JPS6383094A - Ether-type nucleoside-phospholipid complex - Google Patents
Ether-type nucleoside-phospholipid complexInfo
- Publication number
- JPS6383094A JPS6383094A JP22920486A JP22920486A JPS6383094A JP S6383094 A JPS6383094 A JP S6383094A JP 22920486 A JP22920486 A JP 22920486A JP 22920486 A JP22920486 A JP 22920486A JP S6383094 A JPS6383094 A JP S6383094A
- Authority
- JP
- Japan
- Prior art keywords
- nucleoside
- group
- ether
- formula
- phospholipid complex
- 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
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 5-fluorouridin-5'-yl Chemical group 0.000 claims abstract description 10
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 8
- 125000001369 canonical nucleoside group Chemical group 0.000 claims abstract description 5
- 229930182507 Neplanocin Natural products 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000002777 nucleoside Substances 0.000 abstract description 13
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 abstract description 10
- 102000015439 Phospholipases Human genes 0.000 abstract description 10
- 108010064785 Phospholipases Proteins 0.000 abstract description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 150000003904 phospholipids Chemical class 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 5
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 abstract description 3
- XUGWUUDOWNZAGW-VDAHYXPESA-N (1s,2r,5r)-5-(6-aminopurin-9-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1C=C(CO)[C@@H](O)[C@H]1O XUGWUUDOWNZAGW-VDAHYXPESA-N 0.000 abstract description 2
- 206010027476 Metastases Diseases 0.000 abstract description 2
- 230000000840 anti-viral effect Effects 0.000 abstract description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical group C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 abstract description 2
- 229960001231 choline Drugs 0.000 abstract description 2
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 229960004413 flucytosine Drugs 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- XUGWUUDOWNZAGW-UHFFFAOYSA-N neplanocin A Natural products C1=NC=2C(N)=NC=NC=2N1C1C=C(CO)C(O)C1O XUGWUUDOWNZAGW-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 230000003405 preventing effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 125000003835 nucleoside group Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 208000032839 leukemia Diseases 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100037611 Lysophospholipase Human genes 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108010058864 Phospholipases A2 Proteins 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000277269 Oncorhynchus masou Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000187180 Streptomyces sp. Species 0.000 description 1
- 240000003864 Ulex europaeus Species 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000005313 fatty acid group Chemical group 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、新規なエーテル型ヌクレオシド−リン脂質複
合体またはその塩に関する。さらに詳しくは、本発明は
、一般式（１）
％式％
（ただし式中、Ｒ１およびＲ１はそれぞれ炭素数１〜２
４の脂肪族炭化水素基を示し、Ｎ、は５−フルオロウリ
ジン−５゛−イル基、ネプラノシンＡ−６′−イル基お
よびアラビノシル−５−フルオロシトシン−５′−イル
基からなる群より選ばれたヌクレオシド残基を示す）で
表されるエーテル型ヌクレオシド−リン脂質複合体また
はその塩に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel ether-type nucleoside-phospholipid complex or a salt thereof. More specifically, the present invention is based on general formula (1) % formula % (wherein R1 and R1 each have 1 to 2 carbon atoms)
4 represents an aliphatic hydrocarbon group, N is selected from the group consisting of 5-fluorouridin-5'-yl group, neplanocin A-6'-yl group and arabinosyl-5-fluorocytosin-5'-yl group. The present invention relates to an ether-type nucleoside-phospholipid complex or a salt thereof represented by (indicating a nucleoside residue) or a salt thereof.
ヌクレオシド系抗腫瘍剤は、種々のがたの腫瘍細胞の化
学療法に有用な薬剤として従来から広く臨床に応用され
てきた。しかしながら、抗腫瘍化学療法剤としての応用
において、いくつかの問題点が指摘されている。即ち、
これらヌクレオシド系抗ｍｓ剤の作用機作として生体内
で、ヌクレオシドの５゛位水酸基がリン酸化をうけない
限り作用を発現し得ない。また加リン酸分解、脱アミノ
化等の不活化を受は急速に不活性な物質に分解されやす
いこと、Ｉｌ！ｉｒｇｊ細胞がこれら抗腫瘍剤に抵抗性
を有するようになること、分裂しつつある正常細胞に対
しても毒性を表すすことなど種々の欠点があった。この
ようなヌクレオシド系抗腫瘍剤の欠点を改善する目的で
種々のヌクレオシド誘導体が合成されてきた。一方、Ｃ
ＤＰジアシルグリセロールが、生体のグリセロリン脂質
の生合成中間体として重要な役割を演じていることから
そのアナローブとして、アラビノシルシトシン−リン脂
質複合体が、化学的に合成され、ある程度の抗腫瘍効果
が認められていた（ Ｂｉｏｃｈｉｍｉｃａ ｅｔ Ｂ
ｉｏ−ｐｈｙｓ＊ｃａ、Ａｃｔａ、 ６１９＋ （１９
８０） ６１９−６３１： Ｊ、Ｆｔｅｄ、Ｃｈｅｔａ
、。Nucleoside antitumor agents have been widely applied clinically as agents useful for chemotherapy of various types of tumor cells. However, several problems have been pointed out in its application as an antitumor chemotherapeutic agent. That is,
The mechanism of action of these nucleoside anti-MS agents is that they cannot exert their effects in vivo unless the hydroxyl group at the 5'-position of the nucleoside is phosphorylated. Furthermore, when subjected to inactivation such as phosphorolysis and deamination, it is easy to rapidly decompose into inert substances. There have been various drawbacks, such as that irgj cells become resistant to these antitumor agents and that they are toxic even to dividing normal cells. Various nucleoside derivatives have been synthesized for the purpose of improving the drawbacks of such nucleoside antitumor agents. On the other hand, C
Since DP diacylglycerol plays an important role as an intermediate in the biosynthesis of glycerophospholipids in living organisms, an arabinosylcytosine-phospholipid complex is chemically synthesized as an analogue of DP diacylglycerol, and has some antitumor effect. was recognized (Biochimica et B
io-phys*ca, Acta, 619+ (19
80) 619-631: J, Fted, Cheta
,.
益、 （１９８２） １３２２−１３２９） 。Masu, (1982) 1322-1329).
最近、５−フルオロ−２′−デオキシウリジン−リン脂
質複合体が報告されており（特開昭６１−９１１９５号
公報、特開昭６１−１５２６９４号公報）、またホスホ
リパーゼＤＭを用いた複素環化合物−リン脂質複合体の
製造法が報告されている（特開昭６１−８８８９０号公
報）。Recently, 5-fluoro-2'-deoxyuridine-phospholipid complexes have been reported (JP-A-61-91195, JP-A-61-152694), and heterocyclic compounds using phospholipase DM have been reported. - A method for producing a phospholipid complex has been reported (Japanese Unexamined Patent Publication No. 88890/1989).
上記の現在までに報告されているヌクレオシド−リン脂
質複合体は、はとんどリン脂質部分の骨格においてグリ
セリンと疎水性基である脂肪酸がエステル結合によって
結合した化合物であり、生体内においては、ホスホリパ
ーゼＡ、あるいはホスホリパーゼＡ２などの酵素により
分解されやすく、また従来からのヌクレオシド系抗腫瘍
剤として研究されたものは、生体内においては、排泄が
速く、持続性がないため、生体内の各種合成酵素阻害作
用を有する時間依存性の代謝拮抗剤としての性質が十分
に発揮されなくなるという欠点を有するものであった。The above-mentioned nucleoside-phospholipid complexes that have been reported to date are compounds in which glycerin and a hydrophobic fatty acid group are bonded through an ester bond in the skeleton of the phospholipid moiety, and in vivo, The nucleoside antitumor agents that are easily degraded by enzymes such as phospholipase A or phospholipase A2, and have been studied as nucleoside antitumor agents, are rapidly excreted in the body and are not sustainable, so they cannot be synthesized in various ways in the body. It has the disadvantage that its properties as a time-dependent antimetabolite having an enzyme inhibitory effect are not fully exhibited.
また物質自体の安定性においても必ずしも満足のいくも
のではなかった。Furthermore, the stability of the substance itself was not necessarily satisfactory.
上記の如くの問題点を解決すべく、本発明者らは、種々
のヌクレオシドを用いて、生体内で分解がおさえられ、
抗腫瘍活性が強いヌクレオシド−リン脂質複合体を見出
すべく鋭意研究の結果、リン脂質の部分の骨格において
、グリセリンと疎水性基である脂肪族炭化水素基がエー
テル結合によって結合し、５−フルオロウリジン−５−
イル基、ネブラノシンＡ−６′−イル基およびアラビノ
シル−５−フルオロシトシン−５′−イル基からなる群
より選ばれたヌクレオシド残基を有するエーテル型ヌク
レオシド−リン脂質複合体およびその塩が、目的とする
性質を有することを見出し、本発明を完成した。In order to solve the above-mentioned problems, the present inventors used various nucleosides to suppress decomposition in vivo.
As a result of intensive research to find a nucleoside-phospholipid complex with strong antitumor activity, glycerin and a hydrophobic aliphatic hydrocarbon group are bonded through an ether linkage in the backbone of the phospholipid, and 5-fluorouridine is formed. -5-
An ether-type nucleoside-phospholipid complex having a nucleoside residue selected from the group consisting of yl group, nebranosin A-6'-yl group, and arabinosyl-5-fluorocytosine-5'-yl group and a salt thereof, The present invention was completed based on the discovery that it has the following properties.
即ち、本発明は、一般式（１）
％式％
（ただし式中、ＲＩ、ＲｇおよびＮ、は前記した意味を
有する）で表されるエーテル型ヌクレオシド−リン脂質
複合体またはその塩である。That is, the present invention is an ether-type nucleoside-phospholipid complex represented by the general formula (1) %formula% (wherein RI, Rg, and N have the above-mentioned meanings) or a salt thereof.
まず、本発明の一般式〔！〕で表されるエーテル型ヌク
レオシド−リン脂質複合体において、ＲＩおよびＲ２に
おける炭素数１〜２４の脂肪族炭化水素基としては、同
一または異なった炭素数１〜２４の飽和または炭素数２
〜２４の不飽和脂肪族炭化水素基が挙げられる。炭素数
１〜２４の飽和脂肪族炭化水素基としては、例えば、メ
チル。First, the general formula of the present invention [! In the ether-type nucleoside-phospholipid complex represented by
-24 unsaturated aliphatic hydrocarbon groups. Examples of the saturated aliphatic hydrocarbon group having 1 to 24 carbon atoms include methyl.
エチル、プロピル、ブチル、ヘキシル、ヘプチル、３−
ヘプチル、オクチル、ノニル、デシル、８−エチルデシ
ル、ウンデシル、ラウリル、トリデシル、ペンタデシル
、ヘキサデシル（セチル）。Ethyl, propyl, butyl, hexyl, heptyl, 3-
Heptyl, octyl, nonyl, decyl, 8-ethyldecyl, undecyl, lauryl, tridecyl, pentadecyl, hexadecyl (cetyl).
ヘプタデシル、オクタデシル（ステアリル）、ノナデシ
オル、エイコシルなどの炭素数１〜２４の直鎖または分
枝アルキル基が挙げられる。炭素数２〜２４の不飽和脂
肪族炭化水素基としては、例えば、ビニル、アリル、２
−ブテニル、３−へキセニル、４−デセニル、６−チト
ラデセニル、９−オクタデセニル、リルイルなどの炭素
数２〜２４のアルケニル基が挙げられる。本化合物の生
体内における′細胞膜への親和性等の点から、好ましい
くは、少なくもＲＩ、Ｒ富のどちらか一方は、炭素数１
４〜２４の脂肪族炭化水素基を有するものが挙げられる
。更に、本発明の一般式（１）におけるＮ、は、５−フ
ルオロウリジン−５−イル基、ネプラノシンＡ−６′−
イル基およびアラビフシルー５−フルオロシトシン−５
′−イル基からなる群より選ばれたヌクレオシド残基が
挙げられる。Examples include straight chain or branched alkyl groups having 1 to 24 carbon atoms such as heptadecyl, octadecyl (stearyl), nonadesiol, and eicosyl. Examples of the unsaturated aliphatic hydrocarbon group having 2 to 24 carbon atoms include vinyl, allyl, 2
Examples include alkenyl groups having 2 to 24 carbon atoms such as -butenyl, 3-hexenyl, 4-decenyl, 6-titradecenyl, 9-octadecenyl, and lylyl. From the viewpoint of the affinity of the present compound for cell membranes in vivo, it is preferable that at least one of RI and R-rich has 1 carbon number.
Examples include those having 4 to 24 aliphatic hydrocarbon groups. Furthermore, N in the general formula (1) of the present invention is a 5-fluorouridin-5-yl group, neplanocin A-6'-
yl group and arabifucyl-5-fluorocytosine-5
Nucleoside residues selected from the group consisting of '-yl groups are mentioned.
−ａ式（１）で表されるエーテル型ヌクレオシド−リン
脂質複合体の塩としては、アルカリ金属との塩、アルカ
リ土類金属との塩、遷移金属との塩、有機塩基との塩か
ら選ばれる薬学的に許容されうる塩が挙げられる。-a The salt of the ether type nucleoside-phospholipid complex represented by formula (1) is selected from salts with alkali metals, salts with alkaline earth metals, salts with transition metals, and salts with organic bases. Examples include pharmaceutically acceptable salts.
次ぎに本発明のエーテル型ヌクレオシド−リン脂質複合
体またはその塩の製造法について説明する。Next, a method for producing the ether type nucleoside-phospholipid complex or a salt thereof of the present invention will be explained.
一般式（１）で表される本発明のエーテル型ヌクレオシ
ド−リン脂質複合体またはその塩は、例えば、°下記の
一般式（ＩＩ）
ＣＨ！−０−Ｒ１
Ｏ−）（
（ただし式中、Ｒ１およびＲｇは前記と同じ基を示し、
Ｘはコリン残基を示す）で表されるリン脂質誘導体と一
般式Ｎｓ ＯＨで表される５−フルオロウリジン、ネ
プラノシンＡおよびアラビノシル−５−フルオロシトシ
ンからなる群より選ばれるヌクレオシドを、ホスホリパ
ーゼＤ−Ｐの存在下、溶媒中で反応せしめることにより
得られる。The ether-type nucleoside-phospholipid complex of the present invention represented by the general formula (1) or a salt thereof is, for example, the following general formula (II) CH! -0-R1 O-)( (wherein, R1 and Rg represent the same group as above,
A phospholipid derivative represented by (X represents a choline residue) and a nucleoside selected from the group consisting of 5-fluorouridine, neplanocin A, and arabinosyl-5-fluorocytosine represented by the general formula Ns OH are combined with phospholipase D- It is obtained by reacting in the presence of P in a solvent.
用いられるホスホリパーゼＤ−Ｐとしては、例えばスト
レプトミセス属に属するストレプトミセス壷ニス畳ピー
Ａ Ａ ５８６ （Ｓｔｒｅｐｔｏｍｙｃｅｓ ｓｐ
Ａ Ａ５８６ ； ＰＥＲＭＰ−６１００）由来のホ
スホリパーゼＤ−Ｐ （特開昭５８−１５２４８１号公
報、東洋醸造社製カタログ番号Ｐ−３９）が挙げられる
。またその使用量は、下記の一般式（Ｉ［）で表される
リン脂質誘導体ｏ、ｏｏｔモル当すホスホリパーゼＤ−
ＰＯ，Ｏｆ単位以上、好ましくは１−１００単位である
。さらに用いる溶媒としては、例えばエーテル、ベンゼ
ンまたはクロロホルムなどの有ａ溶媒とｐＨ３〜９の緩
衝液、好ましくはｐＨ４〜６の水層−有ａ溶媒層の二層
系溶媒が挙げられる。さらにまた金属イオン形成のため
の水溶性塩類としては、通常塩化カルシウムが用いられ
る。また反応温度は通常２０〜６０℃で、反応温度は３
０分〜３０時間、好ましくは１〜６時間である。このよ
うにして得られた一般式〔Ｉ〕で表される本発明化合物
は、分液法およびシリカゲルクロマトグラフィーにより
簡便に精製することができる。As the phospholipase D-P used, for example, Streptomyces sp.
Examples include phospholipase D-P (JP-A-58-152481, Catalog number P-39, manufactured by Toyo Jozo Co., Ltd.) derived from A586; PERMP-6100). In addition, the amount used is phospholipase D-
It is at least PO,Of units, preferably 1-100 units. Examples of the solvent to be used include, for example, an aqueous solvent such as ether, benzene or chloroform, and a buffer solution having a pH of 3 to 9, preferably a two-layer solvent consisting of an aqueous layer and an aqueous solvent layer having a pH of 4 to 6. Furthermore, calcium chloride is usually used as a water-soluble salt for forming metal ions. In addition, the reaction temperature is usually 20 to 60℃, and the reaction temperature is 3.
The time is 0 minutes to 30 hours, preferably 1 to 6 hours. The compound of the present invention represented by the general formula [I] thus obtained can be easily purified by a liquid separation method and silica gel chromatography.
以上の本発明エーテル型ヌクレオシド−リン脂質複合体
の一段工程合成法は、以下のように示される。The above one-step synthesis method of the ether type nucleoside-phospholipid complex of the present invention is shown as follows.
ＣＨ！−ＯＲ＋
（ＩＩ）
（ただし式中、Ｒ＋ 、ＲｘおよびＮ、は前記した意味
を有する）。CH! -OR+ (II) (wherein R+, Rx and N have the above meanings).
−ｍ式（Ｉｔ）で表されるリン脂質誘導体は、公知の化
合物で、一部市版の化合物であり、また特開昭５９−１
１２９９３号公報開示の化合物で、同公報記載の方法に
よって得ることができる。-m The phospholipid derivative represented by the formula (It) is a known compound, some of which are commercially available compounds, and JP-A-59-1
This is a compound disclosed in Publication No. 12993, and can be obtained by the method described in the publication.
さらに、このようにして得られた一般式（１）で表され
る本発明エーテル型ヌクレオシド−リン脂質複合体は、
ナトリウム塩、カリウム塩などの一般的な無毒性塩とな
すことができる。Furthermore, the ether-type nucleoside-phospholipid complex of the present invention represented by the general formula (1) thus obtained is
It can be made into common non-toxic salts such as sodium salt and potassium salt.
このようにして得られた本発明のエーテル型ヌクレオシ
ド−リン脂質複合体は、元の原料として用いたヌクレオ
シドと比較して、脂溶性が大きいため生体内に長時間留
まり（従って活性が持続することになる）、デアミネー
ション、ホスホリレーション、還元等の不活性化を受け
にくい、生体膜への親和性が高まる、キナーゼの関与な
しに抗腫瘍性ヌクレオシドの５′−モノリン酸体が細胞
内に生成する、等の利点があり、公知のヌクレオシド−
リン脂質と比較して、生体内中のホスホリパーゼＡ、あ
るいはホスホリパーゼＡ２に対して抵抗性があり、経口
投与も可能ならしめるものであリ、活性が持続、増強さ
れ、毒性が低くなる。The ether-type nucleoside-phospholipid complex of the present invention obtained in this manner has greater fat solubility than the nucleoside used as the original raw material, and thus remains in the body for a long time (therefore, its activity is sustained). ), is less susceptible to inactivation such as deamination, phosphorylation, and reduction, has increased affinity for biological membranes, and allows the 5'-monophosphate form of antitumor nucleosides to enter cells without the involvement of kinases. Known nucleoside
Compared to phospholipids, it is resistant to phospholipase A or phospholipase A2 in vivo, and can be administered orally, with sustained and enhanced activity and low toxicity.
本発明の新規なエーテル型ヌクレオシド−リン脂質複合
体は、後に示すように生体内（ｉｎ ｖｉｖｏ ）で顕
著な抗腫瘍作用が認められる。また、更に、生体内に発
生した腫瘍が他の部位に転位するのを阻害する抗転位効
果や抗ウィルス活性も認められる。The novel ether-type nucleoside-phospholipid complex of the present invention has a remarkable antitumor effect in vivo, as will be shown later. Furthermore, anti-metastatic effects and anti-viral activities that inhibit the metastasis of tumors generated in the body to other sites have also been observed.
本発明のエーテル型ヌクレオシド−リン脂質複合体につ
いてＰ−３８８白血病（ｌｅｕｋｅｍｉａ Ｐ−３８
８ｃａｒｃｉｎｏｍａ）に対する抗腫瘍活性を調べた結
果を以下に示す。Regarding the ether type nucleoside-phospholipid complex of the present invention, P-388 leukemia (leukemia P-38
The results of investigating the antitumor activity against 8carcinoma) are shown below.
〈抗腫瘍作用〉
一群５匹のＢＤＰＩ マウス（雄、５週令、チャールス
リバー社より購入）を用いてＰ３８８白血病細胞ｌＸ
ｌ０’個１０．２ｍｌをＢＤＦ＋マウス腹腔内に移植し
た。トリス−塩酸緩衝化食塩水に超音波処理することに
より懸濁させた被検化合物をＢＤＦ、マウスの体重１０
ｇにつき０． １ｍＩの投与量になるように移植の翌日
より１日１回、５日間腹腔内に投与した。対照群として
７匹のＢＤＦ、マウスを用いた。その結果として延命率
は以下のようにして求めた。<Anti-tumor effect> Using a group of 5 BDPI mice (male, 5 weeks old, purchased from Charles River), P388 leukemia cells IX
10' pieces (10.2 ml) were intraperitoneally transplanted into BDF+ mice. Test compounds suspended in Tris-HCl buffered saline by sonication were added to BDF, mouse body weight 10
0 per g. The drug was administered intraperitoneally once a day for 5 days starting the day after transplantation at a dose of 1 mI. Seven BDF mice were used as a control group. As a result, the life extension rate was calculated as follows.
対照群の平均生存日数は７．８６日で、第１表に示す本
発明のエーテル型ヌクレオシド−リン脂質複合体を１日
つきＢＤＦ、マウスｌ ｋｇに対して３〜３０ｔｇ投与
した所、はぼ３０〜２００％の延命率を示し強い抗腫瘍
効果を示したもので、その結果を以下に示す。The average survival period of the control group was 7.86 days, and when 3 to 30 tg of the ether type nucleoside-phospholipid complex of the present invention shown in Table 1 was administered per day to 1 kg of BDF mice, the average survival time was 7.86 days. It showed a survival rate of 30 to 200% and a strong antitumor effect.The results are shown below.
（注）ＦＵＲｉ５−フルオロウリジン−５°−イル基
ＮｅｐＡ；ネプラノシンＡ−６′−イル基７１、ｒａＦ
Ｃ；アラビノシル−５−フルオロシトシン−５′−イル
基
〈マウス急性毒性試験〉
一群５匹＋７）ＢＤＦＩ ？’７ス（ａ、５週令）に、
トリス−塩酸緩衝化食塩水に超音波処理することにより
：ぢ濁させた第１表に示す本発明のエーテル型ヌクレオ
シド−リン脂質複合体２００■／ｋｇの投与量（腹腔内
投与）における急性毒性は認められなかった。(Note) FURi5-fluorouridin-5°-yl group NepA; neplanocin A-6'-yl group 71, raF
C; Arabinosyl-5-fluorocytosine-5'-yl group (mouse acute toxicity test) 5 animals per group + 7) BDFI? '7th grade (A, 5 weeks old)
Acute toxicity at a dose of 200 μg/kg (intraperitoneal administration) of the ether-type nucleoside-phospholipid complexes of the present invention shown in Table 1, which were made turbid by ultrasonication in Tris-HCl buffered saline. was not recognized.
本発明のエーテル型ヌクレオシド−リン脂質複合体およ
びその塩を医薬として用いる場合それ自体でまたは医学
上許容される賦形剤、担体、希釈剤などの添加剤を適宜
混合し、錠剤、カプセル剤、顆粒剤、散剤、注射剤また
は坐剤などの形態で経口的または非経口的に投与できる
。投与量は、通常成人１日当り１〜５００■程度であり
、これを１回または数回に分けて投与するが、投与量は
年令１体重および症状に応じて適宜選択される。When the ether-type nucleoside-phospholipid complex and its salt of the present invention are used as a medicine, they can be used by themselves or mixed with appropriate additives such as medically acceptable excipients, carriers, and diluents, and prepared into tablets, capsules, It can be administered orally or parenterally in the form of granules, powders, injections, or suppositories. The dosage is usually about 1 to 500 cm per day for adults, which is administered once or divided into several doses, and the dosage is appropriately selected depending on the age, body weight, and symptoms.
（実施例〕
以下に本発明の実施例を挙げて本発明を説明するが、本
発明は何らこれによって限定されるものではない。(Example) The present invention will be described below with reference to Examples, but the present invention is not limited thereto in any way.
実施例１〜９
第１表に示すヌクレオシド（Ｎ！ ＯＨ）を２５０ 、
ＭのＣ，ＣＩ、を含む２００．Ｍ酢酸覆衝液（ｐ Ｈ６
，０）同じく第１表に示す量に溶解または懸濁し、４５
℃の水浴中で３分間攪拌した後、ホスホリパーゼＤ−Ｐ
（ＰＬＤＰ；東洋醸造社製カタログ番号Ｐ−３９）同
じく第１表に示す量を加え溶解し、第１表に示す式（ｎ
）で表されるリン脂質誘導体０．３．Ｍを１０ｍ１クロ
ロホルム溶液として加え、６時間攪拌した後、放冷した
０反応液にＩＮ塩酸５−１．クロロホルム３０ｍ！、メ
タノール２５ｍ１を加え分液し、下層を２回水洗した後
、減圧乾固した。更に残渣にエタノールを加えて減圧乾
固した後、残渣を少量のクロロホルムに溶かして、シリ
カゲルフラッシュカラム（２，５Ｘ１０ｃｍ）にかけて
、クロロホルム、クロロホルムーメタノール（２０：１
）、同（１５： ｌ）、同（１２：１）、同（１０：
１） 、同（７：１）、同（５： １） 、同（４：ｌ
）および同（３：ｌ）の順で溶出した。Examples 1 to 9 250 nucleosides (N!OH) shown in Table 1,
200. including C, CI, of M. M acetic acid solution (pH 6
,0) Also dissolved or suspended in the amounts shown in Table 1, 45
After stirring for 3 min in a water bath at °C, phospholipase D-P
(PLDP; Catalog No. P-39 manufactured by Toyo Jozo Co., Ltd.) Add and dissolve the amount shown in Table 1, and then dissolve the formula (n
) Phospholipid derivative represented by 0.3. After adding M as a 10ml chloroform solution and stirring for 6 hours, IN hydrochloric acid 5-1. Chloroform 30m! , 25 ml of methanol was added to separate the layers, and the lower layer was washed twice with water and then dried under reduced pressure. After adding ethanol to the residue and drying it under reduced pressure, the residue was dissolved in a small amount of chloroform and applied to a silica gel flash column (2.5 x 10 cm).
), same (15: l), same (12:1), same (10:
1), same (7:1), same (5:1), same (4:l)
) and the same (3:l) were eluted in this order.
目的のフラクションを集め減圧乾固後、残渣をクロロホ
ルム４０−１、メタノール２０＋ａｌの混液に溶かし、
０．５Ｎ塩酸１２ｍ１を加えて分液し、下層を２回水洗
した後、減圧乾固して目的物を得た。The desired fractions were collected and dried under reduced pressure, and the residue was dissolved in a mixture of 40-1 chloroform and 20-1 methanol + al.
12 ml of 0.5N hydrochloric acid was added to separate the layers, and the lower layer was washed twice with water and then dried under reduced pressure to obtain the desired product.
ＮＭＲ（ＣＤＣｌａ：ｃＤツ０Ｄ＝２ ： １）上：σ
ｐｐｌＩ７．８５ （ｄ、ＩＨ，Ｊａｒ茸６．３Ｈ）、
５．８９（ｂｓ、ＩＨ）、４．３〜３．９（ｍ、７Ｈ
）、３．５３（ｍ、７Ｈ）、１．５５ （ｂｒ、４Ｂ）
、１．２６（ｓ、５２Ｂ）、０．８８（ｔ、６Ｂ）２
： ｅ、、、 ８．２３ （ｓ、ＩＨ）、８．１９
（ｓ、ＩＨ）、 ５．８９（ｂｓ、１８）、５．５２
（ａ、ＩＩＩ）、４．７２（ｍ、３Ｈ）、 ４．２
８（ｓ＋、ＩＨ）４．０２（ｍ、２１１）、３．５９（
ｍ、７Ｈ）、１．５５ （ｂｒ、４Ｈ）、１．２７（ｓ
。NMR (CDCla: cD 0D = 2: 1) Upper: σ
pplI7.85 (d, IH, Jar mushroom 6.3H),
5.89 (bs, IH), 4.3-3.9 (m, 7H
), 3.53 (m, 7H), 1.55 (br, 4B)
, 1.26 (s, 52B), 0.88 (t, 6B)2
: e, , 8.23 (s, IH), 8.19
(s, IH), 5.89 (bs, 18), 5.52
(a, III), 4.72 (m, 3H), 4.2
8 (s+, IH) 4.02 (m, 211), 3.59 (
m, 7H), 1.55 (br, 4H), 1.27 (s
.
５２１１）、０．８８（ｔ、６Ｈ）
Ｌ：σｐｓ−８，２２（ｄ、ＩＨ，Ｊｉｒ・６．５）１
）、 ６．１１（ｂｓ、ＩＨ）、４．３ 〜４．０
（ｍ、７ｎ）、３．５３（ｍ、７ｏ）、１．５５ （
ｂｒ、４Ｈ）、１．２６（ｓ、５２１）、０．８８（ｔ
、６Ｈ）第１表において、
ＰＬＤＰ ；ホスホリパーゼＤ−Ｐ （比活性１６０単
位／ｍｇ）
ＵＶｉ１１１１１定；クロロホルム−メタノール（１：
２０）中で測定した。5211), 0.88 (t, 6H) L: σps-8,22 (d, IH, Jir・6.5) 1
), 6.11 (bs, IH), 4.3 ~ 4.0
(m, 7n), 3.53 (m, 7o), 1.55 (
br, 4H), 1.26 (s, 521), 0.88 (t
, 6H) In Table 1, PLDP; Phospholipase DP (specific activity 160 units/mg) UVi11111 constant; Chloroform-methanol (1:
20).
Ｒｆ （ｉ ｉクロロホルム：メタノール：水（６５：
２５：３０）を展開溶媒とし、メルク社製＾ｒｔ５７１
５プレートを使用し、スポットはＵｖクランプよびモリ
ブデン青試薬により検出した。Rf (ii Chloroform:methanol:water (65:
25:30) as the developing solvent, ^rt571 manufactured by Merck & Co.
5 plates were used and spots were detected by Uv clamp and molybdenum blue reagent.
Claims (1)
〜２４の脂肪族炭化水素基を示し、Ｎ＿５は５−フルオ
ロウリジン−５′−イル基、ネプラノシンＡ−６′−イ
ル基およびアラビノシル−５−フルオロシトシン−５′
−イル基からなる群より選ばれたヌクレオシド残基を示
す）で表されるエーテル型ヌクレオシド−リン脂質複合
体またはその塩。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, in the formula, R_1 and R_2 each have a carbon number of 1
-24 aliphatic hydrocarbon groups, N_5 is 5-fluorouridin-5'-yl group, neplanocin A-6'-yl group and arabinosyl-5-fluorocytosine-5'
An ether-type nucleoside-phospholipid complex or a salt thereof represented by (representing a nucleoside residue selected from the group consisting of -yl group) or a salt thereof.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22920486A JPS6383094A (en) | 1986-09-27 | 1986-09-27 | Ether-type nucleoside-phospholipid complex |
| DE8787308497T DE3778626D1 (en) | 1986-09-27 | 1987-09-25 | NUCLEOSIDE PHOSPHOLIPID CONJUGATE. |
| EP87308497A EP0262876B1 (en) | 1986-09-27 | 1987-09-25 | Nucleoside-phospholipid conjugate |
| US07/102,043 US4921951A (en) | 1986-09-27 | 1987-09-28 | Nucleoside-phospholipid conjugate |
| US07/445,965 US5051499A (en) | 1986-09-27 | 1989-11-28 | Novel nucleoside-phospholipid conjugate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22920486A JPS6383094A (en) | 1986-09-27 | 1986-09-27 | Ether-type nucleoside-phospholipid complex |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6383094A true JPS6383094A (en) | 1988-04-13 |
Family
ID=16888449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22920486A Pending JPS6383094A (en) | 1986-09-27 | 1986-09-27 | Ether-type nucleoside-phospholipid complex |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6383094A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02174787A (en) * | 1988-08-24 | 1990-07-06 | Q P Corp | Phospholipid derivative |
| JP2006520359A (en) * | 2003-03-19 | 2006-09-07 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | Nucleotide lipid ester derivatives |
-
1986
- 1986-09-27 JP JP22920486A patent/JPS6383094A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02174787A (en) * | 1988-08-24 | 1990-07-06 | Q P Corp | Phospholipid derivative |
| JP2006520359A (en) * | 2003-03-19 | 2006-09-07 | ハイデルベルク ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング | Nucleotide lipid ester derivatives |
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