JP2007131558A - Acetoxychavicol acetate analog compound, its preparation method and antiallergic agent - Google Patents
Acetoxychavicol acetate analog compound, its preparation method and antiallergic agent Download PDFInfo
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Abstract
Description
本発明は、脱顆粒抑制作用を有し、アレルギー治療薬として用いられるアセトキシキャビコールアセテート類縁体化合物に関する。本発明は、さらに、この化合物の製造方法、および、この化合物を含有する抗アレルギー剤に関する。 The present invention relates to an acetoxycavicol acetate analog compound that has a degranulation inhibitory activity and is used as a therapeutic agent for allergies. The present invention further relates to a method for producing this compound and an antiallergic agent containing this compound.
花粉症、食物アレルギー、蕁麻疹、アレルギー性喘息や鼻炎などのアレルギー性疾患はＩ−ＩＶ型の中のＩ型アレルギー反応に分類され、このＩ型アレルギー反応の治療薬としてはステロイド剤、抗ヒスタミン剤、脱顆粒抑制剤などが用いられている。 Allergic diseases such as hay fever, food allergies, urticaria, allergic asthma and rhinitis are classified as type I allergic reactions among types I-IV. Steroids, antihistamines, A degranulation inhibitor is used.
このうちステロイド剤は、作用が強力であるが、副作用が非常に強い問題があり、また抗ヒスタミン剤は、急性の炎症症状に有効であるが、予防効果は期待できないとの問題がある。これに対し、脱顆粒抑制剤は、急性症状の直接の原因となるケミカルメディエーターの遊離を抑制する薬物であり、予防効果が高く、ステロイドに比べ副作用も少ないので、その重要性が高まっている。 Of these, steroids have a strong action, but have a very strong side effect, and antihistamines are effective for acute inflammatory symptoms, but cannot prevent preventive effects. On the other hand, degranulation inhibitors are drugs that suppress the release of chemical mediators that directly cause acute symptoms, have a high preventive effect, and have fewer side effects than steroids, and thus their importance is increasing.
このような脱顆粒抑制剤としては、tranilastやketotifen fumarate等が現在臨床で用いられているが、より強力な脱顆粒抑制作用を有する化合物として、下記の構造式（３）で表わされる（1'S-1'-acetoxychavicol acetate）が知られている。また、この化合物は、広く東南アジアから中国まで分布しており、その根茎が健胃や駆風、皮膚疾患の治療などに用いられているアルピニアガランガ（Alpinia galanga）よりの抽出物中に含まれており、アルピニアガランガの抽出物を用いた抗アレルギー剤も提案されている（特開２００４−１８９６６９号公報）。 As such a degranulation inhibitor, tranilast, ketotifen fumarate, etc. are currently used in clinical practice, but are represented by the following structural formula (3) as a compound having a stronger degranulation inhibitory activity (1'S- 1'-acetoxychavicol acetate) is known. In addition, this compound is widely distributed from Southeast Asia to China, and the rhizome is contained in extracts from Alpinia galanga, which is used for treatment of healthy stomach, wind drive, and skin diseases. An antiallergic agent using an extract of Alpinia Galanga has also been proposed (Japanese Patent Application Laid-Open No. 2004-189669).
（式中、Acはアセチル基を表わす。以下の記載においても同様である。）
(In the formula, Ac represents an acetyl group. The same applies to the following description.)
本発明は、前記の1'S-1'-acetoxychavicol acetateと同様、強力な脱顆粒抑制作用を有し、Ｉ型アレルギー反応の治療薬として有用な、新規な化合物を提供することを課題とする。本発明は、また、この新規な化合物の製造方法を提供することも課題とする。本発明は、さらに、この新規な化合物の脱顆粒抑制作用を利用した抗アレルギー剤を提供することを課題とする。 The object of the present invention is to provide a novel compound having a potent degranulation inhibitory effect and useful as a therapeutic agent for type I allergic reaction, similar to the aforementioned 1′S-1′-acetoxychavicol acetate. Another object of the present invention is to provide a method for producing this novel compound. Another object of the present invention is to provide an antiallergic agent utilizing the degranulation inhibitory action of this novel compound.
本発明者は、1'S-1'-acetoxychavicol acetateの脱顆粒抑制機構の解明を行うとともに、種々のアセトキシキャビコールアセテート類縁体についてその脱顆粒抑制作用を検討した結果、特定の種類のアセトキシキャビコールアセテート類縁体が、強力な脱顆粒抑制作用を有することを見出し、本発明を完成した。 The present inventor has elucidated the degranulation inhibitory mechanism of 1'S-1'-acetoxychavicol acetate and examined the degranulation inhibitory action of various acetoxycavicol acetate analogs. The present inventors found that the analog has a strong degranulation inhibitory action and completed the present invention.
本発明は、その第一の態様として、下記の構造式（１）で表されることを特徴とするアセトキシキャビコールアセテート類縁体化合物を提供する（請求項１）。 The present invention provides, as a first aspect thereof, an acetoxycavicol acetate analog compound represented by the following structural formula (1) (claim 1).
本発明は、また、その第二の態様として、下記の構造式（２）で表されることを特徴とするアセトキシキャビコールアセテート類縁体化合物を提供する（請求項２）。 The present invention also provides, as a second aspect thereof, an acetoxycavicol acetate analog compound represented by the following structural formula (2) (claim 2).
これらのアセトキシキャビコールアセテート類縁体化合物は、強力な脱顆粒抑制作用を有し、脱顆粒抑制剤としてＩ型アレルギー反応の治療に優れた効果を奏するものである。 These acetoxycavicol acetate analog compounds have a strong degranulation inhibitory action and exhibit excellent effects in treating type I allergic reactions as degranulation inhibitors.
前記の構造式（１）の化合物、構造式（２）のアセトキシキャビコールアセテート類縁体化合物は、以下に示す方法により製造することができる。本発明は、この製造方法も提供するものである。 The compound of the structural formula (1) and the acetoxycavicol acetate analog compound of the structural formula (2) can be produced by the following method. The present invention also provides this manufacturing method.
すなわち、本発明は、その請求項３において、４−ヒドロキシベンズアルデヒドをハロゲン化エチニルマグネシウムとグリニャール反応させた後、アセチル化反応を行うことを特徴とする構造式（１）の化合物の製造方法を提供する。 That is, the present invention provides the process for producing a compound of structural formula (1) according to claim 3, wherein 4-hydroxybenzaldehyde is subjected to Grignard reaction with ethynylmagnesium halide and then subjected to acetylation reaction. To do.
この製造方法においては、先ず、４−ヒドロキシベンズアルデヒドと下記の構造式のハロゲン化エチニルマグネシウムを、以下に示すグリニャール反応をさせて、下記の構造式（４）で表されるジオール化合物を得る。この反応は、通常のグリニャール反応と同様な条件で行うことができ、例えば、金属ナトリウム等で完全に脱水（乾燥）されたエーテル類、例えばエチルエーテルやテトラヒドロフラン中で行われる。 In this production method, first, 4-hydroxybenzaldehyde and ethynylmagnesium halide having the following structural formula are subjected to the Grignard reaction shown below to obtain a diol compound represented by the following structural formula (4). This reaction can be carried out under the same conditions as in a normal Grignard reaction, and is carried out, for example, in ethers that have been completely dehydrated (dried) with metallic sodium or the like, such as ethyl ether or tetrahydrofuran.
そして、このようにして得られたジオール化合物を、以下に示す反応でアセチル化することにより、構造式（１）で表されるアセトキシキャビコールアセテート類縁体化合物を得ることができる。アセチル化反応も通常の芳香族のアセチル化反応と同様な条件で行うことができ、例えば、無水酢酸を使用して行われる。 And the diol compound obtained in this way is acetylated by the reaction shown below, and the acetoxy cavicol acetate analog compound represented by Structural Formula (1) can be obtained. The acetylation reaction can also be carried out under the same conditions as those of a normal aromatic acetylation reaction, for example, using acetic anhydride.
本発明は、また、その請求項４において、４−ヒドロキシベンゾフェノンをアセチル化してその水酸基を保護した後、還元反応およびアセチル化反応を行うことを特徴とする構造式（２）の化合物の製造方法を提供する。 The present invention also provides the method for producing a compound of the structural formula (2) according to claim 4, wherein the 4-hydroxybenzophenone is acetylated to protect the hydroxyl group, followed by a reduction reaction and an acetylation reaction. I will provide a.
この製造方法においては、先ず、４−ヒドロキシベンゾフェノンの水酸基のアセチル化が以下に示す反応で行われる。 In this production method, first, acetylation of the hydroxyl group of 4-hydroxybenzophenone is carried out by the reaction shown below.
このアセチル化反応も通常の芳香族のアセチル化反応と同様な条件で行うことができ、例えば、無水酢酸を使用して行われる。水酸基のアセチル化後、ＮａＢＨ４などの還元剤を使用して、カルボニル基の還元が行われた後、さらにアセチル化反応が行われて構造式（２）のアセトキシキャビコールアセテート類縁体化合物（芳香族類縁体）が得られる（下記式のルートＩ）。代わりに、カルボニル基の還元およびアセチル化反応を同時に行ってもよい（下記式のルートＩＩ）。 This acetylation reaction can also be carried out under the same conditions as those of a normal aromatic acetylation reaction, for example, using acetic anhydride. After the acetylation of the hydroxyl group, the carbonyl group is reduced using a reducing agent such as NaBH 4 , and then the acetylation reaction is further carried out to produce an acetoxycavicol acetate analog compound of the structural formula (2) (fragrance Family analog) is obtained (Route I in the formula below). Instead, the reduction of the carbonyl group and the acetylation reaction may be performed simultaneously (Route II in the following formula).
前記の構造式（１）、構造式（２）のアセトキシキャビコールアセテート類縁体化合物は、優れた脱顆粒抑制効果を有し、脱顆粒抑制剤、抗アレルギー剤として、Ｉ型アレルギー疾患の治療に好適に用いられる。本発明は、このアセトキシキャビコールアセテート類縁体化合物を含有することを特徴とする抗アレルギー剤も提供するものである（請求項５）。 The acetoxycavicol acetate analog compound represented by the structural formulas (1) and (2) has an excellent degranulation inhibitory effect, and is used as a degranulation inhibitor and an antiallergic agent for treating type I allergic diseases. Preferably used. The present invention also provides an antiallergic agent containing the acetoxycavicol acetate analog compound (claim 5).
次に本発明を実施するためのより具体的な形態を、実施例により説明する。なお、実施例は、本発明の範囲を限定するものではなく、本発明の趣旨を損なわない限り、他の形態へ変更することができる。 Next, a more specific form for carrying out the present invention will be described with reference to examples. In addition, an Example does not limit the scope of the present invention, and can be changed to another form, unless the meaning of the present invention is impaired.
（１）4-(1-Acetoxyprop-2-ynyl)phenyl Acetate（構造式（１）の化合物）の製造 (1) Production of 4- (1-Acetoxyprop-2-ynyl) phenyl Acetate (compound of structural formula (1))
ｉ）4-(1-Hydroxyprop-2-ynyl)phenol（構造式（４）の化合物）の合成（グリニャール反応）
４−ヒドロキシベンズアルデヒド１．２２ｇ（１０ｍｍｏｌ）と、乾燥テトラヒドロフラン５０ｍｌの混合物へ、臭化エチニルマグネシウムの０．５Ｍテトラヒドロフラン溶液６０ｍｌを０℃で３０分かけて滴下した。反応混合物をさらに５時間撹拌し、水２０ｍｌを加えた。反応混合物をセライトでろ過し、セライト上のゲル状固形物をテトラヒドロフランで十分に洗浄した。ろ液と洗浄液をあわせたものを溶媒留去し、得られた残渣を１００ｍｌの水にあけ、５０ｍｌの酢酸エチルで５回抽出した。抽出液を２０ｍｌの飽和食塩水で洗浄し、乾燥後、溶媒留去した。得られた残渣をカラムクロマトグラフィー（クロロホルム：エタノール＝２０：１）で精製して、4-(1-Hydroxyprop-2-ynyl)phenolを１．２５ｇ得た（収率８８％）。
i) Synthesis of 4- (1-Hydroxyprop-2-ynyl) phenol (compound of structural formula (4)) (Grignard reaction)
To a mixture of 1.22 g (10 mmol) of 4-hydroxybenzaldehyde and 50 ml of dry tetrahydrofuran, 60 ml of a 0.5 M tetrahydrofuran solution of ethynylmagnesium bromide was added dropwise at 0 ° C. over 30 minutes. The reaction mixture was stirred for a further 5 hours and 20 ml of water was added. The reaction mixture was filtered through celite, and the gel-like solid on celite was thoroughly washed with tetrahydrofuran. The solvent was distilled off from the combined filtrate and washing solution, and the resulting residue was poured into 100 ml of water and extracted five times with 50 ml of ethyl acetate. The extract was washed with 20 ml of saturated brine, dried and the solvent was distilled off. The obtained residue was purified by column chromatography (chloroform: ethanol = 20: 1) to obtain 1.25 g of 4- (1-Hydroxyprop-2-ynyl) phenol (yield 88%).
得られた化合物は、無色結晶であり、融点、赤外スペクトル、ＮＭＲ測定の結果は以下に示すとおりであった。この結果より、得られた化合物は、4-(1-Hydroxyprop-2-ynyl)phenolであると確認された。 The obtained compound was colorless crystals, and the melting point, infrared spectrum, and NMR measurement results were as shown below. From this result, it was confirmed that the obtained compound was 4- (1-Hydroxyprop-2-ynyl) phenol.
ｍｐ１０４．５−１０６．８℃
ＩＲ（ＫＢｒ）：３３２９ｃｍ−１
１Ｈ−ＮＭＲ（ＣＤ３ＯＤ） δ：2.88(1H,s)，5.23(1H,s)，6.70(2H,d,J=8.6Hz)，6.70(2H,d,J=8.6Hz)，7.27(2H,d,J=8.6Hz)
１３Ｃ−ＮＭＲ（ＣＤＣ１３） δ：64.8(d)，75.2(d)，86.0(s)，116.8(d)，130.0(d)，134.0(s)，159.2(s)
ＥＩ−ＭＳｍ／ｚ：１４８，１３１
mp 104.5-106.8 ° C
IR (KBr): 3329 cm −1
1 H-NMR (CD 3 OD) δ: 2.88 (1H, s), 5.23 (1H, s), 6.70 (2H, d, J = 8.6 Hz), 6.70 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6Hz)
13 C-NMR (CDC1 3 ) δ: 64.8 (d), 75.2 (d), 86.0 (s), 116.8 (d), 130.0 (d), 134.0 (s), 159.2 (s)
EI-MS m / z: 148,131
ii）4-(1-Acetoxyprop-2-ynyl)phenyl Acetate（構造式（１）の化合物）の合成（アセチル化）
前記で得られた4-(1-Hydroxyprop-2-ynyl)phenolの１４８ｍｇ（１ｍｍｏｌ）、無水酢酸（4-(1-Hydroxyprop-2-ynyl)phenolの水酸基に対して２当量）および，ピリジン（無水酢酸に対して１０当量）の混合物を室温で２０分間撹拌した後、ピリジンの５０重量倍の水に注ぎ、Diethyl Etherで抽出した。抽出液を飽和重曹水で十分に洗浄し、乾燥後、溶媒留去した。残留したピリジンはベンゼンとの共沸で除き、4-(1-Acetoxyprop-2-ynyl)phenyl Acetate（構造式（１）の化合物）を２３２ｍｇ得た（収率ほぼ１００％）。
ii) Synthesis (acetylation) of 4- (1-Acetoxyprop-2-ynyl) phenyl Acetate (compound of structural formula (1))
148 mg (1 mmol) of 4- (1-Hydroxyprop-2-ynyl) phenol obtained above, acetic anhydride (2 equivalents to the hydroxyl group of 4- (1-Hydroxyprop-2-ynyl) phenol) and pyridine ( The mixture was stirred at room temperature for 20 minutes, poured into 50 times water by weight of pyridine, and extracted with Diethyl Ether. The extract was thoroughly washed with saturated aqueous sodium hydrogen carbonate, dried and evaporated. Residual pyridine was removed by azeotropy with benzene to obtain 232 mg of 4- (1-Acetoxyprop-2-ynyl) phenyl Acetate (compound of structural formula (1)) (yield approximately 100%).
得られた化合物は、無色油状物であり、赤外スペクトル、ＮＭＲ測定の結果は以下に示すとおりであった。この結果より、得られた化合物は、4-(1-Acetoxyprop-2-ynyl)phenyl Acetateであると確認された。 The resulting compound was a colorless oil, and the results of infrared spectrum and NMR measurement were as shown below. From this result, it was confirmed that the obtained compound was 4- (1-Acetoxyprop-2-ynyl) phenyl acetate.
ＩＲ（ｎｅａｔ）：１７６５，１７４１ｃｍ−１
１Ｈ−ＮＭＲ（ＣＤＣ１３） δ：2.11(3H,s)，2.30(3H,s)，2.66(1H,d,J=2.4Hz)，6.44(1H,d,J=2.4Hz)，7.11(2H,d,J=8.9Hz)，7.55(2H,d,J=8.9Hz)
１３Ｃ−ＮＭＲ（ＣＤＣ１３） δ：21.0(q)，21.1(q)，64.6(d)，73.8(d)，78.0(s)，121.8(d)，128.9(s)，129.0(d)，151.1(s)
ＥＩ−ＭＳｍ／ｚ：２３２（Ｍ＋），１３０，４３
IR (neat): 1765, 1741 cm −1
1 H-NMR (CDC1 3 ) δ: 2.11 (3H, s), 2.30 (3H, s), 2.66 (1H, d, J = 2.4 Hz), 6.44 (1H, d, J = 2.4 Hz), 7.11 ( 2H, d, J = 8.9Hz), 7.55 (2H, d, J = 8.9Hz)
13 C-NMR (CDC1 3 ) δ: 21.0 (q), 21.1 (q), 64.6 (d), 73.8 (d), 78.0 (s), 121.8 (d), 128.9 (s), 129.0 (d), 151.1 (s)
EI-MS m / z: 232 (M +), 130, 43
（２）4-(Acetoxyphenylmethyl)phenyl Acetate（構造式（２）の化合物）の製造
ｉ）4-Benzoylphenyl Acetateの合成（アセチル化）
４−ヒドロキシベンゾフェノンの１．９８ｇ（１０ｍｏｌ）、無水酢酸（４−ヒドロキシベンゾフェノンの水酸基に対して２当量）および，ピリジン（無水酢酸に対して１０当量）の混合物を室温で１時間撹拌した後、ピリジンの５０重量倍の水に注ぎ、Diethyl Etherで抽出した。抽出液を飽和重曹水で十分に洗浄し、乾燥後、溶媒留去した。残留したピリジンはベンゼンとの共沸で除き、4-Benzoylphenyl Acetateを２．４ｇ得た（収率ほぼ１００％）。
(2) Production of 4- (Acetoxyphenylmethyl) phenyl Acetate (Compound of Structural Formula (2)) i) Synthesis of 4-Benzoylphenyl Acetate (acetylation)
After stirring a mixture of 1.98 g (10 mol) of 4-hydroxybenzophenone, acetic anhydride (2 equivalents relative to the hydroxyl group of 4-hydroxybenzophenone) and pyridine (10 equivalents relative to acetic anhydride) at room temperature for 1 hour, The mixture was poured into 50 times the weight of pyridine and extracted with Diethyl Ether. The extract was thoroughly washed with saturated aqueous sodium hydrogen carbonate, dried and evaporated. Residual pyridine was removed by azeotropy with benzene to obtain 2.4 g of 4-Benzoylphenyl Acetate (yield approximately 100%).
得られた化合物は、無色結晶であり、融点、赤外スペクトル、ＮＭＲ測定の結果は以下に示すとおりであった。この結果より、得られた化合物は、4-Benzoylphenyl Acetateであると確認された。 The obtained compound was colorless crystals, and the melting point, infrared spectrum, and NMR measurement results were as shown below. From this result, it was confirmed that the obtained compound was 4-Benzoylphenyl Acetate.
ｍｐ６３−６４℃
ＩＲ（ＫＢｒ）：１７５１，１６５１ｃｍ−１
１Ｈ−ＮＭＲ（ＣＤＣ１３） δ：2.34(3H,s)，7.21(2H,d,J=11.6Hz)，7.43-7.62(3H,m)，7.77-7.82(2H,m)，7.85(2H,d,11.6Hz）
１３Ｃ−ＮＭＲ（ＣＤＣ１３） δ：21.1(q)，121.5(d)，128.4(d)，129.9(d)，131.6(d)，132.4(d)，135.0(s)，137.4(s)，153.8(s)，168.9(s)，195.5(s)
ＥＩ−ＭＳｍ／ｚ：２４０（Ｍ＋），１９８，１２１，７７，４３
mp63-64 ° C
IR (KBr): 1751, 1651 cm −1
1 H-NMR (CDC1 3 ) δ: 2.34 (3H, s), 7.21 (2H, d, J = 11.6 Hz), 7.43-7.62 (3H, m), 7.77-7.82 (2H, m), 7.85 (2H) , d, 11.6Hz)
13 C-NMR (CDC1 3 ) δ: 21.1 (q), 121.5 (d), 128.4 (d), 129.9 (d), 131.6 (d), 132.4 (d), 135.0 (s), 137.4 (s), 153.8 (s), 168.9 (s), 195.5 (s)
EI-MS m / z: 240 (M +), 198, 121, 77, 43
ii）4-(Acetoxyphenylmethyl)phenyl Acetate（構造式（２）の化合物）の合成（還元、アセチル化）
前記で得られた4-Benzoylphenyl Acetateの０．１Ｍメタノール溶液を０℃で撹拌しながら、4-Benzoylphenyl Acetateに対して１．５当量倍の水素化ホウ素ナトリウムを少しずつ加えた。ＴＬＣで4-Benzoylphenyl Acetateの消失を確認した後、溶媒を留去した。残渣に３０当量倍のピリジン、１０当量倍の無水酢酸を順に加え、室温で撹拌した。その後、この反応混合液を水に注ぎ、Diethyl Etherで抽出した。抽出液を飽和重曹水で洗浄し、乾燥後、溶媒留去して生成物を得た。
ii) Synthesis (reduction, acetylation) of 4- (Acetoxyphenylmethyl) phenyl Acetate (compound of structural formula (2))
While stirring the 0.1 M methanol solution of 4-Benzoylphenyl Acetate obtained above at 0 ° C., 1.5 eq sodium borohydride was added little by little with respect to 4-Benzoylphenyl Acetate. After confirming the disappearance of 4-Benzoylphenyl Acetate by TLC, the solvent was distilled off. 30 equivalents of pyridine and 10 equivalents of acetic anhydride were sequentially added to the residue and stirred at room temperature. The reaction mixture was then poured into water and extracted with Diethyl Ether. The extract was washed with saturated aqueous sodium hydrogen carbonate, dried and evaporated to give the product.
得られた生成物は、無色油状物であり、赤外スペクトル、ＮＭＲ測定の結果は以下に示すとおりであった。この結果より、得られた生成物は、4-(Acetoxyphenylmethyl)phenyl Acetate（構造式（２）の化合物）であると確認された。 The obtained product was a colorless oil, and the results of infrared spectrum and NMR measurement were as shown below. From this result, it was confirmed that the obtained product was 4- (Acetoxyphenylmethyl) phenyl Acetate (compound of structural formula (2)).
ＩＲ（ｎｅａｔ）：１７４４，１７５８ｃｍ−１
１Ｈ−ＮＭＲ（ＣＤＣ１３） δ：2.15(3H,s)，2.29(3H,s)，6.88(1H,s)，7.05(2H,d,J=8.6Hz)，7.27-7.37(7H,m)
１３Ｃ−ＮＭＲ（ＣＤＣ１３） δ：21.1(q)，21.2(q)，121.6(d)，127.0(d)，128.0(d)，128.3(d)，128.5(d)，137.7(s)，139.9(s)，150.2(s)，169.3(s)，169.9(s)
ＥＩ−ＭＳｍ／ｚ：４３，１８２，２８４
IR (neat): 1744, 1758 cm −1
1 H-NMR (CDC1 3 ) δ: 2.15 (3H, s), 2.29 (3H, s), 6.88 (1H, s), 7.05 (2H, d, J = 8.6 Hz), 7.27-7.37 (7H, m )
13 C-NMR (CDC1 3 ) δ: 21.1 (q), 21.2 (q), 121.6 (d), 127.0 (d), 128.0 (d), 128.3 (d), 128.5 (d), 137.7 (s), 139.9 (s), 150.2 (s), 169.3 (s), 169.9 (s)
EI-MS m / z: 43, 182, 284
（３）抗アレルギー性の検討
前記で得られた4-(1-Acetoxyprop-2-ynyl)phenyl Acetate（構造式（１）の化合物）、4-(Acetoxyphenylmethyl)phenyl Acetate（構造式（２）の化合物）、tranilast、およびketotifen fumarateについて、下記のようにして抗アレルギー性を検討した。
(3) Examination of antiallergic properties 4- (1-Acetoxyprop-2-ynyl) phenyl Acetate (compound of structural formula (1)), 4- (Acetoxyphenylmethyl) phenyl Acetate (structural formula (2) obtained above) Compound), tranilast, and ketotifen fumarate were examined for antiallergic properties as follows.
肥満細胞のモデル細胞であるラット好塩基性白血病（ＲＢＬ−２Ｈ３）細胞を用い、脱顆粒の際にヒスタミンなどと共に放出されるβ−hexosaminidaseの遊離量を判定することで脱顆粒の指標とし、抗アレルギー作用を検討した。 Rat basophil leukemia (RBL-2H3) cells, which are mast cell model cells, are used as an indicator of degranulation by determining the amount of β-hexosaminidase released together with histamine during degranulation, Allergic effects were examined.
ヒューマンサイエンス研究資源バンクより購入したラット好塩基性白血病（ＲＢＬ−２Ｈ３）細胞を培養後（５％ＣＯ２，３７℃）、２４ウエルマイタロプレートに２．０×１０５ ｃｅｌｌ／ｗｅｌｌずつ播種し、１時間培養した後、ラットモノクロナール抗ＤＮＰ−ＩｇＥ抗体（０．４５μｇ／ｍｌ）を加え２４時間培養することにより細胞を感作させた。感作後Siraganian bufferを加え１０分間予備加温（５％ＣＯ２，３７℃）し、前記のそれぞれの化合物のＤＭＳＯ溶液（終濃度０．１％）を加え、その１０分後に抗原（ＤＮＰ−ＢＳＡ、終濃度１０μｇ／ｍｌ）を添加した。 Rat basophil leukemia (RBL-2H3) cells purchased from Human Science Research Resource Bank are cultured (5% CO 2 , 37 ° C.) and then seeded on a 24-well mitaro plate at 2.0 × 10 5 cells / well. After culturing for 1 hour, rat monoclonal anti-DNP-IgE antibody (0.45 μg / ml) was added and cultured for 24 hours to sensitize the cells. After sensitization, Siraganian buffer was added and pre-warmed for 10 minutes (5% CO 2 , 37 ° C.), DMSO solution of each of the above compounds (final concentration 0.1%) was added, and 10 minutes later, antigen (DNP- BSA, final concentration 10 μg / ml) was added.
１０分後に水冷して反応を停止させ、その上清に０．１Ｍ citrate bufferに溶解したp-nitrophenyl-N-acetyl-β-D-glucosaminideを加えて３７℃で１時間反応させた。反応液にstop bufferを加えて混和し、吸光度（測定波長４０５ｎｍ、参照波長６５５ｎｍ）を測定し遊離率を求めた。 Ten minutes later, the reaction was terminated by cooling with water, and p-nitrophenyl-N-acetyl-β-D-glucosaminide dissolved in 0.1 M citrate buffer was added to the supernatant, followed by reaction at 37 ° C. for 1 hour. Stop buffer was added to the reaction solution and mixed, and the absorbance (measurement wavelength 405 nm, reference wavelength 655 nm) was measured to determine the liberation rate.
表１に示すように、構造式（１）の化合物および構造式（２）の化合物のみに遊離抑制括性が見出され、抗アレルギー性があることが示された。 As shown in Table 1, the release-suppressing generality was found only in the compound of the structural formula (1) and the compound of the structural formula (2), and it was shown to have antiallergic properties.
Claims (5)
An antiallergic agent comprising the acetoxycavicol acetate analog compound according to claim 1 or 2.
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| JP2009191010A (en) * | 2008-02-14 | 2009-08-27 | Univ Kinki | Chavicol analog compound, method for producing chavicol analog compound and map kinase signaling inhibitor |
| CN102198096A (en) * | 2011-05-27 | 2011-09-28 | 河南省医药科学研究院 | ACA (acetoxychavicol acetate) submicron emulsion for intravenous injection, and preparation method and application thereof |
| CN112654347A (en) * | 2018-07-06 | 2021-04-13 | 吉亚生技控股股份有限公司 | Method for treating allergic diseases |
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| JPH11269481A (en) * | 1997-12-22 | 1999-10-05 | Givaudan Roure Internatl Sa | Irritative falvor component |
| JP2004189669A (en) * | 2002-12-11 | 2004-07-08 | Sakamoto Yakuhin Kogyo Co Ltd | Antiallergic agent |
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| JP2009191010A (en) * | 2008-02-14 | 2009-08-27 | Univ Kinki | Chavicol analog compound, method for producing chavicol analog compound and map kinase signaling inhibitor |
| CN102198096A (en) * | 2011-05-27 | 2011-09-28 | 河南省医药科学研究院 | ACA (acetoxychavicol acetate) submicron emulsion for intravenous injection, and preparation method and application thereof |
| CN102198096B (en) * | 2011-05-27 | 2012-12-12 | 河南省医药科学研究院 | ACA (acetoxychavicol acetate) submicron emulsion for intravenous injection, and preparation method and application thereof |
| CN112654347A (en) * | 2018-07-06 | 2021-04-13 | 吉亚生技控股股份有限公司 | Method for treating allergic diseases |
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