JPS5936623A - Inducing agent for interferon - Google Patents
Inducing agent for interferonInfo
- Publication number
- JPS5936623A JPS5936623A JP14743382A JP14743382A JPS5936623A JP S5936623 A JPS5936623 A JP S5936623A JP 14743382 A JP14743382 A JP 14743382A JP 14743382 A JP14743382 A JP 14743382A JP S5936623 A JPS5936623 A JP S5936623A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- interferon
- compound expressed
- methanol
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
【発明の詳細な説明】 有する新規なインターフェロン誘起剤に関する。[Detailed description of the invention] The present invention relates to a novel interferon-inducing agent having the following properties.
−(ンターフエロン(以下IFNと略す)はウィルスの
侵入またはその他の刺激によって動物の細胞が産生ずる
ウィルス増殖抑制因子であり、1957年の発見以来行
なわれた数々の研究により抗ウィルス作用および抗lΦ
瘍作用を有する物質としてたいへん注目されている。- (Interferon (hereinafter abbreviated as IFN) is a viral growth inhibitory factor produced by animal cells in response to virus invasion or other stimuli. Numerous studies conducted since its discovery in 1957 have shown that it has antiviral effects and anti-lΦΦ
It is attracting a lot of attention as a substance that has cancer effects.
IFNは白血球、培養線維芽細胞、腎臓細胞またはヒー
ラ細胞等の細胞により生産されることが知られているが
、工業的生産の観点からは量産化にまだ問題を残してい
る。Although IFN is known to be produced by cells such as leukocytes, cultured fibroblasts, kidney cells, and HeLa cells, there are still problems in mass production from an industrial production standpoint.
また、宿主を刺激してIFNの産生を促進させるIFN
−誘起物質の研究が行なわれ、これまでにいくつかの物
質で臨床試験においてインフルエンザ、ヘルペス、肝炎
等のウィルス性疾患または癌に効果を示すことが報告さ
れているが副作用の点で問題を残しているのが現状であ
る。In addition, IFN stimulates the host to promote IFN production.
-Research on inducers has been conducted, and several substances have been reported to be effective against viral diseases such as influenza, herpes, hepatitis, and cancer in clinical trials, but problems remain in terms of side effects. The current situation is that
かかる状況を鑑み、本発明者らは漢方生薬のメタノール
エキスおよびその成分について研究を重ねた結果、一般
式(1)で示される化合物にIFN−誘起活性を見出し
本発明を完成した。In view of this situation, the present inventors have conducted extensive research on methanol extracts of traditional Chinese herbal medicines and their components, and as a result, have found IFN-inducing activity in the compound represented by general formula (1), and have completed the present invention.
・1′1該化合物は検力で袖精、強壮、止杆、利尿の要
檗として多数の処方に繁用されている黄苔(オウギ)の
成分として本発明者らが単離・確認〔11本生薬学会第
27年会(1980年)、日本薬学会11101年会(
1981年)にて発表〕した化合物であり、その生物/
+Tir1については今まで確認されていなかった。・1'1 This compound was isolated and confirmed by the present inventors as a component of Aspergillus orientalis, which is frequently used in many prescriptions as a key ingredient for energization, tonicity, stasis, and diuresis. 11 27th Annual Meeting of the Pharmaceutical Society of Japan (1980), 11101st Annual Meeting of the Pharmaceutical Society of Japan (1980)
1981), and its biological/
+Tir1 has not been confirmed until now.
以1・、本発明のインターフェロン誘起剤の製造法およ
びインターフェロン誘起効果について1.1細に説明す
る。Hereinafter, 1.1 will explain in detail the method for producing the interferon-inducing agent of the present invention and the interferon-inducing effect.
ただし、1・記試験においては一般式(1)の化合物の
中で代表的な2袖の化合物(化合物Aおよび化合物B)
を用いた。However, in the test described in 1., two representative compounds (compound A and compound B) among the compounds of general formula (1) were used.
was used.
20(R)、24(S)−エポキシ−16β、25−ジ
ヒドロキシ−3/j−0−[JI−n−(2−0−アセ
チル)−キシロピラノシル]−6α−〇−β−D−グル
コピラノシル−9,19−シクロラ20(R)、24(
S)−エポキシ−6α、16β、25−トリヒドロキシ
−3β−0−(β−D−グルコピラノシル(l→2)−
β−D−キシロピラノシル)−9,19−シクロラノス
タン
化合物Aおよび化合物Bは黄養をメタノール、エタノー
ル(いずれも含水であってもよい)、含水アセトン、水
等で加温抽出し、n−ヘキサン、ベンセン、四ル化炭素
、ジクロロメタン、クロロホルム、酢酸エチル、エーテ
ル等で分配転溶して夾雑物を除去したのち、n−ブタノ
ールにて分配転溶して得たエキスをクロロホルム・メタ
ノール・水混液、n−ブタノール・酢酸エチル・水混液
等を展開溶媒としてシリカゲルカラムクロマトグラフィ
ーに(Jすことにより容易に得られる。20(R),24(S)-Epoxy-16β,25-dihydroxy-3/j-0-[JI-n-(2-0-acetyl)-xylopyranosyl]-6α-〇-β-D-glucopyranosyl- 9,19-cyclola 20(R), 24(
S)-epoxy-6α,16β,25-trihydroxy-3β-0-(β-D-glucopyranosyl(l→2)-
β-D-xylopyranosyl)-9,19-cyclolanostane Compound A and Compound B are obtained by heating and extracting aspergillus with methanol, ethanol (both may contain water), water-containing acetone, water, etc. After removing impurities by dissolving and dissolving with hexane, benzene, carbon tetrachloride, dichloromethane, chloroform, ethyl acetate, ether, etc., the extract obtained by dissolving and dissolving with n-butanol was mixed with chloroform, methanol, and water. It can be easily obtained by subjecting it to silica gel column chromatography using a mixture of n-butanol, ethyl acetate, water, etc. as a developing solvent.
1F)l−M超活性はウィルスのRNA合成阻害の程度
をa標として、銘木法[Japan、J、Mjcrob
iol。1F) l-M superactivity is determined by the precious wood method [Japan, J, Mjcrob
iol.
18(6) 、 449−456(1974))にて1
■−ウリジンの取り込み間をシンナレーション・カウン
ターで測定することにより定撤した。18(6), 449-456 (1974)) 1
(2) - The incorporation of uridine was determined by measuring with a scintillation counter.
7r)ス(ddY系、雄性、10M令、体ff133±
2g、各群5匹)を実験動物として、後記製造例におい
て製造した化合物Aおよび化合物Bを各々生理食塩水に
て1illl I!l L、、30mg / kg腹腔
内に投与して8時間、24時間および96時間後にマウ
ス尾切断により採血し、この血液を300Orpmで1
0分間通6分離し、採取した血液中のIFN力価を測定
した。7r) Su (ddY line, male, 10M age, body ff133±
2 g, 5 animals per group) were used as experimental animals, and each of Compound A and Compound B produced in the Production Example described later was added to 1 illll I! of physiological saline. 8 hours, 24 hours and 96 hours after intraperitoneal administration of 30 mg/kg, blood was collected by cutting the mouse tail, and this blood was injected at 300 rpm for 1 hour.
After 6 minutes for 0 minutes, the IFN titer in the collected blood was measured.
IFN力価は稀釈した上記血清を用いて、マウスLY細
胞〔マウス皮下脂肪組織由来の線維芽細胞株〕に対する
水損性口内炎ウィルス(VSV:ニュージャージー株)
の増殖に伴うRN^合成を″H−ウリジンの取り込み量
で測定し、取り込みを50%抑制するIFNの稀釈倍数
を計算し、1Fhl力価とした6なお標準品としては旧
H標準IFNを用いた。その結果を国119j#位にて
下記の表1に示す。The IFN titer was determined using the diluted serum above and tested against water-vesting stomatitis virus (VSV: New Jersey strain) against mouse LY cells [a fibroblast cell line derived from mouse subcutaneous adipose tissue].
The RN^ synthesis accompanying the proliferation of ``H-uridine'' was measured by the amount of uptake of ``H-uridine,'' and the dilution factor of IFN that suppressed the uptake by 50% was calculated, and the titer was determined as 1Fhl6.The old H standard IFN was used as the standard. The results are shown in Table 1 below for country 119j#.
表1 インターフェロン(IFN)力価化合物Aまたは
化合物Bにより誘起されたIFN力価は、いずれも投与
後24時間後に高値を示した。Table 1 Interferon (IFN) titer The IFN titers induced by Compound A or Compound B both showed high values 24 hours after administration.
次に、化合物Aおよび化合物Bの投与量とIFN誘起活
性との関係について説明する。Next, the relationship between the dosage of Compound A and Compound B and the IFN-induced activity will be explained.
マウスCddY系、雌性、lO0週令体重33±2g。Mouse CddY strain, female, 100 weeks old, weight 33±2 g.
各群5匹)を実験動物として、後記製造例において製造
した化合物Aおよび化合物Bを各々生理食鴇水にて調整
し、3 mg / kn、30咄/kg、300 mg
/ kg IILI腔内に投かして24時間後にマウ
ス尾切断により採血し、以下11i前記と同様にしてI
FN−誘起活性を調べた。その結果は国際単位にてIC
記の表2に示す。Using 5 animals in each group as experimental animals, Compound A and Compound B produced in the production example described below were each adjusted in physiological saline at doses of 3 mg/kn, 30 mu/kg, and 300 mg.
24 hours after injecting into the IILI cavity, blood was collected by cutting the tail of the mouse, and the following procedure was performed in the same manner as above.
FN-induced activity was examined. The results are given in international units.
It is shown in Table 2 below.
表2 インターフェロン(IFN)誘起活性化合物Aま
たは化合物BによるIFN誘起活性は、いずれも30暉
/kg以上の投与、量により発現された。Table 2: Interferon (IFN)-inducing activity The IFN-inducing activity of Compound A or Compound B was expressed by administration of 30 days/kg or more.
さらに、上記試験例において、化合物Aまたは化合物B
によりマウス血清中に誘起されたVSVウィルス感染1
!11 止物質ハ、37°0.3時間のトリプシン処理
により失活することが確認された。Furthermore, in the above test example, compound A or compound B
VSV virus infection induced in mouse serum by
! 11 It was confirmed that the inhibitory substance C was inactivated by trypsin treatment at 37° for 0.3 hours.
(6)
従って、化合物Aまたは化合物BによりIFNが誘起さ
れていることは明らかである。(6) Therefore, it is clear that IFN is induced by Compound A or Compound B.
また化合物Aおよび化合物Bの急性毒性(LD%。)は
マウス(ddY系、雌性、5週令、体重20±1g、各
群5匹)において囮腔内および経口投与のいずれの場合
も3000mg / kg以上であり、毒性は極めて低
かった。In addition, the acute toxicity (LD%) of Compound A and Compound B was 3000 mg / kg or more, and the toxicity was extremely low.
一般式(1)の化合物は経口的あるいは非経口的に投与
することができ、経口投与の剤型としては錠剤、コーテ
ィング剤、散剤、顆粒剤、カプセル剤、シロップ剤など
が、また非経口投与の剤型としては注射剤、坐剤などが
使用できる。The compound of general formula (1) can be administered orally or parenterally, and dosage forms for oral administration include tablets, coatings, powders, granules, capsules, syrups, etc. The dosage forms that can be used include injections and suppositories.
これらの剤型の調整は薬学的に許容される賦形剤、結合
剤、滑沢剤、崩壊剤、懸濁剤、乳化剤、防腐剤、安定化
剤および分融剤などを適宜用いて行なわれる。投与量は
m省の症状、体重などに応じて異なるが成人に対する1
日量として20〜2000mg、好ましくは100〜5
00 mgを1〜4回に分けて投与することができる。Adjustment of these dosage forms is carried out using pharmaceutically acceptable excipients, binders, lubricants, disintegrants, suspending agents, emulsifiers, preservatives, stabilizers, and dispersing agents as appropriate. . The dosage varies depending on symptoms, body weight, etc., but 1 for adults.
The daily dose is 20-2000 mg, preferably 100-5
00 mg can be administered in 1 to 4 divided doses.
□ 以上述べたごとく、化合物Aまたは化合物B(9)
に代表される一般式〔1〕の化合物はIF)l誘起剤と
して有用であり、ウィルス性疾患並びに癌の治療剤どし
てit独または併用して用いることのできるものである
。□ As mentioned above, compounds of the general formula [1] represented by Compound A or Compound B (9) are useful as IF) inducers, and are widely used as therapeutic agents for viral diseases and cancer. They can be used in combination.
以下に製造例を掲げて具体的に説明すると共に製剤例に
ついてその代表的組成を例示する。Production examples are listed below for specific explanation, and representative compositions of formulation examples are illustrated.
製造例
細切した市販のMl(オウギ、韓国産)1 kgを3Q
のメタノール中に浸し70’Oで3時間抽出した。抽出
残渣は同様の方法で4回抽出を繰返し、抽出?Vv液を
まとめて減圧下溶媒を留去し、抽出物150gを得た。Production example: 1 kg of commercially available Ml (Australian japonica, produced in Korea), cut into small pieces, was mixed with 3Q
of methanol and extracted at 70'O for 3 hours. The extraction residue was extracted 4 times using the same method. The Vv liquid was combined and the solvent was distilled off under reduced pressure to obtain 150 g of an extract.
この抽出物全71を3鉦の50%含水メタノールに溶解
し、まずn−ヘキサン3Q、次いでクロロホルム311
1を用いてそれぞれ4回分配転溶させ、転溶物を除去し
た。残った含水メタノール液層より減圧下でメタノール
を留去し、残渣にn、ブタノール1.5Qを加えて分配
転溶させ、同様の操作を4回繰り返した。転溶に用いた
トブタノールをまとめ、減圧下で溶媒を留去して抽(1
0)
出エキス50gを得た。All 71 of this extract was dissolved in three 50% aqueous methanol, first 3Q of n-hexane, then 311 of chloroform.
1 was used to transfer the solution four times each, and the transferred material was removed. Methanol was distilled off from the remaining water-containing methanol liquid layer under reduced pressure, and 1.5 Q of butanol was added to the residue for distribution and dissolution, and the same operation was repeated four times. The tobutanol used for the dissolution was combined, the solvent was distilled off under reduced pressure, and the extraction was carried out (1
0) 50g of extract was obtained.
このエキス20gをクロロホルム・メタノール・水の混
合溶媒〔クロロホルム:メタノール:水=7:1:0−
5の割合(容量比)で混合し一昼夜静置後の下層〕を用
いてシリカゲルカラムクロマトグラフィーに付し、溶出
開始後12〜14Qの両分を分取し、乾燥後域1]三下
で溶媒を留去して化合物A OJgを得た。また、溶出
開始後18〜20Mの画分を分取し、乾燥後減圧下で溶
媒を留去して化合物B O,4gを得た。得られた化合
物の融点、赤外吸収スペクトルは下記のとおりであった
。20g of this extract was added to a mixed solvent of chloroform, methanol, and water [chloroform:methanol:water=7:1:0-
After mixing at a ratio of 5 parts (volume ratio) and allowing it to stand for a day and night, the lower layer was subjected to silica gel column chromatography, and after the start of elution, both fractions 12 to 14Q were collected, and after drying, the lower layer was The solvent was distilled off to obtain compound A OJg. Further, after the start of elution, a 18-20M fraction was collected, dried, and then the solvent was distilled off under reduced pressure to obtain 4 g of compound BO. The melting point and infrared absorption spectrum of the obtained compound were as follows.
化合物A 融点: 268〜271°0赤外吸収スペ
クトル(all−″)
シY:a’、 : 3400(by、) 、 1739
化合物B 融点、216〜220”0赤外吸収スペク
トル(φ−″)
KBr: 3350(br−)
′maよ
製剤例
(1)錠剤
(11)
化合物A 100mgマンニト
ール 35mg微結晶セルロース
26mg10イタルシリカ
13+ngタ ル り
12mgポリビニルピロリドン
10mgステアリンMマグネシウム
4暉0)顆粒剤
化合物B 100mgデンプン
30暉乳 糖
32mg結晶セルロ
ース 42mgポリビニルアルコール
6mg〔3〕注射剤Compound A Melting point: 268-271°0 Infrared absorption spectrum (all-'') Y: a', : 3400 (by,), 1739
Compound B Melting point, 216-220"0 infrared absorption spectrum (φ-") KBr: 3350 (br-) 'mayo Formulation example (1) Tablet (11) Compound A 100mg mannitol 35mg microcrystalline cellulose
26mg10 Ital Silica
13+ng tarri
12mg polyvinylpyrrolidone 10mg stearin M magnesium
4 hours 0) Granule Compound B 100 mg starch 30 hours lactose sugar
32mg crystalline cellulose 42mg polyvinyl alcohol 6mg [3] Injection
Claims (1)
ェロン誘起剤。[Scope of Claims] 1) An interferon inducer containing a compound represented by general formula (1): as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14743382A JPS5936623A (en) | 1982-08-25 | 1982-08-25 | Inducing agent for interferon |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP14743382A JPS5936623A (en) | 1982-08-25 | 1982-08-25 | Inducing agent for interferon |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS5936623A true JPS5936623A (en) | 1984-02-28 |
Family
ID=15430211
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP14743382A Pending JPS5936623A (en) | 1982-08-25 | 1982-08-25 | Inducing agent for interferon |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5936623A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6298816A (en) * | 1985-10-24 | 1987-05-08 | Matsushita Electric Ind Co Ltd | Attenuation device |
US7674784B2 (en) | 2004-09-29 | 2010-03-09 | Morinaga Milk Industry Co., Ltd. | Drug and food or drink for improving hyperglycemia |
US20100092584A1 (en) * | 2006-12-20 | 2010-04-15 | Jung Sik Lee | Composition Comprising the Extract of Combined Herbs for Preventing and Treating Liver Disease |
-
1982
- 1982-08-25 JP JP14743382A patent/JPS5936623A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6298816A (en) * | 1985-10-24 | 1987-05-08 | Matsushita Electric Ind Co Ltd | Attenuation device |
US7674784B2 (en) | 2004-09-29 | 2010-03-09 | Morinaga Milk Industry Co., Ltd. | Drug and food or drink for improving hyperglycemia |
US20100092584A1 (en) * | 2006-12-20 | 2010-04-15 | Jung Sik Lee | Composition Comprising the Extract of Combined Herbs for Preventing and Treating Liver Disease |
US8986756B2 (en) * | 2006-12-20 | 2015-03-24 | Jung Sik Lee | Composition comprising the extract of combined herbs for preventing and treating liver disease |
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