JPS61126093A - Subunit analog on nonreducing side of lipid a - Google Patents
Subunit analog on nonreducing side of lipid aInfo
- Publication number
- JPS61126093A JPS61126093A JP59249019A JP24901984A JPS61126093A JP S61126093 A JPS61126093 A JP S61126093A JP 59249019 A JP59249019 A JP 59249019A JP 24901984 A JP24901984 A JP 24901984A JP S61126093 A JPS61126093 A JP S61126093A
- Authority
- JP
- Japan
- Prior art keywords
- group
- tetradecanoyl
- deoxy
- compound
- phosphoryl
- 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
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
一般に細菌の細胞壁成分が生体の防御機構を調節する多
彩な生物活性を有することは知られていた。近年これら
の活性の本体を化学的に追求し、さらにその有効利用を
図ろうとする研究が各方面の関心を集めている。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) It has been generally known that bacterial cell wall components have a variety of biological activities that regulate the defense mechanisms of living organisms. In recent years, research aimed at chemically pursuing the substance of these activities and attempting to utilize them more effectively has attracted interest from various fields.
一方、ダラム陰性菌細胞壁外膜に局在するリポ多糖(L
PS)は古くから内毒素の主成分として知られ、抗腫瘍
性を含むさまざまな生物活性を発現することも知られて
いたが、その化学的、生物学的多様性、不均一性に加え
て物理性の複雑さが単離、精製を困難にし、研究の大き
な妨げとなっているのが実情であった。On the other hand, lipopolysaccharide (L
PS) has long been known as the main component of endotoxins, and is also known to exhibit various biological activities including antitumor properties, but in addition to its chemical and biological diversity and heterogeneity, The reality is that the complexity of their physical properties makes isolation and purification difficult, and is a major hindrance to research.
(従来の技術)
このリポ多糖の構成々分であるリピドAなる物質は有機
合成化学の積極的な介入により1985年に欠配するよ
うな新構造式が確立され、この構造式中の生物活性発現
部位を明らかにするための研究が本発明者らのグループ
及び大阪大学の芝哲夫、補水 正−氏らのグループによ
りそれぞれ開拓的に研究されつつある:
(几は水素または脂肪酸アシル基を示す)すなわち、そ
の構造の特徴はβ−1,6結合した2個のグルコサミン
骨格のアミノ基並びにC−5,5′位水酸基に5−ヒド
ロキシミリスチン酸がアミド及びエステル結合し、さら
にC−1,4位にリン酸基を有する両親媒性のユニーク
な分子構造である。この2個のグルコサミン骨格の左側
が非還元性サブユニットと呼ばれる部分である。(Prior art) A new structural formula for lipid A, which is a component of lipopolysaccharide, was established in 1985 through the active intervention of organic synthetic chemistry, and the biological activity in this structural formula was Research to clarify the expression site is being pioneered by the group of the present inventors and the group of Tetsuo Shiba and Tadashi Fumizu of Osaka University. ) That is, its structure is characterized by amide and ester bonds of 5-hydroxymyristic acid to the amino groups of the two β-1,6-bonded glucosamine skeletons and the hydroxyl group at the C-5,5'position; It has a unique amphipathic molecular structure with a phosphate group at the 4th position. The left side of these two glucosamine skeletons is a part called the non-reducing subunit.
本発明はこの分野における開拓的なものであるので、そ
の目的とする新規化合物については直接に参照すべき先
行文献は存しない。Since the present invention is pioneering in this field, there is no prior literature to directly refer to regarding the novel compound aimed at.
(本発明の構成)
本発明は、リビドAの生物活性を発現する最小構造並び
に活性発現部位を究明する目的をもって、まずその様々
な非還元側サブユニットの類縁体を合成し、提供するこ
とに関するものであり、これらの化合物は今後の薬理学
的研究が進むにつれて、程度の差はあるとしても、轟然
に何らかの抗腫瘍性、免疫増強性等が期待されるもので
ある。(Structure of the present invention) The present invention relates to first synthesizing and providing analogs of various non-reducing subunits of Libido A, with the aim of investigating the minimum structure that expresses the biological activity of Libido A and the site where the activity is expressed. As pharmacological research progresses in the future, these compounds are expected to have some kind of anti-tumor, immune-enhancing, etc. properties, even if there are differences in degree.
本発明の目的化合物群は次の一般式で表わされる:
ムl
ことに1 几Fic’12 0−Cl2SC141C1
4−0−014、016−0−Cl6またはC14−O
Hで表わされ、lは”12・C14・Cl6・C14−
OH,C14−0−C14またはHで表わされ、最はP
まだは水素原子で表わされ、そしてにはP、水素原子ま
たはC14で表わされるものとし、かつそのC12はト
チカッイル基、躯はテトラデカノイル基で016はヘキ
サデカノイル基を意味し、c、 −o −012は−6
−ドデカノイルオキシドデカノイル基を、C14−0−
014は−3−テトラデカノイルオキシテトラデカノイ
ル基を、Cl6 0−Cl6は−3−ヘキサデカノイル
オキシヘキサデカノイル基をそれぞれ意味し、C14−
OHは−3−ヒドロキシテトラデカノイル基でPはホス
ホリル基をそれぞれ意味するものとする。The target compounds of the present invention are represented by the following general formula:
4-0-014, 016-0-Cl6 or C14-O
It is represented by H, and l is "12・C14・Cl6・C14-
OH, C14-0-C14 or H, most commonly P
is represented by a hydrogen atom, and is represented by P, a hydrogen atom, or C14, and C12 is a toticyl group, the body is a tetradecanoyl group, and 016 is a hexadecanoyl group, c, -o -012 is -6
-dodecanoyloxidedodecanoyl group, C14-0-
014 means a -3-tetradecanoyloxytetradecanoyl group, Cl6 0-Cl6 means a -3-hexadecanoyloxyhexadecanoyl group, and C14-
OH means a -3-hydroxytetradecanoyl group and P means a phosphoryl group, respectively.
そして、上記一般式で示される本発明の目的化例えば、
上表中の化合物遥1を構造式で表わせば次のようになる
:
則
上表中、化合物&l〜■は脂肪酸の鎖長の違いによる生
物活性への影響を検討するため、リン酸基の活性発現に
対する役割及び位置特異性を明らかにするために化合物
廠v〜■を、次の脂肪酸の数や結合位置の違いによる活
性発現への影響を調べるために化合物&糧〜Mを合成し
、さらに化合物&■と■とが合成された。And, the object of the present invention represented by the above general formula, for example,
Compound Haruka 1 in the table above can be expressed as a structural formula as follows: In the table, compounds In order to clarify the role and positional specificity in the expression of activity, we synthesized the compound V~■, and in order to investigate the influence of the number of fatty acids and the bonding position on the expression of activity, we synthesized the compound &sugar~M. Furthermore, compounds &■ and ■ were synthesized.
例えば、化合物sl製造の概略を述べれば本発明者らに
よるAqrit、Biol、Chtm、第48巻、25
1−252頁(1984年)に発表した方法に準じて予
め裂したべ/ジル 2−デオキシ−2−(6−ヒトロキ
ンドデカノイルアミン)−4,6−0−イソプロピリデ
ン−α−D−グルコヒリノ/ドの2個の水酸基を同時に
ラウロイル化した後、脱インプロピリデン化すると容易
にべ/ジル 2−デオキシ−2−〔(3−0−ドデカノ
イル)ドデカノイルアミノ)−3−o−ドデカノイル−
α−D−グルコヒリノシドが得られる。このc−4位水
酸基をジフェニルホスホロクロリデートにより定量的に
リン酸化した。すべての保護基を脱離すると化合物tP
a(が得られる。For example, the outline of the production of compound sl is described in Aqrit, Biol, Chtm, Vol. 48, 25 by the present inventors.
Be/zyl 2-deoxy-2-(6-hydroquindodecanoylamine)-4,6-0-isopropylidene-α-D-, which was precleaved according to the method published on pages 1-252 (1984). Simultaneous lauroylation of two hydroxyl groups of glucohylino/do followed by deimpropylideneation easily yields be/zyl 2-deoxy-2-[(3-0-dodecanoyl)dodecanoylamino)-3-o-dodecanoyl. −
α-D-glucohyrinoside is obtained. This c-4-position hydroxyl group was quantitatively phosphorylated with diphenylphosphorochloridate. When all protecting groups are removed, the compound tP
a( is obtained.
以下に実施例としてこれを具体的に説明する:実施例工
、化合物洗1の調製
(a)ベンジル 2−デオキシ−2−(,15−ニーヒ
ドロキシドデカノイルアミン)−4,6−0−インプロ
ピリデンーα−D−グルコピラノシドの製造予め調製し
た3−ヒドロキシラウリン酸(0,25F)ルポジイミ
ド(0,31F)を加え、室温にて攪拌し、脂肪酸が完
全に活性化された後にベンジル 2−デオキシ−2−ア
ミノ−46−インブロビリデンーα−D−グルコピラノ
シド(0,43F)を加え室温にて一夜撹拌した。濾過
したp液を減圧濃縮して得たシロップ体をカラムクロマ
トグラフィー 〔Warθ−2dC−200−流出液ク
ロロポルム−メタノール(100容=1容)〕に供し目
的中間fi1m −i 。This will be explained in detail as an example below. Preparation of pyridene-α-D-glucopyranoside 3-hydroxylauric acid (0,25F) luposiimide (0,31F) prepared in advance was added and stirred at room temperature. After the fatty acid was completely activated, benzyl 2- Deoxy-2-amino-46-imbropylidene-α-D-glucopyranoside (0,43F) was added and stirred at room temperature overnight. The syrup body obtained by concentrating the filtered p liquid under reduced pressure was subjected to column chromatography [Warθ-2dC-200-effluent chloroporum-methanol (100 volumes = 1 volume)] to obtain the desired intermediate fi1m-i.
(CD、8、CHC’3 ) o I B−u c
ttt −3600−3200(OH1NB)、 1
650. 1550 (7ミ)”)、860 (M/
2C)、760−700 (/>k)。(CD, 8, CHC'3) o I Bu c
ttt -3600-3200 (OH1NB), 1
650. 1550 (7mi)”), 860 (M/
2C), 760-700 (/>k).
<b>ベンジル 2−デオキシ−2−1:(3−0−ド
デカノイル)ドデカノイルアミノ)−3−0−ドデカノ
イル−α−D−グルコピラノシドの製造前工程の化合物
(o、56P)を無水ピリジン(10ml)に溶解し、
触媒量のDMAPを加え、0°Cに冷却、撹拌しながら
ラウロイルクロライド(0,76P)を滴下し室温にて
一夜攪拌した。過剰のメタノールを加え減圧濃縮して得
たシロップ体をクロロホルムで抽出した。クロロホルム
層を2N−塩酸、10チ炭酸ソーダ水浴液、水の順に洗
浄し、無水硫酸ソーダで脱水後減圧濃縮した。得られた
生成物[IIILν”’ att’ : 3350 (
NH)、ax
1740 (ester)、1640.1540(ア
ミド)、860 (Mg2 C)、740−700 (
戸h) )をクロロホルム−メタノール(1:1.2C
1+t)に溶解し、e酸(1yttt)及び触媒量のp
−トシルスルホン酸を加え室温にて攪拌した。反応終了
後減圧濃縮して得たシロップ体をカラムクロマトグラフ
ィーにて単離精製し、目的中間体(0,43?、60%
)を得た。(a )D+ 59°(CO17、cucg
3 )。<b> Benzyl 2-deoxy-2-1: (3-0-dodecanoyl)dodecanoylamino)-3-0-dodecanoyl-α-D-glucopyranoside The compound (o, 56P) in the pre-production step was dissolved in anhydrous pyridine ( 10ml),
A catalytic amount of DMAP was added, cooled to 0°C, lauroyl chloride (0,76P) was added dropwise with stirring, and the mixture was stirred overnight at room temperature. Excess methanol was added and the mixture was concentrated under reduced pressure to obtain a syrup, which was extracted with chloroform. The chloroform layer was sequentially washed with 2N hydrochloric acid, a 10% sodium carbonate aqueous solution, and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained product [IIILν"'att': 3350 (
NH), ax 1740 (ester), 1640.1540 (amide), 860 (Mg2C), 740-700 (
h) ) in chloroform-methanol (1:1.2C
1+t), e acid (1yttt) and a catalytic amount of p
-Tosylsulfonic acid was added and stirred at room temperature. After the completion of the reaction, the syrup obtained by concentration under reduced pressure was isolated and purified by column chromatography to obtain the desired intermediate (0.43?, 60%
) was obtained. (a) D+ 59° (CO17, cucg
3).
1740 (ester)、1660.1550(ア
ミド)、740−・700(p/l)。1740 (ester), 1660.1550 (amide), 740-700 (p/l).
(C)ベンジル 2−デオキシ−2−[:(3−0−ド
デカノイル)ドデカノイルアミノ3−3−o−ドデカノ
イル−6−0−1’jチル−α−D−グルコピラノシル
の製造
前工程で得た中間体(0,261)を無水ピリジン(4
!R/)に溶解し90°Cにてトリチルクロライド(0
,131)を加え数時間攪拌した。反応終了後過剰のメ
タノールを加え減圧濃縮して得だシロップ体を定法によ
りクロロホルム抽出をした。生成物をカラムクロマトグ
ラフィー(WaCθ−ytlC−200、流出液クロロ
ホルム〕より単離精製tyn1: 3600−3200
(OH,NH)、1740(ester )、165
0.1540(アミド)、780−700(//f)。(C) Benzyl 2-deoxy-2-[: (3-0-dodecanoyl)dodecanoylamino 3-3-o-dodecanoyl-6-0-1'j obtained in the pre-production process of thyl-α-D-glucopyranosyl. The intermediate (0,261) was converted into anhydrous pyridine (4
! Trityl chloride (0
, 131) and stirred for several hours. After the reaction was completed, excess methanol was added and the mixture was concentrated under reduced pressure, and the resulting syrup was extracted with chloroform using a conventional method. The product was isolated and purified by column chromatography (WaCθ-ytlC-200, effluent chloroform) tyn1: 3600-3200
(OH, NH), 1740 (ester), 165
0.1540 (amide), 780-700 (//f).
NMRデータ(6Q MHz 、 CDCJ3 ) :
δ0.75−2.5(67H,Me 1 CH2)
、 7. 4−7.5 (20H,戸h) 。NMR data (6Q MHz, CDCJ3):
δ0.75-2.5 (67H, Me 1 CH2)
, 7. 4-7.5 (20H, door h).
(d)ベンジル 2−デオキシ−4−ジフェニルホスホ
リル−2−[(3−0−ドデカノイル)ドデカノイルア
ミノ:l−3−0−ドデカノイル−α−D−グルコピラ
ノシドの製造
前工程の中間体(0,27))を無水ジクロロメタン(
2atl)と無水ピリジン(1耐)の混合溶媒に溶解し
、DMAP (0,06?)を加え0°Cに冷却、攪拌
しながら、予め無水ジクロロメタン(1ml)に溶解し
たジフェニルホスホロクロリデート(0,2P)を滴下
した。室温にて一夜攪拌し、過剰のメタノールを加え減
圧濃縮した。残渣を定法通りクロロホルム抽出して得ら
れたリン酸化物をりooホルムとメタノールの混合溶媒
に溶かし、酢酸と水を加え45°Cにて攪拌した。反応
終了後減圧濃縮して得られたシロップ体をカラムクロマ
トグラフ イー [Waco−yet C−200、流
出液クロロホルム−メタノール(200容:1容)によ
す精cnr’ : 3600−3200 (OH,NH
)、174 Q (ester)、1670.1530
(アミド)、960 (P −、O−、/A)、
Boo−680(戸h ) 。NLvl Rデータ(q
OMkiz、元素分析 C61f494i’JO12P
として理論値(チ)C,68,83’;If(,8,9
0分析値(%)C,69,23iEI、8.58(t)
2−デオキシ−4−0−ホスホリル−2−〔(3−0−
ドデカノイル)ドデカノイルアミンクー3−0−ドデカ
ノイル−D−グルコース(化合、l/l五I)の調製
前工程で得た中間体全メタノールに溶解し、予め予備還
元したパラジウム炭素を加え、水を少量加えた後50’
Cにて水素添加を行う。反応終了後触媒をp別し、′F
5液を減圧濃縮して得た70ッグ体をプレパラティブク
ロマトグラフイー(キーゼルゲル60F254)に供し
、生成物を単離精製した。〔α〕+56(CO,16、
MrOH)。1几νfi1mp
mar(717” :
3600−3200 (OH,NH)、1740 C
gltlr)、1650.1560(アミド)、960
(P−〇−屑)、800−680 (/2k) 。NM
Rデータ(90MHJ1CDCJ3):δ0.75−1
.0 (9H,Mr)、1,0−2.5 (58H,C
H2)、70−74 (I Qi(、屑)。(d) Benzyl 2-deoxy-4-diphenylphosphoryl-2-[(3-0-dodecanoyl)dodecanoylamino: intermediate (0, 27)) in anhydrous dichloromethane (
Diphenylphosphorochloridate (2 atl) and anhydrous pyridine (1 ml) was added, cooled to 0°C, and stirred while stirring. 0.2P) was added dropwise. The mixture was stirred at room temperature overnight, added with excess methanol, and concentrated under reduced pressure. The residue was extracted with chloroform according to a standard method, and the obtained phosphorous oxide was dissolved in a mixed solvent of ooform and methanol, acetic acid and water were added, and the mixture was stirred at 45°C. After the completion of the reaction, the resulting syrup was concentrated under reduced pressure and subjected to column chromatography (Waco-yet C-200), and the effluent was poured into chloroform-methanol (200 volumes: 1 volume) cnr': 3600-3200 (OH, N.H.
), 174 Q (ester), 1670.1530
(amide), 960 (P −, O −, /A),
Boo-680 (door h). NLvl R data (q
OMkiz, elemental analysis C61f494i'JO12P
The theoretical value (chi) C, 68, 83'; If (, 8, 9
0 analysis value (%) C, 69, 23iEI, 8.58 (t)
2-deoxy-4-0-phosphoryl-2-[(3-0-
Preparation of 3-0-dodecanoyl-D-glucose (compound, l/l 5I) The intermediate obtained in the previous step was dissolved in methanol, pre-reduced palladium on carbon was added, and water was added. 50' after adding a small amount
Hydrogenation is performed at C. After the reaction is complete, separate the catalyst and
The 70-g product obtained by concentrating the 5 liquid under reduced pressure was subjected to preparative chromatography (Kieselgel 60F254) to isolate and purify the product. [α]+56(CO,16,
MrOH). 1liter νfi1mp
mar(717”:
3600-3200 (OH, NH), 1740C
gltlr), 1650.1560 (amide), 960
(P-〇-Kusu), 800-680 (/2k). N.M.
R data (90MHJ1CDCJ3): δ0.75-1
.. 0 (9H, Mr), 1,0-2.5 (58H, C
H2), 70-74 (I Qi(, scraps).
最後にこれを再びメタノールに溶解し、予備還元を済ま
せた酸化白金を加えて40’Cにて水素添加を行なった
。反応終了後クロロホルムを加えて析出した生成物を溶
解し触媒をp別し、p液を減圧濃縮して得た残渣を1.
4−ジオキサン懸濁液よシ凍結乾燥すると目的の化合物
Alの無色粉末が得られた。Finally, this was dissolved in methanol again, and pre-reduced platinum oxide was added thereto, followed by hydrogenation at 40'C. After the reaction was completed, chloroform was added to dissolve the precipitated product, the catalyst was separated, and the P liquid was concentrated under reduced pressure.
The 4-dioxane suspension was freeze-dried to obtain a colorless powder of the target compound Al.
融点180−185°C(分解)。大過剰の熱クロロホ
ルム−メタノール(2容=1容)に可溶。Melting point 180-185°C (decomposed). Soluble in large excess of hot chloroform-methanol (2 volumes = 1 volume).
実施例2 C−6位のホスホリル化の例(化合物五■製
造の中間工程)
ベンジル 2−デオキシ−2−((5−0−テトラデカ
ノイル)テトラデカノイルアミン〕−6−〇−テトラデ
カノイル−α−D−グルコピラノ゛シト(0,2r)を
無水ジクロロメタン(2ml)に溶解し、無水ピリジン
C2m1)および触媒量のDMAPを加えた後0°Cに
冷却、攪拌しながらシフ5ニルホスホロクロリデート(
0,25?)ヲ滴下し室温にて一夜攪拌した。反応液を
メタノールを加えて減圧濃縮し得られたシロップ体を常
法通りクロロホルム抽出し、生成物をカラムクロマトグ
ラフ イー 1:Waco−gel C−200、流出
液りa。Example 2 Example of phosphorylation at C-6 position (intermediate step in the production of compound 5) Benzyl 2-deoxy-2-((5-0-tetradecanoyl)tetradecanoylamine]-6-〇-tetradeca Noyl-α-D-glucopyranosite (0,2r) was dissolved in anhydrous dichloromethane (2 ml), anhydrous pyridine C (2 ml) and a catalytic amount of DMAP were added, and the mixture was cooled to 0°C and dissolved under stirring while stirring. Rochloridate (
0,25? ) was added dropwise and stirred at room temperature overnight. The reaction solution was added with methanol and concentrated under reduced pressure, and the resulting syrup was extracted with chloroform in a conventional manner, and the product was subjected to column chromatography using Waco-gel C-200.
ホルム−メタノール(400容:1容)〕にて単離精製
し目的中間体ベンジル 2−デオキシ−4゜6−ジー0
−ジフェニルホスホリル−2−0−((5−o、−テト
ラデカノイル)テトラデカノイルアミノ)−3−0−テ
トラデカノイル−α〜D−グルコピラノシドCD、2B
?>を得た。The target intermediate benzyl 2-deoxy-4゜6-di0 was isolated and purified using form-methanol (400 volumes: 1 volume).
-diphenylphosphoryl-2-0-((5-o,-tetradecanoyl)tetradecanoylamino)-3-0-tetradecanoyl-α~D-glucopyranoside CD, 2B
? > obtained.
δ7l−73(25H,戸k)0 この中間体を化合物流■製造に使用する。δ7l-73 (25H, door k) 0 This intermediate is used for the production of compound streams.
実施例3 C−6位のテトラデカノイル化の例(化合物
流M製造の中間工程)
アリル 2−ベンジルオキ7カルポニルアミノー2−チ
オキン−46−〇−インプロピリデン−6−〇−テトラ
デカノイルーβ−D−グルコビラノンド(2,Of)を
70チ酢酸水溶液(40a+?)中45°Cで数時間放
置し脱インプロピリデン化し7た。生成物をカラムクロ
マトグラフィー(Wat。Example 3 Example of tetradecanoylation at C-6 position (intermediate step in the production of compound stream M) Allyl 2-benzyloki7carponylamino-2-thioquine-46-〇-impropylidene-6-〇-tetradecanoy Ru β-D-glucobylanondo (2, Of) was left standing at 45°C for several hours in a 70% aqueous thiacetic acid solution (40a+?) to deimpropylidene. The product was purified by column chromatography (Wat.
−りelC−200、流出液クロロホルム−メタノ−・
ル(100容:1容)〕により精製した。-reelC-200, effluent chloroform-methanol
(100 volumes: 1 volume)].
〔α)D 11.3”(Ct12、クロロホルム)。[α)D 11.3” (Ct12, chloroform).
次にこのシロップ体(’1.8y)を無水ジクロロメタ
7(1(Jrttl)及び無水ピリジン(7m/)に溶
解し、0°Cで冷却、攪拌しながらミリストイル クロ
4イド(11)と反応させC−6位水酸基を選択的にア
シル化した。カラムクロマトグラフィーにより精製後、
エーテル−ヘキサンより結晶化し、アリル 2−ベンジ
ルオキシカルボニルアミノ−2−デオキ/−3,6−ジ
ーO−テトラデカノイル−β−D−グルコピラノシドの
針状結晶を得た。融点91.5−92°Co Cα)D
−15(CI、テトラデカノイル−β−D−グルコピラ
ノシド(1,2t、78%)を得た。〔α)、 + 0
.03’″(C1,1、りao*ルム) 。IRv”’
tytt’ : 3260(NH)、1740 (ts
tr)、1680,1540 (7ミト) 、 96
0 (P−0−pk) 、 8 0 0−6 8
0 CI’ll)。NMRデータ(60MHz 、
CDCJす:δ0.75−1、0 (6HlMe )、
1.0 2.4 (48H,CH2)、7〇−74(1
5H,屑)。Next, this syrup body ('1.8y) was dissolved in anhydrous dichloromethane 7 (1 (Jrttl)) and anhydrous pyridine (7 m/), cooled at 0°C, and reacted with myristoyl chloride (11) while stirring. The hydroxyl group at C-6 position was selectively acylated. After purification by column chromatography,
Crystallization from ether-hexane gave needle-like crystals of allyl 2-benzyloxycarbonylamino-2-deoxy/-3,6-diO-tetradecanoyl-β-D-glucopyranoside. Melting point 91.5-92°Co Cα)D
-15 (CI, tetradecanoyl-β-D-glucopyranoside (1,2t, 78%) was obtained. [α), + 0
.. 03''' (C1,1, riao*rum).IRv'''
tytt': 3260 (NH), 1740 (ts
tr), 1680, 1540 (7 mito), 96
0 (P-0-pk), 8 0 0-6 8
0 CI'll). NMR data (60MHz,
CDCJ: δ0.75-1, 0 (6HlMe),
1.0 2.4 (48H, CH2), 70-74 (1
5H, scrap).
この生成物を中間体として用い化合物流Mを製造する。A compound stream M is prepared using this product as an intermediate.
類似の方法によりその他の類縁体である化合物/1m〜
■が製造された。下記にこれらの化合物の物理化学的恒
数を一括して示す:
化合物AI 2−チオキン−4−〇−ホスホリル−2
−テトラデカノイルアミノ−5−o−テトラデカノイル
−D−グルコース
融点 171−173°C(分解)。〔a )p +2
0(C0,3,0,01チNEt3含有NN−ジメチル
ホルムアミド)。無色粉末。Compounds that are other analogs/1m ~ by a similar method
■ was manufactured. The physicochemical constants of these compounds are shown below: Compound AI 2-thioquine-4-〇-phosphoryl-2
-Tetradecanoylamino-5-o-tetradecanoyl-D-glucose Melting point 171-173°C (decomposed). [a) p +2
0 (C0,3,0,01CHNEt3-containing NN-dimethylformamide). Colorless powder.
化合物Affl 2−デオキシ−4−0−ホスホリル
−2−((3−0−テトラデカノイル)テトラデカノイ
ルアミン)−3−o−テトラデカノイル−D−グルコー
ス
無色粉末。融点 159−162°C(分解)。Compound Affl 2-deoxy-4-0-phosphoryl-2-((3-0-tetradecanoyl)tetradecanoylamine)-3-o-tetradecanoyl-D-glucose colorless powder. Melting point 159-162°C (decomposed).
Cα〕D+、 13 (CD、3.0.01チNE1
3含有ジメチルホルムアミド)。Cα]D+, 13 (CD, 3.0.01chi NE1
3-containing dimethylformamide).
化合物a■ 2−デオキ:y−4−0−ホスホリル−2
−C(5−0−ヘキサデカノイル)ヘキサデカノイルア
ミノ]−3−0−ヘキサデカノイル−D−グルコース
無色粉末。大過剰のクロロホルム−メタノール(6容:
1容)に可溶。融点 165−170’C(分解)。Compound a■ 2-deoxy:y-4-0-phosphoryl-2
-C(5-0-hexadecanoyl)hexadecanoylamino]-3-0-hexadecanoyl-D-glucose colorless powder. Large excess of chloroform-methanol (6 volumes:
1 volume). Melting point 165-170'C (decomposed).
化合物塵v 2−チオキン−2−CC5−0−テトラデ
カノイル)テトラデカノイルアミン〕−3−0−f ト
ラテカ/イルー’D−fkコース〔α]D+ 6.4
CCO,41、クロロホルムーメタノール(4容:1
容)〕。Compound dust v 2-thioquine-2-CC5-0-tetradecanoyl)tetradecanoylamine]-3-0-f Torateca/Ilu'D-fk course [α]D+ 6.4
CCO, 41, chloroform-methanol (4 volumes: 1
)].
化合物黒■ 2−デオキシ−2−(C5−0−テトラデ
カノイル)テトラデカノイルアミン〕−5−o−テトラ
デカノイル−1−0−ホスホリル−D−グルコース
無色粉末。融点 180−190°C(分解)。Compound Black 2-deoxy-2-(C5-0-tetradecanoyl)tetradecanoylamine]-5-o-tetradecanoyl-1-0-phosphoryl-D-glucose colorless powder. Melting point 180-190°C (decomposed).
rujol −i 。rujol -i.
IRν 1.3600〒2000 (PO(OB)2
〃4x
、OH,Nu)、1750 (ester)、1660
.1550(アミド)。IRν 1.3600〒2000 (PO(OB)2
〃4x, OH, Nu), 1750 (ester), 1660
.. 1550 (amide).
化合物雁■ 2−デオキシ−2−[(3−0−テトラデ
カノイル)テトラデカノイルアミン〕−3−0−テトラ
デカノイル−4−0−ホスホリルら
−b−0−ホスホリルーD−グルコース〔α)D+
29〔CD、33、クロロホルム−メタノール(2容=
1容)〕。Compound 2-deoxy-2-[(3-0-tetradecanoyl)tetradecanoylamine]-3-0-tetradecanoyl-4-0-phosphoryl-b-0-phosphoryl-D-glucose [α )D+
29 [CD, 33, chloroform-methanol (2 volumes =
1 volume)].
化合’fkJ/xvll12 f*キシ2 ((3
−0−テトラデカノイル)テトラデカノイルアミン〕−
4−0−ホスホリル−D−グルコース
〔α]D+ 24.5 (CO,2、クロロホルムー
メnujol −1゜
タノール(2容:3容)〕。 工凡ν、エ α 。Compound 'fkJ/xvll12 f*xi2 ((3
-0-tetradecanoyl)tetradecanoylamine]-
4-0-phosphoryl-D-glucose [α]D+ 24.5 (CO, 2, chloroform-1°tanol (2 volumes: 3 volumes)).
3600−2000 (PO(OH)2、OH,NHI
、1740 (ester入1650.1550
(アミド)。3600-2000 (PO(OH)2, OH, NHI
, 1740 (1650.1550 with ester
(amide).
化合物/4 2−デオキシ−4−〇−ホスホリルー2−
1”(3−0−テトラデカノイル)テトラデカノイルア
ミン)−6−o−テトラデカノイル−D−グルコース
〔α)D+ 30@[CO,2、クロロホルム−メタ
ノール(3容=1容)]。工エル”” ff1: 56
00ar
−2000(PO(OEI)2、OH,NH)、174
0(ester )、1660.1540(アミド)。Compound/4 2-deoxy-4-〇-phosphoryl-2-
1"(3-0-tetradecanoyl)tetradecanoylamine)-6-o-tetradecanoyl-D-glucose [α)D+ 30@[CO,2, chloroform-methanol (3 volumes = 1 volume)] .Engel"" ff1: 56
00ar -2000 (PO(OEI)2, OH, NH), 174
0 (ester), 1660.1540 (amide).
化合物/iX 2−デオキシ−2−(5−ヒドロキシテ
トラデカノイルアミン)−a−0−ホスホリル−3−〇
−テトラデカノイルーD−グルコース
〔α)D+173 [C! 0.42、クロロホルム
−メタノール(2容:1容)〕。〕エルシβ”ml :
z
3600−2000 CPo(on)2、oH,NH3
,1730Ctsttr)、 1640,1550
(アミ ド) 。Compound/iX 2-deoxy-2-(5-hydroxytetradecanoylamine)-a-0-phosphoryl-3-〇-tetradecanoyl-D-glucose [α)D+173 [C! 0.42, chloroform-methanol (2 volumes: 1 volume)]. ] Elsi β”ml:
z 3600-2000 CPo(on)2, oH, NH3
, 1730Ctsttr), 1640, 1550
(Amido).
化合物aX[2−デオキシ−2−(3−ヒドロキシテト
ラデカノイルアミン) −4−0−ホスホリル−6,6
−ジー0−テトラデカノイル−D−グルコース
〔α)D+36 (CO,7、クロロホルム)。Compound aX[2-deoxy-2-(3-hydroxytetradecanoylamine)-4-0-phosphoryl-6,6
-di0-tetradecanoyl-D-glucose [α)D+36 (CO,7, chloroform).
化合物ム■ 2−デオキシ−2−(6−ヒドロキシテト
ラデカノイルアミン) −5−0−(3−ヒドロキシテ
トラデカノイル)−4−0−ホスホリル−D−グルコー
ス
〔α)D+ 15.7 [00,28、クロロホルム−
メタノール(5容:1容)]。Compound M■ 2-deoxy-2-(6-hydroxytetradecanoylamine) -5-0-(3-hydroxytetradecanoyl)-4-0-phosphoryl-D-glucose [α)D+ 15.7 [00 ,28,chloroform-
Methanol (5 volumes: 1 volume)].
化合物&xI 2−デオキシ−4−〇−ホスホリルー2
−((3−0−テトラデカノイル)テトラデカノイルア
ミン) −5−0−[(3−0−テトラデカノイル)テ
トラデカノイル]−D−グルコース
Ca ID + 11” (C0,14、りo o ホ
ルム−)タノー°ル(3容:1容)〕。Compound &xI 2-deoxy-4-〇-phosphoryl-2
-((3-0-tetradecanoyl)tetradecanoylamine) -5-0-[(3-0-tetradecanoyl)tetradecanoyl]-D-glucose Ca ID + 11" (C0,14, o Formtanol (3 volumes: 1 volume)].
(効果)
本発明の13個の目的化合物中の若干のものは、例えば
マウスを使った実験において顕著なインターフェロンお
よび腫瘍え死因子の誘発活性を有し、またカブトガニ血
液凝固酵素の賦活化力を有することが確認されている。(Effects) Some of the 13 target compounds of the present invention have significant interferon and tumor killing factor inducing activities in experiments using mice, and also have the ability to activate horseshoe crab blood coagulation enzymes. It has been confirmed that it has.
(特許出願人 東宝薬品工業株式会社)(代理人 弁理
士 糟谷 安)(Patent applicant: Toho Pharmaceutical Industries, Ltd.) (Representative: Patent attorney Yasu Kasuya)
Claims (1)
学式、表等があります▼ ここに、R^1はC_1_2−O−C_1_2、C_1
_4、C_1_4−O−C_1_4、C_1_6−O−
C_1_6またはC_1_4−OHで表わされ、R^2
はC_1_2、C_1_4、C_1_6、C_1_4−
OH、C_1_4−O−C_1_4またはHで表わされ
、R^3はPまたは水素原子で表わされ、そしてR^4
はP、水素原子またはC_1_4で表わされるものとし
、かつそのC_1_2はドテカノイル基、C_1_4は
テトラデカノイル基でC_1_6はヘキサデカノイル基
を意味し、C_1_2−O−C_1_2は−3−ドデカ
ノイルオキシドデカノイル基を、C_1_4−O−C_
1_4は−3−テトラデカノイルオキシテトラデカノイ
ル基を、C_1_6−O−C_1_6は−3−ヘキサデ
カノイルオキシヘキサデカノイル基をそれぞれ意味し、
C_1_4−OHは−3−ヒドロキシテトラデカノイル
基でPはホスホリル基をそれぞれ意味するものとする。 2、 ▲数式、化学式、表等があります▼ で表示される13個の特定化合物であることを特徴とす
る特許請求の範囲第1項記載の単糖類誘導体。[Claims] 1. Monosaccharide derivative represented by the following general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Here, R^1 is C_1_2-O-C_1_2, C_1
_4, C_1_4-O-C_1_4, C_1_6-O-
Represented by C_1_6 or C_1_4-OH, R^2
are C_1_2, C_1_4, C_1_6, C_1_4-
OH, C_1_4-O-C_1_4 or H, R^3 is represented by P or a hydrogen atom, and R^4
is represented by P, a hydrogen atom, or C_1_4, and C_1_2 is a dotecanoyl group, C_1_4 is a tetradecanoyl group, C_1_6 is a hexadecanoyl group, and C_1_2-O-C_1_2 is -3-dodecanoyloxide dodecanoyl group. Noyl group, C_1_4-O-C_
1_4 means -3-tetradecanoyloxytetradecanoyl group, C_1_6-O-C_1_6 means -3-hexadecanoyloxyhexadecanoyl group,
C_1_4-OH represents a -3-hydroxytetradecanoyl group, and P represents a phosphoryl group. 2. The monosaccharide derivative according to claim 1, which is one of the 13 specific compounds represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59249019A JPS61126093A (en) | 1984-11-26 | 1984-11-26 | Subunit analog on nonreducing side of lipid a |
EP85114923A EP0188697A3 (en) | 1984-11-26 | 1985-11-25 | 2-deoxy-4-0-phosphoryl-2-[(3'-0-tetradecanoyl)-tetradecanoylamino]-3-0-tetradecanoyl-D-glucose and stereoisomers thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59249019A JPS61126093A (en) | 1984-11-26 | 1984-11-26 | Subunit analog on nonreducing side of lipid a |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS61126093A true JPS61126093A (en) | 1986-06-13 |
Family
ID=17186795
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP59249019A Pending JPS61126093A (en) | 1984-11-26 | 1984-11-26 | Subunit analog on nonreducing side of lipid a |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS61126093A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5191072A (en) * | 1989-09-20 | 1993-03-02 | Japan Tobacco Inc. | Lipid a monosaccharide analogues |
US5278300A (en) * | 1990-04-12 | 1994-01-11 | Japan Tobacco, Inc. | 4,6-o-hydroxyphosphoryl-glucosamine derivatives |
-
1984
- 1984-11-26 JP JP59249019A patent/JPS61126093A/en active Pending
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5191072A (en) * | 1989-09-20 | 1993-03-02 | Japan Tobacco Inc. | Lipid a monosaccharide analogues |
US5278300A (en) * | 1990-04-12 | 1994-01-11 | Japan Tobacco, Inc. | 4,6-o-hydroxyphosphoryl-glucosamine derivatives |
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