JP4324687B2 - Pharmaceuticals containing 2- (3-nitrobenzoyl) benzoic acid derivatives as active ingredients - Google Patents

Description

（式中、Rは、-SR¹（R¹は、水素原子、置換基を有していてもよい脂肪族炭化水素基、または、置換基を有していてもよい芳香族炭化水素基である）、または、-N(R²)₂（R²は、独立して、水素原子、または、置換基を有していてもよい脂肪族炭化水素基であり、少なくとも一方は、置換基を有していてもよい脂肪族炭化水素基である）を表す）で示される化合物またはその塩を有効成分とする医薬を提供するものである。
【００１０】
本発明の医薬は、好ましくは、制癌剤、癌浸潤抑制剤または癌転移抑制剤である。
【００１１】
【発明の実施の形態】
本発明の医薬は、上記一般式で示される化合物またはその塩を有効成分とする。
【００１２】
上記一般式中のＲは、−ＳＲ¹（Ｒ¹は、水素原子、置換基を有していてもよい脂肪族炭化水素基、または、置換基を有していてもよい芳香族炭化水素基である）を表す。
【００１３】
「脂肪族炭化水素基」は、直鎖状、分枝状および環状のいずれでもよく、また、飽和でも不飽和でもよい、炭素数が通常１〜２０の１価の脂肪族炭化水素基を意味し、メチル基、エチル基、プロピル基、オクチル基などのアルキル基、4-ペンテニル基、6-ヘプテニル基、8-デセニル基などのアルケニル基、8-デシニル基、8-ペンタデシニル基、8-ヘプタデシニル基などのアルキニル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などのシクロアルキル基などを例示することができる。
【００１４】
「芳香族炭化水素基」は、ヘテロアリール基をも包含する、炭素数（ヘテロ原子がある場合にはその数も炭素数に含める）が通常５〜２０のアリール基を意味し、フェニル基、ナフチル基、アンスラニル基、ピリジル基、ピリミジニル基、ピラジニル基、イミダゾリル基、ピロリル基、インドリル基、フリル基などを例示することができる。ヘテロアリール基に含まれるヘテロ原子としては、窒素原子、酸素原子、硫黄原子などを例示することができる。ヘテロ原子は複数含まれてもよく、その場合には、複数のヘテロ原子は同じであっても異なっていてもよい。
【００１５】
脂肪族炭化水素基の置換基としては、上記脂肪族炭化水素基、上記芳香族炭化水素基、カルボン酸基、ニトロ基、硫酸基、アミノ基などが挙げられる。
【００１６】
芳香族炭化水素基の置換基としては、上記脂肪族炭化水素基、上記芳香族炭化水素基、カルボン酸基、ニトロ基、硫酸基、アミノ基などが挙げられる。
【００１７】
脂肪族炭化水素基および芳香族炭化水素基は、それぞれ、複数の置換を有していてもよく、その場合、複数の置換基は同じであっても異なっていてもよい。
【００１８】
上記一般式で示される化合物の塩は、薬理上許容しうる塩であれば特に制限はなく、ナトリウム、カリウム、トリエチルアミンなどとの塩を例示することができる。
【００１９】
上記一般式で示される化合物は、公知の方法で得ることができる。例えば、上記一般式においてRの代わりに脱離基を有する化合物は公知であり、この化合物に所望の基を公知の方法に従って導入することにより上記一般式で示される化合物を得ることができる。
【００２０】
上記一般式で示される化合物は、細胞外マトリックス・基底膜への癌細胞の浸潤を抑制する作用を有しており、従って、本発明の医薬は、好ましくは、制癌剤、癌浸潤抑制剤または癌転移抑制剤として用いられる。
【００２１】
本発明の医薬は、上記一般式で示される化合物またはその塩と薬理上許容しうる担体又は賦形剤とからなる組成物としてもよい。
【００２２】
本発明の医薬は、その使用目的や、患者の年齢、体重、感受性、症状の程度などを考慮して、投与経路、投与量、投与頻度、剤形などを適宜決定できる。例えば、本発明の医薬は、経口または非経口的に投与することができる。その投与剤形としては、錠剤、カプセル剤、顆粒剤、散剤、丸剤、シロップ剤、懸濁剤、注射剤などを例示することができる。これらの製剤は、製剤の分野で既知の方法に従って製造することができる。また、本発明の医薬は、他の有効成分と組み合わせて投与してもよい。
【００２３】
【実施例】
以下、本発明を実施例及び試験例によりさらに詳細に説明するが、本発明はこれらに限定されるものではない。
【００２４】
【製造例１】
【化３】

【００２５】
発煙硝酸（30 mL）と酢酸（20 mL）の混合溶液に、2-(4-フルオロベンゾイル)安息香酸（11.0 g、45.0 mmol）を加え、4℃で2時間撹拌後、室温で5時間撹拌した。反応溶液を氷水中に滴下し、生成した沈殿物をクロロホルムで抽出した。クロロホルム層を水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下濃縮し、残渣をアセトンで再結晶し、得られた結晶をメタノールおよびヘキサンで順次洗浄した。粗結晶をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝95／5）で精製して2-(4-フルオロ-3-ニトロベンゾイル)安息香酸（化合物１, 2.8 g, 9.7 mmol, 22%）を白色結晶として得た。
【００２６】
分子量：289
分子式：C₁₄H₈NO₅F
FAB-MS (Neg.): m/z = 288 (M-H)^-
HR-FAB-MS (Neg.): m/z = 288.0311 [288.0308 C₁₄H₇NO₅F, (M-H)^-の計算値]
¹H-NMR (270 MHz, DMSO-d₆): δ = 7.48 (1H, d, J = 7.3 Hz), 7.64-7.80 (3H, m), 7.94 (1H, br-s), 8.02 (1H, d, J = 7.3 Hz), 8.27 (1H, d, J = 6.8 Hz)
【００２７】
【製造例２】
【化４】

【００２８】
2-(4-フルオロ-3-ニトロベンゾイル)安息香酸（226 mg, 781μmol）の1,4-ジオキサン溶液（3 mL）にチオフェノール（86 mg, 781μmol）およびN,N-ジイソプロピルエチルアミン（101 mg, 781μmol）を加え、室温で12時間撹拌した。反応溶液を水とクロロホルムで分液後、クロロホルム層をシリカゲルクロマトグラフィー（クロロホルム／メタノール＝20／1）で精製して2-[3-ニトロ-4-(フェニルチオ)ベンゾイル]安息香酸（化合物２, 292 mg, 770μmol, 98%）を黄色結晶として得た。
【００２９】
分子量：379
分子式：C₂₀H₁₃NO₅S
FAB-MS (Neg.): m/z = 378 (M-H)^-
HR-FAB-MS (Neg.): m/z = 378.0450 [378.0436 C₂₀H₁₂NO₅S, (M-H)^-の計算値]
¹H-NMR (270 MHz, DMSO-d₆): δ = 6.93 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 7.3 Hz), 7.60-7.80 (8H, m), 8.01 (1H, d, J = 7.3 Hz), 8.33 (1H, s), 13.35 (1H, br-s)
【００３０】
【製造例３】
【化５】

【００３１】
2-(4-フルオロ-3-ニトロベンゾイル)安息香酸（217 mg, 749μmol）の1,4-ジオキサン溶液（3 mL）に4-メルカプト安息香酸（117 mg, 759μmol）およびN,N-ジイソプロピルエチルアミン（97 mg, 749μmol）を加え、室温で12時間撹拌した。反応溶液を水とクロロホルムで分液後、クロロホルム層をシリカゲルクロマトグラフィー（クロロホルム／メタノール＝9／1）で精製して2-[4-(4-カルボキシフェニル)チオ-3-ニトロベンゾイル]安息香酸（化合物３, 118 mg, 279μmol, 37%）を黄色結晶として得た。
【００３２】
分子量：423
分子式：C₂₁H₁₃NO₇S
FAB-MS (Neg.): m/z = 422 (M-H)^-
HR-FAB-MS (Neg.): m/z = 422.0334 [422.0334 C₂₁H₁₂NO₇S, (M-H)^-の計算値]
¹H-NMR (270 MHz, DMSO-d₆): δ = 6.94 (1H, d, J = 8.64 Hz), 7.23 (1H, m), 7.52 (2H, m), 7.65 (3H, m), 7.93 (1H, m), 8.03 (2H, d, J = 8.37 Hz), 8.25 (1H, s)
【００３３】
【製造例４】
【化６】

【００３４】
2-(4-フルオロ-3-ニトロベンゾイル)安息香酸（100 mg, 346μmol）の1,4-ジオキサン溶液（3 mL）にメルカプトコハク酸（52 mg, 344μmol）およびN,N-ジイソプロピルエチルアミン（45 mg, 346μmol）を加え、室温で12時間撹拌した。溶媒留去後、水とクロロホルムで分配した。水層をクロロホルムおよび酢酸エチルで抽出後、無水硫酸マグネシウムで乾燥し2-[4-(1,2-ジカルボキシエチル)チオ-3-ニトロベンゾイル]安息香酸（化合物４, 142 mg, 289μmol, 84%）を淡黄色結晶として得た。
【００３５】
分子量：419
分子式：C₁₈H₁₃NO₉S
FAB-MS (Neg.): m/z = 418 (M-H)^-
HR-FAB-MS (Neg.): m/z = 418.0249 [418.0233 C₁₈H₁₂NO₉S, (M-H)^-の計算値]
¹H-NMR (270 MHz, DMSO-d₆): δ = 2.81 (1H, dd, J = 5.67, 17.28 Hz), 2.93 (1H, dd, J = 8.1, 17.28 Hz), 4.47 (1H, dd, J = 5.67, 8.1 Hz), 7.49 (1H, d, J = 7.02 Hz), 7.69 (1H, ddd, J = 1.35, 7.56, 7.56 Hz), 7.76 (1H, ddd, J = 1.35, 7.56, 7.56 Hz), 7.87 (1H, d, J = 8.37 Hz), 7.99 (1H, d, J = 8.37 Hz), 8.01 (1H, d, J = 7.02 Hz), 8.25 (1H, d, J = 1.62 Hz)
【００３６】
【試験例１】
（浸潤阻害活性試験）
文献記載の方法 [A. Albini, et. al., Cancer Res., 47, 3239-3245 (1987)]に準じて行った。すなわち、5μLの基底膜再構成基質マトリゲル（Becton Dickinson Labware）でコートしたポアサイズ8-μmのケモタキセル・チャンバー（クラボウ）を24穴プレートに設置し、ケモタキセル・チャンバー内（上層）にDMEM培地（無血清）で調製した各種細胞浮遊液（5×10⁵ 細胞/mL）を0.2 mL播種し（1×10⁵ 細胞/チャンバー）、24穴プレート内（下層）にDMEM（10% FCS）培養液を0.55 mL添加した。1時間後、上層および下層に各化合物を細胞増殖阻害が起こらない濃度で添加し、37℃、5% CO₂の条件下、24時間インキュベーションした。上層に残った細胞およびマトリゲルを綿棒できれいにふき取り、下層に残った細胞をホルマリン溶液（PBS中0.1%, pH 7.4）で固定後、へマトキシリンで染色した。下層の細胞を顕微鏡で計測し、化合物無添加群をもとに各濃度における阻害活性（％）を下記式により求めた。結果を表１に示す。
【００３７】
【数１】
阻害活性（％）＝ 100−（化合物添加時の浸潤癌細胞数／化合物無添加時の浸潤癌細胞数）×100
【００３８】
【表１】

【００３９】
表１の結果より、化合物２〜４は、ヒト繊維肉腫細胞HT1080細胞、高転移性のマウスメラノーマ細胞B16BL6細胞の両方において、対照に用いたスラミン(suramin)よりも強い浸潤阻害活性を有することが示された。
【００４０】
スラミン(suramin)は抗腫瘍活性、血管新生阻害活性、抗ウィルス活性などが報告されているポリスルホンナフチルウレア化合物で、高転移性のマウスメラノーマ細胞B16BL6細胞の浸潤抑制活性が報告されている[M. Nakajima, et. al., J. Biol. Chem., 266, 9661-9666 (1991)]。また、細胞内受容体ドメインでG-プロテインと受容体の結合を阻害する作用や、Gα-サブユニット活性化の律速段階であるGDP-GTP交換の阻害、逆転写酵素の拮抗阻害、トポイソメラーゼＩおよびII阻害、筋小胞体膜におけるCa²⁺-ATPase阻害、各種成長因子（EGF、PDGF、TGFβなどを含む）の細胞表面への結合阻害、ホスホリパーゼD阻害、ATP結合蛋白質やP2プリン受容体への結合、チロシン脱リン酸化酵素の可逆的・拮抗的阻害作用など多数の生物活性が報告されている。
【００４１】
【発明の効果】
本発明で用いられる2-(3-ニトロベンゾイル)安息香酸誘導体は、優れた癌細胞の浸潤抑制活性を有しており、制癌剤、癌浸潤抑制剤又は癌転移抑制剤として使用できる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an anticancer agent, a cancer infiltration inhibitor, or a cancer metastasis inhibitor.
[0002]
[Prior art]
Recent advances in surgery and radiation therapy have made remarkable progress in the removal of primary cancer. However, most cancer deaths are caused by metastasis, and suppressing cancer metastasis is the most important issue of cancer chemotherapy.
[0003]
Research on the mechanism of metastasis has made rapid progress. Cancer metastasis is a process in which cancer cells leave the primary lesion, infiltrate the extracellular matrix / basement membrane, enter the blood vessel, adhere at a distant site, enter the blood vessel, infiltrate the basement membrane / extracellular matrix, and proliferate. Go through. Among them, the process of infiltration into the extracellular matrix / basement membrane is considered to be an extremely important step because it is performed twice.
[0004]
MMP (matrix metalloprotease) inhibitors are well known as inhibitors of cancer cell extracellular matrix / basement membrane invasion, and many compounds have been synthesized and entered clinical trials. However, what is sufficiently satisfactory in terms of toxicity and effectiveness has not yet been obtained, and a new type of cancer infiltration inhibitor / cancer metastasis inhibitor is required.
[0005]
Regarding 2- (3-nitrobenzoyl) benzoic acid derivatives, there are several reports on biological activity as well as reports on dyes and recording materials. 2- (4-Amino-3-nitrobenzoyl) benzoic acid has been reported as an anthelmintic intermediate (see Patent Document 1). Also, 2- [3-nitro-4- [4- (2-oxo-2H-3,1-benzoxazin-1 (4H) -yl) -1-piperidinyl] benzoyl] benzoic acid is an antagonist of the purine receptor P2X7 As one of these, it has been reported as a therapeutic drug for inflammation, immune disease and heart disease (see Patent Document 2). In addition, 2- (4-chloro-3-nitrobenzoyl) benzoic acid has been reported as one of the compounds that regulates immunology by regulating the activity of tyrosine kinase p56lck (see Patent Document 3). However, there has been no report on the invasion inhibitory activity of cancer cells.
[0006]
[Patent Document 1]
Soviet Patent No. 1095583 [Patent Document 2]
International Publication No. 01/044213 Pamphlet [Patent Document 3]
International Publication No. 02/010191 Pamphlet [0007]
[Problems to be solved by the invention]
An object of this invention is to provide the novel pharmaceutical which can suppress the invasion of a cancer cell, especially an anticancer agent, a cancer infiltration inhibitor, or a cancer metastasis inhibitor.
[0008]
[Means for Solving the Problems]
The present inventors consider that a substance that suppresses invasion of cancer cells into the extracellular matrix / basement membrane is likely to be an excellent anticancer agent, and as a result of searching for compounds that suppress invasion of cancer cells, The present inventors have found that 2- (3-nitrobenzoyl) benzoic acid derivatives strongly suppress cancer cell invasion and have completed the present invention.
[0009]
That is, the present invention has the following general formula:

(In the formula, R is —SR ¹ (R ¹ is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or an aromatic hydrocarbon group which may have a substituent. Or -N (R ² ) ₂ (R ² is independently a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, and at least one of the Which is an aliphatic hydrocarbon group which may be present) or a salt thereof as an active ingredient.
[0010]
The medicament of the present invention is preferably an anticancer agent, a cancer infiltration inhibitor or a cancer metastasis inhibitor.
[0011]
DETAILED DESCRIPTION OF THE INVENTION
The medicament of the present invention comprises a compound represented by the above general formula or a salt thereof as an active ingredient.
[0012]
R in the above general formula is -SR ¹ (R ¹ is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or an aromatic hydrocarbon group which may have a substituent. Is ) .
[0013]
“Aliphatic hydrocarbon group” means a monovalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may be linear, branched or cyclic, and may be saturated or unsaturated. Alkyl groups such as methyl, ethyl, propyl and octyl groups, alkenyl groups such as 4-pentenyl group, 6-heptenyl group and 8-decenyl group, 8-decynyl group, 8-pentadecynyl group and 8-heptadecynyl. Examples thereof include alkynyl groups such as a group, cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
[0014]
“Aromatic hydrocarbon group” means an aryl group having 5 to 20 carbon atoms (including the number of carbon atoms in the case where there are heteroatoms), including a heteroaryl group, usually a phenyl group, Examples thereof include a naphthyl group, anthranyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, imidazolyl group, pyrrolyl group, indolyl group, and furyl group. Examples of the hetero atom contained in the heteroaryl group include a nitrogen atom, an oxygen atom, and a sulfur atom. A plurality of heteroatoms may be included, and in this case, the plurality of heteroatoms may be the same or different.
[0015]
Examples of the substituent of the aliphatic hydrocarbon group include the aliphatic hydrocarbon group, the aromatic hydrocarbon group, a carboxylic acid group, a nitro group, a sulfuric acid group, and an amino group.
[0016]
Examples of the substituent of the aromatic hydrocarbon group include the aliphatic hydrocarbon group, the aromatic hydrocarbon group, a carboxylic acid group, a nitro group, a sulfuric acid group, and an amino group.
[0017]
The aliphatic hydrocarbon group and the aromatic hydrocarbon group may each have a plurality of substitutions, and in this case, the plurality of substituents may be the same or different.
[0018]
The salt of the compound represented by the above general formula is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include salts with sodium, potassium, triethylamine and the like.
[0019]
The compound represented by the above general formula can be obtained by a known method. For example, a compound having a leaving group instead of R in the above general formula is known, and a compound represented by the above general formula can be obtained by introducing a desired group into this compound according to a known method.
[0020]
The compound represented by the above general formula has an action of suppressing the invasion of cancer cells into the extracellular matrix / basement membrane. Therefore, the medicament of the present invention is preferably an anticancer agent, a cancer infiltration inhibitor or a cancer. Used as a metastasis inhibitor.
[0021]
The medicament of the present invention may be a composition comprising a compound represented by the above general formula or a salt thereof and a pharmacologically acceptable carrier or excipient.
[0022]
The administration route, dosage, administration frequency, dosage form, and the like of the pharmaceutical of the present invention can be appropriately determined in consideration of the purpose of use and the age, weight, sensitivity, and symptom level of the patient. For example, the medicament of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, pills, syrups, suspensions, injections and the like. These preparations can be manufactured according to methods known in the field of preparations. In addition, the medicament of the present invention may be administered in combination with other active ingredients.
[0023]
【Example】
EXAMPLES Hereinafter, although an Example and a test example demonstrate this invention further in detail, this invention is not limited to these.
[0024]
[Production Example 1]
[Chemical 3]

[0025]
2- (4-Fluorobenzoyl) benzoic acid (11.0 g, 45.0 mmol) was added to a mixed solution of fuming nitric acid (30 mL) and acetic acid (20 mL), stirred at 4 ° C for 2 hours, and then stirred at room temperature for 5 hours. did. The reaction solution was dropped into ice water, and the generated precipitate was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from acetone, and the resulting crystals were washed successively with methanol and hexane. The crude crystals were purified by silica gel column chromatography (chloroform / methanol = 95/5) to give 2- (4-fluoro-3-nitrobenzoyl) benzoic acid (compound 1, 2.8 g, 9.7 mmol, 22%) as white crystals. Got as.
[0026]
Molecular weight: 289
Molecular formula: C ₁₄ H ₈ NO ₅ F
FAB-MS (Neg.): M / z = 288 (MH) ^-
HR-FAB-MS (Neg.): M / z = 288.0311 [calculated value of 288.0308 C ₁₄ H ₇ NO ₅ F, (MH) ^- ]
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ = 7.48 (1H, d, J = 7.3 Hz), 7.64-7.80 (3H, m), 7.94 (1H, br-s), 8.02 (1H, d, J = 7.3 Hz), 8.27 (1H, d, J = 6.8 Hz)
[0027]
[Production Example 2]
[Formula 4]

[0028]
2- (4-Fluoro-3-nitrobenzoyl) benzoic acid (226 mg, 781 μmol) in 1,4-dioxane (3 mL) was added to thiophenol (86 mg, 781 μmol) and N, N-diisopropylethylamine (101 mg). , 781 μmol) and stirred at room temperature for 12 hours. After separating the reaction solution with water and chloroform, the chloroform layer was purified by silica gel chromatography (chloroform / methanol = 20/1) to give 2- [3-nitro-4- (phenylthio) benzoyl] benzoic acid (compound 2, 292 mg, 770 μmol, 98%) was obtained as yellow crystals.
[0029]
Molecular weight: 379
Molecular formula: C ₂₀ H ₁₃ NO ₅ S
FAB-MS (Neg.): M / z = 378 (MH) ^-
HR-FAB-MS (Neg.): M / z = 378.0450 [calculated value of 378.0436 C ₂₀ H ₁₂ NO ₅ S, (MH) ^- ]
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ = 6.93 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 7.3 Hz), 7.60-7.80 (8H, m), 8.01 (1H, d, J = 7.3 Hz), 8.33 (1H, s), 13.35 (1H, br-s)
[0030]
[Production Example 3]
[Chemical formula 5]

[0031]
2- (4-Fluoro-3-nitrobenzoyl) benzoic acid (217 mg, 749 μmol) in 1,4-dioxane solution (3 mL) and 4-mercaptobenzoic acid (117 mg, 759 μmol) and N, N-diisopropylethylamine (97 mg, 749 μmol) was added, and the mixture was stirred at room temperature for 12 hours. After separating the reaction solution with water and chloroform, the chloroform layer was purified by silica gel chromatography (chloroform / methanol = 9/1) to give 2- [4- (4-carboxyphenyl) thio-3-nitrobenzoyl] benzoic acid. (Compound 3, 118 mg, 279 μmol, 37%) was obtained as yellow crystals.
[0032]
Molecular weight: 423
Molecular formula: C ₂₁ H ₁₃ NO ₇ S
FAB-MS (Neg.): M / z = 422 (MH) ^-
HR-FAB-MS (Neg.): M / z = 422.0334 [calculated value of 422.0334 C ₂₁ H ₁₂ NO ₇ S, (MH) ^- ]
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ = 6.94 (1H, d, J = 8.64 Hz), 7.23 (1H, m), 7.52 (2H, m), 7.65 (3H, m), 7.93 (1H, m), 8.03 (2H, d, J = 8.37 Hz), 8.25 (1H, s)
[0033]
[Production Example 4]
[Chemical 6]

[0034]
2- (4-Fluoro-3-nitrobenzoyl) benzoic acid (100 mg, 346 μmol) in 1,4-dioxane (3 mL) was added mercaptosuccinic acid (52 mg, 344 μmol) and N, N-diisopropylethylamine (45 mg, 346 μmol) was added, and the mixture was stirred at room temperature for 12 hours. After the solvent was distilled off, it was partitioned with water and chloroform. The aqueous layer was extracted with chloroform and ethyl acetate, dried over anhydrous magnesium sulfate, and 2- [4- (1,2-dicarboxyethyl) thio-3-nitrobenzoyl] benzoic acid (Compound 4, 142 mg, 289 μmol, 84 %) As pale yellow crystals.
[0035]
Molecular weight: 419
Molecular formula: C ₁₈ H ₁₃ NO ₉ S
FAB-MS (Neg.): M / z = 418 (MH) ^-
HR-FAB-MS (Neg.): M / z = 418.0249 [calculated value of 418.0233 C ₁₈ H ₁₂ NO ₉ S, (MH) ^- ]
¹ H-NMR (270 MHz, DMSO-d ₆ ): δ = 2.81 (1H, dd, J = 5.67, 17.28 Hz), 2.93 (1H, dd, J = 8.1, 17.28 Hz), 4.47 (1H, dd, J = 5.67, 8.1 Hz), 7.49 (1H, d, J = 7.02 Hz), 7.69 (1H, ddd, J = 1.35, 7.56, 7.56 Hz), 7.76 (1H, ddd, J = 1.35, 7.56, 7.56 Hz) ), 7.87 (1H, d, J = 8.37 Hz), 7.99 (1H, d, J = 8.37 Hz), 8.01 (1H, d, J = 7.02 Hz), 8.25 (1H, d, J = 1.62 Hz)
[0036]
[Test Example 1]
(Infiltration inhibition activity test)
It was performed according to the method described in the literature [A. Albini, et. Al., Cancer Res., 47, 3239-3245 (1987)]. Specifically, an 8-μm pore-size chemotaxel chamber (Kurabo) coated with 5 μL of basement membrane reconstitution matrix Matrigel (Becton Dickinson Labware) was placed in a 24-well plate, and DMEM medium (serum-free) was placed in the chemotaxel chamber (upper layer). ) Seeded with 0.2 mL of various cell suspensions (5 × 10 ⁵ cells / mL) prepared in 1) (1 × 10 ⁵ cells / chamber) and placed DMEM (10% FCS) culture solution in a 24-well plate (lower layer) with 0.55 mL was added. After 1 hour, each compound was added to the upper layer and the lower layer at a concentration at which cell growth inhibition did not occur, and incubated at 37 ° C. under 5% CO ₂ for 24 hours. Cells remaining in the upper layer and Matrigel were wiped off with a cotton swab, and the cells remaining in the lower layer were fixed with a formalin solution (0.1% in PBS, pH 7.4) and then stained with hematoxylin. The cells in the lower layer were measured with a microscope, and the inhibitory activity (%) at each concentration was determined according to the following formula based on the group without compound addition. The results are shown in Table 1.
[0037]
[Expression 1]
Inhibitory activity (%) = 100− (number of invasive cancer cells when compound is added / number of invasive cancer cells when compound is not added) × 100
[0038]
[Table 1]

[0039]
From the results of Table 1, compounds 2 to 4 have stronger invasion inhibitory activity than suramin used as a control in both human fibrosarcoma cells HT1080 cells and highly metastatic mouse melanoma cells B16BL6 cells. Indicated.
[0040]
Suramin is a polysulfone naphthylurea compound that has been reported to have antitumor activity, angiogenesis inhibitory activity, antiviral activity, etc., and has been reported to inhibit the invasion of highly metastatic mouse melanoma cells B16BL6 cells [M. Nakajima, et. Al., J. Biol. Chem., 266, 9661-9666 (1991)]. In addition, it inhibits the binding of G-protein and receptor in the intracellular receptor domain, inhibits the GDP-GTP exchange, which is the rate-limiting step of Gα-subunit activation, competitive inhibition of reverse transcriptase, topoisomerase I and II inhibition, Ca ²⁺ -ATPase inhibition in the sarcoplasmic reticulum membrane, inhibition of binding of various growth factors (including EGF, PDGF, TGFβ, etc.) to the cell surface, phospholipase D inhibition, ATP binding protein and P2 purine receptor Numerous biological activities such as binding and reversible and antagonistic inhibitory effects of tyrosine phosphatases have been reported.
[0041]
【The invention's effect】
The 2- (3-nitrobenzoyl) benzoic acid derivative used in the present invention has excellent cancer cell invasion inhibitory activity and can be used as an anticancer agent, cancer invasion inhibitor or cancer metastasis inhibitor.

Claims (3)

The following general formula

(In the formula, R is —SR ¹ (R ¹ is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or an aromatic hydrocarbon group which may have a substituent. compounds represented by the representative) some) or anticancer agent to a salt thereof as an active ingredient. The following general formula

(In the formula, R is —SR ¹ (R ¹ is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or an aromatic hydrocarbon group which may have a substituent. A compound that is represented by
Cancer infiltration inhibitor which uses a thing or its salt as an active ingredient . The following general formula

(In the formula, R is —SR ¹ (R ¹ is a hydrogen atom, an aliphatic hydrocarbon group which may have a substituent, or an aromatic hydrocarbon group which may have a substituent. A cancer metastasis inhibitor comprising the compound represented by (1)) or a salt thereof as an active ingredient .