JPH03133987A - 2-mitomycin c-succinyl-1,3-dipalmitoylglycerol and production thereof - Google Patents
2-mitomycin c-succinyl-1,3-dipalmitoylglycerol and production thereofInfo
- Publication number
- JPH03133987A JPH03133987A JP1271369A JP27136989A JPH03133987A JP H03133987 A JPH03133987 A JP H03133987A JP 1271369 A JP1271369 A JP 1271369A JP 27136989 A JP27136989 A JP 27136989A JP H03133987 A JPH03133987 A JP H03133987A
- Authority
- JP
- Japan
- Prior art keywords
- mmc
- dpg
- dipalmitoylglycerol
- mitomycin
- succinyl
- 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
- 229960004857 mitomycin Drugs 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims abstract description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-M succinate(1-) Chemical compound OC(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-M 0.000 claims abstract description 6
- GFAZGHREJPXDMH-UHFFFAOYSA-N 1,3-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC GFAZGHREJPXDMH-UHFFFAOYSA-N 0.000 claims abstract description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003443 succinic acid derivatives Chemical class 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims description 8
- BVKFQEAERCHBTG-UHFFFAOYSA-N 17,18,19-trihydroxypentatriacontane-16,20-dione Chemical compound CCCCCCCCCCCCCCCC(=O)C(O)C(O)C(O)C(=O)CCCCCCCCCCCCCCC BVKFQEAERCHBTG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 206010028980 Neoplasm Diseases 0.000 abstract description 9
- 238000013268 sustained release Methods 0.000 abstract description 5
- 239000012730 sustained-release form Substances 0.000 abstract description 5
- 230000014759 maintenance of location Effects 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229940014800 succinic anhydride Drugs 0.000 description 7
- 102000009027 Albumins Human genes 0.000 description 6
- 108010088751 Albumins Proteins 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000021314 Palmitic acid Nutrition 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000010109 chemoembolization Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101500021165 Aplysia californica Myomodulin-A Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- -1 succinyl compound Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- 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］
本発明はマイトマイシンＣ脂溶性プロドラッグとして有
用な２−マイトマイシンＣ−スクシニル−１，３−ジパ
ルミトイルグリセロールおよびその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to 2-mitomycin C-succinyl-1,3-dipalmitoylglycerol useful as a mitomycin C lipophilic prodrug and a method for producing the same.
［従来の技術］
肝細胞癌に対する保存的療法として制癌薬の徐放化を目
的としたりビオドール−化学塞栓療法（以下Ｌｉｐ（１
１ｐｌｏｄｏり−ＴＡＩＥ（ｔｒａｎｓｃａｔｈｅｔｅ
ｒａｒｔｅｒｉａｌ ｅＩｌｂｏｌｌｚａｔｉｏｎ ：
経カテーテル化学塞栓療法）という）が−膜化されつつ
ある。しかしながら、大部分の制癌薬は水溶性でリピオ
ドールへの配合性がわるいために腫瘍組織中での滞溜性
や徐放化に問題があり、充分な効果を発揮できないばあ
いが多い。[Prior art] As a conservative therapy for hepatocellular carcinoma, biodol-chemoembolization therapy (hereinafter referred to as Lip (1)) is used for the purpose of sustained release of anticancer drugs.
1plodori-TAIE (transcatethete
Lateral eIlbollzation:
Transcatheter chemoembolization (transcatheter chemoembolization) is becoming increasingly popular. However, since most anticancer drugs are water-soluble and have poor incorporation into Lipiodol, they have problems with retention in tumor tissues and sustained release, and are often unable to exhibit sufficient effects.
水溶性制癌薬の一つであるマイトマイシンＣ（以下、Ｍ
ＭＣという）は、式：
で示され白血病および肺や消化管の固形癌に対して微量
で効果を有する優秀な制癌薬である。Mitomycin C (hereinafter referred to as M
MC) is represented by the formula: It is an excellent anticancer drug that is effective against leukemia and solid cancers of the lungs and gastrointestinal tract in trace amounts.
しかしながらＭＭＣは骨髄、ヒ臓、消化管などに重篤な
副作用をおよぼすためその使用は制限を受けざるをえな
い。このような副作用を軽減し、より有効な癌治療薬と
するために、腫瘍組織への移行性の改善が行なわれてお
り、ＭＭＣをアルブミン小球体（ニス・フジモト、エフ
拳エントウ、エム・ミャザキ、アール・デイ−・シュレ
ッサ、ケー・オクイおよびワイ・モリモト、ザ・ジャパ
ニーズ・ジャーナル・オブ・サージヤリ−１１４巻、２
５２頁（１９８４年） （Ｓ、 Ｐｕｊｌｍｏｔｏ。However, since MMC causes serious side effects on the bone marrow, human liver, gastrointestinal tract, etc., its use must be restricted. In order to reduce these side effects and make it a more effective cancer treatment drug, efforts have been made to improve the ability of MMC to migrate into tumor tissue. , R.D. Shlessa, K. Okui and Y. Morimoto, The Japanese Journal of Surgery, Vol. 114, 2.
52 pages (1984) (S, Pujlmoto.
Ｐ、 Ｅｎｄｏｈ、 Ｍ、旧Ｙａｚａｋｊ、 Ｒ，Ｄ、
５ｈｒｏｓｔｈａ、 Ｋ。P, Endoh, M, former Yazakj, R,D,
5hrostha, K.
０ｋｕ１ ａｎｄ Ｙ、 Ｍｏｒｌｍｏｔｏ、 Ｊｐｎ
、 Ｊ、 Ｓｕｒｇ、、１４．２５２（１９８４）））
、マイクロカプセル（ティー・カド−およびアール・ネ
モト、プロシーデインゲス・オブ・ザφジャパン・アカ
デミ−５８４巻、４１３頁（１９７８年） （Ｔ、 Ｋ
ａｔｏ ａｎｄ Ｒ，Ｎｅｍｏｔｏ、 Ｐｒｏｃ。0ku1 and Y, Morlmoto, Jpn
, J. Surg, 14.252 (1984))
, Microcapsules (T. Cado and R. Nemoto, Proceedings of the φ Japan Academy - Vol. 584, p. 413 (1978) (T, K
ato and R, Nemoto, Proc.
Ｊｐｎ、 Ａｃａｄ、、 ５４８．４１３（１９７８）
））などの微粒子キャリヤーに含有させる方法や、高分
子プロドラッグとする方法（ワイ赤タカクラ、ニー・タ
カギ、エム・ハシダおよびエイチ・セザキ、ファーマシ
ューティカル・リサーチ、４巻、２９３〜３００頁（１
９８８年） （Ｙ、 Ｔａｋａｋｕｒａ、 Ａ、 Ｔａ
ｋａｇｌ、Ｍ。Jpn, Acad, 548.413 (1978)
)), or as a polymeric prodrug (Takakura Yakakura, Takagi Nie, Hashida M, and H Sezaki, Pharmaceutical Research, Vol. 4, pp. 293-300 ( 1
988) (Y, Takakura, A, Ta
kagl, M.
１１ａｓｈｉｄａ ａｎｄ Ｉｌ、 ５ｅｚａｋ１．
Ｐｈａｒｍ、 Ｒｅｓ、、１．２９３−３００（１９８
ｇ）））が検討されている。中でも高分子プロドラッグ
は、医薬品としての安定性の面からも有用である。一般
に医薬品は高分子化により、その体内挙動が変化する。11ashida and Il, 5ezak1.
Pharm, Res, 1.293-300 (198
g))) is being considered. Among these, polymeric prodrugs are useful from the standpoint of stability as pharmaceuticals. Generally, when pharmaceuticals are made into polymers, their behavior in the body changes.
また癌細胞の倉食能は凡退しており、高分子は癌細胞に
貧食されやすいといわれている。このような考えに基づ
いて、生体高分子である血清アルブミンを制癌薬の高分
子キャリヤーとして利用した例としては、ツルーエツト
らのダウノマイシン（ニー・ツルーエツト、エム争マス
ケラ−、アール拳バウレインおよびデイ−・デイ−・カ
ムベニアー、プロシーディング・オブ・ザ・ナショナル
・アカデミ−・オブ・サイエンス・オブ・ザ・ユナイテ
ッド会ステーツΦオブ・アメリカ、７９巻、６２８〜Ｂ
２９頁（１９１３２） （＾、 Ｔｒｏｕｅｔ、 Ｍ。It is also said that the phagocytic ability of cancer cells has declined, and that polymers are easily phagocytosed by cancer cells. Based on this idea, an example of using the biopolymer serum albumin as a macromolecular carrier for an anticancer drug is daunomycin by Truetz et al.・Dei Camvenier, Proceedings of the National Academy of Sciences of the United States of America, Volume 79, 628-B
Page 29 (19132) (^, Trouet, M.
Ｍａｓｑｕｅｌｌｅｒ、 Ｒ，Ｂａｕｒａｌｎ ａｎｄ
Ｄ、 Ｄ。Masqueller, R. Bauraln and
D, D.
Ｃａｗｐｅｎｅｅｒｅ、 Ｐｒｏ、Ｎａｔｌ、 Ａｃａ
ｄ、 Ｓｃ１． ＵＳＡ、旦。Cawpeneere, Pro, Natl, Aca
d, Sc1. USA, Dan.
６２（ｉ−８２９（１９８２）））ならびにホワイトレ
イらのメトトレキセート（ビー・シー・エフ・チューお
よびジェイ・エム・ホワイトレイ、モレキュラー−ファ
ーマコロンー、１３巻、８０〜８８頁（１９７７年）
（Ｉｌ、 Ｃ，Ｐ、 Ｃｈｕ ａｎｄ Ｊ、 Ｍ、 Ｗ
ｈＨａｌｅｙ、 Ｍｏｌ。62 (i-829 (1982))) and methotrexate of Whiteley et al. (BFC Chu and JM Whiteley, Molecular Pharmacolour, Vol. 13, pp. 80-88 (1977))
(Il, C, P, Chu and J, M, W
hHaley, Mol.
Ｐｈａｒｍａｃｏｌ、、１３．８Ｏ−８８（１９７７）
））の例があげられる。Pharmacol, 13.8O-88 (1977)
)) can be given as an example.
また、特開昭６１−６０８１７号公報には、ヒト血清ア
ルブミンを結合したＭＭＣが開示されている。Further, Japanese Patent Application Laid-Open No. 61-60817 discloses MMC bound to human serum albumin.
しかしながら、ヒトアルブミン結合ＭＭＣは水溶性であ
ってリピオドールには懸濁状態で添加せざるをえない。However, human albumin-bound MMC is water-soluble and must be added to Lipiodol in a suspended state.
゛またアルブミンは蛋白質中では低分子量であるとはい
え、分子ｆｆｉ ３３４の）４ＭＣに比べれば格段に大
きな分子量をもつものなのでアルブミン結合ＭＭＣ１分
子中のＭＭＣの重量比は小さなものとなる。すなわち必
要量を投与するために要するアルブミン結合ＭＭＣの量
は、投与しようとするＭＭＣよりも遥かに大量になって
しまう。これは患者への投与にあたっての大きな負担と
なり問題がある。さらにアルブミンは低分子化合物のよ
うな、一定サイズの分子ではないから、生じたアルブミ
ン結合ＭＭＣ自体も、ある分子量分布を有する。このこ
とは投薬後のアルブミン結合ＭＨＯの挙動にもある巾を
みなければならず、問題がある。Although albumin has a low molecular weight among proteins, it has a much larger molecular weight than 4MC (of the molecule ffi 334), so the weight ratio of MMC in one molecule of albumin-bound MMC is small. In other words, the amount of albumin-bound MMC required to administer the required amount is much larger than the amount of MMC to be administered. This poses a problem as it poses a heavy burden on patients when administering it. Furthermore, since albumin is not a molecule of a fixed size like a low-molecular compound, the resulting albumin-bound MMC itself also has a certain molecular weight distribution. This is a problem, as the behavior of albumin-bound MHO after administration must also be considered to a certain extent.
かように、現状ではＬｉｐ−ＴＡＩＥにおいては、通常
水溶性のＭＭＣがリビオドール懸濁剤として配合使用さ
れている。As described above, currently in Lip-TAIE, water-soluble MMC is usually mixed and used as a Libiodol suspending agent.
したがって、リピオドール配合性の高い、かつ腫瘍組織
での滞溜性および徐放性の改善されたＭＭＣのプロドラ
ッグの出現が広く期待されている。Therefore, the emergence of a prodrug of MMC that is highly compatible with Lipiodol and has improved retention and sustained release properties in tumor tissues is widely expected.
［発明が解決しようとする課題］
本発明者らは前述の実情に鑑み鋭意研究した結果、ＭＭ
Ｃと１．３−ジパルミトイルグリセロールをコハク酸を
介して化学的に結合させた化合物（２−ＭＭＣ−スクシ
ニル−１，３−ジパルミトイルグリセロール（以下ＤＰ
Ｇ−８−ＭＭＣという）およびその合成法を見出し本発
明を完成するに至った。[Problem to be solved by the invention] As a result of intensive research in view of the above-mentioned circumstances, the present inventors have found that MM
A compound in which C and 1,3-dipalmitoylglycerol are chemically bonded via succinic acid (2-MMC-succinyl-1,3-dipalmitoylglycerol (hereinafter referred to as DP)
G-8-MMC) and its synthesis method were discovered and the present invention was completed.
［課題を解決するための手段］
本発明は式（■）：
で示される２−マイトマイシンＣ−スクシニル−１，３
一ジバルミトイルグリセロール化合物、およびｌ、３−
ジパルミトイルグリセロールをコハク酸誘導体と反応せ
しめ、えられた式（■）：ＣＨ２０ＣＯ（Ｃ）＋２）
Ｍ ＣＨｓ冒
で示される１、３−ジパルミトイル−２−グリセロール
ハイドロジエンスクシネートをマイトマイシンＣと反応
させることを特徴とする式（Ｉ）：で示される２−マイ
トマイシンＣ−スクシニル−１，３−ジパルミトイルグ
リセロールの製造法に関する。[Means for Solving the Problems] The present invention provides 2-mitomycin C-succinyl-1,3 represented by the formula (■):
monodivalmitoylglycerol compound, and l,3-
Dipalmitoylglycerol was reacted with a succinic acid derivative, resulting in the formula (■): CH20CO(C)+2)
2-Mitomycin C-succinyl-1,3 represented by formula (I), characterized by reacting 1,3-dipalmitoyl-2-glycerol hydrogen succinate represented by M CHs with mitomycin C. -Relating to a method for producing dipalmitoylglycerol.
［実施例］ 本化合物は、たとえば以下のステップで合成される。[Example] The present compound is synthesized, for example, by the following steps.
（ａｌ ｌ 、 ３−ジパルミトイル−２−グリセロー
ルハイドロジエンスクシネート（以下、ＤＰＧ−３とい
う）の合成
本工程においては１．３−ジパルミトイルグリセロール
と２〜１０倍当量、生成物の分離を効率よく行なう目的
で好ましくは５倍当量の無水コハク酸を、クロロホルム
、ジクロロメタン、テトラヒドロフランなどの無水有機
溶媒に加えさらにトリエチルアミン、ジメチルアミノピ
リジンなどの塩基性触媒の存在下で８〜４８時間、反応
収率と副生成物の兼ねあいから好ましくは２０〜２４時
間、４０℃以上で溶媒の還流を行って反応させる。つい
で常法にしたがい、洗浄、脱水、溶媒の溜去後、再結晶
を行なう。(al l, Synthesis of 3-dipalmitoyl-2-glycerol hydrogen succinate (hereinafter referred to as DPG-3) In this step, 2 to 10 times the equivalent of 1,3-dipalmitoylglycerol, and separation of the product is performed. For the purpose of efficient reaction, preferably 5 times the equivalent of succinic anhydride is added to an anhydrous organic solvent such as chloroform, dichloromethane, or tetrahydrofuran, and the reaction is further reacted for 8 to 48 hours in the presence of a basic catalyst such as triethylamine or dimethylaminopyridine. In view of yield and by-products, the reaction is preferably carried out by refluxing the solvent at 40° C. or above for 20 to 24 hours.Then, after washing, dehydration and distillation of the solvent, recrystallization is carried out according to a conventional method.
山＞ ２−ＭＭＣ−スクシニル−１，３−ジパルミトイ
ルグリセロール（ＤＰＧ−９−ＭＭＣ） （１）の合成
本工程においては前記工程でえられたＤＰＧ−８と１−
エチル−３−（３−ジメチルアミノプロピル）カルボジ
イミド塩酸塩（ＥＤＣ）とをクロロホルム、ジクロロメ
タンなどの無水有機溶媒に溶解し、テトラヒドロフラン
、アセトニトリルなどの無水有機溶媒に溶解したＭＭＣ
をＤＰＣ−９に対して１〜５倍当量、反応収率と生成物
の分離を向上する目的で好ましくは１．１１倍当量を加
え、１０〜２５℃、ＭＭＣの安定性を確保するために好
ましくは２０℃で、８〜４８時間、生成物の安定性を確
保するために好ましくは２４時間反応させる。反応混合
物を常法にしたがい溶媒を溜去し、カラムクロマトグラ
フィーによる分離を行ない、紫色のワックス状化合物と
して目的物をうる。Mountain> Synthesis of 2-MMC-succinyl-1,3-dipalmitoylglycerol (DPG-9-MMC) (1) In this step, DPG-8 obtained in the above step and 1-
MMC prepared by dissolving ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in an anhydrous organic solvent such as chloroform or dichloromethane, and then dissolving it in an anhydrous organic solvent such as tetrahydrofuran or acetonitrile.
Add 1 to 5 times equivalent of DPC-9, preferably 1.11 times equivalent for the purpose of improving reaction yield and product separation, at 10 to 25 ° C., to ensure stability of MMC. The reaction is preferably carried out at 20° C. for 8 to 48 hours, preferably 24 hours to ensure product stability. The solvent is distilled off from the reaction mixture in a conventional manner and the product is separated by column chromatography to obtain the desired product as a purple waxy compound.
実施例１
（ａ）１．３−ジパルミトイル−２−グリセロールハイ
ドロジエンスクシネート（ＤＰＧ−８）の合成マンテリ
（Ｍａｎｔｅｌｌｉ）の方法（ニス・マンテリ、ピー・
スペイーザーおよびエッチ・ハウザーケミストリー・ア
ンド・フィジイックス・オブ・リピッヅ、３７巻、３２
９〜３４３頁（１９８５年）（Ｓ、 Ｍａｎｔｅｌｌｌ
、 Ｐ、 ５ｐｅｉｓｅｒ ａｎｄ Ｈ，Ｈａｕｓｏｒ
。Example 1 (a) Synthesis of 1.3-dipalmitoyl-2-glycerol hydrogen succinate (DPG-8) Mantelli's method (Nis. Mantelli, P.
Spaeser and H. Hauser Chemistry and Physics of Lipids, Volume 37, 32
pp. 9-343 (1985) (S, Mantell
, P. 5peiser and H. Hausor
.
Ｃｈｅｗ、 Ｐｈｙｓ、 ＬｉｐＩｄｓ、 ３７．３２
９−３４３（１９８５）））にしたがって行なった。Chew, Phys, LipIds, 37.32
9-343 (1985))).
１．３−ジパルミトイルグリセロール（１０ｇ）と、微
粉末とした無水コハク酸（９ｇ）に蒸留したクロロホル
ム（１８０ｍｌ）とトリエチルアミン（６，３ｍ１）を
加えて還流した。反応は薄層クロマトグラフィーで追跡
した。２４時間後、反応液を０．ＩＭＩＩ Ｃ１２００
ｍｌと蒸留水２００ｍ１で５回ずつ洗浄した。Distilled chloroform (180 ml) and triethylamine (6.3 ml) were added to 1,3-dipalmitoylglycerol (10 g) and finely powdered succinic anhydride (9 g), and the mixture was refluxed. The reaction was followed by thin layer chromatography. After 24 hours, the reaction solution was reduced to 0. IMII C1200
ml and distilled water 5 times each.
クロロホルム層に無水硫酸ナトリウムを加えて脱水し、
エバポレーターで溶媒を留去し、淡黄色の粗結晶をえた
。ｎ−ヘキサン／アセトン（９／１）（体積比、以下同
様）を用いて再結晶し、白色の綿状品７．９ｇ （収率
８７．２％）をえた（融点７２．５〜７３．３℃（７５
℃、日周第二法））。Add anhydrous sodium sulfate to the chloroform layer to dehydrate it.
The solvent was distilled off using an evaporator to obtain pale yellow crude crystals. Recrystallization was performed using n-hexane/acetone (9/1) (volume ratio, same hereinafter) to obtain 7.9 g (yield 87.2%) of a white flocculent product (melting point 72.5-73. 3℃ (75
°C, diurnal second law)).
山） ２−ＭＭＣ−スクシニル−１，３−ジパルミトイ
ルグリセロール（ＤＰＣ−８−ＭＭＣ）の合成前記工程
（ωでえられたＤＰＧ−８（７２ｍｇ）とＥＤＣ（ｌｌ
Ｂｍｇ）を蒸留したクロロホルム（２，４ｍ１）に溶か
し、室温で２０分間撹拌した。これにＭＭＣ（４０ａ＋
ｇ）を無水テトラヒドロフラン（１８ｍｌ）に溶かした
溶液を加え、室温で撹拌した。２４時間後、反応液をろ
過し溶媒を留去した。これをシリカゲルカラム（２，６
φＸ３０ＣＩ１１．和光純薬工業■製ワコーゲルＣ−２
００）にのせ、クロロホルム：メタノール：１０％（ｖ
／ｗ％） Ｎ１１４０１１水溶液（９：１： ｏ、ｔ
（体積比））で分離した。流出液５ｍｌずつを分取し、
２６〜３５番目のフラクションを集めて溶媒を留去した
。残渣を真空デシケータ中で乾燥し、紫色のワックス状
化合物８２．８＋ｇｇ （収率７８．１％）をえたく融
点３８．７〜４３．１”Ｃ）。Synthesis of 2-MMC-succinyl-1,3-dipalmitoylglycerol (DPC-8-MMC)
Bmg) was dissolved in distilled chloroform (2.4 ml) and stirred at room temperature for 20 minutes. Add to this MMC (40a+
A solution of g) in anhydrous tetrahydrofuran (18 ml) was added, and the mixture was stirred at room temperature. After 24 hours, the reaction solution was filtered and the solvent was distilled off. This was applied to a silica gel column (2,6
φX30CI11. Wakogel C-2 manufactured by Wako Pure Chemical Industries ■
00), chloroform: methanol: 10% (v
/w%) N114011 aqueous solution (9:1: o, t
(volume ratio)). Collect 5 ml of the effluent,
The 26th to 35th fractions were collected and the solvent was distilled off. The residue was dried in a vacuum desiccator to yield 82.8+ gg (78.1% yield) of a purple waxy compound (melting point 38.7-43.1"C).
実施例１でえられた２−ＭＭＣ−スクシニル−■、３−
ジバルミトイルグリセロール（ＤＰＧ−８−ＷＨＯ）に
ついての検討を以下に記す。2-MMC-succinyl-■,3- obtained in Example 1
A study on dibalmitoylglycerol (DPG-8-WHO) is described below.
（薄層クロマトグラフィー）
ＤＰＧ−８およびＤＰＧ−８−ＭＭＣは薄層クロマトグ
ラフィー（ＴＬＣ）において単一スポットを示した。(Thin layer chromatography) DPG-8 and DPG-8-MMC showed a single spot in thin layer chromatography (TLC).
第１表に両者および原料などのＲｒ値をまとめて示す。Table 1 shows the Rr values of both materials and raw materials.
［以下余白］
第１表
（注）
＊■化合物
ＤＰＧ １．３−ジパルミトイルグリセロールＳＡ
無水コハク酸
ＰＡ パルミチン酸
本２展開溶媒（体積比）
ａｎ−へキサン：酢酸エチル−５：２
ｂ 石油エーテル：エチルエーテル：
酢酸−８０：４０： １
Ｃクロロホルム：メタノール＝ｌＯ％水酸化アンモニウ
ム水溶液−９：ｌ：０．１
ｄ イソプロパツール：酢酸エチル−２＝ｌａｎ−ヘキ
サン：酢酸エチル−５：３
展開溶媒ａを用いたばあい、ＤＰＧ−８のスポットはＤ
ＰＧとは異なったＩ？ｆ値を示し、実施例１によってえ
られたＤＰＧ−８ではＤＰＧのスポットを認めなかった
。一方、展開溶媒すを用いたところ、ＤＰＧとＤＰＧ−
９は同一のＲｆ値を示したが、ＤＰＧ−８のスポットは
カルボン酸の存在を示す紅色を呈した。またこのＲｒ値
は反応原料の無水コハク酸（ＳＡ）やＤＰＧ分解物とし
て考えられるパルミチン酸（ＰＡ）のＲｒ値とは異なっ
た。以上、Ｔｌ、Ｃによる検討の結果、ＤＰＧ−８は単
一物質で、ＤＰＧ 、無水コハク酸、パルミチン酸と異
なる物質であることが示された。ＤＰＧ−８−ＭＭＣは
展開溶媒ｃＳｄ。[Margin below] Table 1 (note) *■Compound DPG 1.3-dipalmitoylglycerol SA
Succinic anhydride PA Palmitic acid Book 2 developing solvent (volume ratio) an-hexane: ethyl acetate - 5:2 b petroleum ether: ethyl ether: acetic acid - 80:40: 1 C chloroform: methanol = 10% ammonium hydroxide aqueous solution -9:l:0.1d isopropanol:ethyl acetate-2=lan-hexane:ethyl acetate-5:3 When using developing solvent a, the DPG-8 spot is D
I different from PG? f value, and no DPG spot was observed in DPG-8 obtained in Example 1. On the other hand, when a developing solvent was used, DPG and DPG-
9 showed the same Rf value, but the DPG-8 spot took on a red color indicating the presence of carboxylic acid. Further, this Rr value was different from that of succinic anhydride (SA), which is a reaction raw material, and palmitic acid (PA), which is considered to be a decomposed product of DPG. As a result of the above investigation using Tl and C, it was shown that DPG-8 is a single substance, which is different from DPG, succinic anhydride, and palmitic acid. DPG-8-MMC is a developing solvent cSd.
ｅにおいていずれも紫色の単一スポットを示し単一物で
あることが確かめられた。また第１表で明らかなように
ＤＰＧ−８−ＭＭＣのＲｒ値は、ＤＰＧ−３ならびにＭ
ＭＣと異なるものであった。All of them showed a single purple spot in e, confirming that they were a single substance. Furthermore, as is clear from Table 1, the Rr value of DPG-8-MMC is different from that of DPG-3 and MMC.
It was different from MC.
（ＩＨ核磁気共鳴スペクトル） 測定の結果は以下のとおりであった。(IH nuclear magnetic resonance spectrum) The results of the measurements were as follows.
”ｌ−ＮＭＲ（１００Ｍｌｌｚ 、 ＣＤＣｌ２）δ：
５．２６〜４．８３（２１１゜ｍ、１Ｏ−１１，１０
’−１１） 、４．４［ｆ（１１１，ｄ、Ｊ−１３，２
１１ｚ、３−Ｉ） 、４．２１（１１１，＋ｍ、２−１
１）、４．２０〜３．９５（４＋１゜ｒａ 、 −Ｃ！
Ｉ２０ＣＯ−（ＣＩ！２）詩ＣＩＩ ３ ）、３．７０
（ＩＩＩ、ｄｄ、Ｊ＝４．４．１１．３１１ｚ、９−１
ｆ） 、３．４９（ｌＩｌ、ｓ＋、１−１ｔ）、３．５
１３（１１１，ｄｄ、 Ｊ−２，３，１２，７１１ｚ、
３°−ＩＩ）、３．２１（３１１、ｓ 、−０Ｃ１１３
）、２．８５（４１１，ｓ。"l-NMR (100 Mllz, CDCl2) δ:
5.26-4.83 (211゜m, 1O-11,10
'-11), 4.4[f(111,d, J-13,2
11z, 3-I), 4.21 (111, +m, 2-1
1), 4.20 to 3.95 (4+1°ra, -C!
I20CO-(CI!2) Poem CII 3), 3.70
(III, dd, J=4.4.11.311z, 9-1
f), 3.49 (lIl, s+, 1-1t), 3.5
13 (111, dd, J-2, 3, 12, 711z,
3°-II), 3.21 (311, s, -0C113
), 2.85 (411, s.
−ＣＯＣｊｊ２Ｃ１ｈＣＯ−） 、２．３２（４１１，
ｔ、Ｊ−８，３１１ｚ。-COCjj2C1hCO-) , 2.32 (411,
t, J-8, 311z.
−０ＣＯ−Ｃ虫−（ＣＩ＋２）＋３−Ｃ）１３） 、１
．７８（３１１，ｓ。-0CO-C insect-(CI+2)+3-C)13), 1
．． 78 (311, s.
−Ｃ＝Ｃ−Ｃ）１３） 、１．２８（２１３１１，ｓ、
−０ＣＯ−Ｃ）＋２−（Ｃ）１２） ＋３−Ｃ）１３
） 、０．８９（６）１．ｓ。-C=C-C)13), 1.28(21311,s,
-0CO-C)+2-(C)12) +3-C)13
), 0.89(6)1. s.
−０ＣＯ−（Ｃ１１２） ＄４−ＣＨ３）（高速液体ク
ロマトグラフィー（ＨＰＬＣ） ）ＤＰＧ−８−ＭＭＣ
は高速液体クロマトグラフィーにおいて単一ピークを示
し、単一物質であると認められた。 ）ＩＰＬＣによる
分析は、Ｓｂｌｍａｄｚｕ ＬＣ６Ａのポンプ（■品性
製作所製）にＯＤＳ系のカラムＶａｋｏ ｓｌｌ ５Ｃ
１８（４，８φｘ ２５０ｍｍ） （和光純薬工業■製
）を装着し、移動相としてアセトニトリル：イソプロパ
ノ−ルー５０：５０を１．０ ｍｌ／ｗｉｎで流して行
った。ピークの検出にはＳｈｌｍａｄｚｕＳｐｅｃｔｒ
ｏｐｈｏｔｏｍｅｔｒｉｃ Ｄｅｔｅｃｔｏｒ ５ＰＤ
−６Ａ （Ｒ品性製作所製）を用い、３５０ｎｍにお
ける吸光度を測定した。ＭＭＣの保持時間は２．７分で
あるがＤＰＧ−８−ＭＭＣは５．７分となり脂溶性が増
大していることが明らかとなった。-0CO-(C112) $4-CH3) (High Performance Liquid Chromatography (HPLC)) DPG-8-MMC
showed a single peak in high performance liquid chromatography and was recognized as a single substance. ) For analysis by IPLC, use a Sblmadzu LC6A pump (manufactured by Kansei Seisakusho) and an ODS column Vako sll 5C.
18 (4.8φ x 250 mm) (manufactured by Wako Pure Chemical Industries, Ltd.), and acetonitrile:isopropanol 50:50 was flowed at 1.0 ml/win as a mobile phase. ShlmadzuSpectr for peak detection
Photometric Detector 5PD
The absorbance at 350 nm was measured using -6A (manufactured by R Konsei Seisakusho). The retention time of MMC was 2.7 minutes, but that of DPG-8-MMC was 5.7 minutes, indicating increased fat solubility.
（ＤＰＧ−８−ＭＭＣ（７） ＵＶ吸収）ＤＰＧ−８−
ＭＭＣのＵＶスペクトルは３５５ｎｍに極大吸収を示し
、分子内にＭＭＣが存在することが確認された。(DPG-8-MMC(7) UV absorption)DPG-8-
The UV spectrum of MMC showed maximum absorption at 355 nm, confirming the presence of MMC in the molecule.
（ＤＰＧ−８およびＤＰＧ−８−ＭＭＣの元素分析）Ｄ
ＰＧ−８およびＤＰＧ−８−ＭＭＣの元素分析値はそれ
ぞれ理論値と一致することが確認された。(Elemental analysis of DPG-8 and DPG-8-MMC)D
It was confirmed that the elemental analysis values of PG-8 and DPG-8-MMC each agreed with the theoretical values.
ＤＰＧ−８（分子量６８８）：Ｃ３９Ｈ７２０８として
理論値（％） ： Ｃ７０，０８Ｈ１０，７Ｂ実測値（
％）：Ｃ７０，０８Ｈ１０，８８ＤＰＧ−８−ＭＭＣ（
分子量９８４）： Ｃ５４Ｈ８８Ｎ４０□２として
理論値（％）：ＣＢ５．１ｌ１５ Ｈ８，９４Ｎ５．
６９実測値（％）：ＣＢ５．５８ Ｈ９，１７Ｎ ５
．４８（ＤＰＧ−８−ＭＨＯの溶解性）
ＤＰＧ−８−ＭＭＣ１ｇはりｏｏホルム５．３ｍｌ、ア
セトン５ｍ１ｓｎ−ヘキサン７．９ｍＬベンゼン７．９
ｍｌ、テトラヒドロフラン５．３ｍｌ、メタノールｌｏ
ｏｍｌ、水１００００ ｍｌに溶けて紫色を呈した。ま
たリビオドールには本化合物１ｇがその１８ｍ１に溶は
澄明な紫色を呈した。DPG-8 (molecular weight 688): Theoretical value (%) as C39H7208: C70,08H10,7B actual value (
%): C70,08H10,88DPG-8-MMC(
Molecular weight 984): Theoretical value (%) as C54H88N40□2: CB5.1l15 H8,94N5.
69 Actual value (%): CB5.58 H9,17N 5
．． 48 (Solubility of DPG-8-MHO) 1 g of DPG-8-MMC, 5.3 ml of OO form, 5 ml of acetone, 7.9 ml of sn-hexane, 7.9 ml of benzene
ml, tetrahydrofuran 5.3ml, methanol lo
oml, it dissolved in 10,000 ml of water and turned purple. Furthermore, when 1 g of this compound was dissolved in 18 ml of Libiodol, a clear purple color was obtained.
試験例１
（ＤＰＧ−３−ＭＭＣからのマトイマイシンＣの放出）
１０ｍｌ試験管に０．１Ｍリン酸緩衝溶液（ｕ −０，
３）５ ｍｌを取り、ブレインキュベーションを行った
。Test Example 1 (Release of Matoimycin C from DPG-3-MMC)
In a 10 ml test tube, add 0.1 M phosphate buffer solution (u -0,
3) Take 5 ml and perform brain incubation.
これに１．Ｏｕ ｇ／ｕ ｆｌ ＤＰＧ−８−ＭＭＣメ
タノール溶液５０μｇを加え、インキュベーションを開
始した。1. 50 μg of Oug/ufl DPG-8-MMC methanol solution was added to start incubation.
経時的にサンプリングし２０μｇをＩＩＰＬＣに注入し
てＭＭＣＱの測定を行った。ＩＩＰＬｃによる分析は、
前記５ｈｌａ＋ａｄｚｕ ＬＣ８Ａのポンプに前記ＯＤ
Ｓ系のカラムＶａｋｏ ｓｉｌ ５Ｏ１ｇ（４，６φｘ
２５０ｍ＋ａ）を装着し、移動相として０．Ｈ％臭化
テトラブチルアンモニウム水溶液および４０ｎ＋Ｍリン
酸緩衝溶液（ｐＨ７，（１）含有２０％アセトニトリル
を１．０ ｍｌ／ｍ１ｎで流して行った。ピークの検出
には前記５ｈｌａ＋ａｄｚｕＳｐａｃｔｒｏｐｈｏｔｏ
ｓｅｔｒｉｃ Ｄｅｔｅｃｔｏｒ ５ＰＤ−ＯＡを用い
、３５０ｎｍにおける吸光度を測定した。一方、ＭＭＣ
をインキュベージジン用の溶媒に溶かして検量線とした
。その結果３７℃、９１１７．４およびｐＨ９，０では
ＭＭＣのスクシニル化合物（Ｍ１４Ｃ−８）の放出を認
めず、ＭＭＣの遊離のみが観察された。各ｐＨにおける
ＭＭＣの遊離量（％）と時間の関係をを第１図に示す。MMCQ was measured by sampling over time and injecting 20 μg into IIPLC. Analysis by IIPLc is
Add the OD to the 5hla+adzu LC8A pump.
S-based column Vako sil 5O1g (4,6φx
250m+a) and 0.25m+a) as the mobile phase. H% tetrabutylammonium bromide aqueous solution and 40n+M phosphate buffer solution (pH 7, (1) containing 20% acetonitrile were flowed at 1.0 ml/ml. For peak detection, the above 5hla+adzu Spectrophoto was used.
Absorbance at 350 nm was measured using metric Detector 5PD-OA. On the other hand, MMC
was dissolved in a solvent for incubation and used as a calibration curve. As a result, at 37° C., 9117.4, and pH 9.0, no release of the succinyl compound of MMC (M14C-8) was observed, and only the release of MMC was observed. FIG. 1 shows the relationship between the amount of MMC released (%) and time at each pH.
第１図において、縦軸はＭＭＣの遊離量（％）、横軸は
時間を示す。ＭＭＣの遊離は見かけ上−次速度過程にし
たがい、その速度定数はｐ１１７．４およびｐＨ９，０
においてそれぞれ５．１１ｘｌＱ４ ｈ−１，９，５
８Ｘ １Ｏ−４ｈ−１であった。In FIG. 1, the vertical axis shows the amount of MMC released (%), and the horizontal axis shows time. The release of MMC follows an apparent -order rate process, with rate constants at p117.4 and pH9.0.
respectively 5.11xlQ4 h-1,9,5
It was 8X 1O-4h-1.
さらに、ＤＰＧ−８−ＭＭＣからのＭＭＣの放出に対す
る温度の影響を検討したところ、温度の上昇とともにＭ
ＭＣの放出速度は増加した。各温度におけるＭＭＣの遊
離量（％）と時間の関係を第２図に示す。Furthermore, we investigated the effect of temperature on the release of MMC from DPG-8-MMC, and found that as the temperature increased, MMC
The release rate of MC increased. FIG. 2 shows the relationship between the amount of MMC released (%) and time at each temperature.
第２図において縦軸はＭＭＣの遊離量（％）を、横軸は
時間を示す。In FIG. 2, the vertical axis represents the amount of MMC released (%), and the horizontal axis represents time.
［発明の効果］
ＤＰＧ−８−ＭＭＣの諸特性およびＭＭＣの放出性につ
いてのデータから、本発明の化合物はリビオドールに対
する溶解性が高く、かつＭＭＣの遊離が徐々に進行する
ので腫瘍組織での滞留性と徐放性を格段に改善しうるち
のであって、リピオドール化学塞栓療法、ひいては制癌
薬の投与に極めてすぐれたものであることがわかる。[Effects of the Invention] From the data on the properties of DPG-8-MMC and the release properties of MMC, it has been found that the compound of the present invention has high solubility in Libiodol, and since the release of MMC progresses gradually, it does not remain in tumor tissues. It can be seen that the drug significantly improves the performance and sustained release properties, and is extremely excellent for lipiodol chemoembolization therapy and, by extension, for the administration of anticancer drugs.
第１図は本発明の化合物（ＤＰＳ−８−ＭＭＣ）の３７
℃におけるＭＭＣの遊離量と時間の関係を示すグラフで
ある。
第２図は本発明の化合物（ＤＰＳ−８−ＭＭＣ）のｐＨ
９，０におけるＭＭＣの遊離量と時間の関係を示すグラ
フである。
０−０：ｐＨ７゜４
（ｈｒ）Figure 1 shows 37 of the compound of the present invention (DPS-8-MMC).
It is a graph showing the relationship between the amount of MMC released and time at °C. Figure 2 shows the pH of the compound of the present invention (DPS-8-MMC).
9.0 is a graph showing the relationship between the amount of MMC released and time. 0-0: pH7゜4 (hr)
Claims (1)
−ジパルミトイルグリセロール。２ １，３−ジパルミ
トイルグリセロールをコハク酸誘導体と反応せしめ、え
られた式（II）：▲数式、化学式、表等があります▼（
II） で示される１，３−ジパルミトイル−２−グリセロール
ハイドロジェンスクシネートをマイトマイシンＣと反応
させることを特徴とする式（ I ）：▲数式、化学式、
表等があります▼（ I ） で示される２−マイトマイシンＣ−スクシニル−１，３
−ジパルミトイルグリセロールの製造法。[Claims] 1 Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼2-Mitomycin C-succinyl-1,3 represented by (I)
- Dipalmitoylglycerol. 2. Formula (II) obtained by reacting 1,3-dipalmitoylglycerol with a succinic acid derivative: ▲There are mathematical formulas, chemical formulas, tables, etc.▼
II) Formula (I) characterized by reacting 1,3-dipalmitoyl-2-glycerol hydrogen succinate represented by mitomycin C: ▲Mathematical formula, chemical formula,
There are tables, etc.▼2-Mitomycin C-succinyl-1,3 indicated by (I)
- A method for producing dipalmitoylglycerol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1271369A JPH03133987A (en) | 1989-10-18 | 1989-10-18 | 2-mitomycin c-succinyl-1,3-dipalmitoylglycerol and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1271369A JPH03133987A (en) | 1989-10-18 | 1989-10-18 | 2-mitomycin c-succinyl-1,3-dipalmitoylglycerol and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03133987A true JPH03133987A (en) | 1991-06-07 |
Family
ID=17499110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1271369A Pending JPH03133987A (en) | 1989-10-18 | 1989-10-18 | 2-mitomycin c-succinyl-1,3-dipalmitoylglycerol and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03133987A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994022483A2 (en) * | 1993-03-31 | 1994-10-13 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| US6077837A (en) * | 1995-06-07 | 2000-06-20 | D-Pharm Ltd. | Prodrugs with enhanced penetration into cells |
| US6313106B1 (en) | 1995-06-07 | 2001-11-06 | D-Pharm Ltd. | Phospholipid derivatives of valproic acid and mixtures thereof |
-
1989
- 1989-10-18 JP JP1271369A patent/JPH03133987A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6136796A (en) * | 1993-03-13 | 2000-10-24 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| WO1994022483A2 (en) * | 1993-03-31 | 1994-10-13 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| WO1994022483A3 (en) * | 1993-03-31 | 1994-12-22 | Kosm Gerald Emmanuel | Prodrugs with enhanced penetration into cells |
| US5985854A (en) * | 1993-03-31 | 1999-11-16 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| US6077837A (en) * | 1995-06-07 | 2000-06-20 | D-Pharm Ltd. | Prodrugs with enhanced penetration into cells |
| US6166089A (en) * | 1995-06-07 | 2000-12-26 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| US6313106B1 (en) | 1995-06-07 | 2001-11-06 | D-Pharm Ltd. | Phospholipid derivatives of valproic acid and mixtures thereof |
| US6413949B1 (en) | 1995-06-07 | 2002-07-02 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
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