JPS58170792A - Glycerol derivative - Google Patents

Abstract

NEW MATERIAL:A compound(salt) shown by the formula I (R<1> is 21-30C aliphatic hydrocarbon; R<2>, R<3>, and R<4> are H, lower alkyl, cyclic ammonio shown by the formula II). EXAMPLE:1-(3-Docosyloxy-2-methoxy)-propyl 2-trimethyl ammonioethyl phosphate. USE:An antitumor agent. Having low toxicity and a few side effects. Being administered orally(parenterally). PROCESS:For example, a Na salt of 2-0-methylglycerol shown by the formula IIIis dissolved or dispersed into an inert solvent under anhydrous conditions, and reacted with a compound shown by the formula IV(Q is halogen sulfate, or sulfonate), to give a compound shown by the formula V. The prepared intermediate is reacted with a compound shown by the formula VI(X and Y are halogen), and after the reaction, treated with water, to give a compound shown by the formula VII, which is reacted with a compound shown by the formula VIII.

Description

【発明の詳細な説明】 本発明は医薬として有用な新規グリセロール誘導体に関
する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel glycerol derivatives useful as pharmaceuticals.

さらに詳しくは、本発明は式 ％式％ 〔式中、Ｒ１は廣素数２１−３０　Ｏ脂肪ＪＩＩＩ！廣
化水て環状アンモニオ基を示す〕で表わされるグリセロ
−ｆｉ７Ｍ導体およびその樵に関するものである。More specifically, the present invention is based on the formula % formula % [wherein R1 is a prime number 21-30 O fat JIII! The present invention relates to a glycero-fi7M conductor represented by the following formula, and its material.

上記式（Ｉ）に関し、Ｒ１で示される廣素数２１−３０
の脂肪族膨化水素残基としては直−状もしくは分校状の
飽和または不飽和基、念とえばＣ２□−６゜アルキル基
〔例、ｎ−ヘネイコシ〃、ｎ−トコ＄／＃、ｎ−トリコ
シル、ｎ−テトフコシμｎ−ペンタコシＡ／、ｎ−ヘキ
サコシ、／Ｉ／　、　ｎ−へプタコＳ／Ａ／、ｌ１ｌ−
オクタコシル、ｎ−ノナコシ〃。Regarding the above formula (I), a wide prime number 21-30 represented by R1
Examples of aliphatic swollen hydrogen residues include linear or branched saturated or unsaturated groups, such as C2□-6゜alkyl groups [e.g., n-heneikosyl, n-toco$/#, n-tricosyl] , n-tetofukoshi μn-pentakosi A/, n-hexakoshi, /I/, n-heptaco S/A/, l1l-
Octacocyl, n-nonakoshi.

ｎ−）’Ｊアーｘ　ン＋Ｎ　）　ｓ　Ｃ２１−ｓｏアル
ケニル基〔例、５−トコセニル、工Ａ／Ｓ／〜（１３−
トコセニル）、５．１３−ドコサジェニル、１５−テト
ラコセニ〜〕などがあげられ、ア〜ケ二ル基にはＺなら
びにＥ配位の場合が含まれる。これらの基は置換分とし
て、たとえば水酸基、メルカプト基。n-)'J Arx + N) s C21-so alkenyl group [e.g., 5-tocosenyl, engineering A/S/~(13-
tocosenyl), 5,13-docosagenyl, 15-tetracosenyl, etc., and the ar-kenyl group includes Z- and E-coordination cases. These groups have substituents such as hydroxyl and mercapto groups.

アミノ基、オキソ基、カルバ毫イル基、力〃ボキシル基
、ハロゲンｔ　Ｃ３−７’クロアルキル基、フェニル基
などを有していてもよい。It may have an amino group, an oxo group, a carboxylic group, a hydroxyl group, a halogent C3-7' chloroalkyl group, a phenyl group, etc.

Ｒ２，Ｒ３およびＲ′は水素または低級アルキル基を示
し、低級アルＩｆＡ／基としては、たとえばＣ□−、ア
ルキル基（例、メチ〜、エチμ）があぜては、ピリジニ
オ基、オキサゾリオ基、チアゾリオ晟、ピリダシニオ基
、キノリニオ基、イソキノリニオ基などがあげられ、こ
れらの基はさらにＣ１−４アルキル基（例、メチ〜、エ
チμ）、ヒドロキシ基、ヒドロキＶエチ〜基、アミノエ
チ〜基。R2, R3 and R' represent hydrogen or a lower alkyl group, and examples of the lower alkyl group include, for example, C□-, an alkyl group (e.g., methy~, ethyl), a pyridinio group, an oxazolio group, Examples include thiazolio, pyridacinio, quinolinio, and isoquinolinio groups, and these groups further include C1-4 alkyl groups (eg, methy~, ethyl), hydroxyl groups, hydroxyl groups, and aminoethyl groups.

アミノ（イミノ）基、カルバモイル基、ウレイド基など
の置換基を有していてもよい。上記環状アンモニオ基に
は、Ｒ２、Ｒ３、Ｒ４のい−ｒｔＬか２つの基が４級窒
素原子と環を形成し、残る１つの基が、たとえばＣ１−
４７〜キル（例、メチル、エチμ）である場合、具体的
にはＮ−メチｌｖ４〜ホμニオ基２Ｍ−メチμピペラジ
ニオ基などの基を形成する場合を含むものとする。It may have a substituent such as an amino (imino) group, a carbamoyl group, or a ureido group. In the above-mentioned cyclic ammonio group, two groups of R2, R3, and R4 form a ring with a quaternary nitrogen atom, and the remaining one group is, for example, C1-
47 to methyl (eg, methyl, ethyl μ) specifically includes cases where a group such as N-methyllv4 to hoμnio group and 2M-methyμ piperazinio group is formed.

なお、化合物（Ｉ）は、たとえば式 〔式中、Ｘ−は塩素、ブロム、Ｎつ素イオンなどのアニ
オンを示す〕および ＣＨ０−１１ ２ 〔式中、Ｃはアルカリ金属（例、Ｎ、ａ、Ｋ）イオンま
たはアルカリ土類金属（例、Ｃａｔ　Ｍｇ　）イオンを
示す〕で表わされるような塩の形で存在することもある
。In addition, compound (I) has, for example, the formula [wherein, , K) ion or alkaline earth metal (eg Cat Mg ) ion].

上記化合物（Ｉ）は、たとえば次の方法により製造しう
る。The above compound (I) can be produced, for example, by the following method.

Ａ法 ２−０−メチルグリセロ−Ａ／（１）（ジャーナル・オ
プ・ケミカル・ソサイアテイ（Ｊ、Ｃｈｅ謹。Method A 2-0-Methylglycero-A/(1) (Journal of Chemistry, Che.

８０４１、）、１９，３４．　１２３４またはＡｎｎ、
７Ｑ９　。8041,), 19,34. 1234 or Ann,
7Q9.

２４２１（１９６７）の方法で合成〕のナトリウム塩を
調製し、無水の条件下に不活性溶媒Ｋｊ１解または懸濁
させ、ヒれに式、ＲＩＱＣ式中、Ｂｌハ曲記に同り、Ｑ
はハロゲン、スルフェート、スルホネートを示す〕の化
合物を作用させて化合物（■）〔式中、Ｂｌは前記と同
意義〕を得ることができる。2421 (1967)], dissolved or suspended in an inert solvent Kj1 under anhydrous conditions, and obtained the following formula, RIQC formula, Bl is the same as the inflection, and Q
represents a halogen, sulfate, or sulfonate] to obtain a compound (■) [wherein Bl has the same meaning as above].

０Ｍ２０ＨＣＨＯＨ （１）　　　　（ＩＶ）　　　　　　　　（Ｖ）得られ
た中間体（Ｖ）に式 〔式中、Ｘ、Ｙはハロゲン（例、塩素、臭素、Ｊつ素）
を意味する〕の化合物を反応させ、反応後、水を作用さ
せることによって、式 ％式％ 〔式中、ｎｌ　　、工は前記と同意義〕の化合物を得る
。これに式 〔式中、各記号は前記と同意義〕の化合物を反応させる
ことにより化合物（Ｉ）を得る。0M20HCHOH (1) (IV) (V) The resulting intermediate (V) has the formula [wherein, X and Y are halogens (e.g., chlorine, bromine,
] is reacted, and after the reaction, water is reacted to obtain a compound of the formula % [wherein nl and engineering have the same meanings as above]. Compound (I) is obtained by reacting this with a compound of the formula [wherein each symbol has the same meaning as above].

ｌ（ 化合物（Ｖ）に式 〔式中、ＸＦｉ前記に同じ、Ｂ５またはＲ６の一方は前
記Ｒ２を、他方は−ＣＯＯＣＨ２−Ｃ５Ｈ５，−ＣＯＯ
・反応させた後、水処理、ついで公知の適当な方法にも
とず〈脱係１灰応を行なうことによって化合物（Ｉ）の
うち、式 ％式％ 〔式中、Ｂｌ、Ｂ２　は前記と一意義〕で表わされる化
合物を得る。l (Compound (V) has the formula
・After the reaction, water treatment is carried out, followed by a decoupling reaction based on a known appropriate method to obtain the compound (I) with the formula % formula % [where Bl and B2 are as described above]. A compound represented by the following formula is obtained.

前記式（Ｉ）で示されるアルキｆｉ１９ン脂質の２がオ
クタデシ／ｖＩヘキサデシＡ／、ドデシル、デシルで表
わされるような類似化合物の抗腫瘍性については既に文
献公知である。九とえば、特開昭５２−１３４０２７に
は、式（Ｉ）の化合物でＣ１６−１８のものがＩＩＩＩ
Ｋ好ましいと報告されている。The antitumor properties of similar compounds such as those in which 2 of the alkyl fi19 lipid represented by the formula (I) is represented by octadecy/vI hexadecy A/, dodecyl, or decyl are already known in the literature. For example, in JP-A-52-134027, the compound of formula (I) with C16-18 is
K is reported to be preferred.

しかしながら、本発明者等による検討の結果、Ｃ工。−
０８のものは抗腫瘍剤としては必ずしも好ましくない作
用を有してシシ、この欠点はアルキ〃基をさらに長いＣ
２□う。にすることにより除くことができるばかりでな
く、抗腫瘍作用も増強し得ることを見出し、本発明を完
成し友ものである。However, as a result of studies by the inventors, C-engineering was performed. −
08 has an action that is not necessarily desirable as an antitumor agent, and this drawback is due to the fact that the alkyl group has a longer C
2□Yes. We have now completed the present invention by discovering that it is possible to not only eliminate the tumor but also enhance its antitumor effect by treating the tumor with a tumor.

九とえばＣ工。−０８の化合物の好ましくない作用とし
ては次の点があげられる。For example, C engineering. Unfavorable effects of compound -08 include the following points.

１）式（Ｉ）の化合物でＣ工。−０８のものは血小板凝
集作用が認められる（　ＤＪ、　Ｈａｎａｈａｎａｔ　
ｏｌ、Ｂｉｏｏｈｅｍｉｏａｌ　　ａｎｌ　　Ｂｉｏｐ
ｈｙｓｉｏａｌＲｓｓ＊ａｒｏｈ　　ＣｏｍｍｕｎＩＱ
ａｔｉｏｎ＠、　！　、　１８３−１８８（１’９８１
））。血小板に対するこのような作用社、脳血栓、狭心
症など循環器障害をおこす恐れがある。またＣ工。−０
８のアルキル鎖をもつ化合物は血圧を低下させる作用が
ある。1) Process C with a compound of formula (I). -08 has platelet aggregation effect (DJ, Hanahanat
ol, Biohemioal anl Biop
hysioalRss＊arohCommunIQ
ation @, ! , 183-188 (1'981
)). Such effects on platelets may cause circulatory disorders such as cerebral thrombosis and angina pectoris. Also C engineering. -0
Compounds with 8 alkyl chains have the effect of lowering blood pressure.

これらは共に、副作用の原因となるもので好ましくない
、アルキル基の長い誘導体においては、これらの作用Ｆ
ｉ黒いか、あって屯極めて弱い。本発明者らが比較した
結果を表ＩＫ示す。Both of these are undesirable because they cause side effects, and in derivatives with long alkyl groups, these effects F
It's black, but it's extremely weak. The results of our comparison are shown in Table IK.

１１）式（Ｉ）の化合物でＣよ。、Ｃよ、の化合物社カ
ビおよび原虫の一種であるＴｅｔｒａｈｙｍｅｎａに対
し増殖阻害作用を有する。すなわち細胞に対する直接毒
性が存在する。長鎖の誘導体ではこの細胞毒性は脆いか
、あっても非常に弱く表る。従って、長ａＳＳ導体は副
作用が低減されている。表２および３にＣ工。、Ｃ工８
１０２２について比較しえ結果を示す。11) C in the compound of formula (I). , C. has a growth inhibiting effect on molds and Tetrahymena, a type of protozoa. That is, there is direct toxicity to cells. For long-chain derivatives, this cytotoxicity is weak or very weak. Therefore, long aSS conductors have reduced side effects. Tables 2 and 3 show C engineering. , C-engineer 8
The comparative results for 1022 are shown below.

式（Ｉ）で示される化合物の抗腫瘍性の作用機作は明ら
かでないが、宿主に対する免疫賦活作用が考えられる。Although the mechanism of antitumor action of the compound represented by formula (I) is not clear, it is thought to have an immunostimulatory effect on the host.

ザルコーマ１８０を用いた抗腫瘍作用の強さは表４のと
おり、長いアルキμ鎖を有する化合物が一層良い延命効
果を示した。As shown in Table 4, the strength of the antitumor effect using Sarcoma 180 showed that the compound having a long alkyl μ chain had a better survival effect.

以とのごとく、本発明に記されているＣ２□−８゜の脂
肪族膨化水素残基を有するグリセロ−ｆｉ／＃！ｉｌ導
体（Ｉ）は、特開昭５２−１３４０２７に開示されてい
る化合物に比較してすぐれた抗腫瘍効果を有するばかり
でなく、血小板凝集、血圧降下作用および細胞毒性など
Ｏｓ作用屯少いなど優れ九特徴を有している。すなわち
、化合物（Ｉ）は比較的低毒性で副作用も少なく、抗腫
瘍剤として種々の悪性腫瘍（例、白血病、固形がん）Ｋ
罹病した温血動物（と珈わけ哺乳動物）に投与し、顕著
な延命効果會奏しうる。ｔ’＋化合物（Ｉ）は通常、結
晶性粉末ｔえは粉末として得られ、親水性、ＩＩ油性と
４に充分な性質を示す。従って本発明の抗鳳嶋剤は、化
合物（Ｉ）ｔその１１でも用いることができるが、通常
、注射剤１錠剤、カプセル剤。As described below, glycero-fi/#! having a C2□-8° aliphatic swelling hydrogen residue described in the present invention. IL conductor (I) not only has superior antitumor effects compared to the compound disclosed in JP-A-52-134027, but also has less Os effects such as platelet aggregation, hypotensive effect, and cytotoxicity. It has nine excellent characteristics. That is, compound (I) has relatively low toxicity and few side effects, and is used as an antitumor agent for various malignant tumors (e.g., leukemia, solid tumors).
When administered to diseased warm-blooded animals (and other mammals), it can have a significant life-prolonging effect. The t'+ compound (I) is usually obtained as a crystalline powder, and exhibits sufficient properties such as hydrophilicity and oiliness. Therefore, the anti-hoshima drug of the present invention can also be used with Compound (I)t No. 11, but it is usually administered in the form of one tablet or capsule for injection.

液剤、軟膏など各種剤層の医薬組成物として用い、非経
口的まえは経口的に安全に投与できる。It can be used as a pharmaceutical composition in various drug layers such as liquids and ointments, and can be safely administered orally before parenterally.

注射剤２点滴注射剤等の製剤化は、たとえば生湯食塩水
を九はブドウ糠やその他の補助薬を含む水溶液を用い、
常法に従って行われる。錠剤、カプセル剤等も常法に従
ってｌ１ｌｉＩ！シうる。これらの剤型は投薬単位形部
としてその投与目的に応じて、喪とえは注射剤の場合、
静脈内、皮下、Ｊ１部への直接投与など適当＆投与経路
によシ使用される。Injections 2 Injections can be formulated using, for example, raw water and saline solution, or an aqueous solution containing grape bran and other adjuvants.
It is carried out according to common law. Tablets, capsules, etc. are also prepared using the usual method. I can do it. These dosage forms are divided into dosage unit forms depending on the purpose of administration; in the case of injections,
It is used by any appropriate administration route such as intravenous, subcutaneous, or direct administration to the J1 area.

担がん温血動物に対する投与量は通常的０．０５〜７５
ダ／峠（体重）程度、好ましくは０．５〜３０〜／ｋｇ
ｃ体重）程度の範囲で症状、投与経路等に応じて適宜決
定されうる。投与回数としては当該薬剤を毎日または２
〜５日間隔で適用することができる。を九、長時間組織
におする薬物濃度を必要水弟に持続させるために１日１
〜４回投与または長時間かりて点滴静注すること屯可能
である。The dosage for tumor-bearing warm-blooded animals is usually 0.05-75
da/touge (weight), preferably 0.5-30~/kg
It can be determined as appropriate depending on the symptoms, route of administration, etc. The number of administrations is to administer the drug daily or twice.
Can be applied at ~5 day intervals. 9. In order to maintain the drug concentration in the tissues for a long time, it is necessary to maintain the drug concentration once a day.
It is possible to administer ~4 doses or administer intravenous drip over a long period of time.

試験例１ 血小板凝集作用 （試験方法および結果〕 雄性ウサギより、血液凝固防止剤として３．１５％クエ
ン酸（血液９に対して１０割合＞１含む注射ｍを用いて
、直接採血し友０次いでｉｉ！謳下、Ｌ　Ｏ００ｒｐｍ
で１０分関連心分離することにより多血小板血漿（Ｐ　
ＲＰ　：　Ｐｌａｔｅｌｅｔ　　ｒｉｃｈｐｌａｓｍａ
　）を得九。Ｐ１？ＰをさらＫ　Ｌ　４００ｒｐ■にて
１５分関連心分離しＰｌ、４ｔ、５ｌｅｔ　−ｐｅｌｌ
ｅｔ、を得、これをＣａ　　　ｆｒｅｅ　　Ｔｙｒｏｄ
ｓ　（ｇｅｌａｔｉｎＱ、２５％含有）に懸濁し、Ｗａ
ｓｈｓａ　　Ｐ　ＲＰ　を調製した。このｗａｓｈｅａ
　　ＰＲＰ　　２５０μｍを３７Ｃにて２分攪拌後、０
．２〜０．５　ｍ　ＭのＣａ　　液、２５ｓｌ　を加え
、さらに３Ｇ秒攪拌した。ついで薬物を３Ｘ１０　　Ｍ
となるように加えた。血小板凝集は、凝集計←珊化電機
製）で測定した。被検薬物の活性は、対照ＰＥＰＩＩＣ
おけるＰＡｌｉ’による最大の光透過度（最大凝集率）
に対する抑制率から求めた。Test Example 1 Platelet aggregation effect (test method and results) Blood was collected directly from male rabbits using an injection m containing 3.15% citric acid (10 to 9 blood > 1) as a blood coagulation inhibitor. ii! Song, L O00rpm
Platelet-rich plasma (P
RP: Platelet rich plasma
) got nine. P1? P is removed, K L is separated for 15 minutes at 400 rpm, Pl, 4t, 5let -pell.
et, and this is Ca free Tyrod.
s (containing gelatin Q, 25%),
shsa P RP was prepared. This washea
After stirring PRP 250μm at 37C for 2 minutes, 0
．． 25 sl of 2-0.5 mM Ca solution was added, and the mixture was further stirred for 3 G seconds. Then add 3x10 M of drug
I added it so that Platelet aggregation was measured using an aggregometer (manufactured by Sanka Denki). The activity of the test drug was compared to the control PEPIIC.
Maximum light transmittance (maximum aggregation rate) by PAli' in
It was calculated from the inhibition rate against.

結果を表ＩＫｔとめえ。なお、表中Ｍｅはメチル基（Ｃ
Ｈ，）を示す（以下同様）。Put the results in Table IKt. In addition, Me in the table is a methyl group (C
H,) (the same applies hereafter).

表１ 血小板凝集作用 Ｃ工、Ｉ！３ツ　　　−ＩＭ６３６２．７試験例２ 細１１１に対する作用 表２の抗原虫作用については、テトフヒメナ・ビリホル
ミス（Ｔｅｔｒａｈｙｍｅｎａ　　ｐｙｒｌｆｏｒｍｉ
ｓ　）　Ｗ株を試験微生物とし、検定培地〔トリプトー
ス・ベフ゛トン（ディフコ社製）２０ｆ、＃母エキス１
ｆ、グルコース２１．蒸留水１０００ｓＪ、１モル燐酸
緩田液ｐＨ７，０、１０ｓＪ）を用い、２８℃。Table 1 Platelet aggregation effect C, I! 3 - IM6362.7 Test Example 2 Effect on Thin 111 Regarding the antiprotozoal effect in Table 2, Tetrahymena pyrlformis
s) The W strain was used as the test microorganism, and the assay medium [tryptose betatone (manufactured by Difco) 20f, #mother extract 1
f, glucose 21. Distilled water (1000 sJ), 1M phosphoric acid (Yuda's solution pH 7.0, 10 sJ), and 28°C.

４４時間ないし４８時間培養して、液体稀釈検定法によ
シ化合物の該微生物発育阻止能（ＭＭＣ）を検した。After culturing for 44 to 48 hours, the microbial growth inhibiting ability (MMC) of the compound was tested by liquid dilution assay.

表３の抗真ＩＩ（抗カビ）作用については、各種の代表
的な植物病害面を試験−とし、１襲グρコース・ブイ腫
ン障天培地を用いて、倍Ｉｋ１１１釈法によシ最小阻止
濃度（ＭＩＣ）を求めた。Regarding the antifungal activity in Table 3, various representative plant disease surfaces were tested, and the test was performed using a 1-stroke ρ course Buoy tumour-disturbed medium using the double Ik111 method. The minimum inhibitory concentration (MIC) was determined.

表２ ０１８　Ｈ３７−ＭＭ　、、　　　　　　　ＩＣ２２Ｈ
４５−ＮＭ、Ｈ３＞　４ Ｊ１工し 抗カビ作用　〔輩工Ｃ（μｇ／５Ｊ））試験例３ 抗腫瘍作用 ＮＣＲマウスに試験化合物を一匹につき２５０声ｇづつ
４日関連続腹腔内投与した。さらに２８後ザルコーマ１
８Ｇ癌細胞Ｉ　Ｘ　１０５　　個を腹腔内に投与し、食
塩水を投与しえ対照塀と比較し、その延命効果（Ｔ／Ｃ
）を調べた。結果を表４に示す。Table 2 018 H37-MM,, IC22H
45-NM, H3 > 4 J1 Antifungal Effect [Mold C (μg/5J)) Test Example 3 Antitumor Effect The test compound was administered intraperitoneally to NCR mice at a dose of 250 g per mouse for 4 days. . Another 28 years later Sarcoma 1
Ix 105 8G cancer cells were administered intraperitoneally and saline was administered, and the survival effect (T/C) was compared with that of a control wall.
) was investigated. The results are shown in Table 4.

表４ Ｃ１６Ｈ３３−ＮＭ・３１９１ Ｃ１ｓＨ３ｙ　　　　　−ＮＭｓ３　　　　２１６実施
例１ ｌ−（３−ＦコシルオキＶ−２−メトキシ）プロピル　
２−トリメチルアンモニオエチル　ホスフェート ３−ドコシｙオキシー２−メトキＶグロバ／＝−Ａ／１
．６１および２−ブロモエチルホス−５クロリデート１
．３６　ｆ　ｔベンゼン１５−に溶解し、ピリジン０．
５ｆを滴下、１１１ｍにて３時間攪拌する。ベンゼンを
留去し、水を加えて１；５時間還流する。Table 4 C16H33-NM 3191 C1sH3y -NMs3 216 Example 1 l-(3-F cosyloxyV-2-methoxy)propyl
2-trimethylammonioethyl phosphate 3-docoxy-2-methoxy Vgloba/=-A/1
．． 61 and 2-bromoethylphos-5 chloridate 1
．． 36 ft dissolved in 15-benzene and 0.36 ft in pyridine.
5f was added dropwise and stirred at 111m for 3 hours. Benzene was distilled off, water was added, and the mixture was refluxed for 1:5 hours.

冷後、濃ａｃ１３−を加えエーテル抽出、水洗後、Ｈａ
２８０．で乾燥する。溶媒を留去し、残渣に２０％トリ
メチルアミンのトルエン溶Ｍ３９ｄｔ加えて溶かし、封
管中、ｍｍに５日間放置する。反応液を乾固し、残渣に
メタノ−Ａ’３０Ｗ＃ｔおよび炭酸銀１．３３１を加え
て１．５時間還流する。熱時濾過、沈澱物を、ｈｏｔメ
タノールで十分洗浄、炉液を濃縮乾固し、残渣をシリカ
ゲｆｉＩ６０ｆを用いてカラムクロマトグラフィーをお
こない精製するっＣＨＣｌ３−　ＭｅＯＨ−Ｈ２Ｏ（６
５’　２５　：　４　）流出分画液を集め、濃縮乾固、
ＣＨＣｌ３−アセトン混液から再結晶して無色結晶０．
２２ｆ（１０襲）を得る。After cooling, add concentrated ac13- and extract with ether. After washing with water, Ha
280. Dry with. The solvent was distilled off, and 20% trimethylamine dissolved in toluene M39dt was added to the residue to dissolve it, and the mixture was allowed to stand in a sealed tube for 5 days. The reaction solution was dried and methano-A'30W#t and 1.331 g of silver carbonate were added to the residue, and the mixture was refluxed for 1.5 hours. After filtration while hot, the precipitate was thoroughly washed with hot methanol, the filtrate was concentrated to dryness, and the residue was purified by column chromatography using silicage fiI60F (CHCl3-MeOH-H2O (6
5'25:4) Collect the effluent fractions, concentrate to dryness,
Recrystallization from a CHCl3-acetone mixture gave colorless crystals of 0.
Get 22f (10 hits).

赤外吸収スペクトｗ（ＫＢｒ）ｃｍ　−２９２０ｔ　２
８５０ｅ１４８０．１２３０（Ｐ−０）、１０８０．９
６５元素分析：Ｃ３□Ｈ６６Ｎ０６Ｐ彎２Ｈ２０計算値
　Ｃ，６０，４６ｔ　”、１１．４６；Ｍ、　２．２７
；　ｐ、　５．０３ 寮ｊｌｌｌｌ　　ｃ、ｆｉｏ、８８ＳＨ，１１，８０＋
Ｍ、　２．３０ｉ　Ｐ、　４．５９ 実施例２ ｌ−（３−１＝ｘＶｆｉ／オキシ−２−メトキシ）１０
ピＡ／２−ビリジニオエチ〜　ホスフェート３−トコｖ
〜オキシー２−メトキシグロバノー／Ｌ／２．９２Ｆお
よび２−ブロモエチルホスホロジクロリゾ−）　２．１
５　ｆをベンゼン２７−に溶解し、ピリジン０．７１を
滴下し、ｗ１編にて３時間攪拌する。ベンゼンを留去し
、水を加えて１時間３０分加熱還流する。冷後、Ｑ、Ｈ
Ｃｌ　２ｗｌを加えエーテル抽出、水洗後、Ｎａ！８０
．で乾燥する。溶媒留去し、残渣にピリジン１２ｓｔを
加え６０℃で２０時間加温する。反応液を乾固し、残渣
にメタノール６０ｄおよび炭酸銀２，５ｆを加えて１時
間３０分加熱還流する。熱時ｌ過、ろ液を濃縮乾固し、
残渣をシリカゲルカラムクロマトグラフイーで精製する
。Infrared absorption spectrum w (KBr) cm -2920t 2
850e1480.1230 (P-0), 1080.9
65 elemental analysis: C3□H66N06P 2H20 calculated value C, 60, 46t'', 11.46; M, 2.27
; p, 5.03 dormitory jllll c, fio, 88SH, 11, 80+
M, 2.30i P, 4.59 Example 2 l-(3-1=xVfi/oxy-2-methoxy)10
PiA/2-Viridinioethyl~ Phosphate 3-Tocov
~Oxy-2-methoxyglobanol/L/2.92F and 2-bromoethylphosphorodichloroliso-) 2.1
5f was dissolved in benzene 27°C, 0.71ml of pyridine was added dropwise, and the mixture was stirred for 3 hours on the w1 volume. Benzene was distilled off, water was added, and the mixture was heated under reflux for 1 hour and 30 minutes. After cooling, Q, H
After adding 2 ml of Cl and extracting with ether, washing with water, Na! 80
．． Dry with. The solvent was distilled off, pyridine 12st was added to the residue, and the mixture was heated at 60°C for 20 hours. The reaction solution was dried, 60 d of methanol and 2.5 f of silver carbonate were added to the residue, and the mixture was heated under reflux for 1 hour and 30 minutes. Filter while hot, concentrate the filtrate to dryness,
The residue is purified by silica gel column chromatography.

ＣＨＣｘ３”−１１ｅＯＨ−ｎ２ｏ　（６５：　２５　
”　４　）流出分−液を集め、濃縮乾固、ＣＨＣｌ、−
アセトン混液から再結晶して目的物０．５１　（１２，
２％）を得る。CHCx3”-11eOH-n2o (65: 25
4) Collect the effluent, concentrate to dryness, CHCl, -
Recrystallize from the acetone mixture to obtain the desired product 0.51 (12,
2%).

赤外吸収スペクトＡ’（ＫＢｒ）ｆｆｉ　　：２９２０
（ＣＨ）。Infrared absorption spectrum A' (KBr)ffi: 2920
(CH).

２８５０（ＣＭ）、１２３０（Ｐ−０）、１０７Ｇ元素
分析：ＣＨＮｏ　　Ｐ・２１Ｈ８０３６２６ 計算値　Ｃ，６２，３３＋　Ｈ，１０４６ｓＮ、　２．
２０＋　ｐ、　４．８７！ 夾測値　Ｃ，６２，１４ｓ　Ｈ，１０，１０；１．２．
３３ｉ　　Ｐ、４．８９ 実施例３ （→、３−ヘキサコＶｋ’オキｙ　−２−、Ｉトキシー
１＝プロパノール ヘキナコＶμ　）ＶＬ／−ト１．０７ｆ、２−メトキＳ
’−１，３−プロパンジオ−Ａ’８４９１１および１規
定の第三級ブトキンカリ５−を第三ブチルアｐコー＃２
０−に加え攪拌下に、３．５時間還流する６反応液を減
圧下に濃縮乾固し、残渣に水１〇−９濃樵酸０２５＠ｔ
を加えクロロホルム（４〇−Ｘ２）抽出：ｊ＃酸カリウ
ム（無水）で乾燥する。2850 (CM), 1230 (P-0), 107G elemental analysis: CHNo P・21H803626 Calculated value C, 62,33+ H, 1046sN, 2.
20+p, 4.87! Expected value C, 62, 14s H, 10, 10; 1.2.
33i P, 4.89 Example 3 (→, 3-hexacoVk'oxy-2-, I-toxy 1=propanol hexacoVμ) VL/-to 1.07f, 2-methoxyS
'-1,3-propanedio-A'84911 and 1N tert-butyl alcohol 5-
6 The reaction solution was added to 0- and refluxed for 3.5 hours while stirring, and concentrated to dryness under reduced pressure, and the residue was mixed with 10-9 water, 0-9 concentrated woodcarcinic acid, and 025@t
Add and extract with chloroform (40-X2): dry with potassium acid (anhydrous).

溶媒を留去し、残渣にメタノ−μ３０ｍ？を加え沈澱物
を濾過にて集め無色固型物８５０ダ（８０％）を得る。The solvent was distilled off, and the residue was diluted with methanol-μ30m? The precipitate was collected by filtration to obtain 850 Da (80%) of a colorless solid.

赤外吸収スペクト＊（ＫＢｒ）ｃＭ　：２９２０゜２８
５０．１４７２，１４６０．１１２２（ｂ）、１−（３
−へキサコシｐオキシー２−メトキＶ）プロピｌｖ　２
−）リメチ〜アンモニオエチルホスフェート ３−ヘキサコＶ〃オキシー２−メトキシ−１−プロパノ
−７に’７５２１１１および２−プロモエチμホ辛 スホジクロリデート５０３ダをベンゼン８ｄに溶解し、
ピリジン１６５１＃Ｉをベンゼン１ｄＫ溶かし九溶液を
滴下、ｗ１温にて５時間攪拌する。反応液を減圧下に乾
固し、残渣に水１２ｍ１を加えて１．５時間還流する。Infrared absorption spectrum * (KBr) cM: 2920°28
50.1472, 1460.1122(b), 1-(3
-hexakoxypoxy-2-methoxyV)propylv 2
-) Rimethy~ammonioethylphosphate 3-hexacoV〃'752111 in oxy-2-methoxy-1-propano-7 and 2-promoethyl phosphate 503 da dissolved in benzene 8d,
Pyridine 1651#I was dissolved in 1 dK of benzene and a solution of 9 was added dropwise, followed by stirring at W1 temperature for 5 hours. The reaction solution was dried under reduced pressure, 12 ml of water was added to the residue, and the mixture was refluxed for 1.5 hours.

冷後、濃塩酸０．５−を加えクロロホルム（７０ｍｘ２
）で抽出、水洗後、硫酸ナトリウム（無水）で乾燥する
。溶媒を留去し、Ｊ！ＩＷ１に２０％トリメチルアミン
のトルエンｊｌＦ液３０　ｄを加え、封管中、ｉ１温下
に３日間放置する。反応液を減圧下に乾固、残渣に脚酸
銀５７４＃およびメタノール４ａｗｔを加えて１時間還
流する。冷後、クロロホルム−メタノ−μ−水（６５：
２５：４）８０ｇ／を加えて濾過、炉液を減圧下に乾固
、無色固型物を得九。クロロホルム−メタノール−水（
６５：２５：４）を流出溶媒とするシリカゲルカラムク
ロマトグラフィーをおこない精製する。After cooling, add 0.5-ml of concentrated hydrochloric acid and chloroform (70m x 2
), wash with water, and dry with sodium sulfate (anhydrous). The solvent was distilled off and J! Add 30 d of 20% trimethylamine toluene JIF solution to IW1 and leave it in a sealed tube at I1 temperature for 3 days. The reaction solution was dried under reduced pressure, and to the residue were added 574 # of silver legate and 4 awt of methanol, and the mixture was refluxed for 1 hour. After cooling, chloroform-methanol-μ-water (65:
25:4) was added and filtered, and the filtrate was dried under reduced pressure to obtain a colorless solid. Chloroform-methanol-water (
Purification is performed by silica gel column chromatography using 65:25:4) as the effluent solvent.

目的物を含有するフラクションを集め濃縮乾固し、無色
粉末５０ＯＮＩ（５２囁）を得る。The fractions containing the target substance are collected and concentrated to dryness to obtain 50 ONI (52 ONI) of colorless powder.

赤外吸収スベク）Ａ／（ＫＢｒ）Ｃａｌ−’　：　２９
２０゜２８５０．１４７３，１４６０，１２４０，１０
９０゜１０８０、　９７０ 実施例４ （ａ）、２−メトキＶ−３−トリアコンチルオキＶ−１
−１０パノール トリアコンチル　トシレート１．３５２１Ｆ、２−メト
キシ−１，３−プロパンジオ−〜９６８１ｆおよび１規
定の第三級ブトキンカリウム５．フ−を第ミプチ〜アμ
コー、４’２２ａｇに加え、攪拌下に３．５時間還流す
る。反応液を減圧下に濃縮乾固し、残渣に水１０ｍを加
えクロロホルム（４０ｇｔｘ２）抽出、羨酸カリウム（
無水）で乾燥する。溶媒を留去し、残渣を熱メタノール
に溶解した後、室温にて放置する。沈澱物を濾過にて集
め、無色固型物１．０７３ｆ＜８９％＞を得；ｂ。Infrared absorption Subek)A/(KBr)Cal-': 29
20°2850.1473,1460,1240,10
90°1080, 970 Example 4 (a), 2-methoxyV-3-triacontyloxyV-1
-10 panoltriacontyl tosylate 1.3521F, 2-methoxy-1,3-propanedio-~9681f and 1N tert-butquine potassium 5. The first mi petite~aμ
4'22ag and reflux for 3.5 hours with stirring. The reaction solution was concentrated to dryness under reduced pressure, 10 ml of water was added to the residue, extracted with chloroform (40 gtx2), and potassium envyate (
Dry with water (anhydrous). After evaporating the solvent and dissolving the residue in hot methanol, it was left to stand at room temperature. The precipitate was collected by filtration to obtain 1.073f<89%> of a colorless solid; b.

赤外吸収スペクトＮ（ＫＢｘ−）ａｒｌ：２９２０゜２
８５０．１４７２．１４５８．１１２０（ｔｌ）、１−
（２−メトキシ−３−トリアコンチルオキシ）プロピＪ
４／２−トリメチ〜アンモニオエチ〃ホスフェート ２−メトキシ−３−トリアコンチルオキシ−１溶解し、
ピリジン２２６１Ｆをベンゼン４ｄＫ溶・解し九溶液を
滴下し、１１ｆｆｌにて４．５時間攪拌する。Infrared absorption spectrum N (KBx-) arl: 2920°2
850.1472.1458.1120(tl), 1-
(2-methoxy-3-triacontyloxy)propyl J
4/2-trimethy~ammonioethyl phosphate 2-methoxy-3-triacontyloxy-1 dissolved,
Pyridine 2261F was dissolved in 4 dK of benzene, a solution of 9 was added dropwise, and the mixture was stirred at 11 ffl for 4.5 hours.

反応液を減圧下に乾固し、残渣に水３５ｍを加えて２．
５時間還流する。冷後、濃塩酸１ｄを加えクロロホルム
（８０ｓＪＸ５）で抽出、硫酸ナトリウム（無水）で乾
燥する。溶媒を留去し、残渣に２０％トリメチルアミン
のトルエン溶液２５ＴＩＩｔｓＰヨヒクロロホμム７ｄ
を加え、封管中６４℃にて９０時間攪拌する０反応液を
減圧下に乾固し、残渣に炭酸銀１ｆおよびメタノ−Ｊｖ
４０ｓＪを加えて１．５時間還流する。冷後クロロホル
ムーメタノールー水（６５：２５：４）８Ｇ＋ｗＪを加
えて濾過し、炉液を減圧下に乾固、無色ｌｉｌ形物を得
え。クロロホルム−メタノール−水（ｌｉ５：２５：４
）を流出溶媒とするシリカゲルカフムクロマＦグｆｆフ
ィーおよびクロロホルム−メタノ−１ｖ（３：　７　）
を流出溶媒とするシリカゲルカラムクロマトグラフィー
にテ１１１１Ｌ、無色粉末７８６１１Ｆ（６０％）を得
る。The reaction solution was dried under reduced pressure, and 35 ml of water was added to the residue.
Reflux for 5 hours. After cooling, add 1 d of concentrated hydrochloric acid, extract with chloroform (80s JX5), and dry with sodium sulfate (anhydrous). The solvent was distilled off, and the residue was mixed with a 20% toluene solution of trimethylamine 25TIIItsP 7d
and stirred in a sealed tube at 64°C for 90 hours. The reaction solution was dried under reduced pressure, and the residue was mixed with silver carbonate 1f and methanol-Jv.
Add 40 sJ and reflux for 1.5 hours. After cooling, 8G+wJ of chloroform-methanol-water (65:25:4) was added and filtered, and the filtrate was dried under reduced pressure to obtain a colorless lil-shaped product. Chloroform-methanol-water (li5:25:4
) as the effluent solvent and chloroform-methano-1v (3:7)
Silica gel column chromatography using 1111L and 78611F (60%) as a colorless powder was obtained as an effluent solvent.

赤外１［ｊＺべ９　）＊（ＫＢｒ）　ａｒ’：　　２９
００゜２８３Ｇ、１４７５，１４６１，１２４５，１０
９０゜１０６・０．　９６８Infrared 1 [jZbe9) * (KBr) ar': 29
00°283G, 1475, 1461, 1245, 10
90°106・0. 968

Claims (1)

【特許請求の範囲】 式 〔式中、Ｒ１は次素数２１−３０の脂肪族膨化水て環状
アンモニオ基を示す〕で表わされるグリセロ−ｐ誘導体
またはその樵。[Scope of Claims] A glycero-p derivative represented by the formula [wherein R1 represents an aliphatic swollen water cyclic ammonio group having a prime number of 21 to 30] or its derivative.