JPS62298561A - Novel synthetic lipid - Google Patents
Novel synthetic lipidInfo
- Publication number
- JPS62298561A JPS62298561A JP14176586A JP14176586A JPS62298561A JP S62298561 A JPS62298561 A JP S62298561A JP 14176586 A JP14176586 A JP 14176586A JP 14176586 A JP14176586 A JP 14176586A JP S62298561 A JPS62298561 A JP S62298561A
- Authority
- JP
- Japan
- Prior art keywords
- lipid
- formula
- chain
- reacting
- salt
- 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.)
- Granted
Links
- 150000002632 lipids Chemical class 0.000 title claims abstract description 32
- 150000003505 terpenes Chemical group 0.000 claims abstract description 10
- 150000001450 anions Chemical class 0.000 claims abstract description 7
- 150000001768 cations Chemical class 0.000 claims abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000012528 membrane Substances 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 229920006254 polymer film Polymers 0.000 abstract description 7
- 229910052736 halogen Inorganic materials 0.000 abstract description 6
- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical compound CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 abstract description 5
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 150000003512 tertiary amines Chemical class 0.000 abstract description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 230000002140 halogenating effect Effects 0.000 abstract description 2
- 229910052708 sodium Inorganic materials 0.000 abstract description 2
- 239000011734 sodium Substances 0.000 abstract description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 1
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 229940079826 hydrogen sulfite Drugs 0.000 abstract 1
- -1 aluminum ion Chemical class 0.000 description 15
- 239000000232 Lipid Bilayer Substances 0.000 description 13
- 239000003012 bilayer membrane Substances 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 7
- 230000007704 transition Effects 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 235000007586 terpenes Nutrition 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 230000009975 flexible effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000001707 (E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-ol Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- BLUHKGOSFDHHGX-UHFFFAOYSA-N Phytol Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)C=CO BLUHKGOSFDHHGX-UHFFFAOYSA-N 0.000 description 3
- HNZBNQYXWOLKBA-UHFFFAOYSA-N Tetrahydrofarnesol Natural products CC(C)CCCC(C)CCCC(C)=CCO HNZBNQYXWOLKBA-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- BOTWFXYSPFMFNR-OALUTQOASA-N all-rac-phytol Natural products CC(C)CCC[C@H](C)CCC[C@H](C)CCCC(C)=CCO BOTWFXYSPFMFNR-OALUTQOASA-N 0.000 description 3
- BOTWFXYSPFMFNR-PYDDKJGSSA-N phytol Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO BOTWFXYSPFMFNR-PYDDKJGSSA-N 0.000 description 3
- CRDAMVZIKSXKFV-FBXUGWQNSA-N (2-cis,6-cis)-farnesol Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C/CO CRDAMVZIKSXKFV-FBXUGWQNSA-N 0.000 description 2
- 239000000260 (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000005266 casting Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940043259 farnesol Drugs 0.000 description 2
- 229930002886 farnesol Natural products 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000003010 ionic group Chemical group 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940006186 sodium polystyrene sulfonate Drugs 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 2
- FCWHMWNJUUXVFW-IZKFDIQUSA-N (e,7r,11r)-3,7,11,15-tetramethylhexadec-2-en-1-ol;hydrochloride Chemical compound Cl.CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC\C(C)=C\CO FCWHMWNJUUXVFW-IZKFDIQUSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- GXELGIJWVYOLQW-UHFFFAOYSA-N 2,2,3-trimethylheptadecane Chemical compound CCCCCCCCCCCCCCC(C)C(C)(C)C GXELGIJWVYOLQW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 238000004435 EPR spectroscopy Methods 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 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
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- NAPSCFZYZVSQHF-UHFFFAOYSA-N dimantine Chemical compound CCCCCCCCCCCCCCCCCCN(C)C NAPSCFZYZVSQHF-UHFFFAOYSA-N 0.000 description 1
- 229950010007 dimantine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229920000075 poly(4-vinylpyridine) Polymers 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000001132 ultrasonic dispersion Methods 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
Abstract
Description
【発明の詳細な説明】
〔技術分野〕
本発明は２分子膜形成能を有する新規な合成脂質に関す
るものである。DETAILED DESCRIPTION OF THE INVENTION [Technical Field] The present invention relates to a novel synthetic lipid having the ability to form a bilayer membrane.
従来より、２分子脂形成能を有する脂質は知られており
、例えば１次の構造のものが提案されている〔文献基：
Ｔ、Ｋｕｎｉｔａｋｅ、Ｙ、０ｋａｈａｔａ、Ｂｕｌ
ｌ、Ｃｈｅｍ。Lipids that have the ability to form bimolecular lipids have been known for a long time, and for example, lipids with a primary structure have been proposed [References:
T, Kunitake, Y, 0kahata, Bul
l, Chem.
Ｓｏｃ、Ｊｐｎ、、５１，１８７７（１９７８）、Ｔ、
Ｋｕｎｉｔａｋｅ、Ｙ、０ｋａｈａｔａ。Soc, Jpn, 51, 1877 (1978), T.
Kunitake, Y., 0kahata.
Ｊ、Ａｍｅｒ、Ｃｙｈｅｍ、Ｓｏｃ、、Ｈ，３８６０（
１９７７）３ ｍ（ｏ３ｃ（ｃｕ、）ｎ）ｚＮ”（ｃｕ
３）ｉ ・Ｂｒ−（前記式中、ｎは１１，１３，１５又
は１７である）しかしながら、このような脂質は、２分
子膜形成能を有するものの、得られる２分子膜は、相転
移温度が高く、室温ではゲル状態（一種の固体状ｍ）を
示し、流動性に欠けるという欠点がある。J, Amer, Cyhem, Soc,, H, 3860 (
1977) 3 m(o3c(cu,)n)zN”(cu
3) i Br- (in the above formula, n is 11, 13, 15, or 17) However, although such a lipid has the ability to form a bilayer membrane, the resulting bilayer membrane has a phase transition temperature It has a drawback that it has a high fluidity, exhibits a gel state (a kind of solid state) at room temperature, and lacks fluidity.
一般に、生体膜は脂質２分子膜を基本骨格とし。Generally, biological membranes have a lipid bilayer membrane as their basic skeleton.
また生体膜の機能は２分子膜の流動性を必要としている
が、この生体膜の場合、その流動性は極めて多種類の脂
質の混合によって保持されている。Furthermore, the function of biological membranes requires the fluidity of bimolecular membranes, and in the case of biological membranes, this fluidity is maintained by a mixture of extremely many types of lipids.
従って、生化学分野や薬学分野における研究では、流動
性の脂質２分子膜を得るために、天然より得、られる混
合脂質を用いたり、あるいはそれ単独では相転移温度の
高い脂質にコレステロール等を配合して用いているのが
現状であり、単一脂質で流動性の高い２分子膜形成能を
有する脂質が強く要望されている。また、工学的にも、
流動性のある２分子膜は要望されている。従来、脂質２
分子膜を高分子フィルムに固定化したものが知られてい
るが、この場合の脂質２分子膜固定化高分子フィルムも
、その脂質２分子膜の相転移温度が室温以上であるため
に、硬い上に、中には脆いものさえある。Therefore, in research in the biochemistry and pharmaceutical fields, in order to obtain fluid lipid bilayer membranes, mixed lipids obtained from nature are used, or lipids with a high phase transition temperature are combined with cholesterol, etc. Currently, it is used as a single lipid, and there is a strong demand for a single lipid that has the ability to form a bilayer membrane with high fluidity. Also, from an engineering perspective,
A fluid bilayer membrane is desired. Conventionally, lipid 2
It is known that a molecular membrane is immobilized on a polymer film, but in this case, the lipid bilayer membrane-immobilized polymer film is also hard because the phase transition temperature of the lipid bilayer membrane is above room temperature. On top of that, some of them are even fragile.
本発明は、相転移温度が室温以下の２分子膜を形成し得
る合成脂質を提供することを目的とする。An object of the present invention is to provide a synthetic lipid capable of forming a bilayer membrane having a phase transition temperature of room temperature or lower.
本発明によれば、下記一般式（１）〜（ＩＩ）で表わさ
れる脂質が提供される。According to the present invention, lipids represented by the following general formulas (1) to (II) are provided.
炉
前記式中、ｎｌ、ｎ２は長鎖炭化水素基であるが、少な
くともその一方は鎖式テルペン構造炭化水素基である。In the above formula, nl and n2 are long chain hydrocarbon groups, and at least one of them is a chain terpene structure hydrocarbon group.
これらの炭化水素基の炭素数は１０〜２０個程度である
ＢＳ、Ｈｄｋはアルキル基であり、その炭素数は１〜
２０個程度である０Ｍは塩形成性陽イオンを表わし、ア
ルカリ金属やアルカリ土類金属、アルミニウム等の金属
イオンや、アルミニウムイ１ン等であり、Ｘは塩形成性
陰イオンを表わし。The number of carbon atoms in these hydrocarbon groups is about 10 to 20. BS and Hdk are alkyl groups, and the number of carbon atoms is about 1 to 20.
About 20 0M represents a salt-forming cation, such as an alkali metal, an alkaline earth metal, a metal ion such as aluminum, or an aluminum ion, and X represents a salt-forming anion.
ｄ素、臭素、ヨウ素等のハロゲンイオンや、Ｐ −トル
エンスルホン酸イオン等である。These include halogen ions such as d, bromine, and iodine, and P-toluenesulfonic acid ions.
本発明で言う鎖式テルペン構造炭化水素基とは。What is the chain terpene structure hydrocarbon group referred to in the present invention?
その構造が鎖式構造のテルペンの炭化水素残基と同一な
いし類似構造の炭化水素基を意味し、天然の鎖式テルペ
ン由来のものの他、合成テルペンから誘導されたものが
包含される。この鎖式構造テルペン炭化水素基は、通常
、１０〜２０個の炭素数を有し、かつ複数のメチル基を
有するもので、その具体例としては、例えば、フィトー
ル由来の炭化水素基Ｃ２゜Ｌｓ−や、ファルネソール由
来の炭化水素基ＣＩＭ）Ｉ２．−等を挙げることができ
る。なお、この場合、フィトールやファルネソール等の
鎖式テルペンは、天然品又は合成品であることができる
。It means a hydrocarbon group whose structure is the same as or similar to the hydrocarbon residue of a terpene having a chain structure, and includes those derived from natural chain terpenes as well as those derived from synthetic terpenes. This chain structure terpene hydrocarbon group usually has 10 to 20 carbon atoms and a plurality of methyl groups, and specific examples thereof include, for example, a hydrocarbon group derived from phytol C2゜Ls -, farnesol-derived hydrocarbon group CIM) I2. - and so on. In this case, the chain terpene such as phytol or farnesol can be a natural product or a synthetic product.
また、これらのテルペン中の不飽和２重結合は、還元し
て飽和結合とし、その化学的安定性を高めることが好ま
しい。Further, it is preferable that unsaturated double bonds in these terpenes be reduced to saturated bonds to improve their chemical stability.
前記一般式（１）で表わされる化合物のうち、Ｘがハロ
ゲンであるものは、鎖式テルペンアルコールを原料とし
て用い、これをハロゲン化剤と反応さ・せてその水酸基
をハロゲンに変換させた後、第３級アミンと反応させる
ことによって得ることがで、きる、また、Ｘがハロゲン
以外の陰イオンであるものは、その陰イオンを含む酸又
は塩と反応させることによって形成することができ１例
えば、ｐ−トルエンスルホン酸ナトリウムと反応させる
ことにより、ＸがＰ−トルエンスルホン酸イオンである
化合物を得・ることができる。Among the compounds represented by the general formula (1), those in which X is a halogen are obtained by using a chain terpene alcohol as a raw material and reacting it with a halogenating agent to convert its hydroxyl group into a halogen. , can be obtained by reacting with a tertiary amine, and those in which X is an anion other than halogen can be formed by reacting with an acid or salt containing that anion. For example, a compound in which X is a p-toluenesulfonate ion can be obtained by reacting with sodium p-toluenesulfonate.
一般式（ＩＩ）で表わされるものは、鎖式テルペンアル
コールを無水マレイン酸と反応させた後、亜硫酸水素塩
と反応させることによって得ることができる。The compound represented by the general formula (II) can be obtained by reacting a chain terpene alcohol with maleic anhydride and then reacting it with bisulfite.
本発明の脂質は超音波処理や加熱処理を併用して水中や
分散させることができ、そしてこの分散によって２分子
膜構造を有する会合体が形成される。この２分子膜は、
その疎水基を樋成する炭化水素基の少なくとも１個が炭
素数１０〜２０個のテルペン構造炭化水素基であること
から、その相転移温度は室温以下であり、高い運動性と
流動性を有する。脂質の運動性及び流動性は、熱分析、
核磁気共鳴、電子スピン共鳴蛍光分析等で測定できるが
、脂質２分子膜固定化高分子フィルムを作り、このもの
の性質を調べることによっても確認することができる１
本発明の脂質より得られた脂質２分子膜固定化フィルム
は、その脂質２分子膜の相転移温度が室温以下であるた
め、しなやかな性状を有する。The lipid of the present invention can be dispersed in water using a combination of ultrasonication and heat treatment, and this dispersion forms an aggregate having a bilayer membrane structure. This bilayer membrane is
Since at least one of the hydrocarbon groups forming the hydrophobic group is a terpene structure hydrocarbon group having 10 to 20 carbon atoms, its phase transition temperature is below room temperature, and it has high mobility and fluidity. . Lipid motility and fluidity can be determined by thermal analysis,
It can be measured by nuclear magnetic resonance, electron spin resonance fluorescence analysis, etc., but it can also be confirmed by making a polymer film immobilized with a lipid bilayer membrane and examining the properties of this film1.
The lipid bilayer membrane-immobilized film obtained from the lipid of the present invention has flexible properties because the phase transition temperature of the lipid bilayer membrane is below room temperature.
本発明の脂質を用いて脂質２分子膜固定化高分子フィル
ムを製造するには、本発明の脂質を水中に分散させ、こ
の分散液に高分子水溶液を混合して、脂質２分子膜の固
定化した高分子沈殿物を得る。この沈殿物を有機溶媒に
溶解し、キャスティング法により製膜し、脂質２分子膜
固定化高分子フィルムを得ることができる。この場合、
高分子としては、脂質のイオン性基との間でイオン結合
や水素結合等の錯形成の可能であるイオン性基を有する
ものが用いられる。このような高分子としては、例えば
、ポリ（４−ビニルベンジルトリメチルアンモニウムク
ロリド）、ポリ（４−ビニルピリジン）、ポリ（４−ビ
ニル−Ｎ−メチルピリジニウムブロマイド）、ポリアク
リルアミン、ポリスチレンスルホン酸ナトリウム、キト
サン、ヘパリン等が挙げられる。また、脂質２分子膜固
定化高分子を溶解させる溶媒としては、クロロホルム、
ジクロロメタン、１，２−ジクロロエタン等が用いられ
る。脂質２分子膜とその固定化用高分子との割合は、高
分子１重量部に対し、脂質２〜ｌＯ重量部、好ましくは
３〜４重量部の割合である。In order to produce a lipid bilayer membrane-immobilized polymer film using the lipid of the present invention, the lipid of the present invention is dispersed in water, and an aqueous polymer solution is mixed with this dispersion to immobilize the lipid bilayer membrane. Obtain a polymeric precipitate. This precipitate is dissolved in an organic solvent and formed into a film by a casting method to obtain a lipid bilayer membrane-immobilized polymer film. in this case,
As the polymer, one having an ionic group capable of forming a complex such as an ionic bond or a hydrogen bond with an ionic group of a lipid is used. Examples of such polymers include poly(4-vinylbenzyltrimethylammonium chloride), poly(4-vinylpyridine), poly(4-vinyl-N-methylpyridinium bromide), polyacrylamine, and sodium polystyrene sulfonate. , chitosan, heparin, etc. In addition, as a solvent for dissolving the lipid bilayer membrane-immobilized polymer, chloroform,
Dichloromethane, 1,2-dichloroethane, etc. are used. The ratio of the lipid bilayer membrane and the polymer for immobilizing it is 2 to 10 parts by weight, preferably 3 to 4 parts by weight, of the lipid per 1 part by weight of the polymer.
本発明の脂質は、前記したように、室温以下の相転移温
度を有する２分子膜を形成する性質を有する０本発明の
脂質によって形成される２分子膜はそれ単独で生体膜に
近い流動性を持ち、生化学、薬学分野における生体膜モ
デルとして用いられる他、薬物キャリアとしてのリポリ
ーム材料としても利用し得る。また１本発明の脂質２分
子膜固定化高分子フィルムは、軟かく、しなやかで１強
度にもすぐれており、生体膜類似の機能材料として〔実
施例〕
次に本発明を実施例によりさらに詳細に説明する。As mentioned above, the lipid of the present invention has the property of forming a bilayer membrane having a phase transition temperature below room temperature. In addition to being used as a biological membrane model in the biochemical and pharmaceutical fields, it can also be used as a lipolyme material as a drug carrier. In addition, the lipid bilayer membrane-immobilized polymer film of the present invention is soft, flexible, and has excellent strength, and can be used as a functional material similar to biological membranes. Explain.
実施例１
フィトール１２ｇ、２，６−シメチルピリジン５ｇ及び
塩化リチウム２ｇのジメチルホルムアミド溶液に水冷下
メタンスルホニルクロリド６ｇを反応させることによっ
て、相当するフィトールの塩化物（１−クロロ−３，７
，１１，１５−テトラメチル−２−へキサデセン）１１
ｇを得た。この塩化物をアルコール中で等モル量のジメ
チルオクタデシルアミンと反応させることによって次の
構造の脂質を合成した。Example 1 The corresponding phytol chloride (1-chloro-3,7
, 11,15-tetramethyl-2-hexadecene) 11
I got g. A lipid with the following structure was synthesized by reacting this chloride with an equimolar amount of dimethyloctadecylamine in alcohol.
この化合物は室温で無色粘稠性のもので、その同定は、
ＩＲ及びＮＭＲによって行った。次に、そのＮＭＲ測定
値を示す。This compound is colorless and viscous at room temperature, and its identification is
Performed by IR and NMR. Next, the NMR measurement values are shown.
δ値（溶媒ＣＤＣＱ 、 ）
０．８〜１．９（ｍ、１１Ｈ，ＣＨｓ、−Ｃ）ＩＣＨ，
）３．２〜３．５（ｍ、８Ｈ１−Ｎ”−Ｃ且１、− Ｎ
”ＣＨ，−）４．２（ｄ、２１１、＝ＣＨＣ１１２Ｎ”
）５．３（ｍ、 ＩＨ１＝Ｃ川Ｃ１１用−）次に、この
脂質の１％超音波分散液及び脂質に対し等荷電量の１％
ポリスチレンスルホン酸ナトリウム水溶液を５０〜７０
℃において混合し、脂質とポリマーとの間のイオン対形
成によって２分子膜を固定し、これを沈澱物として回収
した。この沈澱物を再沈澱により精製後、クロロホルム
溶液としてキャスティング法によりフィルム状に成形し
た。このフィルムは機械的強度もあり、透明でしなやか
な性状であった。δ value (solvent CDCQ, ) 0.8-1.9 (m, 11H, CHs, -C)ICH,
) 3.2-3.5 (m, 8H1-N”-C and 1,-N
"CH,-)4.2(d,211,=CHC112N"
) 5.3 (m, for IH1 = C river C11 -) Next, 1% ultrasonic dispersion of this lipid and 1% of the same charge amount for the lipid.
Sodium polystyrene sulfonate aqueous solution 50-70
The mixture was mixed at 0.degree. C. to fix the bilayer membrane by ion pair formation between the lipid and polymer, which was collected as a precipitate. After the precipitate was purified by reprecipitation, it was made into a chloroform solution and formed into a film by a casting method. This film had mechanical strength, was transparent and flexible.
実施例２
フィトール５０ｇをエタノール中で５％パラジウムカー
ボン２．５ｇで接触水素添加して、飽和アルコール（３
，７，１１，１５−テトラメチルへキサデカ−１−オー
ル）３４ｇを得た。このアルコール１２ｇを４８％臭化
水素酸１３ｇと少量の硫酸とともに加熱することによっ
て相当する臭化物（１−ブロモ−３，７，１１，１５−
テトラメチルヘキサデカン）７ｇを得た。また、この臭
化物７ｇを含水アルコール中でジメチルアミンと加熱反
応させることによって三級アミン（Ｎ、Ｎ−ジメチル−
３，７，１１，１５−テトラメチルベキサブシルアミン
）５ｇを得た。Example 2 50 g of phytol was catalytically hydrogenated in ethanol with 2.5 g of 5% palladium on carbon to form a saturated alcohol (3
, 7,11,15-tetramethylhexadec-1-ol) was obtained. The corresponding bromide (1-bromo-3,7,11,15-
7 g of tetramethylhexadecane) was obtained. In addition, tertiary amine (N,N-dimethyl-
5 g of 3,7,11,15-tetramethylbexabucilamine) was obtained.
次に、このアミンと先に合成した臭化物をアルコール中
で加熱反応することによって、はぼ定量的に次の構造式
の脂質を得た。Next, this amine and the previously synthesized bromide were heated and reacted in alcohol to obtain a lipid with the following structural formula in a quantitative manner.
この化合物は無色粘稠性のもので、その同定は、ＩＲ及
びＮＭＲで行った。次にこのＮＭＲ測定値を示す。This compound was colorless and viscous, and its identification was performed by IR and NMR. Next, the NMR measurement values are shown.
δ値（溶媒ＣＤＣＱ３）
０．８〜１．０（ｍ、３０Ｈ１−Ｃシ）１．２〜１．６
（＋ａ、４８）１．−Ｃシー、−Ｃ且−ＣＨ，）３．６
（ｂｓ、ｌ０Ｈ１Ｎ”ＣＨ２−１Ｎ”Ｃ旦、）次に、こ
の脂質を用い、実施例１と同様にして２分子脂質固定化
フィルムを得た。このものは透明で、室温でしなやかな
性状を示した。δ value (solvent CDCQ3) 0.8 to 1.0 (m, 30H1-C) 1.2 to 1.6
(+a, 48)1. -C C, -C and -CH,)3.6
(BS, 10H1N"CH2-1N"Cdan,) Next, using this lipid, a bimolecular lipid-immobilized film was obtained in the same manner as in Example 1. This material was transparent and showed supple properties at room temperature.
実施例３
実施例２と同様にして得た３、７，１１．１５−テトラ
メチルへキサデカ−１−オール１４．９ｇ、無水マレイ
ン酸２．２３ｇ、濃硫酸０．１＋ａＱ及びトルエン１０
０ｍ Ｑの混合物を２時間加熱還流した。副生じた水は
共沸留去した。炭酸水素ナトリウム水溶液、続いて水で
反応液を水洗後、硫酸マグネシウムで乾燥し、溶媒を留
去してコハク酸ジエステルを得た。Example 3 14.9 g of 3,7,11.15-tetramethylhexadec-1-ol obtained in the same manner as in Example 2, 2.23 g of maleic anhydride, 0.1+aQ of concentrated sulfuric acid, and 10 of toluene.
The 0mQ mixture was heated to reflux for 2 hours. The by-produced water was azeotropically distilled off. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution and then with water, dried over magnesium sulfate, and the solvent was distilled off to obtain a succinic acid diester.
次に、このコハク酸ジエステル４．５ｇを１５０℃に加
熱しておき、これに５ｍΩの水に溶解した亜硫酸水素ナ
トリウム２．１ｇを滴下した。２時間加熱反応後、放冷
し、無機塩を濾別後、カラムクロマトグラフ（シリカゲ
ル−メタノール／クロロホルム系）で精製し、目的のア
ニオン性脂質、ジ（３，７，１１，１５−テトラメチル
ヘキサデシル）スルホコハク酸ナトリウムを得た。Next, 4.5 g of this succinic acid diester was heated to 150° C., and 2.1 g of sodium bisulfite dissolved in 5 mΩ water was added dropwise thereto. After heating for 2 hours, the reaction was allowed to cool, the inorganic salts were filtered off, and the target anionic lipid, di(3,7,11,15-tetramethyl) was purified by column chromatography (silica gel-methanol/chloroform system). Sodium hexadecyl) sulfosuccinate was obtained.
この化合物は無色粘稠性のもので、その構造をＩＲとＮ
ＭＲで確認した１次に、そのＮＭＲ測定値を示す。This compound is colorless and viscous, and its structure is IR and N
The NMR measurement values are shown for the first order confirmed by MR.
δ値（溶媒ＣＤＣＱ ３）
０．８〜１．０（ｍ、３０Ｈ１−ＣＨ３）１．１〜１．
６（ｍ、４８Ｈ１−ＣＨ，−１−ＣＨＣＨ，）２．７〜
３．１（■、３Ｈ１−ＣＯＣシＣ旦Ｃ０−）４．０〜４
．３（＋ｍ、４Ｈ，−ＱＣち−）次に、前記で得たアニ
オン性脂質とポリ（アクリルアミドプロピルトリメチル
アンモニウムクロライド）と反応させて、無色透明の柔
軟なフィルムを得た。δ value (solvent CDCQ 3) 0.8-1.0 (m, 30H1-CH3) 1.1-1.
6 (m, 48H1-CH, -1-CHCH,) 2.7~
3.1 (■, 3H1-COCしCdanC0-)4.0~4
．． 3(+m, 4H, -QCchi-) Next, the anionic lipid obtained above was reacted with poly(acrylamidopropyltrimethylammonium chloride) to obtain a colorless and transparent flexible film.
特許出願人 工業技術院長 飯 塚 幸 三指定代
理人 工業技術院製品科学研究所長高橋教司Patent applicant Koji Iizuka, Director of the Agency of Industrial Science and Technology Designated agent: Keiji Takahashi, Director, Product Science Research Institute, Agency of Industrial Science and Technology
Claims (1)
、少なくともその一方は鎖式テルペン構造炭化水素基で
あり、Ｒ＾３、Ｒ＾４はアルキル基を示し、Ｍは塩形成
性陽イオン及びＸは塩形成性陰イオンを示す） で表わされる合成脂質。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the above formula, R^1 and R^2 are long-chain hydrocarbon groups. However, at least one of them is a chain terpene structure hydrocarbon group, R^3 and R^4 represent an alkyl group, M represents a salt-forming cation, and X represents a salt-forming anion). synthetic lipids.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14176586A JPS62298561A (en) | 1986-06-18 | 1986-06-18 | Novel synthetic lipid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14176586A JPS62298561A (en) | 1986-06-18 | 1986-06-18 | Novel synthetic lipid |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10569690A Division JPH02288849A (en) | 1990-04-20 | 1990-04-20 | New synthetic lipid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62298561A true JPS62298561A (en) | 1987-12-25 |
| JPH0366299B2 JPH0366299B2 (en) | 1991-10-16 |
Family
ID=15299656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14176586A Granted JPS62298561A (en) | 1986-06-18 | 1986-06-18 | Novel synthetic lipid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62298561A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500892B1 (en) | 2000-06-16 | 2002-12-31 | Basell Poliolefine Italia S.P.A. | Intercalated clay useful for making an α-olefin polymer material nanocomposite |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57192343A (en) * | 1981-05-18 | 1982-11-26 | Nisshin Flour Milling Co Ltd | Isoprenylamine derivative |
-
1986
- 1986-06-18 JP JP14176586A patent/JPS62298561A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57192343A (en) * | 1981-05-18 | 1982-11-26 | Nisshin Flour Milling Co Ltd | Isoprenylamine derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6500892B1 (en) | 2000-06-16 | 2002-12-31 | Basell Poliolefine Italia S.P.A. | Intercalated clay useful for making an α-olefin polymer material nanocomposite |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0366299B2 (en) | 1991-10-16 |
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