【発明の詳細な説明】この発明は一般式（式中、Ｒは水素原子又はアシル基）で示される新規なゲンチアノースニトロソ尿素誘導体に
関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel gentianose nitrosourea derivative represented by the general formula (wherein R is a hydrogen atom or an acyl group).
本発明の化合物は優れた抗白血病、抗腫場作用を有しな
がら磯臓萎縮などの副作用が極めて少ない化合物であっ
て医薬品としての用途を有する。The compound of the present invention is a compound that has excellent anti-leukemia and anti-tumor effects and has extremely few side effects such as isophoric atrophy, and has use as a pharmaceutical.
本発明の化合物は次の一般式（式中は、Ｒは前記一般式
（１）と同じ意味を有する。The compound of the present invention has the following general formula (wherein R has the same meaning as in the above general formula (1)).
）で表わされるゲンチアノースウレィド誘導体をニト。) is a gentianose ureido derivative.
ソ化することにより製造することができる。ニトロソ化
剤としては公知のアルカリ金属亜硝酸塩、三酸化窒素、
四酸化窒素、塩化ニトシル等が使用できる。なお、アル
カリ金属亜硝酸塩としては亜硝酸ナトリウム又は頭硝酸
カルリゥムが好ましい。反応溶媒としてはアセトン、メ
タノール、酢酸エチル、エーテル、ジオキサン、テトラ
ヒドロフラン等の有機溶媒、ギ酸、酢酸等の有機酸、ま
たはその水溶液あるいは塩酸等の錫酸の水溶液を用いる
ことができる。It can be manufactured by SO. Known alkali metal nitrites, nitrogen trioxide,
Nitrogen tetroxide, nitosyl chloride, etc. can be used. In addition, as the alkali metal nitrite, sodium nitrite or potassium nitrate is preferable. As the reaction solvent, organic solvents such as acetone, methanol, ethyl acetate, ether, dioxane, and tetrahydrofuran, organic acids such as formic acid and acetic acid, or aqueous solutions thereof, or aqueous solutions of stannic acids such as hydrochloric acid can be used.
反応は通常−１０℃〜３０ｑｏの温度で行なわれる。反
応終了後、必要に応じて、溶媒除去、結晶化、カラムク
ロマトグラフイー、イオン交換樹脂等の公知の分離精製
操作によって、目的化合物（１）を得ることができる。
ここで本発明によって得られた化合物の抗白血病作用を
示す動物実験結果を下記表に示す。The reaction is generally carried out at a temperature of -10°C to 30qo. After the reaction is completed, the target compound (1) can be obtained by known separation and purification operations such as solvent removal, crystallization, column chromatography, ion exchange resin, etc., if necessary.
The following table shows the results of animal experiments showing the anti-leukemic effects of the compounds obtained according to the present invention.
〔動物実験〕供説動物ＣＤＦ，マウス（６週令、体重２４±２夕、１群オス４
匹）供試化合物：化合物Ａ ２″〔〔〔（２−クロロェチル）ニトロソア
ミノ〕力ルボニル〕アミノ〕一２″−デオキシゲンチア
ノース化合物Ｂ デカー○ーアセチル−２″〔〔〔（２ークロ
ロヱチル）ニトロソアミノ〕力ルボニル〕アミノ〕−２
″ーデオキシゲンチアノース実験方法：リンホィド・ロィケミアＬ２１０細胞１×１び個／マウ
スをマウスの腹腔内に移植、２独特間後に供試化合物を
腹腔内に投与し、６０日間観察する。[Animal experiment] Animals: CDF, mice (6 weeks old, weight 24 ± 2 days, 4 males per group)
Test compound: Compound A 2″ [[[(2-chloroethyl)nitrosamino]carbonyl]amino]-2″-deoxygentianose Compound B Decac○-acetyl-2″[[[(2-chloroethyl)nitroso] Amino〔carbonyl〕amino〕-2
-Deoxygentianose experimental method: 1×1 cells/mouse of Lynxoid leukemia L210 cells are implanted into the peritoneal cavity of a mouse, and after 2 hours, the test compound is intraperitoneally administered and observed for 60 days.
実験結果：マウスの平均生存日数、延命率「６０日生存
マウス数を次表に示す。Experimental results: Average survival days of mice, survival rate The number of mice surviving 60 days is shown in the following table.
表く動物実験結果）但し、上表において※１ 平均生存日数はＭＳＤ（ＭｅｄｉａｎＳｕｗｉｖ
ａＩＤａ災）で示されており、※２延命率（％）処雌群のＬｒ均Ｉ日日数−対照群の１ｒ均Ｅ】子日数対
照群の平均生存日数×１００（％）で計算された。However, in the table above, the average survival days are MSD (Median Suwiv).
*2 Life extension rate (%) Lr average number of days in the virgin group - 1r average number of days in the control group] Average survival days of the control group x 100 (%) .
以上の結果から、本発明によって得られた目的化合物は
マウスＬ１２１０白血病に対して延命効果が高いことが
確められ、顕著な抗白血作用を有する。From the above results, it was confirmed that the target compound obtained by the present invention has a high survival effect on mouse L1210 leukemia, and has a remarkable antileukemic effect.
次に、一般式（ロ）で示される本発明の出発物質である
ゲンチァノースゥレィド誘導体の製造法を参考例として
示す。Next, a method for producing a gentianothureide derivative represented by general formula (b), which is a starting material of the present invention, will be shown as a reference example.
参考例 １２″一〔〔〔（２ークロロエチル）アミノ〕力ルボニル
〕アミノ〕−２″ーデオキシーゲンチアノース〔化合物
３，一般式（０）でＲが全て水素原子の場合〕の製造法
‘１’１′，２，３，３′，３″，４，４′，４″，６
′，６″−デカ−○−アセチル−２″−（ベンジルオキ
シカルボニル）アミノーメーデオキシゲンチアノース（
化合物１）の製造法乾燥ベンゼン５０地中に１′，２，
３，３′，４，４，６−へプタ−○ーアセチルショ糖１
．１夕を溶解した溶液を磯拝しつつ３，４，６ートリ−
○−アセチルー２−（ベンジルオキシカルボニル）アミ
ノ−２ーデオキシ−Ｑ−Ｄ−グルコピラノシルフロマィ
ド８．１夕を加えた。Reference Example 1 Method for producing 2"-[[(2-chloroethyl)amino]carbonyl]amino]-2"-deoxygentianose [Compound 3, when all R's are hydrogen atoms in general formula (0)]'1'1', 2, 3, 3', 3'', 4, 4', 4'', 6
',6''-deca-○-acetyl-2''-(benzyloxycarbonyl)aminomedeoxygentianose (
Method for producing compound 1) 1', 2,
3,3',4,4,6-hepta-○-acetyl sucrose 1
．． 3, 4, and 6 treatments while soaking the solution that was dissolved for 1 night.
8.1 hours of O-acetyl-2-(benzyloxycarbonyl)amino-2-deoxy-Q-D-glucopyranosylfuromide were added.
次いで、シアノ化水銀（ロ）４．８夕、および無水硫酸
カルシウム（商品名，Ｄｒｉｅｒｉｔｅ）６夕を添加し
てから３時間加熱、還流する。室温で一夜静止後、不溶
物をロ去し、ロ液をクロロホルム２００の‘で希釈する
。Next, 4.8 hours of mercury cyanide (2) and 6 hours of anhydrous calcium sulfate (trade name, Drierite) are added, and the mixture is heated and refluxed for 3 hours. After standing overnight at room temperature, insoluble materials were removed by filtration, and the filtrate was diluted with 200% chloroform.
この溶液を水洗、次に無水硫酸ナトリウムで乾燥後、濃
縮する。得られた残笹をシリカゲルカラムクロマトグラ
フイー〔溶媒系；ベンゼンーアセトン（５：１）〕で精
製するとグラス状物質として上記化合物１が得られる。This solution is washed with water, then dried over anhydrous sodium sulfate, and then concentrated. The obtained residue is purified by silica gel column chromatography [solvent system: benzene-acetone (5:1)] to obtain the above compound 1 as a glassy substance.
さらにこれをエーテルで結晶化すると針状晶として上記
化合物１が得られる。収量：６２２雌（収率３３％）ｍＰ．：９６〜９８０○〔Ｑ〕答：＋４８．６０（ＣＩ．０，クロロホルム）Ｉ
Ｈ核磁気共鳴スペクトル（１００ＭＨＺ，ＣＤＣ１３／
ＴＭＳ）：６１．９４（Ｓ，細，Ａｃ），１．９６（Ｓ
，が，Ａｃ），２．０１（Ｓ，３日，Ａｃ），２．０３
（Ｓ，粕，ａｃ），２．１０（Ｓ，１田，球Ａｃ），２
．１４（Ｓ，幻，Ａｃ），４．７０（ｄ，ＩＨ，Ｊ＝９
．５日２，Ｈ−１″），５．６３（ｄ，ＩＨ，Ｊニ３．
５ＨＺ，Ｈ−１），７．３３（Ｓ，班，Ｃ虹５）元素分
析値：Ｃ４６日５ぶ０２９（分子量１０８９，９９）として計
算値：Ｃ，５２．２２：日，５．６２；Ｎ，１．３２％
実験値：Ｃ，５２．３８；日，５．６３：Ｎ，１．４７
％■ ２″−（ベンジルオキシカルボニル）アミ／−２
″−デオキシーゲンチアノース（化合物２）の製造法上
記化合物１，２８５を０．０２Ｍナトリウムメトキシド
メタノール溶液に溶解し、室温で１時間静暦後イオン交
換樹脂アンバーライトＩＲ−１２０（Ｈ＋）を用いてナ
トリウムイオンを除去し、ついで濃縮すると、吸湿性グ
ラス状固体として上記化合物２が得られる。Further, when this is crystallized with ether, the above compound 1 is obtained as needle-shaped crystals. Yield: 622 females (yield 33%) mP. :96-980○ [Q] Answer: +48.60 (CI.0, chloroform) I
H nuclear magnetic resonance spectrum (100MHZ, CDC13/
TMS): 61.94 (S, Thin, Ac), 1.96 (S
, is, Ac), 2.01 (S, 3 days, Ac), 2.03
(S, Kasu, ac), 2.10 (S, 1 field, ball Ac), 2
．． 14 (S, phantom, Ac), 4.70 (d, IH, J=9
．． 5 days 2, H-1''), 5.63 (d, IH, J d 3.
5HZ, H-1), 7.33 (S, group, C rainbow 5) Elemental analysis value: Calculated value as C46 day 5bu 029 (molecular weight 1089,99): C, 52.22: day, 5.62; N, 1.32%
Experimental value: C, 52.38; Sun, 5.63: N, 1.47
%■ 2″-(benzyloxycarbonyl)ami/-2
''-Production method of deoxygentianose (compound 2) The above compound 1,285 was dissolved in 0.02M sodium methoxide methanol solution, and after standing at room temperature for 1 hour, ion exchange resin Amberlite IR-120 (H+) was added. is used to remove sodium ions and then concentrated to yield the above compound 2 as a hygroscopic glassy solid.
収量：１７９の９（定量的）〔Ｑ〕客：＋３７０Ｃｏ．５，メタノール）元素分析値
：Ｃ２６日３ぶ○，７（分子量６３７．６１）として計
算値：Ｃ，４８．９８：日，６．１７：Ｎ，２．２０％
実験値：Ｃ，４８．６９；日，６．３６：Ｎ，２．４９
％｛３ｉ ２″〔〔〔（２−クロロエチル）アミノ〕力
ルボニル〕アミノ〕ーメーデオキシーゲンチアノース（
化合物３）の製造法上記化合物２，３６２雌を水素雰囲
気（３．４ｋ９／地）中、パラジウム・ブラック１００
の９の存在下、２０％メタノール水溶液中で接触還元す
る。Yield: 9 of 179 (quantitative) [Q] Customer: +370Co. 5, methanol) Elemental analysis value: C26 days 3bu○, Calculated value as 7 (molecular weight 637.61): C, 48.98: days, 6.17: N, 2.20%
Experimental value: C, 48.69; Sun, 6.36: N, 2.49
%{3i 2″
Method for producing compound 3) The above compound 2,362 was heated with palladium black 100 in a hydrogen atmosphere (3.4k9/ground).
Catalytic reduction is carried out in a 20% methanol aqueous solution in the presence of 9.
触媒を炉別後、炉液を濃縮すると、シロップ状残澄が得
られる。この残澄をメタノール６の‘に熔解し、２ーク
ロロェチルイソシアナート（０．１の上）と氷冷櫨梓下
に反応させる。After the catalyst is separated from the furnace, the furnace liquid is concentrated to obtain a syrupy residue. This residue is dissolved in 6 parts of methanol and reacted with 2-chloroethyl isocyanate (0.1%) under ice-cold water.
反応混合物より団体を炉遇し、これを酢酸エチルで洗浄
後、メタノール水溶液より再結晶して、上記化合物３を
得る。収量：１８８の９（収率５４％）ｍｐ：１３１〜１３ｙ０〔Ｑ〕宵：＋１６．００（ＣＩ．０，水）元素分析値：Ｃ２，日３７Ｎ２０，６ＣＩ・星○（分子量６２７．０
０）として計算値：Ｃ，４０．２３；日，６．２７；Ｎ
，４．４７；ＣＩ，５．６５％実験値：Ｃ，４０．２８
；日，５．９２；Ｎ，４．３３：ＣＩ，５．５６％参考
例 ２デカー○−アセチル−２″〔（〔（２−クロロエチル）
アミノ〕力ルボニル〕アミノ〕ーメーデオキシゲンチア
ノース〔化合物４，一般式（ロ）でＲが同時に全てアセ
チル基の場合〕の製造法上記化合物３，２６の９を室温
で無水酢酸１の‘とピリジン１肌の混液中で２餌時間反
応させる。A mass of the reaction mixture is heated, washed with ethyl acetate, and then recrystallized from an aqueous methanol solution to obtain the above compound 3. Yield: 9 of 188 (yield 54%) mp: 131-13y0 [Q] Evening: +16.00 (CI.0, water) Elemental analysis value: C2, day 37N20,6CI・star○ (molecular weight 627.0
Calculated value as 0): C, 40.23; day, 6.27; N
, 4.47; CI, 5.65% Experimental value: C, 40.28
; Sun, 5.92; N, 4.33: CI, 5.56% Reference example 2 Decal○-acetyl-2'' [([(2-chloroethyl)
Process for producing amino[carbonyl]amino]-medeoxygentianose [compound 4, when all R's in general formula (b) are acetyl groups] The above compound 3, 26-9 was mixed with acetic anhydride 1' at room temperature. React in a mixture of 1 part pyridine for 2 feeding hours.
この溶液を濃縮し、浅薄をエーテルと酢酸エチルから再
結晶すると、上記化合物４が得られる。収量：３６の９
（収率８６％）ｍＰ：１４１〜１４３ｑ○〔Ｑ〕啓：＋４７．５０（ＣＯ．８０，ク。The solution is concentrated and the thin layer is recrystallized from ether and ethyl acetate to obtain the above compound 4. Yield: 9 of 36
(Yield 86%) mP: 141-143q○ [Q] Re: +47.50 (CO.80, Ku.
ロホルム）元素分析値：Ｃ４，日５７Ｎ２０２６ＣＩ（
分子量１０２９．３７）として計算値：Ｃ，４７．８４
：日，５．５８；Ｎ，２．７２；ＣＩ，３．４４％実験
値：Ｃ，４７．９７；日，５．６１：Ｎ，２．７５：Ｃ
Ｉ，３．４７％以下に本発明を上記一般式（１）のＲが
水素原子およびアセチル基の場合の実施例によりさらに
詳細に説明するがＲが他のアシル基の場合もほぼ同様の
操作によって製造し得ることは明らかであろう。Roform) Elemental analysis value: C4, day 57N2026CI (
Calculated value as molecular weight 1029.37): C, 47.84
: Day, 5.58; N, 2.72; CI, 3.44% Experimental value: C, 47.97; Day, 5.61: N, 2.75: C
I, 3.47% or less The present invention will be explained in more detail by examples in which R in the above general formula (1) is a hydrogen atom and an acetyl group, but almost the same operation can be performed when R is another acyl group. It will be clear that it can be manufactured by
実施例 １２″〔〔〔（２−クロロエチル）ニトロソアミノ〕カル
ボニル〕アミノ〕ーメーデオキシゲンチアノース〔化合
物Ａ，一般式（１）でＲが全て水素原子の場合〕の製造
法上記化合物３，１００の９をギ酸２の‘に溶解し、次
いで亜硝酸ナトリウム２０雌を氷冷下、櫨拝しつつ添加
する。Example 1 Method for producing 2″ [[[(2-chloroethyl)nitrosamino]carbonyl]amino]-medeoxygentianose [Compound A, when all R in the general formula (1) is a hydrogen atom] The above compound 3, Dissolve 9 parts of 100 parts in 2 parts of formic acid, and then add 20 parts of sodium nitrite while cooling on ice.
１時間後、この反応液からイオン交換樹脂アンバーライ
トＩＲ−１２０（日十）を用いてナトリウムイオンを除
去する。After 1 hour, sodium ions are removed from the reaction solution using ion exchange resin Amberlite IR-120 (Niju).
樹脂を炉去後、炉液を減圧濃縮する。残秀をイソプロピ
ルェーテルで洗浄すると、淡黄色無定形吸湿性固体とし
て上記化合物Ａが得られる。収量：７２の９（収率７０
．８％）〔Ｑ〕客：＋３．１０（ＣＯ．３２，水）元素分析値：Ｃ２，日３６Ｎ３０，７ＣＩ（分子量６３７．９９）と
して、計算値：Ｃ，３９．５３；日，５．６９：Ｎ，６
．５９；ＣＩ，５．５６％実験値：Ｃ，３９．５１：日
，５．６４；Ｎ，６．３４：ＣＩ，５．３０％実施例
２デカー○−アセチルー２″〔〔〔（２ークロロエチル）
ニトロソアミノ〕力ルボニル〕アミノ〕ー２″ーデオキ
シゲンチアノース（化合物Ｂ，一般式（１）でＲが全て
アセチル基の場合〕の製造法上記化合物４，１００雌を
アセトン３の‘に溶解したのち、氷冷蝿梓下に三酸化窒
素を吹込む。After removing the resin from the furnace, the furnace liquid is concentrated under reduced pressure. Washing the residue with isopropyl ether gives the above compound A as a pale yellow amorphous hygroscopic solid. Yield: 9 of 72 (yield 70
．． 8%) [Q] Customer: +3.10 (CO.32, water) Elemental analysis value: C2, day 36N30,7CI (molecular weight 637.99), calculated value: C, 39.53; day, 5.69 :N, 6
．． 59; CI, 5.56% Experimental value: C, 39.51: Day, 5.64; N, 6.34: CI, 5.30% Example
2 Dekar○-acetyl-2″ [[[(2-chloroethyl)
Method for producing nitrosamino[carbonyl]amino]-2''-deoxygentianose (compound B, when all R's are acetyl groups in general formula (1)) Dissolve the above compound 4,100 in 3 parts of acetone. After that, nitrogen trioxide is injected into the ice-cooled fly Azusa.
反応液を減圧濃縮して得られる淡黄色残燈をアセトンと
ィソプロピルェーテルで処理すると黄白色固体として上
記化合物Ｂが得られる。収量：７５の９（収率７３％）ｍＰ．：６９〜７〆０（分解）〔ｏ〕奪：十５８。The pale yellow residual light obtained by concentrating the reaction solution under reduced pressure is treated with acetone and isopropyl ether to obtain the above compound B as a yellowish-white solid. Yield: 9 of 75 (yield 73%) mP. :69~7〆0 (decomposition) [o] Robbery: 158.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15544480AJPS6041078B2 (en) | 1980-11-05 | 1980-11-05 | Genthianose nitrosourea derivatives |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15544480AJPS6041078B2 (en) | 1980-11-05 | 1980-11-05 | Genthianose nitrosourea derivatives |
| Publication Number | Publication Date |
|---|---|
| JPS5780396A JPS5780396A (en) | 1982-05-19 |
| JPS6041078B2true JPS6041078B2 (en) | 1985-09-13 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15544480AExpiredJPS6041078B2 (en) | 1980-11-05 | 1980-11-05 | Genthianose nitrosourea derivatives |
| Country | Link |
|---|---|
| JP (1) | JPS6041078B2 (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60331367D1 (en) | 2002-12-30 | 2010-04-01 | Angiotech Int Ag | ACTIVE COMPOSITION OF FAST GELING POLYMERIC COMPOSITION |
| EP3779446A1 (en) | 2013-12-11 | 2021-02-17 | University of Massachusetts | Compositions and methods for treating disease using salmonella t3ss effector protein (sipa) |
| Publication number | Publication date |
|---|---|
| JPS5780396A (en) | 1982-05-19 |
| Publication | Publication Date | Title |
|---|---|---|
| CA1049004A (en) | Nitrosourea derivatives | |
| CH500203A (en) | Preparation of nucleosides | |
| Anderson et al. | Stereochemical Studies in the Aminodesoxyinositol Series. meso-Inosamine-2 and scyllo-Inosamine1 | |
| JPS6247196B2 (en) | ||
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