JPH01160918A - Anti-inflammatory drug containing 3,7,11-trimethyl-2,6,10-dodecatrienoic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester(knc-225) - Google Patents
Anti-inflammatory drug containing 3,7,11-trimethyl-2,6,10-dodecatrienoic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester(knc-225)Info
- Publication number
- JPH01160918A JPH01160918A JP32102787A JP32102787A JPH01160918A JP H01160918 A JPH01160918 A JP H01160918A JP 32102787 A JP32102787 A JP 32102787A JP 32102787 A JP32102787 A JP 32102787A JP H01160918 A JPH01160918 A JP H01160918A
- Authority
- JP
- Japan
- Prior art keywords
- knc
- dimethyl
- dioxolan
- methyl ester
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- WJHFZYAELPOJIV-UHFFFAOYSA-N (2E,6E)-3,7,11-trimethyl-2,6,10-dodecatrienoic acid Natural products CC(C)=CCCC(C)=CCCC(C)=CC(O)=O WJHFZYAELPOJIV-UHFFFAOYSA-N 0.000 title claims abstract 3
- 239000002260 anti-inflammatory agent Substances 0.000 title abstract description 3
- 150000004702 methyl esters Chemical class 0.000 title abstract description 3
- WJHFZYAELPOJIV-IJFRVEDASA-N (2E,6E)-farnesoic acid Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\C(O)=O WJHFZYAELPOJIV-IJFRVEDASA-N 0.000 title abstract 2
- 229940124599 anti-inflammatory drug Drugs 0.000 title abstract 2
- 239000003085 diluting agent Substances 0.000 abstract description 12
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- 239000000843 powder Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
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- 241000191967 Staphylococcus aureus Species 0.000 abstract 1
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- -1 2,2-dimethyl-1,3-dioxolan-4-yl Chemical group 0.000 description 17
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- 125000000217 alkyl group Chemical group 0.000 description 2
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- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
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- 235000000346 sugar Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は３．７．１１−トリメチル−２，６，１０−ド
デカトリエン酸（２，２−ジメチル−１，３−ジオキソ
ラン−４−イル）メチルエステル（以下ＫＮＣ−２２５
と略称する）を含有する抗炎症剤に関する。Detailed Description of the Invention [Industrial Field of Application] The present invention provides 3.7.11-trimethyl-2,6,10-dodecatrienoic acid (2,2-dimethyl-1,3-dioxolan-4-yl) ) Methyl ester (hereinafter KNC-225
(abbreviated as )).
ＮＫＣ−２２５は裸鯰類（Ｄｏｒｉｄ ｎｕｄｉｂｒａ
ｎｃｈａ）に属するＡｒｃｈｌｄｏｒｉａ ｏｄｎｅｒ
ｉのメタノール抽出物から得られた化合物で、このもの
は生体外でスタフィロコッカス０アウレウス（Ｓｔａｐ
ｈｙｌｏｃｏｃｃｕｇ ａｕｒｅｕｓ ）に対して殺菌
作用を示すことが知られているが（Ｔｅｔｒａｈｅｄｒ
ｏｎ Ｌｅｔｔｅｒｓ ｖｏｌ、 ２１ ｐ ７９７
（１９８０）：ｌ、抗炎症作用については全く知られ
ていない。NKC-225 is a naked catfish (Dorid nudibra).
Archldoria odner belonging to ncha)
This compound is obtained from the methanol extract of Staphylococcus 0. aureus in vitro.
It is known that it has a bactericidal effect against Tetrahedr aureus).
on Letters vol, 21 p 797
(1980): nothing is known about its anti-inflammatory effects.
本発明者らは種々検討の結果、ＫＮＣ−２２５が意外に
も優れた抗炎症作用を有することを見い出し本発明を完
成するに至った。すなわち本発明の目的はＫＮＣ−２２
５を含有する新規な抗炎症剤を提供することにある。As a result of various studies, the present inventors discovered that KNC-225 has a surprisingly excellent anti-inflammatory effect and completed the present invention. That is, the purpose of the present invention is to
An object of the present invention is to provide a novel anti-inflammatory agent containing 5.
ＫＮＣ−２２５はすでに明らかなごとく公知化合物であ
って、又前記文献に記載の方法によって得ることも可能
である。しかしながら以下の方法によって合成すること
も可能である。すなわちゲラニルアセトンとジアルコキ
シホスホノ酢酸（２，２−ジメチル１．３−ジオキソラ
ン−４−イル）メチルエステルとを用いてＨｏｙＨｅｒ
反応（Ｂｅｒ 、 ９５．５８１（１９６２） ）とし
て知られている方法に従って合成する方法である。下記
に一般式で示す。As is already clear, KNC-225 is a known compound and can also be obtained by the method described in the above-mentioned literature. However, it is also possible to synthesize it by the following method. That is, HoyHer
This is a method of synthesis according to a method known as a reaction (Ber, 95.581 (1962)). The general formula is shown below.
（式中Ｒはアルキル基、アリール基又はアラルキル基を
示す）
ジアルコキシホスホノ酢酸（２，２−ジメチル−１，３
ジオキソラン−４−イル）メチルエステルはつぎのよう
にして合成できる。(In the formula, R represents an alkyl group, an aryl group, or an aralkyl group) Dialkoxyphosphonoacetic acid (2,2-dimethyl-1,3
Dioxolan-4-yl) methyl ester can be synthesized as follows.
２．２−ジメチル−１，３−ジオキソラン−４−メタノ
ール（公知化合物）とこれに対して約０．５〜１．２当
量、好ましくは０．８〜１．０当量のモノハロゲン酢酸
ハライド、好ましくはモノクロル酢酸クロリドとを不活
性溶媒の存在下又は不存在下に該モノハロゲン酢酸ハラ
イドに対して約１．０当量ないしは溶媒量のピリジン、
トリエチルアミンなどの有機第３級塩基の存在下、Ｏ℃
〜室温で１〜１０時間反応させることによシモノノ〜ロ
グン酢酸（２，２−ジメチル−１，３−ジオキソラン−
４−イル）メチルエステルを得ることができる。不活性
の溶媒としては例えばトルエン、ベンゼン、ｎ−ヘキサ
ンなどの炭化水素系溶媒；四塩化炭素、クロロホルム、
ジクロルメタン、ジクロルエタン、トリクレンなどのハ
ロダン化炭化水素系溶媒；ソエチルエーテル、ｔ−ブチ
ルメチルエーテル、ジイソプロピルエーテル、テトラヒ
ドロフラン、ジメトキシエタンなどのエーテル系溶媒な
どを使用できる。つぎに（ＲＯ）３Ｐ （式中Ｒは前記
定義のとおシである〕で表わされる亜リン酸エステルと
これに対して約０．５〜１．２当量、好ましくは０．８
〜１．０当量のモノハロダン酢酸（２，２−ツメチル−
１，３−ジオキソラン−４−イル）メチルエステルとを
１００°〜２００℃で１〜５時間反応させることによシ
ジアルコキシホスホノ酢酸（２，２−ジメチル−１，３
−ジオキソラン−４−イル）メチルエステルを得ること
ができる。なおＲの定義中、アルキル基はメチル基、エ
チル基環炭素数１〜２゜のアルキル基を、アリール基は
フェニル基、トリル基等を、アラルキル基はペンシル基
等を包含する。2.2-dimethyl-1,3-dioxolane-4-methanol (known compound) and about 0.5 to 1.2 equivalents, preferably 0.8 to 1.0 equivalents of monohalogen acetic acid halide, Preferably, monochloroacetic acid chloride and pyridine in an amount of about 1.0 equivalent to a solvent amount based on the monohalogen acetic acid halide in the presence or absence of an inert solvent,
O ℃ in the presence of an organic tertiary base such as triethylamine
By reacting at room temperature for 1 to 10 hours, simononologonic acetic acid (2,2-dimethyl-1,3-dioxolane-
4-yl) methyl ester can be obtained. Examples of inert solvents include hydrocarbon solvents such as toluene, benzene, and n-hexane; carbon tetrachloride, chloroform,
Halodanized hydrocarbon solvents such as dichloromethane, dichloroethane and trichlene; ether solvents such as soethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, etc. can be used. Next, a phosphite ester represented by (RO)3P (in the formula, R is as defined above) and about 0.5 to 1.2 equivalents, preferably 0.8
~1.0 equivalents of monohalodaneacetic acid (2,2-tmethyl-
Cydialkoxyphosphonoacetic acid (2,2-dimethyl-1,3
-dioxolan-4-yl) methyl ester can be obtained. In the definition of R, the alkyl group includes a methyl group and an ethyl group having a ring carbon number of 1 to 2 degrees, the aryl group includes a phenyl group, tolyl group, etc., and the aralkyl group includes a pencil group.
さらにジアルコキシホスホノ酢酸（２，２−ジメチル−
１，３−ジオキソラン−４−イル）メチルエステルとこ
れに対して０．８〜１．５当量、好ましくは１．０〜１
．１当量の水素化ナトリウム、ナトリウムメチラートな
どの塩基とをベンゼン、トルエン等の炭化水素系溶媒、
ジエチルエーテル、ジイソプロピルエーテル、テトラヒ
ドロフラン、ジメトキシエタン等のエーテル系溶媒など
の溶媒の存在下、θ℃〜室温で３〜１０時間反応さ誓た
のち、その反応混合物にジアルコキシホスホノ酢酸（２
，２−ジメチル−１，３−ジオキソラン−４−イル）メ
チルエステルに対して０．８〜１．２当量のｒラニルア
セトンを加えて０〜１００℃で１０〜４８０〜４８時間
反応ＮＣ−２２５を得ることができる。Furthermore, dialkoxyphosphonoacetic acid (2,2-dimethyl-
1,3-dioxolan-4-yl) methyl ester and 0.8 to 1.5 equivalents thereof, preferably 1.0 to 1
．． 1 equivalent of a base such as sodium hydride or sodium methylate and a hydrocarbon solvent such as benzene or toluene,
After reacting for 3 to 10 hours at θ°C to room temperature in the presence of a solvent such as an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, or dimethoxyethane, dialkoxyphosphonoacetic acid (2
, 2-dimethyl-1,3-dioxolan-4-yl) methyl ester, add 0.8 to 1.2 equivalents of r-ranyl acetone and react NC-225 at 0 to 100°C for 10 to 480 to 48 hours. Obtainable.
上記の合成反応によって得られたＫＮＣ−２２５の分離
精製は通常の方法によシ行なうことができる。KNC-225 obtained by the above synthesis reaction can be separated and purified by a conventional method.
例えば分子蒸留によるかあるいはカラムクロマトグラフ
ィーに付することによってＫＮＣ−２２５を分離取得す
ることができる。For example, KNC-225 can be separated and obtained by molecular distillation or by subjecting it to column chromatography.
次に本発明化合物であるＫＮＣ−２２５についての抗炎
症作用の試験およびその結果を示す。Next, an anti-inflammatory effect test for KNC-225, which is a compound of the present invention, and its results will be shown.
試験例
１、紫外線紅斑抑制作用
（１） Ｈａｒｔｌａｙ系雄性モルモット（体重的３
００９）を１週間予備飼育し、健常なものを試、＠に供
した。これらのモルモットをランダムに１群５匹とし、
試験前日に腹部を除毛しその部位にＫＮＣ−２２５を２
％（重量）含む親水ワセリン基剤軟膏の一定量を塗布し
た。ついでその塗布部位をポリ塩化ビニリデンラップで
１時間覆ったのち塗布部位の軟膏を軽く拭き取った。脱
毛部に１．５ ｃｍ間隔で直径６■の３つの小孔をあけ
た絆創膏をあて、紫外線ランｆを用いて１５ｃｒｌ＆の
高さから１分間紫外線を照射した。照射後、１時間、３
時間、６時間および９時間毎に肉視的観察して紅斑の程
度を下記の紅斑係数によシ指数化し、紅斑の強度を求め
た。Test Example 1, Ultraviolet erythema suppression effect (1) Hartlay male guinea pig (weight 3
009) was preliminarily bred for one week, and healthy ones were tested and subjected to @. These guinea pigs were randomly divided into groups of 5,
The day before the test, hair was removed from the abdomen and two doses of KNC-225 were applied to that area.
% (by weight) of a hydrophilic petrolatum-based ointment was applied. The application site was then covered with polyvinylidene chloride wrap for 1 hour, and the ointment was then gently wiped off from the application site. A bandage with three small holes of 6 cm in diameter made at 1.5 cm intervals was applied to the hair removal area, and ultraviolet rays were irradiated for 1 minute from a height of 15 crl using an ultraviolet lamp f. After irradiation, 1 hour, 3
The degree of erythema was visually observed every hour, 6 hours, and 9 hours, and the degree of erythema was expressed as an index using the following erythema coefficient, and the intensity of erythema was determined.
Ｏ：紅斑が認められない。O: No erythema observed.
１：境界が不鮮明な軽度の紅斑が認められる。1: Mild erythema with unclear borders is observed.
２：境界が不鮮明な中程度の紅斑が認められる。2: Moderate erythema with unclear borders is observed.
３：境界が鮮明であるが腫脹を伴なわない紅斑が認めら
れる。3: Erythema with clear borders but no swelling is observed.
試験結果を対照薬としてインドメタシンをＫＮＣ−２２
５と同一方法で塗布した群およびＫＮＣ−２２５を含む
親水ワセリン剤軟膏を皮膚表面に塗布していない対照群
（無処置）の結果と比較して第１図に示す。Indomethacin was used as a control drug in KNC-22 based on the test results.
The results are shown in FIG. 1 in comparison with the results of the group applied in the same manner as in No. 5 and the control group (untreated) in which the hydrophilic petrolatum ointment containing KNC-225 was not applied to the skin surface.
（２） Ｈａ ｒ ｔ ｌ ａ ｙ系雄性モルモット
（体重約３００１ｉ）ｔ−１週間予備飼育し、健常なも
のを試験に供した。これらのモルモットをランダムに１
群５匹とし、試験前日に腹部を除毛し、その脱毛部に１
．５儒の間隔で直径６鵡の３つの小孔をあけた絆創膏を
あて、紫外線ランプを用いて１５ｍの高さから１分間紫
外線を照射した。照射後、照射部位にＫＮＣ−２２５を
０．５％（重量）含む親水ワセリン基剤軟膏の一定量を
塗布した。ついでその塗布部位をサランラッグで１時間
覆ったのち塗布部位の軟膏を軽く拭き取った。ついで拭
き取シ後０時間、１時間・３時間、６時間毎に肉視的観
察して紅斑の強度を試験例（１）と同様にして求めた。(2) Harutya male guinea pigs (body weight approximately 3001i) were preliminarily bred for t-1 weeks, and healthy ones were used for the test. Randomly select one of these guinea pigs
There were 5 animals in each group, and the abdominal hair was removed on the day before the test, and 1
．． A bandage with three small holes of 6 mm in diameter made at 5 mm intervals was placed on the patient, and ultraviolet light was irradiated for 1 minute from a height of 15 m using an ultraviolet lamp. After irradiation, a fixed amount of hydrophilic petrolatum-based ointment containing 0.5% (by weight) of KNC-225 was applied to the irradiated area. The application site was then covered with a saran rag for one hour, and the ointment was then gently wiped off from the application site. Then, macroscopic observations were made every 0 hours, 1 hour, 3 hours, and 6 hours after wiping, and the intensity of the erythema was determined in the same manner as in Test Example (1).
試験結果を対照薬としてインドメタシンをＫＮＣ−２２
５と同一方法で塗布した群およびＫＮＣ−２２５を含む
親水ワセリン剤軟膏を皮膚表面に塗布していない対照群
（無処置）の結果と比較して第２図に示す。Indomethacin was used as a control drug in KNC-22 based on the test results.
The results are shown in FIG. 2 in comparison with the results of the group applied in the same manner as in No. 5 and the control group (untreated) in which the hydrophilic petrolatum ointment containing KNC-225 was not applied to the skin surface.
本発明によればＫＮＣ−２２５を含有してなる薬剤組成
物が提供される。薬剤組成物の投与は経口用又は非経口
用のいずれであってもよい。経口用剤量としては散剤、
錠剤、乳剤、カプセル剤、顆粒剤、液剤（チンキ剤、流
エキス剤、酒糟剤、懸濁剤、リモナーゼ剤、シロラグ剤
などｉ含む）などが挙げられる。また非経口用剤型とし
ては注射剤、点滴剤、軟膏剤、硬膏剤、液剤（酒糟剤、
チンキ剤、ローション剤などを含む）、湿布剤、塗布剤
、噴霧剤、散布剤、リニメント剤、クリーム剤、乳剤、
溶剤などが挙げられる。According to the present invention, a pharmaceutical composition containing KNC-225 is provided. Administration of the pharmaceutical composition may be either oral or parenteral. Oral doses include powder,
Examples include tablets, emulsions, capsules, granules, and liquid preparations (including tinctures, liquid extracts, laxatives, suspensions, limonase preparations, and sillag preparations). In addition, parenteral dosage forms include injections, drops, ointments, plasters, and liquids (rosacea,
(including tinctures, lotions, etc.), poultices, liniments, sprays, dusting agents, liniments, creams, emulsions,
Examples include solvents.
投与量は症状に応じて異なるが、経口用の製剤、注射剤
、点滴剤の場合、ＫＮＣ−２２５として成人１日当、９
２５〜５００７１１９、好ましくは５０〜１００ｍ９の
範囲とすることができ、この投与量を１日１回又は数回
に分けて投与することができる。また非経口用の外用の
場合、ＫＮＣ−２２５として０．０１〜１０％濃度の配
合でよく、好ましくは０．１〜３％の製剤として使用す
るのがよい。The dosage varies depending on the symptoms, but in the case of oral preparations, injections, and infusions, the daily dose for adults as KNC-225 is 9.
The dosage can range from 25 to 5007119 m9, preferably from 50 to 100 m9, and this dosage can be administered once a day or in several divided doses. In the case of parenteral external use, KNC-225 may be formulated at a concentration of 0.01 to 10%, preferably 0.1 to 3%.
ＫＮＣ−２２５は適当な薬理学的に許容される希釈剤（
又は担体）を用いて常法に従って上記の種々の剤型に成
形するために適合した薬剤組成物とすることができる。KNC-225 is prepared in a suitable pharmacologically acceptable diluent (
Pharmaceutical compositions suitable for molding into the various dosage forms mentioned above can be prepared by using conventional methods using the above-mentioned pharmaceutical compositions (or carriers).
錠剤及びカプセル剤に成形するために適合した薬剤組成
物（例えば粒剤）に用いられる希釈剤としては例えば次
のものが挙げられる。Diluents for use in pharmaceutical compositions (eg granules) adapted for forming into tablets and capsules include, for example:
（ａ） 充填剤及び増量剤、例えば澱粉、砂糖、マニ
トール、ケイ酸など；（ｂ）結合剤、例えばカルボキシ
メチルセルロース及び他のセルロース誘導体、アルギン
酸塩、ゼラチン、ポリビニルピロリドンなど；（Ｃ）湿
潤剤、例えばグリセリンなど；（ｄ）崩解剤、例えば寒
天、炭酸カルシウム、重炭酸ナトリウムなど；（ｅ）溶
解埋効剤、例えば・やラフインなど；（ｆ］ 再吸収
促進剤、例えば第４級アンモニウム化合物など；（ｇ）
表面活性剤、例えばセチルアルコール、グリセリン
モノステアレイトなト；（ｈ） 吸着担体、例えばカ
オリン、ベントナイトなど；（１） 滑沢剤、例えば
メルク、ステアリン酸カルシウム、ステアリン酸マグネ
シウム、固体のポリエチレングリコールなど。本発明の
薬剤組成物を成形して得られた錠剤及びカプセル剤には
普通用いられる被覆、エンペログ（ｅｎｖｅｌｏｐｅ
）及び保護基質を含ませることができ、これらは乳白剤
を含むことができる。被覆、エンペログ及び保護基質は
例えば重合体物質又はロウからつくることができる。(a) Fillers and extenders, such as starch, sugar, mannitol, silicic acid, etc.; (b) Binders, such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone, etc.; (C) Wetting agents, (d) Disintegrants, such as agar, calcium carbonate, sodium bicarbonate, etc.; (e) Dissolving bulking agents, such as roughin; (f) Resorption enhancers, such as quaternary ammonium compounds. etc; (g)
(h) Adsorption carriers, such as kaolin, bentonite, etc.; (1) Lubricants, such as Merck, calcium stearate, magnesium stearate, solid polyethylene glycol, etc. The tablets and capsules obtained by molding the pharmaceutical composition of the present invention are coated with a commonly used coating, an envelope.
) and protective substrates, which may include opacifying agents. Coatings, envelopes and protective matrices can be made of polymeric materials or waxes, for example.
生薬に成形するために適する薬剤組成物に用いる希釈剤
は、例えば普通の水溶性又は非水溶性の希釈剤、例えば
ポリエチレングリコール、脂肪（例えばココア油、高級
エステル〔例えばＣ１６−脂肪酸のＣ４４−アルコール
エステルなど〕など）又はこれらの希釈剤の混合物など
であることができる。Diluents used in pharmaceutical compositions suitable for formulation into herbal medicines are, for example, common water-soluble or water-insoluble diluents, such as polyethylene glycols, fats (e.g. cocoa oil, higher esters [e.g. C44-alcohols of C16-fatty acids), etc. ester, etc.) or a mixture of these diluents.
軟膏剤、塗布剤及びクリーム剤である薬剤組成物には、
例えば普通の希釈剤、例えば動物性又は植物性の脂肪、
ロウ、パラフィン、澱粉、トラガカント、セルロース誘
導体、ポリエチレングリコール、シリコーン、ベントナ
イト、ケイ酸、メルク、酸化亜鉛又はこれらの物質の混
合物などを含ませることができる。粉末及びスプレーで
ある薬剤組成物には、例えば普通の希釈剤、例えばラク
トース、メルク、ケイ酸、水酸化アルミニウム、ケイ酸
カルシウム、ポリアミド粉末又はこれらの物質の混合物
などを含ませることができる。Pharmaceutical compositions that are ointments, liniments and creams include:
For example, common diluents such as animal or vegetable fats,
Waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, Merck, zinc oxide, or mixtures of these substances may be included. Pharmaceutical compositions which are powders and sprays may, for example, contain the usual diluents such as lactose, Merck, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder or mixtures of these substances.
エーロゾルスプレーには、例えば普通の噴射基剤、例え
ばクロルフルオル炭化水素などを含ませることができる
。溶液及び乳液である薬剤組成物には、例えば普通の希
釈剤、例えば溶媒、溶解剤及び乳化剤を含ませることが
できる。かかる希釈剤の代表例として、水、エチルアル
コール、インプロピルアルコール、炭酸エチル、酢酸エ
チル、ベンジルアルコール、安息香酸ベンジル、プロピ
レングリコール、１．３−ブチレングリコール、ジメチ
ルホルムアミド、油（例えば落花生油など）、グリセリ
ン、テトラヒドロフルフリルアルコール、ポリエチレン
グリコール若しくはンルピトールの脂肪酸エステル又は
これらの、混合物などが挙げられる。Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions that are solutions and emulsions may, for example, contain common diluents such as solvents, solubilizers, and emulsifying agents. Representative examples of such diluents include water, ethyl alcohol, inpropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils (e.g. peanut oil). , glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid ester of nlupitol, or a mixture thereof.
非経口投与される溶液及び乳液である薬剤組成物は無菌
にそして適当には血液等張に調製すべきである。懸濁液
である薬剤組成物には普通の希釈剤、例えば水、エチル
アルコール、プロピレングリコール、表面活性剤（例え
ばエトキシル化イソステアリルアルコール、ポリオキシ
エチレンンルビット、ソルビタンエステルなど）の液体
希釈剤、微結晶性セルロース、メタ水酸化アルミニウム
、ベントナイト、寒天、トラガカント又はこれらの混合
物などを含ませることができる。また本発明のすべての
薬剤組成物には着色剤、保存剤、芳香及び風味添加物（
例えばはっか油、ユーカリ油など）、甘味剤（例えばサ
ッカリンなど）などを含ませることができる。Pharmaceutical compositions that are solutions and emulsions for parenteral administration should be prepared aseptically and suitably blood isotonic. For pharmaceutical compositions that are suspensions, common diluents are used, such as water, ethyl alcohol, propylene glycol, liquid diluents such as surfactants (such as ethoxylated isostearyl alcohol, polyoxyethylene rubit, sorbitan esters, etc.); Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth or mixtures thereof, etc. can be included. All pharmaceutical compositions of the invention may also contain colorants, preservatives, aroma and flavor additives (
For example, mint oil, eucalyptus oil, etc.), sweeteners (for example, saccharin, etc.), etc. can be included.
以下に本発明を実施例により具体的に説明する。 The present invention will be specifically explained below using examples.
なお本発明はこれらの実施例によシ限定されるものでは
ない。□
実施例１ 錠剤
ＫＮＣ−２２５１０Ｆ
コーンスターチ ６５ｇ
カルカルシセルロース ２０．９ポリビニルピロ
リド７ ３ｇ
ステアリン酸カルシウム ２１
００ｙ
常法によ９１錠１００ｍ９の錠剤ｔ−調整した。錠剤１
錠中、ＫＮＣ−２２５を１０１ｎ９含有する。Note that the present invention is not limited to these Examples. □ Example 1 Tablet KNC-22510F Cornstarch 65g Calcalcicellulose 20.9 Polyvinylpyrrolid 7 3g Calcium stearate 2100y 91 tablets of 100m9 were prepared by a conventional method. tablet 1
The tablet contains 101n9 of KNC-225.
（１）ステアリン酸 ９．０セ
タノール ３．５鯨ロク
２，５ラノリン
２．０ホリオキシエチレンンルビタン
モノステアレート ３．０ポリオキシエチレ
ンソルビタンモノオレート１．０ミリスチン酸２−オク
チルドデシル １０．０ＫＮＣ−２
２５４，０
重量％
（２）パラオキシ安息香酸エステル
０．０２プロピレングリコール ３．０ト
リエタノールアミン ０．５蒸留水
６１．５
上記（２）の各成分を混合加熱（７５〜８０℃）して溶
解し、これに（１）の各成分を混合加熱（７５〜８０℃
）して溶解したものを加えて乳化し、ついでこの乳化液
を室温まで冷却した。(1) Stearic acid 9.0 Cetanol 3.5 Kujiroku
2,5 lanolin
2.0 Polyoxyethylene rubitan monostearate 3.0 Polyoxyethylene sorbitan monooleate 1.0 2-octyldodecyl myristate 10.0KNC-2
254.0% by weight (2) Paraoxybenzoic acid ester
0.02 Propylene glycol 3.0 Triethanolamine 0.5 Distilled water
61.5 Mix and heat each component in (2) above (75 to 80°C) to dissolve, and then mix and heat each component in (1) (75 to 80°C).
) was added and emulsified, and then the emulsion was cooled to room temperature.
実施例３ 軟膏
重量％
（１）アラセルＣ２，５
セレシン ７．５ワセリン
１０．０ＫＮＣ−２２５５，
０
ラノリ７ １０．０（２）蒸
留 水 ２５．０上記（１）の各
成分を混合加熱（７５〜８０℃）して溶解し、これに８
０℃に加熱した（２）の蒸留水を攪拌しながら混合し、
室温まで冷却した。Example 3 Ointment weight % (1) Aracel C2,5 Ceresin 7.5 Vaseline
10.0KNC-2255,
0 Lanori 7 10.0 (2) Steaming
Distilled water 25.0 Mix and heat each component in (1) above (75 to 80°C) to dissolve, and add 8
Mix distilled water from (2) heated to 0°C with stirring,
Cooled to room temperature.
参考例Ｉ ＫＮＣ−２２５の製造
２．２−ジメチル−１，３−ジオキソラン−４−メタノ
ール３７０．５Ｊ （２，７１ｍｏｌ ）とピリジン２
２１．２ｇ（２，８ｍｏｌ ）とをジインノロビルエー
テル７００ｄに混合し、氷冷したのちモノクロロ酢酸ク
ロリド ３０７Ｆ（２，７１ｍｏｌ ）をゆっくり１０
°Ｃ以下に反応温度を保つように滴下した。滴下終了後
さらに１時間攪拌したのち反応液を水にあけついで、有
機層を５％硫酸水溶液、水、１０％炭酸水素ナトリウム
水の順で洗浄した。ついで有機層よシジインプロビルエ
ーテルを蒸発除去し、得られた残留物を減圧蒸留し、８
３℃１０．１■Ｈｇの留分を５０５．５ｇ得た。このも
のはＧＬＣ分析によると純度９３％のモノクロロ酢酸２
．２−ジメチル−１，３ジオキソラン−４−メタノール
エステルであった。Reference Example I Production of KNC-225 2.2-Dimethyl-1,3-dioxolane-4-methanol 370.5J (2,71 mol) and pyridine 2
21.2 g (2.8 mol) was mixed with diinnorobyl ether 700d, and after cooling on ice, monochloroacetic acid chloride 307F (2,71 mol) was slowly added to 10
The mixture was added dropwise while keeping the reaction temperature below °C. After the addition was completed, the mixture was stirred for an additional hour, and then the reaction solution was poured into water, and the organic layer was washed with a 5% aqueous sulfuric acid solution, water, and a 10% aqueous sodium bicarbonate solution in this order. Next, sidiimprobil ether was removed from the organic layer by evaporation, and the resulting residue was distilled under reduced pressure.
505.5 g of a fraction of 10.1 ■Hg at 3°C was obtained. According to GLC analysis, this product has a purity of 93% monochloroacetic acid 2.
．． It was 2-dimethyl-1,3 dioxolane-4-methanol ester.
得られたモノクロロ酢酸２，２−ツメチル−１，３ジオ
キンラン−４−メタノールエステル８９．７１１（０，
４ｍｏｌ ）とトリエチルホスファイト ６６．５ｇ（
０，４ｍｏｌ ）を混合し１３０℃に加熱して３．５時
間攪拌した。反応終了後減圧蒸留して１４５℃１０．２
頷Ｈｇの留分を１２３．６．Ｆ得た。このものはＧＬＣ
分析によると純度９５．７％のジェトキシホスホノ２．
２−ジメチル−１，３ジオキソラン−４−メチルアセテ
ートであった。The obtained monochloroacetic acid 2,2-methyl-1,3dioquinrane-4-methanol ester 89.711 (0,
4 mol) and triethyl phosphite 66.5 g (
0.4 mol) were mixed, heated to 130°C, and stirred for 3.5 hours. After the reaction is completed, distill it under reduced pressure to 145℃10.2
The fraction of Hg is 123.6. I got F. This one is GLC
Jetoxyphosphono2. has a purity of 95.7% according to analysis.
It was 2-dimethyl-1,3 dioxolane-4-methyl acetate.
ついで得られた・フェトキシホスホノ２．２−ジメチル
−１，３−オキソラン−４−メチルアセテート１２１．
５ｇ（０，３９ｍｏｌ ）を水素化ナトリウム（６０％
）３１．２１１（０，３９ｍｏｌ）のトルエン１１溶液
へ室温下で滴下し、さらにゲラニルアセトン７６ｇ （
０，３９ｍｏｌ ）を加え一夜攪拌した。Then the obtained .fethoxyphosphono-2,2-dimethyl-1,3-oxolane-4-methyl acetate 121.
5g (0.39mol) of sodium hydride (60%
) 31.211 (0.39 mol) in toluene 11 solution at room temperature, and further added 76 g of geranylacetone (
0.39 mol) was added thereto and stirred overnight.
反応終了後、反応液を水にあけたのち、有機層を水洗し
た。有機層よシトルエンを減圧蒸留除去し、ついで減圧
蒸留し１７０℃／ ０．１ ｍ Ｈｇの留分を８７、２
Ｆ得た。このものの分析結果をつぎに示す。After the reaction was completed, the reaction solution was poured into water, and then the organic layer was washed with water. Citoluene was removed from the organic layer by distillation under reduced pressure, and then distilled under reduced pressure to obtain a fraction of 87.2 m Hg at 170°C.
I got F. The results of this analysis are shown below.
Ｈ’ −ＮＭＲ（６０ＭＨｚ ）δＣＤＣＬ５ＭＳ
１．３（ｄ 、 Ｊ＝０．５Ｈｚ 、 ６Ｈ） 、 １
．６（ｂｒｏａｄ、 ９Ｈ） 。H'-NMR (60MHz) δCDCL5MS 1.3 (d, J=0.5Hz, 6H), 1
．． 6 (broad, 9H).
１．８０〜２．２５（ｍ、ＩＩＨ）、 ３．３０〜４．
２０（ｍ、５Ｈ）５．０５（ｂｒｏａｄ、２Ｈ）、５．
６１（ｓ、ＩＨ）この分析結果よシ上記留分がＫＮＣ−
２２５であることを確認した。ＧＬＣ分析の結果、該留
分中のこの化合物の純度は９７．４％であった。1.80-2.25 (m, IIH), 3.30-4.
20 (m, 5H) 5.05 (broad, 2H), 5.
61 (s, IH) According to the results of this analysis, the above fraction is KNC-
It was confirmed that it was 225. As a result of GLC analysis, the purity of this compound in the fraction was 97.4%.
本発明によシ提供される３、７．１１−）ジメチル−２
，６，１０−ドデカトリエン酸２．２−ジメチル−１，
３ジオキソラン−４−メタノールエステルは前記の薬理
試験の結果から明らかなとおシ優れた抗炎症作用を有し
ている。3,7.11-)dimethyl-2 provided by the present invention
, 2,2-dimethyl-1, 6,10-dodecatrienoate,
3-dioxolane-4-methanol ester has an excellent anti-inflammatory effect as evidenced by the results of the pharmacological tests mentioned above.
【図面の簡単な説明】
第１図は紫外線照射前３．７．１１− ） ＩＪツメチ
ル２、６．１０−ドデカトリエン酸２，２−ジメチル−
１゜３ジオキンラン−４−メタノールエステルを２％（
重量）含む親水ワセリン基剤軟膏を皮膚表面に塗布した
もの（本発明）、インドメタシンを塗布した群および無
処置のもの（対照群）について時間経過による紫外線紅
斑抑制作用を比較した結果を示す。
第２図は紫外線照射後３，７，１ ｉ −） ジメチル
−２、６，１０−ドデカトリエン酸２．２−ツメチル１
．３ジオキソラン−４−メタノールエステルを０．５％
（重量）含む親水ワセリン基剤軟膏を塗布したもの（本
発明）、インドメタシン（対照薬）を塗布した群および
無処置のもの（対照群）について時間経過による紫外線
紅斑抑制作用を比較した結果を示す。
特許出願人 株式会社 り ラ し
代理人 弁理士 本 多 堅[Brief explanation of the drawings] Figure 1 shows 3.7.11-) IJ-methyl 2,6.10-dodecatrienoic acid 2,2-dimethyl- before ultraviolet irradiation.
1゜3dioquinrane-4-methanol ester at 2% (
The results of a comparison of the ultraviolet erythema suppressive effect over time are shown for a group in which a hydrophilic petrolatum-based ointment containing (weight) was applied to the skin surface (the present invention), a group to which indomethacin was applied, and an untreated group (control group). Figure 2 shows 2,2-methyl 3,7,1 i -) dimethyl-2,6,10-dodecatrienoate after ultraviolet irradiation.
．． 0.5% 3-dioxolane-4-methanol ester
(weight) of a group to which a hydrophilic petrolatum-based ointment containing (the present invention) was applied, a group to which indomethacin (control drug) was applied, and a group to which no treatment was applied (control group). . Patent applicant: RiRashi Co., Ltd. Agent: Ken Honda
Claims (1)
エン酸（２，２−ジメチル−１，３−ジオキソラン−４
−イル）メチルエステルを含有する抗炎症剤。3,7,11-trimethyl-2,6,10-dodecatrienoic acid (2,2-dimethyl-1,3-dioxolane-4
-yl) methyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32102787A JPH01160918A (en) | 1987-12-17 | 1987-12-17 | Anti-inflammatory drug containing 3,7,11-trimethyl-2,6,10-dodecatrienoic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester(knc-225) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32102787A JPH01160918A (en) | 1987-12-17 | 1987-12-17 | Anti-inflammatory drug containing 3,7,11-trimethyl-2,6,10-dodecatrienoic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester(knc-225) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01160918A true JPH01160918A (en) | 1989-06-23 |
Family
ID=18127978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32102787A Pending JPH01160918A (en) | 1987-12-17 | 1987-12-17 | Anti-inflammatory drug containing 3,7,11-trimethyl-2,6,10-dodecatrienoic acid(2,2-dimethyl-1,3-dioxolan-4-yl)methyl ester(knc-225) |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01160918A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020079214A (en) * | 2001-04-13 | 2002-10-19 | 변영광 | Toilet set with a built-in foundation |
| KR20030001052A (en) * | 2001-06-28 | 2003-01-06 | 변영광 | Jet apparatus for foundation and foundation-retained cosmetic implement having it |
-
1987
- 1987-12-17 JP JP32102787A patent/JPH01160918A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020079214A (en) * | 2001-04-13 | 2002-10-19 | 변영광 | Toilet set with a built-in foundation |
| KR20030001052A (en) * | 2001-06-28 | 2003-01-06 | 변영광 | Jet apparatus for foundation and foundation-retained cosmetic implement having it |
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