JP2007290981A - COUMARIN COMPOUND FOR INHIBITING INDUCIBLE NITRIC MONOXIDE SYNTHASE (iNOS) - Google Patents

COUMARIN COMPOUND FOR INHIBITING INDUCIBLE NITRIC MONOXIDE SYNTHASE (iNOS) Download PDF

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JP2007290981A
JP2007290981A JP2006118234A JP2006118234A JP2007290981A JP 2007290981 A JP2007290981 A JP 2007290981A JP 2006118234 A JP2006118234 A JP 2006118234A JP 2006118234 A JP2006118234 A JP 2006118234A JP 2007290981 A JP2007290981 A JP 2007290981A
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coumarin compound
inos
group
substituent
inducible nitric
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Tsutomu Ishikawa
勉 石川
Shingo Yano
眞吾 矢野
Tomonori Nakamura
智徳 中村
Takuya Kumamoto
卓哉 熊本
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Chiba University NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new coumarin compound having stronger activity. <P>SOLUTION: The coumarin compound for inhibiting an inducible nitric monoxide synthase is represented by formula (1) (X is a hydrogen atom, a hydrocarbon group which may contain a substituent group or an aryl group which may contain a substituent group; R<SB>1</SB>and R<SB>2</SB>are each a hydrocarbon group which may contain a substituent group; Y and Z are each a hydrogen atom or a hydrocarbon group which may contain a substituent group; R<SB>1</SB>, R<SB>2</SB>, Y and Z may be each different or the same). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

本発明は、クマリン化合物に関するものであり、さらに詳しくは、アレルギー性気道炎、肺炎、関節炎、血管炎、膵β細胞の自己破壊、臓器移植時の同種移植片急性拒絶反応など数々の炎症疾患を抑制することを可能とするｉＮＯＳ阻害活性を有するものに関する。   The present invention relates to a coumarin compound. More specifically, the present invention relates to various inflammatory diseases such as allergic airway inflammation, pneumonia, arthritis, vasculitis, pancreatic β-cell self-destruction, and allograft acute rejection during organ transplantation. The present invention relates to those having iNOS inhibitory activity that can be suppressed.

一酸化窒素（ＮＯ）は、各種生体維持機構に関わる必須な内因性物質である一方、炎症等の原因物質にもなるというマイナス面を併せもつ。このマイナス面に働くＮＯの産生には誘導型一酸化窒素合成酵素（ｉＮＯＳ）が関わっていると考えられており、ｉＮＯＳを阻害する化合物を見出すことは、新規抗炎症薬の創製につながると考えられている。   While nitric oxide (NO) is an essential endogenous substance involved in various biological maintenance mechanisms, it also has a negative aspect of becoming a causative substance such as inflammation. It is thought that inducible nitric oxide synthase (iNOS) is involved in the production of NO that works on this negative side, and finding compounds that inhibit iNOS will lead to the creation of new anti-inflammatory drugs. It has been.

ｉＮＯＳ阻害活性を示す天然化合物としてはショウガ科ウコンから単離されたクルクミンや大豆のイソフラボンが有名であるが、クマリン化合物においてもその報告例が数例見られる（下記非特許文献公知文献 １乃至５参照）。   As natural compounds exhibiting iNOS inhibitory activity, curcumin isolated from ginger turmeric and soy isoflavone are well known, but there are several reports of coumarin compounds (Non-Patent Documents 1 to 5 listed below). reference).

Ｊ．Ａｇｒｉｃ．Ｆｏｏｄ Ｃｈｅｍ．、１９９９年、４７巻、３３３〜３３９頁J. et al. Agric. Food Chem. 1999, 47, 333-339. Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．、２０００年、８巻、２７０１〜２７０７頁Bioorg. Med. Chem. 2000, Vol. 8, pp. 2701-2707 Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．、２００４年、５２巻、１２１５〜１２１８頁Chem. Pharm. Bull. 2004, 52, 1215-1218. Ｊ．Ｎａｔ．Ｃｈｅｍ．、２００４年、６７巻、４３２〜４３６頁J. et al. Nat. Chem. 2004, 67, 432-436. Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．、２００５年、１３巻、２７２３〜２７３９頁Bioorg. Med. Chem. 2005, vol. 13, p. 2723-2739.

しかしながら、上記各文献に記載のｉＮＯＳ阻害活性を示す物質は、その作用の強さに関し解決すべき問題点を残しており、さらに活性が強い新規クマリン化合物の出現が望まれている。   However, the substances showing iNOS inhibitory activity described in each of the above documents still have problems to be solved regarding the strength of their action, and the appearance of a novel coumarin compound having a higher activity is desired.

本発明者らは、熱帯産植物についてｉＮＯＳ阻害活性を指標にしたスクリーング試験を行ったところ、ミカン科 Ｃｌａｕｓｅｎａ植物に強い阻害活性を認め、その活性本体がクマリン化合物であることを解明し、本発明を完成するに至った。   The present inventors conducted a screening test using an iNOS inhibitory activity as an index for a tropical plant. As a result, it was found that the Citrusaceae Clausena plant showed a strong inhibitory activity, and that the active body was a coumarin compound. The invention has been completed.

即ち、本発明の一形態に係る誘導型一酸化窒素合成酵素を阻害するクマリン化合物は、下記式（１）で示される。

（ここでＸは水素原子、置換基を有してよい炭化水素基又は置換基を有してよいアリール基であり、Ｒ１及びＲ２は、置換基を有していてもよい炭化水素基であり、Ｙ及びＺは、水素原子又は置換基を有してもよい炭化水素基である。Ｒ１、Ｒ２、Ｙ及びＺは、それぞれ同じであっても良いし異なっていてもよい。） That is, a coumarin compound that inhibits inducible nitric oxide synthase according to one embodiment of the present invention is represented by the following formula (1).

(Where X is a hydrogen atom, a hydrocarbon group that may have a substituent, or an aryl group that may have a substituent, and R 1 and R 2 are hydrocarbon groups that may have a substituent. Y and Z are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R 1 , R 2 , Y and Z may be the same or different from each other. )

また本発明の他の一形態に係る誘導型一酸化窒素合成酵素を阻害するクマリン化合物は、下記式（２）又は（３）で示される。
A coumarin compound that inhibits inducible nitric oxide synthase according to another embodiment of the present invention is represented by the following formula (2) or (3).

本発明によれば、よりｉＮＯＳ阻害活性の強い新規クマリン化合物を提供することができ、更に、それを用いたｉＮＯＳ阻害剤を提供することができる。   ADVANTAGE OF THE INVENTION According to this invention, the novel coumarin compound with stronger iNOS inhibitory activity can be provided, and also the iNOS inhibitor using the same can be provided.

以下、本発明を実施するための最良の形態について、図面及び表を用いて説明する。ただし、本発明は多くの異なる態様による実施が可能であって、以下に示す実施形態、実施例に狭く限定されるものではない。   The best mode for carrying out the present invention will be described below with reference to the drawings and tables. However, the present invention can be implemented in many different modes and is not limited to the embodiments and examples shown below.

実施形態に係るクマリン化合物は、下記式（１）で表わされる５，７−ジオキシクマリン化合物となっている。
The coumarin compound according to the embodiment is a 5,7-dioxycoumarin compound represented by the following formula (1).

なお、上記式（１）中、Ｘは水素原子、置換基を有してよい炭化水素基又は置換基を有してよいアリール基である。炭化水素基の場合、炭素の数は限定されるわけではないが１〜４の範囲にあることが好ましい。なおここで置換基としては限定されるわけではないが、例えばアルデヒド基、ケトン基、ヒドロキシル基、アミノ基、アルコキシ基、カルボキシル基、アルコキシカルボニル基、カルボニルオキシ基、ハロゲン原子をあげることができる。   In the above formula (1), X represents a hydrogen atom, a hydrocarbon group which may have a substituent, or an aryl group which may have a substituent. In the case of a hydrocarbon group, the number of carbons is not limited but is preferably in the range of 1-4. Here, the substituent is not limited, and examples thereof include an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a carbonyloxy group, and a halogen atom.

また、上記式（１）中、Ｒ１及びＲ２は、置換基を有していてもよい炭化水素基であり、炭素の数は限定されるわけではないが１〜４の範囲が好ましい。なおここで炭化水素基の例としては限定されるわけではないが例えばメチル、エチル、プロピル、ブチル、イソブチル、ｔ−ブチルをあげることができる。なおここで置換基としては限定されるわけではないが、例えばアルデヒド基、ケトン基、ヒドロキシル基、アミノ基、アルコキシ基、カルボキシル基、アルコキシカルボニル基、カルボニルオキシ基、ハロゲン原子をあげることができる。 Moreover, in said formula (1), R < 1 > and R < 2 > is the hydrocarbon group which may have a substituent, Although the number of carbon is not necessarily limited, The range of 1-4 is preferable. Here, examples of the hydrocarbon group are not limited, but examples thereof include methyl, ethyl, propyl, butyl, isobutyl, and t-butyl. Here, the substituent is not limited, and examples thereof include an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a carbonyloxy group, and a halogen atom.

また、上記式（１）中、Ｙ及びＺは、水素原子又は置換基を有してもよい炭化水素基であり、ＹとＺは同じであっても異なっていてもよい。Ｙ及びＺが炭化水素である場合、炭化水素基の炭素の数は限定されるわけではないが２〜５の範囲が好ましく、炭化水素基中に二重結合を含んでいてもよい。なお、ここで置換基としては限定されるわけではないが、例えばアルデヒド基、ケトン基、ヒドロキシル基、アミノ基、アルコキシ基、カルボキシル基、アルコキシカルボニル基、カルボニルオキシ基、ハロゲン原子をあげることができる。   Moreover, in said formula (1), Y and Z are the hydrocarbon groups which may have a hydrogen atom or a substituent, and Y and Z may be the same or different. When Y and Z are hydrocarbons, the number of carbons of the hydrocarbon group is not limited, but is preferably in the range of 2 to 5, and the hydrocarbon group may contain a double bond. Here, the substituent is not limited, and examples thereof include an aldehyde group, a ketone group, a hydroxyl group, an amino group, an alkoxy group, a carboxyl group, an alkoxycarbonyl group, a carbonyloxy group, and a halogen atom. .

また、上記式（１）で示される５，７−ジオキシクマリン化合物を入手する方法としては、限定されることなく種々の方法で入手可能であり、例えば天然の植物、より望ましくはミカン科Ｔｏｄｄａｌｉａ属植物から抽出することができるし、“Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．、１９８年、３１巻、３３３０〜３３３３頁”、“薬学雑誌、１９９１年、１１１巻、３６５〜３７５頁”や“Ｊ．Ｏｒｇ．Ｃｈｅｍ．、２００４年、６９巻、２７６０〜２７６７頁”等に記載の方法を適用することによっても製造することができる。   In addition, the method for obtaining the 5,7-dioxycoumarin compound represented by the above formula (1) is not limited and can be obtained by various methods, for example, natural plants, more preferably Citrus family Toddalia. It can be extracted from the genus plant, “Chem. Pharm. Bull., 198, 31, 3330-3333”, “Pharmaceutical Journal, 1991, 111, 365-375” and “J. Org”. Chem., 2004, Vol. 69, pages 2760 to 2767 ”and the like.

以上、本実施形態により新規なｉＮＯＳ阻害活性を有するクマリン化合物を提供することができる。   As described above, the present embodiment can provide a coumarin compound having a novel iNOS inhibitory activity.

また、本実施形態のクマリン化合物はｉＮＯＳ阻害剤に用いることができる。ｉＮＯＳ阻害剤は、上記クマリン化合物の他、薬学的に許容しうる通常の担体、結合剤、安定化剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤等の各種調剤用配合成分を添加することができる。またこのｉＮＯＳ阻害剤を用いる予防若しくは治療方法としては、患者の性別・体重・症状に見合った適切な投与量を経口的又は非経口的に投与することができる。即ち通常用いられる投与形態、例えば粉末、顆粒、カプセル剤、シロップ剤、懸濁液等の剤型で経口的に投与することができ、又は例えば溶液、乳剤、懸濁液等の剤型にしたものを注射の型で非経口投与することができる他、スプレー剤の型で鼻腔内投与することもできる。   Moreover, the coumarin compound of this embodiment can be used for an iNOS inhibitor. iNOS inhibitors include the above-mentioned coumarin compounds, pharmaceutically acceptable ordinary carriers, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, solubilizers, solubilizers, Various preparation blending components such as isotonic agents can be added. As a preventive or therapeutic method using this iNOS inhibitor, an appropriate dose suitable for the sex, weight, and symptoms of the patient can be administered orally or parenterally. That is, it can be administered orally in commonly used dosage forms, such as powders, granules, capsules, syrups, suspensions, etc., or, for example, in the form of solutions, emulsions, suspensions, etc. In addition to being able to be administered parenterally in the form of injections, it can also be administered intranasally in the form of sprays.

ここで、上記実施形態に係るクマリン化合物について効果について説明する。もちろん、以下の例によって発明が限定されることがないのはいうまでもない。   Here, an effect is demonstrated about the coumarin compound which concerns on the said embodiment. Of course, it goes without saying that the invention is not limited by the following examples.

（被験サンプルの調製）
本発明者らは、熱帯産植物についてエタノールエキスをジメチルスルホキシドに溶解して濃厚溶液（１ｍｇ／ｍｌ）を調製し、５μｇ／ｍｌに希釈してｉＮＯＳ阻害活性を指標にしたスクリーング試験を行ったところ、ミカン科 Ｃｌａｕｓｅｎａ植物に強い阻害活性を認め、その活性本体がクマリン化合物であることを解明した。そこで、複数のクマリン化合物を用意し、そのそれぞれをジメチルスルホキシドに溶解して濃厚溶液（１μＭ）として調製し、適宜希釈（１〜１００ｎＭ）し被験サンプルとした。 (Preparation of test sample)
The present inventors conducted a screening test on tropical plants using ethanol extract dissolved in dimethyl sulfoxide to prepare a concentrated solution (1 mg / ml), diluted to 5 μg / ml and using iNOS inhibitory activity as an index. However, a strong inhibitory activity was recognized in the Citrus Clauena plant, and it was elucidated that the active body is a coumarin compound. Therefore, a plurality of coumarin compounds were prepared, and each of them was dissolved in dimethyl sulfoxide to prepare a concentrated solution (1 μM), which was appropriately diluted (1 to 100 nM) to prepare a test sample.

（１）Ｉｍｍｕｎｏｂｌｏｔ Ａｎａｌｙｓｉｓ
マウスマクロファージＲＡＷ２６４．７細胞を２４ｗｅｌｌ ｐｌａｔｅに播種し、セミコンフルエントになるまで培養後、無血清培地に変え、ＬＰＳ（５０ｎｇ／ｍｌ）及び上記被験サンプルの添加を行った。１６時間のインキュベート後、細胞をホモジナイズしタンパク定量の後ウエスタンブロットを行い、ｉＮＯＳおよびＴＮＦ−αタンパクの発現量を測定した。
（２）ＮＯ ｍｅａｓｕｒｅｍｅｎｔ
ＬＰＳ刺激によるＮＯ発生（ｉＮＯＳ酵素活性）に対する影響についてはグリース−ロメン法（Ｇｒｉｅｓｓ−Ｒｏｍｉｊｎ’ｓ ｍｅｔｈｏｄ）を用いて測定した。すなわち、１６時間培養後の各ｗｅｌｌの培養液を１００μｌずつ９６ｗｅｌｌ ｐｌａｔｅに移し、公定法に従いグリースロミイン亜硝酸試薬（４０ｍｇ／ｍｌ）を１００μｌずつ添加し、よく撹拌して室温下で１５分間静置した。その後、マイクロプレートリーダーを用いて５５０ｎｍにおける吸光度を測定した。なお、標準液として亜硝酸ナトリウム溶液を用い、培地で希釈して検量線を作成し、サンプルのＮＯ濃度を算出した。
（結果、考察）
ＬＰＳ刺激により過剰発現したｉＮＯＳは、Ｃｌａｕｓｅｎａ ｇｌａｕｉｌｌａｕｍｉｎｉｉの由来のｘａｎｔｈｏｘｙｌｅｔｉｎ（下記式（Ａ）に示される化合物参照）により、濃度依存的に有意に抑制されることを確認した。またこのｘａｔｈｏｘｙｌｅｔｉｎは他の炎症関連因子であるＴＮＦ−α発現、ＮＯ産生も濃度依存的に抑制した。なお式（Ａ）で示されるｘａｎｔｈｏｘｙｌｅｔｉｎは構造にクマリン骨格を含む化合物であって、クマリン類に関しては、抗腫瘍活性、感作促進、冠状血管拡張、抗菌作用、そして抗炎症などの生理・薬理作用が報告されている。
(1) Immunoblot Analysis
Mouse macrophage RAW264.7 cells were seeded on a 24 well plate, cultured until semi-confluent, then changed to serum-free medium, and LPS (50 ng / ml) and the test sample were added. After 16 hours of incubation, the cells were homogenized, protein quantification followed by Western blotting, and the expression levels of iNOS and TNF-α protein were measured.
(2) NO measurement
About the influence with respect to NO generation | occurrence | production (iNOS enzyme activity) by LPS irritation | stimulation, it measured using the Grease-Romijn's method. That is, 100 μl of the culture solution of each well after 16 hours of culture was transferred to a 96-well plate, 100 μl of greaselomiine nitrite reagent (40 mg / ml) was added in accordance with the official method, stirred well, and allowed to stand at room temperature for 15 minutes. I put it. Thereafter, the absorbance at 550 nm was measured using a microplate reader. A sodium nitrite solution was used as a standard solution, diluted with a medium to prepare a calibration curve, and the NO concentration of the sample was calculated.
(Result, discussion)
It was confirmed that iNOS overexpressed by LPS stimulation was significantly suppressed in a concentration-dependent manner by xanthoxyletin (see the compound represented by the following formula (A)) derived from Clausena glauillaminii. The xathoxyletin also inhibited other inflammation-related factors such as TNF-α expression and NO production in a concentration-dependent manner. The xanthoxyletin represented by the formula (A) is a compound containing a coumarin skeleton in the structure. Regarding coumarins, physiological and pharmacological actions such as antitumor activity, sensitization promotion, coronary vasodilation, antibacterial action, and anti-inflammatory action Has been reported.

そこで、クマリン系化合物１５０種についてｉＮＯＳ発現抑制に対するスクリーニングを行ったところ、少なくとも下記（２）、（３）で示される２種類のクマリン化合物（以下、それぞれを化合物（２）、化合物（３）という。）がｘａｎｔｈｏｘｙｌｅｔｉｎよりも強いｉＮＯＳ発現抑制作用を示すことを確認した。この結果を下記表１に示す。なお、表１は、クマリン化合物をジメチルスルホキシドに溶解した濃厚溶液（１μＭ）を１ｎＭまで希釈したものの結果である。
Therefore, when screening for iNOS expression suppression was performed on 150 coumarin compounds, at least two coumarin compounds represented by the following (2) and (3) (hereinafter referred to as compound (2) and compound (3), respectively): ) Was confirmed to exhibit a stronger iNOS expression inhibitory action than xanthoxyletin. The results are shown in Table 1 below. Table 1 shows the results of diluting a concentrated solution (1 μM) obtained by dissolving a coumarin compound in dimethyl sulfoxide to 1 nM.

また、上記化合物（２）、化合物（３）は、炎症性サイトカインの１種であるＴＮＦ−αのタンパク発現も比較的強く抑制することも分かった。この結果を下記表２に示しておく。なお、表２は、クマリン化合物をジメチルスルホキシドに溶解した濃厚溶液（１μＭ）を１ｎＭまで希釈したものの結果である。
It was also found that the compounds (2) and (3) relatively strongly suppressed the protein expression of TNF-α, which is one kind of inflammatory cytokine. The results are shown in Table 2 below. Table 2 shows the results of diluting a concentrated solution (1 μM) obtained by dissolving a coumarin compound in dimethyl sulfoxide to 1 nM.

また、上記ｉＮＯＳのタンパク発現抑制の結果を受け、上記化合物（２）、（３）についてＮＯの発生量（ｉＮＯＳ酵素活性）に対する作用を検討したところ、ｉＮＯＳ発現抑制活性の強度を反映するＮＯ発生抑制作用を観察することができた。この結果を図１に示す。この結果によると、クマリン化合物の濃度が３０μＭ以上であると顕著にＮＯ発生抑制を抑制できることがわかる。一方、細胞への毒性を考慮すると１００μＭ以下であることが望ましく、上記の結果から、狭く限定されるわけではないが、クマリン化合物の濃度としては２０μＭ以上１００μＭ以下の範囲にあることが望ましく、更に望ましくは３０μＭ以上５０μＭ以下の範囲内であると考えられる。   Moreover, when the effect | action with respect to the generation amount (iNOS enzyme activity) of NO was investigated about the said compound (2) and (3) based on the result of the protein expression suppression of said iNOS, NO generation | occurrence | production reflecting the intensity | strength of iNOS expression suppression activity was examined. The inhibitory effect could be observed. The result is shown in FIG. According to this result, it can be seen that when the concentration of the coumarin compound is 30 μM or more, the suppression of NO generation can be remarkably suppressed. On the other hand, considering the toxicity to cells, it is preferably 100 μM or less. From the above results, the concentration of the coumarin compound is desirably in the range of 20 μM or more and 100 μM or less. Desirably, it is considered to be within the range of 30 μM or more and 50 μM or less.

以上により、活性が強い新規クマリン化合物を提供することができることが確認でき、特に、上記化合物の相関性から、上記式（１）で示されるクマリン化合物が有用であると結論付けることができた。   From the above, it was confirmed that a novel coumarin compound having strong activity could be provided, and it was concluded that the coumarin compound represented by the above formula (1) was particularly useful from the correlation of the above compound.

以上の通り、本発明に係るクマリン化合物は、抗アレルギー性気道炎活性、抗肺炎活性、抗関節炎活性、抗血管炎活性、膵細胞の自己破壊阻害、同種移植片急性拒絶反応阻害を有すると期待され、数々の炎症疾患を抑制する薬（抗炎症薬）として産業上の利用可能性がある。   As described above, the coumarin compound according to the present invention is expected to have antiallergic airway inflammation activity, antipneumonia activity, antiarthritis activity, antiangiitis activity, pancreatic cell self-destruction inhibition, allograft acute rejection inhibition. It has industrial applicability as a drug that suppresses numerous inflammatory diseases (anti-inflammatory drug).

実施例に係るクマリン化合物のｉＮＯＳ酵素活性を示す図。The figure which shows the iNOS enzyme activity of the coumarin compound which concerns on an Example.

Claims (4)

下記式（１）で示される誘導型一酸化窒素合成酵素を阻害するクマリン化合物。
（ここでＸは水素原子、置換基を有してよい炭化水素基又は置換基を有してよいアリール基であり、Ｒ１及びＲ２は、置換基を有していてもよい炭化水素基であり、Ｙ及びＺは、水素原子又は置換基を有してもよい炭化水素基である。Ｒ１、Ｒ２、Ｙ及びＺは、それぞれ同じであっても良いし異なっていてもよい。） A coumarin compound that inhibits an inducible nitric oxide synthase represented by the following formula (1).
(Where X is a hydrogen atom, a hydrocarbon group that may have a substituent, or an aryl group that may have a substituent, and R 1 and R 2 are hydrocarbon groups that may have a substituent. Y and Z are each a hydrogen atom or a hydrocarbon group which may have a substituent, and R 1, R 2, Y and Z may be the same or different from each other. ) 下記式（２）又は（３）で示される誘導型一酸化窒素合成酵素を阻害するクマリン化合物。
A coumarin compound that inhibits inducible nitric oxide synthase represented by the following formula (2) or (3).
請求項１又は２に記載のクマリン化合物を有効成分とするｉＮＯＳ阻害剤。   The iNOS inhibitor which uses the coumarin compound of Claim 1 or 2 as an active ingredient. 前記クマリン化合物を２０μＭ以上１００μＭ以下含む請求項１又は２記載のｉＮＯＳ阻害剤。   The iNOS inhibitor according to claim 1 or 2, comprising the coumarin compound in an amount of 20 µM to 100 µM.
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