいずれの結晶形も包含する。  In addition, some of the compounds according to the present invention have a polymorphism, and the present invention includes any of the crystal forms.
本発明においては、 R1は C02R5 (R5は前記と同意義である。 ) とすること が好ましく、 R2は水素原子とすることが好ましい。 さらには R1は C〇2Hとする ことがより好ましい。 R3は水素原子とすることが好ましい。 R4は炭素原子数 14〜22のアルキル 基とすることが好ましく、 さらには R4は炭素原子数 18のアルキル基とすること がより好ましい。 本発明に係る化合物を例示すれば、 以下を挙げることができる。 In the present invention, R 1 is preferably C 0 2 R 5 (R 5 is as defined above), and R 2 is preferably a hydrogen atom. Further R 1 is more preferably a C_〇 2 H. R 3 is preferably a hydrogen atom. R 4 is preferably an alkyl group having 14 to 22 carbon atoms, and more preferably R 4 is an alkyl group having 18 carbon atoms. Examples of the compounds according to the present invention include the following.
5 - [3 - (4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] ー2， 4' —ォキシニ安息香酸狻  5-[3-(4-octyldecyloxyphenyl) -1-3-oxopropionylamino] -2, 4 '-oxinibenzoic acid
5 - [3 - (4 _ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] ー2， 4' —ォキシニ安息香酸ジメチルエステル  5-[3-(4-Oxyl decyloxyphenyl) 1-3-oxopropionylamino] -2, 4 '-Oxinibenzoic acid dimethyl ester
5— [3— （4一ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —2， 3' —ォキシニ安息香酸  5— [3— (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2,3′—oxinibenzoic acid
5— [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ ] _2， 3' —ォキシニ安息香酸ジメチルエステル  5- [3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] _2,3'-oxinibenzoic acid dimethyl ester
5- [3- (4—ォク夕デシルォキシフエニル） 一 3 _ォキソプロピオニルァ ミノ] —2, 2' —ォキシニ安息香酸  5- [3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2, 2'-oxinibenzoic acid
5 - [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2， 2' —ォキシニ安息香酸ジメチルエステル  5-[3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] — 2,2'-oxinibenzoic acid dimethyl ester
3— [3— （4一ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —3' , 4—ォキシ二安息香酸  3— [3— (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —3 ′, 4-oxodibenzoic acid
3 - [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —3' ， 4—ォキシ二安息香酸ジメチルエステル  3-[3-(4-octyl decyloxyphenyl) 1-3-oxopropionylamino]-3 ', 4- oxodibenzoic acid dimethyl ester
5— [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2, 4' —チォ二安息香酸  5— [3— (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2,4′—thiodibenzoic acid
5 - [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —2， 4' —チォ二安息香酸ジメチルエステル  5-[3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2, 4'-thiodibenzoic acid dimethyl ester
5— [3— （4—ォク夕デシルォキシフエニル） 一 3 _ォキソプロピオニルァ ミノ] — 2， 3' —チォ二安息香酸  5— [3— (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2,3′—thiodibenzoic acid
5— [3— （4—ォクタデシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —2， 3' —チォ二安息香酸ジメチルエステル  5- [3- (4-octadecyloxyphenyl) -1-3-oxopropionylamino] —2,3'-thiodibenzoic acid dimethyl ester
5— [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2, 4' —ィミノ二安息香酸 c 5— [3— (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] —2,4′—Iminodibenzoic acid c
5  Five
5 - [3 - (4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] —2， 4' —ィミノ二安息香酸ジメチルエステル  5- [3- (4-Ocdecyldecyloxyphenyl) -1-3-oxopropionylamino] —2,4'-Iminodibenzoic acid dimethyl ester
5— [3— （4—ォクタデシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2, 3' —ィミノ二安息香酸  5— [3— (4-octadecyloxyphenyl) -1-3-oxopropionylamino] —2,3′—iminodibenzoic acid
5— [3— （4—ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2， 3 ' —ィミノ二安息香酸ジメチルエステル  5- [3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] — 2,3'-imino dibenzoic acid dimethyl ester
5 - [3 - (4一ォク夕デシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ] — 2, 2 ' —ィミノ二安息香酸  5-[3- (4-octyldecyloxyphenyl) -1-3-oxopropionylamino] — 2, 2'-Iminodibenzoic acid
5 - [3— （4—ォクタデシルォキシフエニル） 一 3—ォキソプロピオニルァ ミノ Ί — 2, 2' —ィミノ二安息香酸ジメチルエステル 上記式 （ 1 ) で表される化合物は、 以下の反応式で示す方法で製造することが できる （式中、 X、 Y、 R R2、 R3及び R4は前記と同意義であり、 haloはハ ロゲン原子、 Rは低級アルキル基である。 ） 。 5- [3- (4-octadecyloxyphenyl) -l-oxopropionylamino}-2,2'-iminodibenzoic acid dimethyl ester The compound represented by the above formula (1) is as follows. Wherein X, Y, RR 2 , R 3 and R 4 are as defined above, halo is a halogen atom, and R is a lower alkyl group. ).
Figure imgf000007_0001
R2 [縮合]
Figure imgf000007_0001
R 2 [condensation]
C〇2R C〇 2 R
( 6 ) 丫ー R'
Figure imgf000007_0002
式 （3) の化合物と式 （4) のニトロ化合物を塩基存在下、 及び触媒量の銅粉末 の存在下又は非存在下、 適当な溶媒中、 0°Cから 150°Cの間の温度にて攪拌し、 式 （5) の化合物を得る。 塩基としては、 炭酸カリウム、 炭酸ナトリウム、 炭酸 水素ナトリウム、 炭酸水素カリウム.、 炭酸セシウム、 水素化ナトリウム、 水素化 カリウムなどの無機塩基、 トリェチルァミン、 ジイソプロピルェチルァミン、 ピ リジンなどの有機塩基などが用いられる。 溶媒としては、 N, N—ジメチルホル ムアミ ドなどの反応に不活性な溶媒などが用いられる。 (6) P-R '
Figure imgf000007_0002
The compound of formula (3) and the nitro compound of formula (4) are brought to a temperature between 0 ° C and 150 ° C in a suitable solvent in the presence of a base and in the presence or absence of a catalytic amount of copper powder. To give the compound of formula (5). Examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride, and the like, and organic bases such as triethylamine, diisopropylethylamine, and pyridine. Used. As the solvent, a solvent inert to the reaction such as N, N-dimethylformamide is used.
必要に応じて、 式 （5) の化合物を低級アルキルハロゲン化物と塩基存在下、 適当な溶媒中、 0°Cから 100°Cの間の温度にて撹拌し、 R1及び R2が水素原子 又はアルコキシカルボニル基、 R3がアルキル基である式 （5) の化合物を得る。 塩基としては、 炭酸カリウム、 炭酸ナトリウム、 炭酸水素ナトリウム、 炭酸水素 カリウム、 炭酸セシウムなどが用いられる。 溶媒としては、 N， N—ジメチルホ ルムアミ ドなどの反応に不活性な溶媒などが用いられる。 If necessary, the compound of formula (5) is stirred in a suitable solvent at a temperature between 0 ° C and 100 ° C in the presence of a lower alkyl halide and a base, and R 1 and R 2 are hydrogen atoms. Or a compound of the formula (5) in which R 3 is an alkyl group or an alkoxycarbonyl group is obtained. As the base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate and the like are used. As the solvent, a solvent inert to the reaction such as N, N-dimethylformamide is used.
次いで、 R1及び R2がカルボキシル基ではなく、 R3がアルキル基である式（ 5 ) の化合物のニトロ基をァミノ基に還元して、 式 （6) の化合物を得る。 還元方法 としては塩化アンモニゥム、 塩酸又は酢酸などの酸存在下での鉄又はスズなどの 金属及び金属塩を用いた還元、 パラジウム—炭素、 ラネーニッケル、 酸化白金な どの触媒を用いた接触還元、 パラジウム—炭素触媒存在下ギ酸アンモニゥムによ る還元などが挙げられる。 溶媒としてはメタノール、 エタノール、 イソプロピル アルコールなどの反応に不活性な溶媒が挙げられる。 Next, the nitro group of the compound of the formula (5) in which R 1 and R 2 are not a carboxyl group and R 3 is an alkyl group is reduced to an amino group to obtain a compound of the formula (6). The reduction methods include reduction using a metal or metal salt such as iron or tin in the presence of an acid such as ammonium chloride, hydrochloric acid or acetic acid, catalytic reduction using a catalyst such as palladium-carbon, Raney nickel, platinum oxide, palladium- Reduction with ammonium formate in the presence of a carbon catalyst. Examples of the solvent include solvents inert to the reaction, such as methanol, ethanol, and isopropyl alcohol.
ここで得られた式（ 6 )の化合物は式（ 7 )のケトエステルとトルエン又はキシレ ンなどの反応に不活性な溶媒存在下又は非存在下、 100°Cから 200°Cの間の 温度にて反応させて式（ 1 )の本発明に係る化合物に導くことができる。  The compound of formula (6) obtained here can be treated at a temperature between 100 ° C and 200 ° C in the presence or absence of a solvent inert to the reaction of the ketoester of formula (7) with toluene or xylene. To give the compound of formula (1) according to the present invention.
式 （1) におけるアルコキシカルボニル基は、 エステルを加水分解する通常の 方法で加水分解することによって、 カルボキシル基とすることができる。  The alkoxycarbonyl group in the formula (1) can be converted into a carboxyl group by hydrolyzing the ester by a usual method for hydrolyzing an ester.
式 （1) で表される化合物又はその医薬上許容される塩は、 上記 VEGF受容 体拮抗剤として、 特に VEGFが関与する疾患の治療薬及びその製造において使 用される。 本発明の VEGF受容体拮抗剤は、 VEGF受容体へのリガンド （V EGF) の結合を阻害することにより VE G F依存性の血管内皮細胞増殖を阻害 5 The compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used as the VEGF receptor antagonist, in particular, in the treatment of VEGF-related diseases and in the production thereof. The VEGF receptor antagonist of the present invention inhibits VEGF-dependent vascular endothelial cell proliferation by inhibiting the binding of a ligand (VEGF) to VEGF receptor. Five
7  7
し、 血管新生を阻害するものであり、 また VEGFによる血管透過性亢進を阻害 するものである。 In addition, it inhibits angiogenesis and inhibits vascular permeability enhancement by VEGF.
ここで、 VEGFが関与する疾患及び病的症状とは、 例えば、 糖尿病性網膜症 及びその他の網膜症、 慢性関節リウマチ、 固形腫瘍、 虚血再灌流傷害関連の脳浮 腫及び損傷、 乾癬、 ァテローム硬化、 後水晶体繊維増殖、 血管新生緑内障、 加齢 性黄斑変性、 甲状腺過形成 （グレーブス病を含む） 、 慢性炎症、 肺炎、 ネフ口一 ゼ症候群、 腫瘍免疫機能低下、 腹水貯留、 心内膜液滲出 （心膜炎に関係するもの など） 及び胸水貯留などが挙げられる。  Here, the diseases and pathological symptoms related to VEGF include, for example, diabetic retinopathy and other retinopathies, rheumatoid arthritis, solid tumors, cerebral edema and injury related to ischemia-reperfusion injury, psoriasis, atheroma Sclerosis, post-lens fibroplasia, neovascular glaucoma, age-related macular degeneration, thyroid hyperplasia (including Graves' disease), chronic inflammation, pneumonia, Neff's syndrome, reduced tumor immune function, ascites retention, endocardial fluid Effusions (such as those associated with pericarditis) and pleural effusion.
以上のうち特に下記の疾患では、 VEGFの阻害による病態の改善が報告され ている。  Among the above diseases, in particular, the following diseases have been reported to be improved by VEGF inhibition.
①糖尿病性網膜症及び他の網膜症 ① Diabetic retinopathy and other retinopathies
糖尿病性網膜症は、 長期間高血糖状態にさらされたことにより引き起こされた 網膜血管の異常により、 網膜や硝子体に多彩な病変を形成する疾患であり、 病状 の進行に伴い眼球内の異常血管新生と出血により失明に至ることが知られている。 一方、 糖尿病患者において眼球内の VEGFレベルの上昇と眼球内の異常な血管 新生との間に正の相関関係があることが報告されている （New Engl. J. Med.、 第 3 31卷、 第 1480頁—第 1487頁、 1994年） 。 また、 サルの網膜症モデ ルにおいて抗 VE G F中和モノクローナル抗体の眼内投与により VE G F活性を 抑制すると血管新生が抑制されること （Arch.0pthalmol.、 第 114巻、 第 66頁 —第 71頁、 1996年） 、 マウスの網莫症モデルにおいて VEGFのシグナル 伝達阻害剤の投与により網膜血管新生が抑制されること （Am.J. Pathol.、 第 15 6卷、 第 697頁—第 707頁、 2000年） が報告されている。 以上より、 V E G F受容体拮抗剤は、 糖尿病性網膜症および他の虚血性網膜症に有効と考えら れる。  Diabetic retinopathy is a disease in which various abnormalities in the retinal blood vessels caused by prolonged exposure to hyperglycemic conditions cause a variety of lesions in the retina and vitreous body, and abnormalities in the eyeball as the disease progresses It is known that angiogenesis and bleeding lead to blindness. On the other hand, it has been reported that there is a positive correlation between elevated intraocular VEGF levels and abnormal intraocular neovascularization in diabetic patients (New Engl. J. Med., Vol. 331, 1480--1487, 1994). Also, in monkey retinopathy model, angiogenesis is suppressed by suppressing intravenous administration of anti-VEGF neutralizing monoclonal antibody by inhibiting VEGF activity (Arch. 0pthalmol., Vol. 114, p. 66—71. P. 1996), Inhibition of retinal neovascularization by administration of a VEGF signaling inhibitor in a mouse reticulomegaly model (Am. J. Pathol., 156, 697-707). , 2000). Based on the above, the VEGF receptor antagonist is considered to be effective for diabetic retinopathy and other ischemic retinopathies.
②慢性関節リウマチ ② Rheumatoid arthritis
慢性関節リゥマチ患者の血清 VEGF値は健常人に比べ有意に高値であり、 病 巣局所において VEGFの産生が増大していることが報告されており （J.I顧 uno l.、 第 152卷、 第 4149頁—第 4156頁、 1994年） 、 病態の形成に V EGFが深く関与していることが示唆されている。 また、 マウスコラーゲン関節 炎モデルでは、 抗 VEGF抗血清投与による病態改善作用が報告されている （J. Immunol., 第 164卷、 第 5922頁一第 5927頁、 2000年） 。 Serum VEGF levels in patients with rheumatoid arthritis are significantly higher than in healthy individuals, and it has been reported that VEGF production is increased in localized lesions (JI Adjunct uno l., Vol. 152, pp. 4149-p. 4156, 1994), suggesting that VEGF is deeply involved in the formation of pathological conditions. In a mouse collagen arthritis model, an anti-VEGF antiserum administration has been reported to improve the disease state (J. Immunol., Vol. 164, pp. 5922- 5927, 2000).
VEGFは、 悪性腫瘍血管の新生においても重要な役割を果たしていると考え られている （Biochem.Biophys.Res.Commun.、 第 161卷、 第 851頁—第 858 頁、 1989年） 。 VEGF is also thought to play an important role in the neovascularization of malignant tumors (Biochem. Biophys. Res. Commun., Vol. 161, pp. 851-858, 1989).
VEGFは、 グリオ一マ、 悪性リンパ腫、 下垂体腺腫、 髄膜腫などの脳腫瘍、 メラノーマ、 大腸癌、 卵巣癌、 滕癌、 食道癌、 横紋筋肉腫、 平滑筋肉腫、 力ポジ 肉腫および肺腺癌等多くの固形悪性腫瘍でその産生が亢進していることが知られ ている （Nature、 第 362卷、 第 841頁—第 844頁、 1993年、 Biochem. Biophys.Res.Com un.、 第 183巻、 第 1167頁—第 1174頁、 1992年） c 腫瘍細胞から分泌された VEGFは、 血管内皮細胞に特異的に存在するチロシン キナーゼ型受容体と結合することにより血管内皮細胞を増殖させ、 腫瘍血管新生 の誘導による腫瘍の増殖又は転移に関与していると考えられている （0ncogene、 第 5卷、 第 519頁—第 524頁、 1990年； Science、 第 255巻、 第 98 9頁—第 991頁、 1992年） 。 VEGF is used for brain tumors such as gliomas, malignant lymphomas, pituitary adenomas, meningiomas, melanomas, colorectal cancer, ovarian cancer, Teng cancer, esophageal cancer, rhabdomyosarcoma, leiomyosarcoma, lipopositive sarcoma and lung gland It is known that the production of many solid malignant tumors such as cancer is enhanced (Nature, Vol. 362, pp. 841-844, 1993, Biochem. Biophys. Res. 183, p. 1167-p. 1174, p. 1992) c VEGF secreted from tumor cells proliferates vascular endothelial cells by binding to tyrosine kinase-type receptors present specifically on vascular endothelial cells, It is thought to be involved in tumor growth or metastasis by inducing tumor angiogenesis (0ncogene, vol. 5, p. 519-p. 524, 1990; Science, vol. 255, p. 899- Pp. 991, 1992).
グリオブラストーマ、 横紋筋肉腫及び平滑筋肉腫のヌードマウス移植モデルに おいて、 抗 VEGFモノクローナル抗体の投与によって腫瘍増殖が抑制されるこ とが報告されており （Nature、 第 362卷、 第 841頁—第 844頁、 1993 年） 、 VEGF受容体拮抗剤は、 種々の固形腫瘍に対して抗腫瘍効果を示すこと が示唆されている。  It has been reported that administration of an anti-VEGF monoclonal antibody suppresses tumor growth in a nude mouse transplant model of glioblastoma, rhabdomyosarcoma, and leiomyosarcoma (Nature, Vol. 362, No. 841). P. 844, 1993), it has been suggested that VEGF receptor antagonists have antitumor effects on various solid tumors.
④虚血再灌流障害関連の脳浮腫及び損傷 脳 Ischemic reperfusion injury-related cerebral edema and injury
V E G Fは、 その血管透過性亢進作用による浮腫の発生に関与すると考えられ ており、 マウス脳虚血モデルにおいて、 マウス VEGF受容体タンパク [mFl t (1-3) ] と I gGの融合タンパクの投与による脳浮腫及び損傷の抑制が報 告されている （J.Clin. Invest., 第 1 0 4卷、 第 1 6 1 3頁一第 1 6 2 0頁、 1 9 9 9年） 。 本発明に係る V E G F受容体拮抗剤、 本発明に係る V E G Fが関与する疾患の 治療薬は、 経口又は非経口的に投与することができる。 VEGF is thought to be involved in the development of edema due to its vascular hyperpermeability, and in a mouse cerebral ischemia model, administration of a fusion protein of mouse VEGF receptor protein [mFlt (1-3)] and IgG Suppresses brain edema and damage (J. Clin. Invest., Vol. 104, pp. 1613-1 pp. 1620, 1999). The VEGF receptor antagonist according to the present invention and the therapeutic agent for a disease associated with VEGF according to the present invention can be administered orally or parenterally.
その投与剤型は錠剤、 カプセル剤、 顆粒剤、 散剤、 粉剤、 トローチ剤、 軟膏剤、 クリーム剤、 乳剤、 懸濁剤、 坐剤、 注射剤などであり、 いずれも慣用の製剤技術 (例えば、 第 1 2改正日本薬局方に規定する方法） によって製造することができ る。 これらの投与剤型は、 患者の症状、 年齢及び治療の目的に応じて適宜選択す ることができる。 各種剤型の製剤の製造においては、 常用の賦形剤 （例えば、 結 晶セルロース、 デンプン、 乳糖、 マンニトールなど） 、 結合剤 （例えば、 ヒドロ キシプロピルセルロース、 ポリビニルピロリ ドンなど） 、 滑沢剤 （例えば、 ステ アリン酸マグネシウム、 タルクなど） 、 崩壊剤 （例えば、 カルボキシメチルセル ロースカルシウムなど） などを用いることができる。  The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc. It can be manufactured by the method specified in the 12th revised Japanese Pharmacopoeia). These dosage forms can be appropriately selected depending on the condition, age, and purpose of treatment of the patient. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, For example, magnesium stearate, talc, and the like, and disintegrants (eg, carboxymethyl cellulose calcium) can be used.
本発明に係る化合物の投与量は、 成人を治療する場合で 1日 l〜2 0 0 0 m g であり、 これを 1日 1回又は数回に分けて投与する。 この投与量は、 患者の年齢、 体重及び症状によつて適宜増減することができる。 製造例  The dose of the compound of the present invention is 1 to 2000 mg per day when treating an adult, and the compound is administered once or several times a day. This dosage may be adjusted as appropriate according to the patient's age, weight and condition. Manufacturing example
[製造例 1 ]  [Production Example 1]
4—ヒドロキシ安息香酸メチルエステル 35.5g及び 2—クロ口— 5—ニトロ安 息香酸メチルエステル 50.2gを N , N—ジメチルホルムアミ ド （D M F ) 500ml に溶解した溶液に無水炭酸カリウム 48.4gを加え、 8 0 °Cにて 3時間撹拌した。 反応液に水を加えて酢酸ェチルにて抽出し、 有機層を飽和食塩水にて洗浄後、 無 水硫酸マグネシゥムにて乾燥した。 溶媒を減圧下留去して得られた粗生成物をメ 夕ノールにて再結晶し、 2— ( 4—メ トキシカルボニルフエノキシ） 一 5—ニト 口安息香酸メチルエステル （融点： 1 0 3〜1 0 5 °C) 67.7gを得た （下記反応式 ( 8 ) ) 。
Figure imgf000012_0001
48.4 g of anhydrous potassium carbonate was dissolved in a solution of 35.5 g of 4-hydroxybenzoic acid methyl ester and 50.2 g of 2-chloro-5-nitrobenzoic acid methyl ester in 500 ml of N, N-dimethylformamide (DMF). The mixture was stirred at 80 ° C for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from methanol to give 2- (4-methoxycarbonylphenoxy) -15-nittobenzoic acid methyl ester (melting point: 10) 67.7 g (3 to 105 ° C) was obtained (reaction formula (8) below).
Figure imgf000012_0001
(8) (8)
上記反応式 （8) で得た化合物 11.6gをメタノール 300mlに懸濁させた混合物 に、 10%パラジウム—炭素 1.00 g を加えて水素雰囲気下、 室温にて 2時間撹 拌した。 反応液をろ過して触媒を除去し、 ろ液を減圧下留去して粗生成物を得た c これをシリカゲルカラムクロマトグラフィー （へキサン：酢酸ェチル = 2 ： 3に て溶出） にて精製後、 メタノールにて再結晶して 2— (4—メ トキシカルボニル フエノキシ） ― 5—ァミノ安息香酸メチルエステル （融点： 144〜 146°C) 8.53gを得た （下記反応式 （9) ) 。 To a mixture of 11.6 g of the compound obtained by the above reaction formula (8) suspended in 300 ml of methanol was added 1.00 g of 10% palladium-carbon, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered to remove the catalyst, this c the filtrate to give the crude product was distilled off under reduced pressure by silica gel column chromatography (hexane: acetic acid Echiru = 2: Hand eluted 3) purified by Thereafter, the product was recrystallized from methanol to obtain 8.53 g of 2- (4-methoxycarbonylphenoxy) -5-aminobenzoic acid methyl ester (melting point: 144 to 146 ° C.) (the following reaction formula (9)).
Figure imgf000012_0002
Figure imgf000012_0002
(9) (9)
上記反応式 （9) で得た化合物 2.84g及び 3— (4—ォク夕デシルォキシフエ ニル） — 3—ォキソプロビオン酸ェチルエステル 4.34gの混合物を 140°Cにて 7時間加熱した。 得られた粗生成物をシリカゲルカラムクロマトグラフィー （へ キサン：クロ口ホルム：酢酸ェチル =2 ： 3 ： 1にて溶出） にて精製後、 酢酸ェ チルにて再結晶して化合物 1 (融点： 1 15〜1 17°C) 3.64 gを得た （下記反 応式 （ 10 ) ) 。 .
Figure imgf000013_0001
化合物 1 ( 10) A mixture of 2.84 g of the compound obtained by the above reaction formula (9) and 4.34 g of 3- (4-oxodecyloxyphenyl) -3-ethyl oxopropionate was heated at 140 ° C. for 7 hours. The obtained crude product was purified by silica gel column chromatography (eluted with hexane: cloth form: ethyl acetate = 2: 3: 1), and recrystallized from ethyl acetate to give Compound 1 (melting point: 3.15 g (115 ° -117 ° C.) was obtained (the following reaction formula (10)). .
Figure imgf000013_0001
Compound 1 (10)
[製造例 2 ]  [Production Example 2]
製造例 1と同様の操作により、 一般式 （ 1 1) で表され、 R11と R12が表 1に 示す構造の化合物 2〜化合物 8を得た。 それらの融点も表 1に併せて示す。 By the same operation as in Production Example 1, Compounds 2 to 8 represented by the general formula ( 11 ) and having R 11 and R 12 shown in Table 1 were obtained. Their melting points are also shown in Table 1.
Figure imgf000013_0002
Figure imgf000013_0002
( 1 1) (1 1)
表 1 table 1
R11 R12 融点 （°c) 化合物 2 H 90-92R 11 R 12 Melting point (° c) Compound 2 H 90-92
Me02C^^O 化合物 3 H 50-52Me0 2 C ^^ O compound 3 H 50-52
C02 e 化合物 4 H 85-87 化合物 5 C0 2 e Compound 4 H 85-87 Compound 5
O 。 H 42-43 CH e2 化合物 6 H χ 138-142 化合物 7 H 113-115 e02C^^O 化合物 8 H 83-93 O. H 42-43 CH e 2 Compound 6 H chi 138-142 Compound 7 H 113-115 e0 2 C ^^ O compound 8 H 83-93
[製造例 3 ] [Production Example 3]
製造例 1の反応式 （8) と同様の操作により得られた 2— （4—メトキシカル ボニルフエ二ルチオ） — 5 _ニトロ安息香酸メチルエステル 1.09 g及び鉄粉 1. 75 gの混合物にイソプロピルアルコール 3 ml 及び塩化アンモニゥム水溶液 （塩 化アンモニゥム 0.05 g、 水 0.95 ml ) を加え、 85°Cにて 10分間撹拌した。 反応混合物にクロ口ホルムを加えてセライ 卜にてろ過、 引き続きクロ口ホルムに て洗浄した。 ろ液及び洗液を合わせて飽和食塩水にて洗浄後、 無水硫酸マグネシ ゥムにて乾燥した。 溶媒を減圧下留去して、 5—ァミノ一 2— (4—メトキシカ ルポニルフエ二ルチオ） 安息香酸メチルエステル （黄色粘性物質） 0.996 g を得 た （下記反応式 （ 12) ) 。  A mixture of 1.09 g of 2- (4-methoxycarbonylphenylthio) -5-nitrobenzoic acid methyl ester and 1.75 g of iron powder obtained by the same operation as in the reaction formula (8) of Production Example 1 was mixed with isopropyl alcohol 3 ml and aqueous ammonium chloride solution (0.05 g of ammonium chloride, 0.95 ml of water) were added, and the mixture was stirred at 85 ° C for 10 minutes. To the reaction mixture was added chloroform and the mixture was filtered through celite, and then washed with chloroform. The filtrate and the washing solution were combined, washed with a saturated saline solution, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.996 g of methyl 5-amino-2- (4-methoxycarbonylphenylthio) benzoate (yellow viscous substance) (the following reaction formula (12)).
Figure imgf000015_0001
Figure imgf000015_0001
(12) 製造例 1の反応式 （ 10) と同様の操作により、 上記反応式 （12) で得た化 合物から化合物 9 (融点： 121~124°C) を得た （下記反応式 （13) ) 。 (12) Compound 9 (melting point: 121 to 124 ° C) was obtained from the compound obtained in the above reaction formula (12) by the same operation as in the reaction formula (10) in Production Example 1 (the following reaction formula ( 13) ) .
Figure imgf000015_0002
化合物 9 3) [製造例 4]
Figure imgf000015_0002
Compound 9 3) [Production Example 4]
製造例 2と同様の操作により、 一般式 （14) で表され、 R13、 R14及び R15 が表 2に示す構造の化合物 10〜化合物 18を得た。 それらの融点も表 2に併せ て示す。 By the same operation as in Production Example 2, Compounds 10 to 18 represented by the general formula (14) and having R 13 , R 14, and R 15 shown in Table 2 were obtained. Their melting points are also shown in Table 2.
Figure imgf000016_0001
Figure imgf000016_0001
(14) (14)
W 1 W 1
15 表 2  15 Table 2
化合物 R13 R14 R15 融点（°c) 化合物 10 H OC10H21 126-128 Compound R 13 R 14 R 15 Melting point (° c) Compound 10 H OC 10 H 21 126-128
化合物 11 H OC18H37 124-128 Compound 11 H OC 18 H 37 124-128
化合物 12 H OC18H37 58-60 Compound 12 H OC 18 H 37 58-60
C02Me 化合物 13 H NHCOC17H35 116-121 C0 2 Me compound 13 H NHCOC 17 H 35 116-121
C02Me 化合物 14 H OC18H37 100-101 C0 2 Me compound 14 H OC 18 H 37 100-101
s  s
c  c
化合物 15 H OC18H37 111-112 Compound 15 H OC 18 H 37 111-112
化合物 16 H OC18H37 97-99
Figure imgf000017_0001
化合物 17 H OC18H37 86-89 Compound 16 H OC 18 H 37 97-99
Figure imgf000017_0001
Compound 17 H OC 18 H 37 86-89
化合物 18 H OC18H37 111-115 [製造例 5 ] Compound 18 H OC 18 H 37 111-115 [Production Example 5]
3.63gの化合物 1をエタノール 50mlに懸濁させた混合物に、 水酸化ナトリウム 水溶液 （水酸化ナトリウム 2.03 g、 水 50ml) を加えて Ί 0°Cにて 90分間撹拌 した。 反応液に 5%塩酸を加えて酸性とし、 析出した固体をろ過して水にて洗浄 後、 減圧乾燥して化合物 19 (融点： 2 19〜221°C) 3.31gを得た （下記反応 式 （ 15) ) 。  To a mixture of 3.63 g of Compound 1 suspended in 50 ml of ethanol was added an aqueous sodium hydroxide solution (2.03 g of sodium hydroxide, 50 ml of water), and the mixture was stirred at 0 ° C for 90 minutes. The reaction solution was acidified by adding 5% hydrochloric acid, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 3.31 g of compound 19 (melting point: 219 to 221 ° C) (the following reaction formula). (15)).
化合物 1
Figure imgf000018_0001
Compound 1
Figure imgf000018_0001
化合物 19  Compound 19
( 15) (15)
[製造例 6 ] [Production Example 6]
化合物 2〜化合物 18を用いて製造例 5と同様の操作を行い、 一般式 （16) で表され、 R16、 R 17及び R 18が表 3及び表 4に示す構造の化合物 20〜化合物 36を得た。 それらの融点も表 3及び表 4に併せて示す。 The same operation as in Production Example 5 was carried out using Compounds 2 to 18, and represented by the general formula (16), wherein R 16 , R 17 and R 18 had the structures shown in Tables 3 and 4 and Compounds 20 to 36 I got Their melting points are also shown in Tables 3 and 4.
Figure imgf000018_0002
Figure imgf000018_0002
( 16) 表 3 (16) Table 3
R16 R17 R18 融点 （°c) 化合物 20 H OCigH37 165-169 化合物 21 H OC18H37 180-182R 16 R 17 R 18 Melting point (° c) Compound 20 H OCigH 37 165-169 Compound 21 H OC 18 H 37 180-182
Figure imgf000019_0001
Figure imgf000019_0001
化合物 22 H OC18H37 124-127 Compound 22H OC18H37 124-127
k^。 化合物 23 H しl oM 3ゥ，/ 106-109 k ^. Compound 23 H 3 lOM 3 /, 106-109
Figure imgf000019_0002
Figure imgf000019_0002
匕^ ·¾0 ク 4 H J 。 H。， 214-217 化合物 25 H OC18H37 198-201匕 ^ ¾ ク 0 4 4 HJ. H. , 214-217 Compound 25 H OC 18 H 37 198-201
H02C^^O 化合物 26 H C OC18H37 186-189 。 H0 2 C ^^ O compound 26 HC OC 18 H 37 186-189.
表 4 Table 4
R16 R17 R18 融点 （°c) 化合物 27 H OC18H37 190-193 化合物 28 H OC10H21 216-219 化合物 29 H OC18H37 168-171R 16 R 17 R 18 Melting point (° c) Compound 27 H OC 18 H 37 190-193 Compound 28 H OC 10 H 21 216-219 Compound 29 H OC 18 H 37 168-171
Figure imgf000020_0001
化合物 30 H OG18H37 228-231
Figure imgf000020_0001
Compound 30 H OG 18 H 37 228-231
C02H 化合物 31 H NHCOC17H35 261-264C0 2 H compound 31 H NHCOC 17 H 35 261-264
C02H 化合物 32 H OC18H37 54-56 化合物 33 H OC18H37 217-222 化合物 34 H OC18H37 204-209 化合物 35 H OC18H37 166-170 化合物 36 H OC18H37 165-169C0 2 H compound 32 H OC 18 H 37 54-56 compound 33 H OC 18 H 37 217-222 compound 34 H OC 18 H 37 204-209 compound 35 H OC 18 H 37 166-170 compound 36 H OC 18 H 37 165-169
Figure imgf000020_0002
[製造例 Ί ]
Figure imgf000020_0002
[Production example Ί]
4—ァミノ安息香酸 11.4 g及び 2—フルオロー 5—二トロ安息香酸 15.4 g を N, N—ジメチルホルムアミ ド 500 ml に溶解した溶液に無水炭酸カリウム 2 2.9 g及び 粉末 0.462 g を加え、 100°Cにて 1時間、 12 CTCにて 3時間、 140°Cにて 8時間撹拌した。 反応液に水及び塩酸を加えて酸性とし、 析出した 固体をろ取して粗生成物 20.6 g を得た。  To a solution of 11.4 g of 4-aminobenzoic acid and 15.4 g of 2-fluoro-5-nitrobenzoic acid in 500 ml of N, N-dimethylformamide, add 22.9 g of anhydrous potassium carbonate and 0.462 g of powder, and add 100 ° C. The mixture was stirred at C for 1 hour, at 12 CTC for 3 hours, and at 140 ° C for 8 hours. The reaction solution was acidified by adding water and hydrochloric acid, and the precipitated solid was collected by filtration to obtain 20.6 g of a crude product.
上記粗生成物 20.6 g を N, N—ジメチルホルムアミ ド 500 ml に溶解した溶 液に無水炭酸カリウム 14.1 及びヨウ化メチル 19.3 を加え、 室温にて 2時 間撹拌した。 反応液に水を加えて酢酸ェチルにて抽出し， 有機層を飽和食塩水に て洗浄して無水硫酸マグネシウムにて乾燥した。 溶媒を減圧下留去して得られた 粗生成物を酢酸ェチルに懸濁後、 ろ過して 5—二トロ— 2, 4' —ィミノ二安息 香酸ジメチルエステル （融点： 205〜206°C) 13.5 g を得た （下記反応式 ( 17) ) 。  Anhydrous potassium carbonate 14.1 and methyl iodide 19.3 were added to a solution of 20.6 g of the above crude product in 500 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure is suspended in ethyl acetate, filtered and filtered to give 5-dimethyl-2,4'-iminodibenzoic acid dimethyl ester (melting point: 205-206 ° C) 13.5 g was obtained (the following reaction formula (17)).
Figure imgf000021_0001
Figure imgf000021_0001
(17) 上記反応式 （17) で得た化合物 12.3 g をメタノール 300 ml に溶解させた 溶液に 10%パラジウム—炭素 1.23 g を加え、 水素雰囲気下室温にて 4時間撹 拌した。 反応液をろ過して触媒を除き、 溶媒を減圧下留去して得た粗生成物をシ リカゲルカラムクロマトグラフィー （へキサン：酢酸ェチル = 1 ： 1にて溶出） にて精製後、 メタノールにて再結晶して 5—アミノー 2， 4' ーィミノ二安息香 酸ジメチルエステル （融点： 1 13〜1 15°C) 8.87 を得た （下記反応式 （ 18) ) (17) To a solution of 12.3 g of the compound obtained in the above reaction formula (17) in 300 ml of methanol was added 1.23 g of 10% palladium-carbon, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction solution was filtered to remove the catalyst, and the crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 1: 1). And recrystallized to give 8.87 of 5-amino-2,4'-iminodibenzoic acid dimethyl ester (melting point: 113 to 115 ° C) (the following reaction formula ( 18))
Figure imgf000022_0001
Figure imgf000022_0001
18) 上記反応式 （18) で得た化合物 5.14 及び 3— (4—ォク夕デシルォキシ フエニル） — 3—ォキソプロビオン酸ェチルエステル 8.66 g の混合物を 140 °Cにて 13時間加熱撹拌した。 得られた粗生成物をシリカゲルカラムクロマトグ ラフィー （へキサン：クロロホルム ：酢酸ェチル = 3 : 1 : 1にて溶出） にて精 製し、 化合物 37 (融点： 1 12〜： L 14°C) 7.77 g を得た （下記反応式 （19) ) 18) A mixture of the compound 5.14 obtained by the above reaction formula (18) and 8.66 g of 3- (4-octyldecyloxyphenyl) -3-ethyloxoethyl ester was heated and stirred at 140 ° C. for 13 hours. The obtained crude product was purified by silica gel column chromatography (eluted with hexane: chloroform: ethyl acetate = 3: 1: 1) to give Compound 37 (melting point: 112 12: L at 14 ° C) 7.77 g (reaction formula (19) below)
Figure imgf000022_0002
化合物 37 ( 19)
Figure imgf000022_0002
Compound 37 (19)
[製造例 8 ] [Production Example 8]
3—ァミノ安息香酸 3.92 g及び 2—フルオロー 5—ニトロ安息香酸 5.30 g を N， N—ジメチルホルムアミ ド 180 ml に溶解した溶液に無水炭酸カリウム 9. 88 g及び銅粉末 0.16 g を加え、 120°Cにて 10時間撹拌した。 反応液に水及 び塩酸を加えて酸性とし、 析出した固体をろ取して粗生成物 11.7 g を得た。 上記粗生成物 11.7 g を N, N—ジメチルホルムアミ ド 200 ml に溶解した溶 液に無水炭酸カリウム 8.02 g及びヨウ化メチル 8.23 g を加え、 室温にて 4時 間撹拌した。 反応液に水を加えて酢酸ェチルにて抽出し， 有機層を飽和食塩水に て洗浄して無水硫酸マグネシウムにて乾燥した。 溶媒を減圧下留去して得られた 粗生成物をシリカゲルカラムクロマトグラフィー （へキサン：酢酸ェチル = 2 ： 1にて溶出） にて精製し、 5—ニトロ一 2, 3' —ィミノ二安息香酸ジメチルェ ステル （融点： 149〜151°C) 6.23 g を得た （下記反応式 （20) ) 。 To a solution of 3.92 g of 3-aminobenzoic acid and 5.30 g of 2-fluoro-5-nitrobenzoic acid in 180 ml of N, N-dimethylformamide was added 9.88 g of anhydrous potassium carbonate and 0.16 g of copper powder. The mixture was stirred at ° C for 10 hours. The reaction solution was acidified by adding water and hydrochloric acid, and the precipitated solid was collected by filtration to obtain 11.7 g of a crude product. To a solution of the above crude product (11.7 g) in N, N-dimethylformamide (200 ml) was added anhydrous potassium carbonate (8.02 g) and methyl iodide (8.23 g), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 2: 1) to give 5-nitro-1,2,3'-iminodibenzo. 6.23 g of dimethyl ester (melting point: 149 to 151 ° C.) was obtained (the following reaction formula (20)).
Figure imgf000023_0001
Figure imgf000023_0001
(20) 上記反応式 （20) で得た化合物 6.23 g をメタノール 150 ml に溶解させた 溶液に 10%パラジウム—炭素 0.623 g を加え、 水素雰囲気下室温にて 17時間 撹拌した。 反応液をろ過して触媒を除き、 溶媒を減圧下留去して得た粗生成物を シリカゲルカラムクロマトグラフィー （へキサン：酢酸ェチル = 2 ： 1にて溶出） にて精製し、 5—ァミノ一 2， 3' —イミノニ安息香酸ジメチルエステル （黄色 油状物質） 5.37 g を得た （下記反応式 （2 1) ) 。  (20) To a solution of 6.23 g of the compound obtained in the above reaction formula (20) in 150 ml of methanol was added 0.623 g of 10% palladium-carbon, and the mixture was stirred at room temperature under a hydrogen atmosphere for 17 hours. The reaction solution was filtered to remove the catalyst, the solvent was distilled off under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 2: 1) to give 5-amino. 5.37 g of 1,2′-imino dibenzoic acid dimethyl ester (yellow oily substance) was obtained (the following reaction formula (21)).
Figure imgf000023_0002
Figure imgf000023_0002
(21) 上記反応式 （2 1) で得た化合物 3.40 g及び 3— (4—ォク夕デシルォキシ フエニル） 一 3—ォキソプロピオン酸ェチルエステル 5.22 gの混合物を 140 °Cにて 10時間加熱撹拌した。 得られた粗生成物をシリカゲルカラムクロマトグ ラフィー （へキサン：クロ口ホルム ：酢酸ェチル =3 : 2 : 1にて溶出） にて精 製後、 メタノールにて再結晶して化合物 38 (融点： 100〜102°C) 4.75 g を得た （下記反応式 （22) ) 。 (twenty one) A mixture of 3.40 g of the compound obtained by the above reaction formula (21) and 5.22 g of 3- (4-oxodecyloxyphenyl) ethyl 3-oxopropionate was heated and stirred at 140 ° C. for 10 hours. The obtained crude product was purified by silica gel column chromatography (eluted with hexane: chloroform: ethyl acetate = 3: 2: 1), and recrystallized from methanol to give Compound 38 (melting point: 100 4.75 g was obtained (the following reaction formula (22)).
Figure imgf000024_0001
Figure imgf000024_0001
化合物 38 (22)  Compound 38 (22)
[製造例 9 ] [Production Example 9]
製造例 7及び製造例 8と同様の操作により、 一般式 （23) で表され、 R19が 表 5に示す構造の化合物 39及び化合物 40を得た。 それらの融点も表 5に併せ て示す。 By the same operation as in Production Example 7 and Production Example 8, Compound 39 and Compound 40 represented by General Formula (23) and having R 19 having the structure shown in Table 5 were obtained. Their melting points are also shown in Table 5.
Figure imgf000024_0002
表 5
Figure imgf000024_0002
Table 5
Figure imgf000025_0002
Figure imgf000025_0002
[製造例 10 ] [Production Example 10]
5.00 の化合物 37をエタノール 50 ml に懸濁させた混合物に、 水酸化ナト リゥム水溶液 （水酸化ナトリウム 2.80 g、 水 50 ml ) を加えて 80°Cにて 3時 間撹拌した。 反応液に 5%塩酸を加えて酸性とし、 析出物をろ取して水にて洗浄 後、 乾燥して化合物 41 (融点： 214〜219°C) 4.28 g を得た （下記反応 式 （24) ) 。  An aqueous sodium hydroxide solution (2.80 g of sodium hydroxide, 50 ml of water) was added to a mixture of the compound 37 of 5.00 suspended in 50 ml of ethanol, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was acidified by adding 5% hydrochloric acid, and the precipitate was collected by filtration, washed with water, and dried to obtain 4.28 g of compound 41 (melting point: 214 to 219 ° C) (the following reaction formula (24) )).
化合物 37
Figure imgf000025_0001
Compound 37
Figure imgf000025_0001
化合物 41 (24)  Compound 41 (24)
[製造例 1 1 ] [Production Example 1 1]
4.73 gの化合物 38をエタノール 140 ml に懸濁させた混合物に、 水酸化ナト リゥム水溶液 （水酸化ナトリウム 2.65 g、 水 70 ml ) を加えて 70°Cにて 1時 間撹拌した。 反応液に 5%塩酸を加えて酸性とし、 析出物をろ取して水 (こて洗浄 後、 乾燥して化合物 42 (融点： 21 1〜2 15°C) 4.20 g を得た （下記反応 式 （25) ) To a mixture of 4.73 g of compound 38 suspended in 140 ml of ethanol was added an aqueous sodium hydroxide solution (2.65 g of sodium hydroxide, 70 ml of water), and the mixture was stirred at 70 ° C for 1 hour. The reaction mixture was acidified by adding 5% hydrochloric acid, and the precipitate was collected by filtration, washed with a trowel and dried to obtain 4.20 g of compound 42 (melting point: 211 to 215 ° C) (the following reaction). (Equation (25))
化合物 38
Figure imgf000026_0001
Compound 38
Figure imgf000026_0001
[製造例 12 ] [Production Example 12]
化合物 39及び化合物 40を用いて製造例 10及び製造例 1 1と同様の操作を 行い、 一般式 （26) で表され、 R2Qが表 6に示す構造の化合物 43及びィ匕合物 44を得た。 それらの融点も表 6に併せて示す。 The same operations as in Production Example 10 and Production Example 11 were carried out using Compound 39 and Compound 40 to give Compound 43 and Compound 44 represented by General Formula (26), wherein R 2Q had the structure shown in Table 6. Obtained. Their melting points are also shown in Table 6.
Figure imgf000026_0002
Figure imgf000026_0002
(26) (26)
表 6 Table 6
R20 融点 (°c) 化合物 43 C02H 231-235 化合物 44 H 147-150 [試験例 1 ] R 20 Melting point (° c) Compound 43 C0 2 H 231-235 Compound 44 H 147-150 [Test Example 1]
文献 (Cell Growth & Differentiation, 第 7巻、 第 213頁-第 221頁、 1996年) 記載の方法に準拠し、 以下の試験を行った。  The following tests were performed according to the method described in the literature (Cell Growth & Differentiation, Volume 7, pages 213 to 221, 1996).
Flt-1を強制発現させた NIH3T3細胞 （7x 104個/ well) を 24ゥエルコラーゲン コートプレートに播種し、 10%子牛血清及び 200 zg/ml Geneticin G418を含 む Dulbecco's modified Eagle's medium (DMEM) 中、 5 %炭酸ガス雰囲気下、 3 7°Cにて 24時間培養した。 その細胞を緩衝液 A [DMEM中に 10mM HEPES( Ν-2-hy droxyethylpiperazine-N' -2-ethanesulfonic acid)と 0.1% BSA(bovine serum a lbumin)を含む] 中、 4°Cにて 30分間プレインキュペートした。 その後、 培地を 緩衝液 B (DMEM中に lOmM HEPESと 0.5 % BSAを含む） に交換し、 表 7に示す各々の 試験化合物をジメチルスルホキシドに溶解後緩衝液 Bで所定の濃度に希釈して調 製した試験液と [125 I]- VEGF (最終濃度を 25pMにする） を添加し、 4°Cにて 90分間結合反応を行わせた。 反応終了後、 細胞を氷冷した緩衝液 Aにて 3回洗 浄した。 引き続き、 各ゥエルに 0.5M NaOH 0.5mlを加え、 室温にて 30分かけて 細胞を融解した。 各ゥエルの細胞融解物の放射活性をガンマカウン夕一にて測定 して [1251 ]-VE GFの総結合量を算出した。 [1251 ]- VE GFの非特異的結合 を、 ΙΟηΜの非標識 VE GF共存下での競合アツセィ （competition assay) により 測定し、 [125 I ]-¥£0 の総結合量との差から[1251]- £0 の特異的結合 量を算出した。 NIH3T3 cells (7 × 10 4 cells / well) in which Flt-1 was forcibly expressed were seeded on a 24-well collagen-coated plate, and Dulbecco's modified Eagle's medium (DMEM) containing 10% calf serum and 200 zg / ml Geneticin G418 was added. ), And cultured at 37 ° C for 24 hours in a 5% carbon dioxide atmosphere. Place the cells in buffer A [containing 10 mM HEPES (Ν-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) and 0.1% BSA (bovine serum a lbumin) in DMEM] at 4 ° C for 30 minutes Planned paste. After that, the medium was exchanged for buffer B (containing 10 mM HEPES and 0.5% BSA in DMEM), and each of the test compounds shown in Table 7 was dissolved in dimethyl sulfoxide and diluted to the specified concentration with buffer B to prepare. The prepared test solution and [ 125 I] -VEGF (final concentration: 25 pM) were added, and the binding reaction was performed at 4 ° C for 90 minutes. After completion of the reaction, the cells were washed three times with ice-cold buffer A. Subsequently, 0.5 ml of 0.5 M NaOH was added to each well, and the cells were thawed at room temperature for 30 minutes. The radioactivity of the cell lysate for each Ueru measured at Ganmakaun evening one to calculate the total amount of binding of [125 1] -VE GF. [125 1] - non-specific binding of VE GF, was determined by competitive Atsusi (competition assay) of unlabeled VE GF presence of ΙΟηΜ, [125 I] - from the difference between ¥ £ total binding of 0 The specific binding of [ 1251 ]-£ 0 was calculated.
試験化合物の結合阻害率を次の式により計算した。 結合阻害率 （％) = 試験化合物添加群の [1251] — VEGF特異的結合量 The binding inhibition rate of the test compound was calculated by the following equation. Binding inhibition rate (%) = [ 125 1] of test compound added group — VEGF specific binding amount
[1 ] X 100  [1] X 100
コントロール群の [125I] —VEGF特異的結合量 この値から試験化合物の 50%結合阻害濃度 （IC5。） を算出した。 その結果 を表 7に示す。 表 7 [ 125 I] -VEGF specific binding amount of control group From this value, 50% binding inhibitory concentration (IC 5 ) of the test compound was calculated. Table 7 shows the results. Table 7
Figure imgf000028_0001
Figure imgf000028_0001
[試験例 2 ] [Test Example 2]
KDRを強制発現させた NIH3T3細胞を用いて、 表 8に示す各々の試験化合物につい て、 上記試験例 1と同様の方法にて試験を実施した。 その結果を表 8に示す。 Using NIH3T3 cells in which KDR was forcibly expressed, each of the test compounds shown in Table 8 was tested in the same manner as in Test Example 1 above. Table 8 shows the results.
表 8 1 Tし150 ( it Μ I U、Table 8 1 T 1 50 (it Μ IU,
1し会口物，ク J 1 Q7 Π ft ィ 1卜し会口物 1VJ ク Ωリ Ω fiク J 1 Q7 ft ft 1 1 1 VJ Ω Ω Ω fi
，し口 1YJ \、 し 口 1YJ \
V^H クク I .ou V ^ H
，し口 1¾l < , Mouth 1¾l <
I ΰ I ΰ
Π A Π A
1.4U
Figure imgf000029_0001
1.4U
Figure imgf000029_0001
ic口 U.O 1 ic mouth U.O 1
U.C30 ィ Ί卜し会口物 'yyj 1 fiク 化合物 36 0.63 化合物 41 0.48 化合物 42 0.53 化合物 43 0.75 [試験例 3 ] U.C30 Distilled Mouthpiece 'yyj 1 fi Compound 36 0.63 Compound 41 0.48 Compound 42 0.53 Compound 43 0.75 [Test Example 3]
in vivo 腫瘍増殖阻害試験  In vivo tumor growth inhibition test
. ヌードマウス皮下にて継代したヒト結腸癌株 Co 1— 1腫瘍を摘出後細切し、 2mmx 2mmx 2 mmの大きさの腫瘍塊を移植針にてヌードマウスの右側腹部 皮下に移植した （dayO) 。 試験化合物 （化合物 19) を等張リン酸緩衝液 （ PH9) に溶解して調製した試験液を、 腫瘍を移植したヌードマウスに 28日間 (day 1から day 28まで） 連日、 表 9に示す投与量にて腹腔内投与した。 腫瘍体積は、 day 30にノギスを用いて測定した腫瘍の長径と短径の値から 次式により計算した。 腫瘍体積 (mm3) =0. 5 X [長径 （mm) ] x [短径 （mm) ] 2 試験化合物の腫瘍増殖阻害作用は、 未処置のコントロール群の腫瘍体積に対す る T/C (%) として次式により計算した。 その結果を表 9に示す。 試験化合物投与群の腫瘍体積 The human colon cancer cell line Co 1-1 tumor passaged subcutaneously in a nude mouse was excised, cut into small pieces, and a 2 mm x 2 mm x 2 mm tumor mass was implanted subcutaneously into the right flank of nude mice with a needle. dayO). A test solution prepared by dissolving a test compound (compound 19) in isotonic phosphate buffer (PH9) was administered to tumor-implanted nude mice for 28 days (from day 1 to day 28) daily, as shown in Table 9. The dose was administered intraperitoneally. The tumor volume was calculated from the values of the major axis and minor axis of the tumor measured using calipers on day 30 according to the following formula. Tumor volume (mm 3 ) = 0.5 X [major axis (mm)] x [minor axis (mm)] 2 The tumor growth inhibitory effect of the test compound was expressed as T / C ( %) By the following equation. Table 9 shows the results. Tumor volume of test compound administration group
T/C (%) = X I 00  T / C (%) = X I 00
コントロール群の腫瘍体積 表 9  Tumor volume of control group Table 9
投与量 TZC(%) Dose TZC (%)
(mgZkgZaay) 産業上の利用可能性 (mgZkgZaay) Industrial applicability
本発明の VE G F受容体拮抗剤は、 VE G F依存性の血管内皮細胞増殖を阻害 することによつて血管新生を阻害したり、 V E G Fによる血管透過性亢進を抑制 すると考えられる。  The VEGF receptor antagonist of the present invention is considered to inhibit angiogenesis by inhibiting VEGF-dependent vascular endothelial cell proliferation, and to suppress VEGF-induced increase in vascular permeability.
したがって、 本発明の VEGF受容体拮抗剤は、 糖尿病性網膜症、 慢性関節リ ゥマチ、 固形腫瘍などの VEGFによって誘導される血管新生が関与する疾患の 治療剤として期待される。 また、 本発明の VEGF受容体拮抗剤には、 虚血再灌 流障害時の脳浮腫などの VEGFによって誘導される血管透過性亢進が関与する 病的症状の抑制効果が期待される。  Therefore, the VEGF receptor antagonist of the present invention is expected to be used as a therapeutic agent for diseases involving angiogenesis induced by VEGF, such as diabetic retinopathy, rheumatoid arthritis, and solid tumors. In addition, the VEGF receptor antagonist of the present invention is expected to have an effect of suppressing pathological symptoms associated with VEGF-induced vascular hyperpermeability such as cerebral edema during ischemia-reperfusion injury.

Claims

請求の範囲 The scope of the claims
1. 下記式 （ 1 ) 1. The following equation (1)
Figure imgf000032_0001
Figure imgf000032_0001
(1) (1)
(式 （1) 中、 R1は水素原子、 C02R5又は OR6 (ここで、 R5及び R6はそれ それ水素原子又は C卜 6アルキル基である。 ） で表される基であり、 R2は水素原 子又は C02R7 (ここで、 R 7は水素原子又は d- 6アルキル基である。 ） で表さ れる基であり、 R 3は水素原子又は Cい 6アルキル基であり、 R 4は C 5アルキル 基であり、 Xは 0、 S又は NHであり、 Yは 0又は NHCOである。 ） で表され る化合物又はその医薬上許容される塩を有効成分として含むことを特徴とする V EGF受容体拮抗剤。 (In the formula (1), R 1 is a hydrogen atom, C 2 R 5 or OR 6 (where R 5 and R 6 are each a hydrogen atom or a C 6 alkyl group.) R 2 is a hydrogen atom or a group represented by C 0 2 R 7 (where R 7 is a hydrogen atom or d- 6 alkyl group), and R 3 is a hydrogen atom or C 6 alkyl R 4 is a C 5 alkyl group, X is 0, S or NH, and Y is 0 or NHCO.) Or a pharmaceutically acceptable salt thereof as an active ingredient A VEGF receptor antagonist.
2. 式 （1) において、 R4が C14-22アルキル基である請求項 1に記載の VE GF受容体拮抗剤。 2. In formula (1), R 4 is C 14 - VE GF receptor antagonist of claim 1 which is 22 alkyl group.
3. 式 （1) において、 R4が C18アルキル基である請求項 1に記載の VEGF 受容体拮抗剤。 3. The VEGF receptor antagonist according to claim 1, wherein in the formula (1), R 4 is a C 18 alkyl group.
4. 式 （1) において、 R1が C02R5 (ここで、 R5は水素原子又は d 6アル キル基である。 ） で表される基であり、 R 2が水素原子である請求項 3に記載の V EGF受容体拮抗剤。 4. In the formula (1), R 1 is a group represented by C 0 2 R 5 (where R 5 is a hydrogen atom or a d 6 alkyl group), and R 2 is a hydrogen atom. Item 4. The VEGF receptor antagonist according to Item 3.
5. 下記式 （ 2 )
Figure imgf000033_0001
5. The following formula (2)
Figure imgf000033_0001
(2)  (2)
(式 （2) 中、 R3及び R5はそれそれ水素原子又は CHアルキル基であり、 は 0、 S又は NHである。 ） で表される化合物又はその医薬上許容される塩を有効 成分として含むことを特徴とする請求項 1に記載の VE G F受容体拮抗剤。 (In the formula (2), R 3 and R 5 are each a hydrogen atom or a CH alkyl group, and is 0, S or NH.) Or a pharmaceutically acceptable salt thereof as an active ingredient 2. The VEGF receptor antagonist according to claim 1, which is contained as
6. 式 （2) において、 R3及び R5が共に水素原子である請求項 5に記載の V EGF受容体拮抗剤。 6. The VEGF receptor antagonist according to claim 5, wherein in the formula (2), R 3 and R 5 are both hydrogen atoms.
7. 請求項 1ないし 6のいずれか 1項記載の V E G F受容体拮抗剤を含むこと を特徴とする V E G Fが関与する疾患の治療薬。 7. A therapeutic agent for a disease associated with VEGF, comprising the VEGF receptor antagonist according to any one of claims 1 to 6.
8. VEGFが関与する疾患が、 糖尿病性網膜症、 慢性関節リウマチ、 固形腫 瘍、 虚血再灌流障害時の脳浮腫からなる群より選ばれる請求項 7記載の治療薬。 8. The therapeutic agent according to claim 7, wherein the disease associated with VEGF is selected from the group consisting of diabetic retinopathy, rheumatoid arthritis, solid tumor, and cerebral edema at ischemia-reperfusion injury.
9. 請求項 1ないし 6のいずれか 1項記載の V E G F受容体拮抗剤を投与する ことを特徴とする VEGFが関与する疾患の治療方法。 9. A method for treating a disease associated with VEGF, which comprises administering the VEGF receptor antagonist according to any one of claims 1 to 6.
10. VEGFが関与する疾患が、 糖尿病性網膜症、 慢性関節リウマチ、 固形 腫瘍、 虚血再灌流障害時の脳浮腫からなる群より選ばれる請求項 9記載の治療方 法。 10. The method according to claim 9, wherein the disease associated with VEGF is selected from the group consisting of diabetic retinopathy, rheumatoid arthritis, solid tumor, and cerebral edema at ischemia-reperfusion injury.
1 1. VEGFが関与する疾患の治療薬の治療のための式 （ 1) で表される化 合物又はその医薬上許容される塩の使用。 1 1. Use of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the treatment of a therapeutic agent for a disease associated with VEGF.
12. VEGFが関与する疾患が、 糖尿病性網膜症、 慢性関炎リウマチ、 固形 腫瘍、 虚血再灌流障害時の脳浮腫からなる群より選ばれる請求項 11記載の使用 c12. The use according to claim 11, wherein the disease associated with VEGF is selected from the group consisting of diabetic retinopathy, rheumatoid arthritis, solid tumors, and cerebral edema during ischemia-reperfusion injury.
13. VEGF受容体拮抗剤を製造するための式 （1) で表される化合物又は その医薬上許容される塩の使用。 13. Use of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for producing a VEGF receptor antagonist.
14. VEGFが関与する疾患の治療用薬剤を製造するための式 （1)で表さ れる化合物又はその医薬上許容される塩の使用。 14. Use of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease associated with VEGF.
15. VEGFが関与する疾患が、 糖尿病性網膜症、 慢性関節リウマチ、 固形 腫瘍、 虚血再灌流障害時の脳浮腫からなる群より選ばれる請求項 14記載の使用- 15. The use according to claim 14, wherein the disease associated with VEGF is selected from the group consisting of diabetic retinopathy, rheumatoid arthritis, solid tumor, and cerebral edema at ischemia-reperfusion injury.
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US8153327B2 (en) 2005-03-23 2012-04-10 Forschungszentrum Juelich Gmbh Interconnector for high temperature fuel cells
WO2008135448A1 (en) * 2007-05-03 2008-11-13 Neurosearch A/S Beta-keto-amide derivatives useful as ion channel modulators
EP2271341A4 (en) * 2008-05-08 2012-04-18 Univ Nova Southeastern Specific inhibitors for vascular endothelial growth factor receptors
KR101538822B1 (en) 2008-05-08 2015-07-22 노바 사우쓰이스턴 유니버시티 Specific inhibitors for vascular endothelial growth factor receptors

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