JPH0132832B2 - - Google Patents
Info
- Publication number
- JPH0132832B2 JPH0132832B2 JP8882381A JP8882381A JPH0132832B2 JP H0132832 B2 JPH0132832 B2 JP H0132832B2 JP 8882381 A JP8882381 A JP 8882381A JP 8882381 A JP8882381 A JP 8882381A JP H0132832 B2 JPH0132832 B2 JP H0132832B2
- Authority
- JP
- Japan
- Prior art keywords
- tetramethyl
- nonadecatetraen
- phosphoric acid
- salt
- compound
- 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.)
- Expired
Links
- -1 6,10,14,18-tetramethyl- 5,9,13,17-nonadecatetraen-2-yl phosphoric acid Chemical compound 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 4
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 102000003886 Glycoproteins Human genes 0.000 description 6
- 108090000288 Glycoproteins Proteins 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003699 antiulcer agent Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HSNVNALJRSJDHT-UHFFFAOYSA-N P(=O)(=O)[Mo] Chemical compound P(=O)(=O)[Mo] HSNVNALJRSJDHT-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- HRBGUGQWTMBDTR-UHFFFAOYSA-N 2,3,4-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC=C(S(Cl)(=O)=O)C(C(C)C)=C1C(C)C HRBGUGQWTMBDTR-UHFFFAOYSA-N 0.000 description 1
- PQOZEIOCRSIRHY-UHFFFAOYSA-N 6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol Chemical compound CC(O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C PQOZEIOCRSIRHY-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 102000006722 Mannosyltransferases Human genes 0.000 description 1
- 108010087568 Mannosyltransferases Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 1
- IUZZNTZZSKOMGY-DGTMBMJNSA-N [(2r,3r,4s,5s,6s)-3,4,5-triacetyloxy-6-phosphonooxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OP(O)(O)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O IUZZNTZZSKOMGY-DGTMBMJNSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- POZHUHFRKXTWPR-UHFFFAOYSA-N nonadeca-5,9,13,17-tetraen-2-one Chemical compound CC=CCCC=CCCC=CCCC=CCCC(C)=O POZHUHFRKXTWPR-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 210000003635 pituitary gland Anatomy 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
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000000405 serological effect Effects 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
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は医薬品として有用な新規な６，10，
14，18−テトラメチル−５，９，13，17−ノナデ
カテトラエン−２−イル燐酸エステルに関する。
更に詳しく述べれば、
一般式
〔式中Ｘは式
The present invention provides novel 6,10,
14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-yl phosphoric acid ester. In more detail, the general formula [In the formula, X is the formula
【式】（式中ｎは１〜２
の整数を意味する。）で示される基、または式
A group represented by [Formula] (wherein n means an integer of 1 to 2) or a formula
【式】で示される基を意
味する。〕
で表わされる６，10，14，18−テトラメチル−
５，９，13，17−ノナデカテトラエン−２−イル
リン酸エステル若しくはその塩に関する。
本発明者等は新規で優れた抗潰瘍効果を有する
化合物を長年鋭意研究を継続してきたが、次に示
す構造式
で表わされる６，10，14，18−テトラメチル−
５，９，13，17−ノナデカテトラエン−２−オン
（）が優れた抗潰瘍剤であることを見い出した
（特開昭53−145922号）。そこで更に（）の化合
物の周辺化合物について探索を重ねた結果、上記
（）の化合物の２の位置が水酸基である６，10，
14，18−テトラメチル−５，９，13，17−ノナデ
カテトラエン−２−オール（）の化合物の２の
位置の水酸基を種々のリン酸エステルにすること
によつて有用な薬理活性を有することを見い出し
た。
すなわち、本発明化合物は、優れた糖蛋白質代
謝作用を有することを見い出し、本発明を完成し
たものである。
本発明化合物は、生体の糖蛋白質合成の促進作
用を有するので、これらの作用に基づく種々の医
薬として有用である。
医薬としての具体的な一例を示せば、抗潰瘍剤
として有用な上記の化合物（）が、胃粘膜にお
いて糖蛋白質合成に関与している可能性が高いこ
とから、本発明化合物（）も抗潰瘍剤として有
用である。
本発明化合物（）は文献未収載の新規化合物
であるが、代表的な化合物を列挙すれば次のとお
りである。
Γ６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イル燐酸エステ
ル
Γ６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イルピロ燐酸エ
ステル
Γ６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イルβ−Ｄ−マ
ンノピラノシル燐酸ジエステル
上記の化合物において、燐酸エステルは塩を形
成しうるが、本発明においてはこれらの塩をも含
むものである。塩としての代表的なものをあげれ
ば、リチウム塩、アンモニウム塩、ナトリウム
塩、カリウム塩、カルシウム塩などをあげること
ができる。
本発明化合物を製造する方法は種々考えられる
が代表的な方法の一例を示せば次のとおりであ
る。
〔製造法１〕
一般式（）においてＸが式Means a group represented by the formula. ] 6,10,14,18-tetramethyl-
The present invention relates to 5,9,13,17-nonadecatetraen-2-yl phosphoric acid ester or a salt thereof. The present inventors have continued intensive research for many years to find a new compound with excellent anti-ulcer effect. 6,10,14,18-tetramethyl-
It has been discovered that 5,9,13,17-nonadecatetraen-2-one () is an excellent antiulcer agent (Japanese Patent Application Laid-Open No. 145922/1982). Therefore, as a result of further searching for surrounding compounds of the compound (), we found that 6, 10, where position 2 of the compound () above is a hydroxyl group,
14,18-Tetramethyl-5,9,13,17-nonadecatetraen-2-ol () has useful pharmacological activity by converting the hydroxyl group at the 2-position into various phosphoric acid esters. It was discovered that That is, it has been discovered that the compound of the present invention has an excellent glycoprotein metabolic effect, and the present invention has been completed. Since the compounds of the present invention have the effect of promoting glycoprotein synthesis in living organisms, they are useful as various medicines based on these effects. To give a specific example as a medicine, the above-mentioned compound (), which is useful as an anti-ulcer agent, is likely to be involved in glycoprotein synthesis in the gastric mucosa, so the compound () of the present invention is also useful as an anti-ulcer agent. It is useful as a drug. Although the compound of the present invention () is a new compound that has not been described in any literature, representative compounds are listed below. Γ6,10,14,18-tetramethyl-5,9,13,
17-nonadecatetraen-2-yl phosphoric acid ester Γ6,10,14,18-tetramethyl-5,9,13,
17-nonadecatetraen-2-ylpyrophosphate Γ6,10,14,18-tetramethyl-5,9,13,
17-Nonadecatetraen-2-yl β-D-mannopyranosyl phosphoric acid diester In the above compound, the phosphoric acid ester can form a salt, and the present invention also includes these salts. Typical salts include lithium salt, ammonium salt, sodium salt, potassium salt, and calcium salt. Although various methods can be considered for producing the compound of the present invention, one typical method is as follows. [Manufacturing method 1] In the general formula (), X is the formula
一般式（）においてＸが式
In the general formula (), X is the formula
【式】で示される基を
意味する場合
次の構造式
で示される６，10，14，18−テトラメチル−５，
９，13，17−ノナデカテトラエン−２−イル２，
３，４，６，−テトラ−Ｏ−アセチル−β−Ｄ−
マンノピラノシル燐酸ジエステルを常法により加
水分解して脱アセチル化することにより製造する
ことができる。脱アセチル化する方法は常法によ
るが、例えばナトリウムメチラート、ナトリウム
エチラート、酢酸ソーダ、重そうなどでアルカリ
加水分解する方法が一般的である。
出発物質として用いる６，10，14，18−テトラ
メチル−５，９，13，17−ノナデカテトラエン−
２−イル２，３，４，６−テトラ−Ｏ−アセチル
−β−Ｄ−マンノピラノシル燐酸ジエステルは、
例えば２，３，４，６−テトラ−Ｏ−アセチル−
β−Ｄ−マンノピラノシル燐酸エステルと、６，
10，14，18−テトラメチル−５，９，13，17−ノ
ナデカテトラエン−２−オール（）と反応さ
せ、常法によりエステル化させることにより得ら
れる。
本発明化合物はいずれも生体の糖蛋白質合成の
促進作用を有することは、実験によつて確認して
いる。すなわち、SD系雄性ラツトの肝マイクロ
ゾームを用いSatoらの方法〔Sato、M.、
Deluca、L.M.and Muto、Y.（1978）J.Nutr.Sci.
Vitaminol.24、９−23〕に準じてマンノシルトラ
ンスフエラーゼ（mannosyl trans ferase）活性
の測定を本発明化合物についておこなつたとこ
ろ、蛋白質へのマンノース転移が約２〜４倍増大
することを見い出したものである。
したがつて、本発明化合物は、生体内の糖蛋白
質合成の促進作用に基づく種々の医薬に用いるこ
とができる。糖蛋白質は、例えば脳下垂体、胃粘
膜などのセン様臓器、皮膚、関節、軟骨などの結
合組織、ダ液、胃液、血液などの分泌液などに存
在し、組織の形成物質となつていたり、生体機能
の潤滑作用および保護作用を営んでいたり、免疫
学的および血清学的に重要な役割を果たしている
ものであるが、本発明化合物は上述の如く糖蛋白
質合成の促進作用を有することから、これらの組
織における各種疾患に有効である可能性が高い。
最も代表的な具体例を示せば、胃潰瘍、十二指
腸潰瘍などの消化性潰瘍の治療および予防に用い
られる。本発明化合物は毒性が極めて弱いので、
これらの疾患がその性質上連用を余儀なくされる
ことから抗潰瘍剤として極めて有利である。
本発明化合物は、疾患の相違、程度などにより
異なるが、通常は成人１日あたり50〜2000mgを経
口若しくは非経口的に投与される。投与剤形とし
ては、散剤、顆粒剤、錠剤、カプセル剤、注射剤
などがあげられるが、これらは通常の製剤用担体
をもちい、常法により製造することが可能であ
る。
次に本発明の実施例を掲げるが、本発明がこれ
らのみに限定されることがないことはいうまでも
ない。
実施例 １
６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イル燐酸エステ
ル・２リチウム塩および６，10，14，18−テト
ラメチル−５，９，13，17−ノナデカテトラエ
ン−２−イルピロ燐酸エステル・３リチウム塩
(1) ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−オールの合
成
６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−オン１ｇを
20mlのメタノールに溶解し、水素化ホウ素ナト
リウム60mgを加え、30分間撹拌した。反応液を
氷水に注ぎ、希塩酸を加えて液を酸性とし、ｎ
−ヘキサン50mlで抽出した。抽出液を水洗した
後、硫酸マグネシウムで乾燥した。溶媒を留去
し、注状物１ｇを得た。これをシリカゲルのカ
ラムクロマトグラフイーにより精製し、10％エ
ーテル／ｎ−ヘキサン流出部より無色油状の標
題化合物0.95ｇを得た。
質量スペクトル（ｍ／ｅ）：332（M+）
元素分析値：C23H40Oとして
Ｃ Ｈ
理論値（％） 83.06 12.13
実測値（％） 83.12 12.09
NMRスペクトル（δ、CDCl3）：
1.16（3H、ｄ、Ｊ＝７Hz）
1.58（9H、ｓ）
1.65（6H、ｓ）
1.2〜1.6（2H）
1.8〜2.3（15H）
3.74（1H、ｔ、ｑ、Ｊ＝６Hz、６Hz）
5.04（4H、ｍ）
(2) (1)の方法で得られた６，10，14，18−テトラ
メチル−５，９，13，17−ノナデカテトラエン
−２−オール50ｇとトリクロルアセトニトリル
130ｇの溶液に、室温下、撹拌しながら燐酸・
ビストリエチルアンモニウム塩108ｇのアセト
ニトリル溶液３を４時間で滴下する。
更に２時間、撹拌した後、減圧下、40℃で溶
媒を濃縮する。濃縮物にエチルエーテル１を
加え、撹拌しながら希塩酸にて酸性化する。有
機層を分離し、水洗した後、硫酸マグネシウム
で乾燥し、濃縮する。
濃縮物をメタノールに溶かし、ジエチルアミ
ノエチル（DEAE）−セルロースの酢酸型でカ
ラムクロマトを行い、0.01〜0.1規定酢酸アン
モニウムのメタノール溶液で溶出すると、燐酸
エステル、ピロリン酸エステルがそれぞれ分離
精製される。これらのエステル各々に水を加
え、希塩酸にて酸性化し、エチルエーテルで抽
出し、水洗した後濃縮する。濃縮物をメタノー
ルに溶かし、これに塩化リチウムのメタノール
溶液を加え、希アンモニア・メタノール液を加
え、中和する。析出した白色結晶を遠沈過
し、メタノールで洗い減圧乾燥して標題化合物
６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イル燐酸エステ
ル・２リチウム塩8.5ｇ〔燐分析：（湿式リンモ
リブデン青法による）C23H39O4PLi2として理
論値7.30％、実測値7.08％〕および標題化合物
６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イルピロ燐酸エ
ステル・３リチウム塩6.2ｇ〔燐分析：（湿式リ
ンモリブデン青法による）C23H39O7P2Li3とし
て理論値12.14％，実測値11.90％〕を得た。
実施例 ２
６，10，14，18−テトラメチル−５，９，13，
17−ノナデカテトラエン−２−イルβ−Ｄ−マ
ンノピラノシル燐酸ジエステル
(1) ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イル２，
３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−
マンノピラノシル燐酸ジエステルの合成
２，３，４，６−テトラ−Ｏ−アセチル−β
−Ｄ−マンノピラノシル燐酸エステル・２ピリ
ジニウム塩2.0ｇに６，10，14，18−テトラメ
チル−５，９，13，17−ノナデカテトラエン−
２−オール1.0ｇを加える。これに無水トルエ
ンを加え、減圧下トルエンを留去する。次いで
トリイソプロピルベンゼンスルホニルクロライ
ド1.0ｇを加え、また無水トルエンを加え、留
去し、十分に脱水する。
この混合物に無水ピリジン10mlを加え、４日
間、室温にて撹拌する。ついで、メタノール20
mlを加え、室温にて３時間撹拌した後、減圧
下、溶媒を留去する。
濃縮物をクロロホルム100mlに溶かし、水洗、
硫酸マグネシウムで乾燥し、濃縮する。
濃縮物をシリカゲルカラムクロマトにかけ、
５％メタノール・クロロホルム溶液で溶出する
と６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イル２，
３，４，６−テトラ−Ｏ−アセチル−β−Ｄ−
マンノピラノシル燐酸ジエステル450mgが得ら
れる。
(2) ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イルβ−Ｄ
−マンノピラノシル燐酸ジエステル
上記の(1)の方法で得られた６，10，14，18−
テトラメチル−５，９，13，17−ノナデカテト
ラエン−２−イル２，３，４，６−テトラ−Ｏ
−アセチル−β−Ｄ−マンノピラノシル燐酸ジ
エステル450mgを１％ナトリウムメチラート・
メタノール溶液100mlに溶かし、30分間室温で
撹拌する。その後、イオン交換樹脂AG・50W
−X8ピリジン型で中和し、過する。
液を濃縮すると標題化合物６，10，14，18
−テトラメチル−５，９，13，17−ノナデカテ
トラエン−２−イルβ−Ｄ−マンノピラノシル
燐酸ジエステル390mgが得られる。
NMRスペクトル（δ、D2O）：
1.1〜1.4（5H）
1.56（12H、ｓ）
1.63（3H、ｓ）
1.8〜2.3（14H）
3.5〜4.1（6H）
4.30（1H、ｍ）
5.10（4H、bs）
5.44（1H、ｄ、Ｊ＝６Hz）When meaning a group represented by [formula] The following structural formula 6,10,14,18-tetramethyl-5,
9,13,17-nonadecatetraen-2-yl 2,
3,4,6,-tetra-O-acetyl-β-D-
It can be produced by hydrolyzing and deacetylating mannopyranosyl phosphoric acid diester by a conventional method. Deacetylation can be carried out by conventional methods, such as alkaline hydrolysis using sodium methylate, sodium ethylate, sodium acetate, heavy soybean, etc., which is common. 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene- used as starting material
2-yl 2,3,4,6-tetra-O-acetyl-β-D-mannopyranosyl phosphoric acid diester is
For example, 2,3,4,6-tetra-O-acetyl-
β-D-mannopyranosyl phosphate ester, 6,
It is obtained by reacting with 10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-ol () and esterifying it by a conventional method. It has been confirmed through experiments that all of the compounds of the present invention have the effect of promoting glycoprotein synthesis in living organisms. That is, using the liver microsomes of SD male rats, the method of Sato et al. [Sato, M.,
Deluca, LMand Muto, Y. (1978) J. Nutr. Sci.
When the compound of the present invention was measured for mannosyl transferase activity according to [Vitaminol. 24 , 9-23], it was found that mannose transfer to proteins was increased approximately 2 to 4 times. It is something. Therefore, the compounds of the present invention can be used in various medicines based on their action of promoting glycoprotein synthesis in vivo. Glycoproteins exist, for example, in Sen-like organs such as the pituitary gland and gastric mucosa, connective tissues such as the skin, joints, and cartilage, and secretions such as Da fluid, gastric juice, and blood, and serve as tissue-forming substances. The compound of the present invention has a lubricating and protective effect on biological functions and plays an important immunological and serological role. , is likely to be effective against various diseases in these tissues. The most typical example is the treatment and prevention of peptic ulcers such as gastric ulcer and duodenal ulcer. Since the compound of the present invention has extremely low toxicity,
It is extremely advantageous as an anti-ulcer agent because these diseases necessitate continuous use due to their nature. The compound of the present invention is usually administered orally or parenterally in an amount of 50 to 2000 mg per day for adults, although it varies depending on the disease and severity. Dosage forms include powders, granules, tablets, capsules, and injections, which can be manufactured by conventional methods using conventional pharmaceutical carriers. Examples of the present invention will be listed next, but it goes without saying that the present invention is not limited to these only. Example 1 6,10,14,18-tetramethyl-5,9,13,
17-nonadecatetraen-2-yl phosphate ester, dilithium salt and 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-yl pyrophosphate ester, trilithium salt (1) 6,10,14,18-tetramethyl-5,9,
Synthesis of 13,17-nonadecatetraen-2-ol 6,10,14,18-tetramethyl-5,9,
1 g of 13,17-nonadecatetraen-2-one
It was dissolved in 20 ml of methanol, 60 mg of sodium borohydride was added, and the mixture was stirred for 30 minutes. Pour the reaction solution into ice water, add dilute hydrochloric acid to make the solution acidic, and
- Extracted with 50 ml of hexane. The extract was washed with water and then dried with magnesium sulfate. The solvent was distilled off to obtain 1 g of a poured product. This was purified by column chromatography on silica gel, and 0.95 g of the title compound as a colorless oil was obtained from the 10% ether/n-hexane outflow. Mass spectrum (m/e): 332 (M + ) Elemental analysis value: C 23 H 40 O C H Theoretical value (%) 83.06 12.13 Actual value (%) 83.12 12.09 NMR spectrum (δ, CDCl 3 ): 1.16 ( 3H, d, J = 7Hz) 1.58 (9H, s) 1.65 (6H, s) 1.2 ~ 1.6 (2H) 1.8 ~ 2.3 (15H) 3.74 (1H, t, q, J = 6Hz, 6Hz) 5.04 (4H, m) (2) 50 g of 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-ol obtained by the method of (1) and trichloroacetonitrile
Add phosphoric acid to 130 g of solution at room temperature while stirring.
A solution 3 of 108 g of bistriethylammonium salt in acetonitrile is added dropwise over 4 hours. After stirring for an additional 2 hours, the solvent is concentrated under reduced pressure at 40°C. Add 1 portion of ethyl ether to the concentrate, and acidify with dilute hydrochloric acid while stirring. The organic layer is separated, washed with water, dried over magnesium sulfate, and concentrated. The concentrate is dissolved in methanol and subjected to column chromatography using diethylaminoethyl (DEAE)-cellulose in the acetic acid form, and eluted with a methanol solution of 0.01-0.1 N ammonium acetate to separate and purify the phosphate ester and pyrophosphate ester. Water is added to each of these esters, acidified with dilute hydrochloric acid, extracted with ethyl ether, washed with water, and concentrated. Dissolve the concentrate in methanol, add a methanol solution of lithium chloride, and add dilute ammonia/methanol solution to neutralize. The precipitated white crystals were filtered by centrifugation, washed with methanol and dried under reduced pressure to obtain the title compound 6,10,14,18-tetramethyl-5,9,13,
8.5 g of 17-nonadecatetraen-2-yl phosphoric acid ester dilithium salt [phosphorus analysis: (by wet phosphomolybdenum blue method) theoretical value 7.30% as C 23 H 39 O 4 PLi 2 , actual value 7.08%] and Title compound 6,10,14,18-tetramethyl-5,9,13,
17-nonadecatetraen-2-yl pyrophosphate ester trilithium salt 6.2 g [phosphorus analysis: (wet phosphomolybdenum blue method) C 23 H 39 O 7 P 2 Li 3 theoretical value 12.14%, actual value 11.90% ] was obtained. Example 2 6,10,14,18-tetramethyl-5,9,13,
17-nonadecatetraen-2-yl β-D-mannopyranosyl phosphoric acid diester (1) 6,10,14,18-tetramethyl-5,9,
13,17-nonadecatetraen-2-yl 2,
3,4,6-tetra-O-acetyl-β-D-
Synthesis of mannopyranosyl phosphoric acid diester 2,3,4,6-tetra-O-acetyl-β
-D-mannopyranosyl phosphate 2.0g pyridinium salt and 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-
Add 1.0 g of 2-ol. Anhydrous toluene is added to this, and the toluene is distilled off under reduced pressure. Next, 1.0 g of triisopropylbenzenesulfonyl chloride was added, and anhydrous toluene was added, followed by distillation and thorough dehydration. Add 10 ml of anhydrous pyridine to this mixture and stir at room temperature for 4 days. Then methanol 20
After stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. Dissolve the concentrate in 100ml of chloroform, wash with water,
Dry with magnesium sulfate and concentrate. The concentrate was subjected to silica gel column chromatography,
Elution with 5% methanol/chloroform solution yields 6,10,14,18-tetramethyl-5,9,
13,17-nonadecatetraen-2-yl 2,
3,4,6-tetra-O-acetyl-β-D-
450 mg of mannopyranosyl phosphoric acid diester are obtained. (2) 6,10,14,18-tetramethyl-5,9,
13,17-nonadecatetraen-2-yl β-D
-mannopyranosyl phosphoric acid diester 6,10,14,18- obtained by method (1) above
Tetramethyl-5,9,13,17-nonadecatetraen-2-yl 2,3,4,6-tetra-O
-Acetyl-β-D-mannopyranosyl phosphoric acid diester 450 mg in 1% sodium methylate.
Dissolve in 100 ml of methanol solution and stir at room temperature for 30 minutes. After that, ion exchange resin AG・50W
- Neutralize with X8 pyridine type and filter. When the liquid is concentrated, the title compound 6, 10, 14, 18
390 mg of -tetramethyl-5,9,13,17-nonadecatetraen-2-yl β-D-mannopyranosyl phosphoric acid diester are obtained. NMR spectrum (δ, D2O ): 1.1-1.4 (5H) 1.56 (12H, s) 1.63 (3H, s) 1.8-2.3 (14H) 3.5-4.1 (6H) 4.30 (1H, m) 5.10 (4H, bs) 5.44 (1H, d, J=6Hz)
Claims (1)
【式】で示される基を意 味する。〕 で表わされる６，10，14，18−テトラメチル−
５，９，13，17−ノナデカテトラエン−２−イル
燐酸エステル若しくはその塩。 ２ ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イル燐酸エス
テルである特許請求の範囲第１項記載の化合物若
しくはその塩。 ３ ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イルピロ燐酸
エステルである特許請求の範囲第１項記載の化合
物若しくはその塩。 ４ ６，10，14，18−テトラメチル−５，９，
13，17−ノナデカテトラエン−２−イルβ−Ｄ−
マンノピラノシル燐酸ジエステルである特許請求
の範囲第１項記載の化合物若しくはその塩。[Claims] 1. General formula [wherein, ] 6,10,14,18-tetramethyl-
5,9,13,17-nonadecatetraen-2-yl phosphoric acid ester or a salt thereof. 2 6,10,14,18-tetramethyl-5,9,
13. The compound or salt thereof according to claim 1, which is 13,17-nonadecatetraen-2-yl phosphoric acid ester. 3 6,10,14,18-tetramethyl-5,9,
The compound according to claim 1 or a salt thereof, which is 13,17-nonadecatetraen-2-yl pyrophosphate. 4 6,10,14,18-tetramethyl-5,9,
13,17-nonadecatetraen-2-yl β-D-
The compound according to claim 1, which is a mannopyranosyl phosphoric acid diester, or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8882381A JPS57206691A (en) | 1981-06-11 | 1981-06-11 | 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-yl phosphoric ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8882381A JPS57206691A (en) | 1981-06-11 | 1981-06-11 | 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-yl phosphoric ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57206691A JPS57206691A (en) | 1982-12-18 |
| JPH0132832B2 true JPH0132832B2 (en) | 1989-07-10 |
Family
ID=13953644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8882381A Granted JPS57206691A (en) | 1981-06-11 | 1981-06-11 | 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-yl phosphoric ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57206691A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4911285B2 (en) * | 2006-03-13 | 2012-04-04 | Ｊｓｒ株式会社 | Block copolymer and method for producing the same |
| FR2958541B1 (en) * | 2010-04-08 | 2012-05-18 | Sederma Sa | COSMETIC USE OF GERANYLGERANYL-2-PROPANOL |
-
1981
- 1981-06-11 JP JP8882381A patent/JPS57206691A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57206691A (en) | 1982-12-18 |
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