WO1986002349A1 - Lipid derivatives - Google Patents

Lipid derivatives Download PDF

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Publication number
WO1986002349A1
WO1986002349A1 PCT/JP1984/000476 JP8400476W WO8602349A1 WO 1986002349 A1 WO1986002349 A1 WO 1986002349A1 JP 8400476 W JP8400476 W JP 8400476W WO 8602349 A1 WO8602349 A1 WO 8602349A1
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WO
WIPO (PCT)
Prior art keywords
compound
dissolved
silica gel
methyl
mmol
Prior art date
Application number
PCT/JP1984/000476
Other languages
French (fr)
Japanese (ja)
Inventor
Hiroaki Nomura
Kohei Nishikawa
Susumu Tsushima
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to PCT/JP1984/000476 priority Critical patent/WO1986002349A1/en
Priority to DE8585302202A priority patent/DE3586746D1/en
Priority to EP85302202A priority patent/EP0157609B1/en
Priority to DE8585302202T priority patent/DE3586746T2/en
Priority to AT85302202T priority patent/ATE81501T1/en
Priority to JP60069628A priority patent/JPH0745454B2/en
Priority to CA000478129A priority patent/CA1281324C/en
Priority to KR1019850002240A priority patent/KR930004361B1/en
Publication of WO1986002349A1 publication Critical patent/WO1986002349A1/en
Priority to US06/906,310 priority patent/US4737518A/en
Priority to US07/556,280 priority patent/US5025005A/en
Priority to JP4068728A priority patent/JPH0819080B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/48—Y being a hydrogen or a carbon atom
    • C07C275/50—Y being a hydrogen or an acyclic carbon atom
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    • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
    • C07C275/58—Y being a hetero atom
    • C07C275/60—Y being an oxygen atom, e.g. allophanic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • the present invention relates to novel lipid derivatives useful as medicaments.
  • P A F P latelet Acting Factor
  • lipid derivatives having an ether bond or a dextrin bond may bind to these bonds.
  • cancer cells are deficient in enzymes that cleave them, so they easily accumulate in cancer cells, alter lipid metabolism in cancer cells, and have the effect of causing cancer cells to die.
  • the present inventors have intensively searched for lipid derivatives that have a PAF inhibitory effect, prevent various circulatory disorders and allergic monogenic diseases, and are useful as therapeutic agents and antitumor agents.
  • the production was successful and the present invention was completed.
  • the present invention uses the formula
  • R 1 represents alkyl or alkyl rubamoyl
  • R 2 represents hydrogen, optionally substituted hydroxy, optionally substituted amino or cyclic amino
  • R 3 represents alkylene
  • R 4 represents X and Y each represent 0 (oxygen atom), S (sulfur atom) or an optionally substituted imino group
  • Y represents X may form a ring together with the imino group or R * represented by X
  • Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring] and a salt thereof.
  • the alkyl group represented by R 1 may be either linear or branched, for example, decyl, pendecyl: tridecyl, tetradecyl, pentadecyl.hexadecyl, heptadecyl.octadecyl, nonadecyl, Alkyl having about 10 to 30 carbon atoms, such as eicosanil, heneicosanil, docosanil, tricosanil, tetracosanil; pentacosanil, hexacosanil, heptacosanil, octacosanil, nonacosanil, triaconthani'le, phnareseal, dihydrofityl, and the like.
  • an alkyl group having 14 to 20 carbon atoms is preferable, and an alkyl group having 15 to 18 carbon atoms is more preferable
  • R 5 NHC 0-( ⁇ )
  • R 5 is an alkyl group having about 10 to 30 carbon atoms similar to the alkyl group of R 1 described above.
  • the alkyl group of the alkylcarbamoyl group is preferably an alkyl group having 14 to 20 carbon atoms, and more preferably an alkyl group having 15 to 18 carbon atoms.
  • R 2 examples include, for example, hydroxy, alkoxy, aralkyloxy, acyloxy and
  • W represents an oxygen atom or a sulfur atom
  • R 6 and R 7 each represent hydrogen or alkyl, or both form a ring together with an adjacent nitrogen atom.
  • the alkoxy group represented by R 2 includes an alkoxy group having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoquin, isopropoquin, butoxy, isobutoxy, pentoxy and the like.
  • the aralkyloxy group represented by R 2 includes phenyl-C alkoxy, such as benzyloxy, phenethyloxy, —methylbenzyloxy, 1-methylphenethyloxy, and / 3-methylphenethyloxy.
  • acyloxy group represented by R 2 examples include, but are not limited to, allyloxy, benzoyloxy having about 1 to 5 carbon atoms, such as formyloxy, acetyloxy, prpylionyloxy, butyryloxy, isoptyryloxy, pareryloxy, and isovaleryloxy. , Phenoxycarbonyloxy, carboxy, C alkoxycarbonyloxy (methoxycarboxy, ethoxyquincarbonyl, propoxycarbonyloxy, butoxycarbonyloxy) and the like.
  • ring formed together with the nitrogen atom examples include a 3- to 7-membered heterocyclic ring which may have a hetero atom such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom.
  • acylamino group represented by R 2 examples include, for example, formamide, acetoamide, propionamide, butanamide, isobutaneamide, relamide, isovaleramide, etc., having a carbon number of about alkanoylamino or benzoylamino. Group.
  • Examples of the cyclic amino represented by R 2 include 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydrodolazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-hydroxylazepinyl, 4 Examples thereof include 3- to 7-membered heterocycles such as perhydroxoxazepinyl and 4-perhydrothiazepinyl, such as fused rings having about 8 to 9 carbon atoms such as 2-isoindolinyl.
  • the heterocyclic ring and the condensed ring may have a substituent such as oxo at a replaceable position, and examples of the substituted heterocyclic ring and condensed ring include 2,5-dioxopyrrolidinyl, , 3-dioxoisoindolinyl and the like.
  • R 2 is more preferably alkoxy.
  • Examples of the alkylene chain represented by R 3 include linear or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and the like. And methylene, ethylene, and the like.
  • Replacement Trimethylene is more preferable, and methylene or ethylene is more preferable.
  • alkyl group represented by R 4 examples include alkyl groups having about 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, t-butyl, pentyl, and hexyl.
  • the aralkyl group represented by R 4 includes, for example, phenyl-C 8 alkyl groups such as benzyl, phenethyl, phenylpropyl, phenylbutyl, ⁇ -methylphenethyl and —methylphenyl.
  • R 8 represents hydrogen, optionally substituted alkyl, acyl, or optionally substituted radical].
  • alkyl group represented by the above formula (R and R 8 examples include alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl.
  • the alkyl group is, for example, carboxyl, C alkylcarbonyl (eg, methyl Carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
  • acyl group represented by R 8 examples include alkynyl having about 1 to 5 carbon atoms (eg, formyl, acetyl, propionyl, butyryl, isoptyryl, relyl, isovaleryl), benzoyl, phenoxycarbonyl, carboxyl, C t- 15 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
  • alkynyl having about 1 to 5 carbon atoms eg, formyl, acetyl, propionyl, butyryl, isoptyryl, relyl, isovaleryl
  • benzoyl phenoxycarbonyl, carboxyl, C t- 15 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
  • R 8 examples of the optionally substituted carbamoyl group represented by R 8 include
  • C 5 alkyl force Rubamoiru e.g., methyl carbamoylthiopheno Le, E Ji carbamoyl, propyl force Rubamoiru, butylcarbamoyl
  • G C i-5 alkyl force Rubamoiru eg, dimethylcarbamoyl, Mechirue Ji carbamoyl, Jechirukaruba ⁇ 3-, 7-membered cyclic amino (eg, (aziridin-1-yl) carbonyl, (azetidin-1-yl) carbonyl, (pyrrolidine-1-yl) ) Carbonyl, piperidinocarbonyl, (perhydrodazepine-11-yl) carbonyl, (piperazine-1-yl) carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl].
  • R 8 and R 9 may be the same or different, and R 8 and R 3 may be linked to form alkenyl'alkylene. It may be formed.
  • alkenylene and alkylene bridges formed by combining R 8 and R 3 include alkenylene and alkylene bridges having about 4 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and propenylene. And may have a substituent such as oxo at a substitutable position.
  • alkenylene and alkylene bridges having about 4 to 4 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and propenylene. And may have a substituent such as oxo at a substitutable position.
  • substituted alkylene and alkenylene include 1-oxoethylene, 3-oxopropenylene, 1,2-dioxoethylene and the like. Specifically, the expression One XC one Y
  • R 3 and R + may combine to form alkenylene and alkylene
  • R 9 and R 4 combine to form an alkylene j
  • Examples of the len and alkylene bridges include alkenylene and alkylene bridges having about 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and propenylene. These groups can be substituted. It may have a substituent such as oxo at the position.
  • Examples of the substituted alkylene and alkenylene include oxoethylene, 3-oxoprobenylene, 2-dioxoethylene and the like. Specifically, the expression
  • Y is preferably an optionally substituted imino group, and more preferably a substituted imino group.
  • Examples of the optionally substituted imino group represented by ⁇ include an imino group and an imino group substituted with an alkyl group having about carbon atoms (eg, methylimino group).
  • OiVPI Mino Echiruimino, propylimino, isopropyl imino, Puchiruimi Roh, Isobuchiruimino, sec- Buchiruimi Roh, tert- Puchiruimino, Penchirui Mino, to Kishirui. Mino :), substituted with Ararukiru group such as phenylene Lou c one ⁇ -alkyl And imino groups (eg, benzylimino, phenethylimino, phenylpropylimino, phenylbutylimino, (1-methylphenethyl) imino, (-methylphenethyl) imino).
  • Ararukiru group such as phenylene Lou c one ⁇ -alkyl And imino groups (eg, benzylimino, phenethylimino, phenylpropylimino, phenylbutylimino, (1-methylpheneth
  • the imino group represented by Z may be quaternized to form an iminio group
  • the iminio group may be an alkyl group having about 1 to 6 carbon atoms or an aralkyl group (eg, phenyl). Two-way C alkyl).
  • the substituted iminio group include dimethyliminio, methylethyliminio, methylpropyliminio, methylbutyliminio, methylpentyliminio, methylhexyliminio, ethyliminho, ethylpropyliminio, and ethylheptyl.
  • Minio ethylpentyliminio, ethylhexyliminio, dipropyliminio, propylbutyliminio, propylpentyliminio, propylhexyliminio, dibutyliminio, butylpentyliminio, butylhexyliminio
  • Examples include dipentyliminio, pentylhexyliminio, dihexyliminio, benzylmethyliminio, dibenzyliminio, phenethylmethyliminio, and diphenethyliminio.
  • ⁇ is dimethyliminio and R 4 is methyl.
  • Examples of the nitrogen-containing heterocyclic ring represented by Z include a heterocyclic ring containing at least one nitrogen atom, and include, for example, a nitrogen atom, an oxygen atom or a sulfur atom as a ring-constituting atom in addition to the nitrogen atom. And monocyclic or bicyclic heterocyclic rings which may be substituted.
  • the heterocycle may be saturated, partially saturated, or the lowest hydrogenated heterocycle such as a heteroaromatic ring, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, pyrrolinyl, pyrazolinyl, pyrrolyl, Pyridyl, oxazolyl, thia 3 R
  • a heteroaromatic ring for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, pyrrolinyl, pyrazolinyl, pyrrolyl, Pyridyl, oxazolyl, thia 3 R
  • C t _ + alkyl groups eg, methyl, ethyl, propyl, butyl
  • hydroxy groups amino (imino) groups, mono- or di-C + alkylamino (eg, , Mechiruamino, Jimechiruami Roh), Scarpa ⁇ I group, Urei de group, human Dorokishi or C 4 alkyl group substituted with Amino group (for example, human Dorokishechiru, Aminoechiru), carboxyl, carboxylase DOO, C t _ + alkoxy
  • the nitrogen atom in the nitrogen-containing heterocyclic ring may be quaternized with R 4 , for example, ⁇ , ⁇ -dimethylpyrrolidinio, ⁇ -methylpyridinio, ⁇ -methylpyrethylpyrrolidinio, 3 —Methylthiazolio, and the like. Further, the nitrogen atom may be quaternized by bonding to R 3.
  • heterocyclic ring containing the quaternized nitrogen atom examples include, for example, pyridinio-1-yl and oxazolio-1 3 —Ir, thiazolio 1-yl, pyridazirniol 11-yl, pyrimidinin 1-yl, virazinio 1-yl, quinolino— 1-yl, isokino-linol 2-yl, 4-Methylmorpholino-1-yl, 1-methylbiperidinyl 1-1-yl, 1-methylbiperazinyl 1-1-yl, 1-methylpyrrolidinio 1-yl, 1-ethylpyrroli Ginyo—11
  • a heterocyclic ring containing a quaternary nitrogen atom is more preferable.
  • the position of the heterocyclic ring bonded to R 3 may be any position that can be bonded, but the nitrogen atom or its adjacent position (position next to the nitrogen atom) is more preferable.
  • salt of compound (I) examples include pharmacologically acceptable salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like. Acid addition salts are preferred.
  • Z has a quaternized nitrogen atom, anion anions such as chloride ion, bromine ion, iodine ion, sulfate ion, nitrate ion, phosphate ion, acetate ion, and hydroxide ion, etc.
  • a salt may be formed with the anion of the compound, or a salt may be formed in the molecule.
  • Compound (I) may have an asymmetric carbon in the molecule depending on the type of substituent represented by R 2 , but has two stereoisomers, R-coordination and S-coordination. In each case, each of them or a mixture thereof is included in the present invention.
  • Compound (I) and its salts have excellent PAF inhibitory effects, and circulatory disorders caused by PAF such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris. Inflammation, glomerulonephritis, shock (eg, endotoxin shock, intravascular blood clotting syndrome caused by endotoxin, anaphylaxis, sok, hemorrhagic shock) and diseases related to allergies (eg, bronchial asthma) ), Etc. ⁇ It is useful as a therapeutic and antitumor agent.
  • Compound (I) and its salt have excellent properties in both hydrophilicity and lipophilicity;. Low toxicity, so that they can be orally administered to mammals as powders or as appropriate pharmaceutical compositions. Alternatively, it can be safely administered parenterally.
  • the dosage varies depending on the subject of administration, target disease, symptoms, administration route, etc. For example, when used for the prevention and treatment of shock in adults 4.
  • compound (I) or a salt thereof is used as a single dose, usually at a dose of about 0.1 (U to about 20 mg / kg body weight, preferably about 0.1 to about 10 mg / kg body weight, more preferably about Q.l to about 2 mg / kg body weight.
  • Compound (I) or a salt thereof is usually 0.1 to 20 mg / kg body weight as a single dose, 1 to 5 times a day. It is convenient to administer the drug, preferably about 1 to 3 times. More specifically, if the purpose is to prevent thrombosis, a single dose of 0.5 to 4 For the purpose of treatment, it is preferable to administer a dose of about 4 to 10 mg / kg body weight each time, about 1 to 3 times a day. In the case of other parenteral administration, an equivalent dose can be administered.
  • the pharmaceutical composition used for administration contains an effective amount of compound (I) or a salt thereof and a pharmacologically acceptable carrier or excipient, and the composition is suitable for oral or parenteral administration. It is provided in a suitable dosage form.
  • compositions for oral administration include, for example, solid or liquid dosage forms, such as tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, and capsules (soft capsules). Agents, emulsions, suspensions, etc.
  • Such a composition is produced by a method known per se and contains a carrier or an excipient usually used in the field of formulation.
  • carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.
  • compositions for parenteral administration include, for example, injections, suppositories, etc.
  • injections include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection, etc. Dosage form.
  • Such injections are prepared by a method known per se, for example, by dissolving, suspending or emulsifying compound (I) or a salt thereof in a sterile aqueous or oily solution used for ordinary injections.
  • Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other scavengers, and suitable dissolution scavengers such as alcohol (eg, ethanol) and polyalcohols (eg, propylene glycol).
  • polyethylene glycol Polyethylene glycol
  • nonionic surfactants eg polysorbate 80, HC0-50 (polyoxyethylene (50mol) adduct of hydrogenated catalyst)
  • oily liquid examples include sesame oil and soybean oil.
  • Benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizer.
  • the prepared injection is usually filled in an appropriate ampoule,
  • Suppositories to be used for rectal administration are prepared by a method known per se, for example, by mixing compound (I) or a salt thereof with a usual suppository base and molding.
  • compositions may contain other active ingredients as long as unfavorable interaction does not occur by compounding with compound (I) or a salt thereof.
  • Compound (I) or a salt thereof can be produced, for example, by the following method.
  • C represents a group which easily substitutes for nitrogen (eg, a halogen such as chlorine, bromine, iodine, OTosyl, OMesyl group, etc.), and the other symbols are as defined above]
  • optionally substituted amine (VE) or nitrogen-containing cyclic compound () to obtain compound (I).
  • VE optionally substituted amine
  • VI nitrogen-containing cyclic compound
  • 1 equivalent to a large excess of compound (Vtt) or (VI) is added to compound (VI), resulting in 0 to 10 200.
  • C can be carried out in the presence or absence of a solvent.
  • the solvent examples include toluene, benzene, ether, dioxane, and tetrahydrofuran, and the compound (VE) or (VI) itself can be used as the solvent.
  • the reaction may be performed in a sealed tube.
  • Q 2 represents a group that activates a carbonyl group (eg, halogen (eg, chlorine), phenoxy, etc.), and other symbols have the same meanings as described above].
  • a base may be added. Further, (X) is reacted with sodium hydride, n-butyllithium, or the like in the above-mentioned solvent, converted into a metal salt, and then compound () and
  • Q 3 is a group that activates a carbonyl group, a logen (eg, chlorine, pheno
  • the reaction can be carried out according to the reaction between () and (XI).
  • the compound (XIY) can be prepared, for example, by reacting a compound represented by the formula H 2 N—R 3 —Z—R 4 (XV) with each symbol having the same meaning as described above, with diphosgene; —R 3 —Z—R + (XVI) [wherein the symbols are as defined above], and can be easily synthesized by reacting the compound with DPPA.
  • a compound in which X and / or Y is an unsubstituted imino group is reacted with, for example, an acid anhydride, an acid halide, or an alkyl halide to obtain a compound represented by the formula (I).
  • a compound in which Y is a substituted imino group can be obtained.
  • the reaction is generally carried out in a solvent (eg, benzene, toluene, chloroform, dichloromethane, ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide) at a reaction temperature of -iO. From C + i50. Proceed by keeping it at about C.
  • a solvent eg, benzene, toluene, chloroform, dichloromethane, ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide
  • a base eg, triethylamine, pyridine, dimethylaminopyridine, sodium hydroxide, sodium hydride
  • a base eg, triethylamine, pyridine, dimethylaminopyridine, sodium hydroxide, sodium hydride
  • a compound in which the nitrogen atom contained in the group represented by Z is an i-, tertiary, or tertiary amine is reacted with, for example, an alkyl halide to obtain a compound represented by the formula (I).
  • Compounds in which the nitrogen atom contained in the group represented by Z is a secondary, tertiary, or quaternary amine can also be obtained.
  • This reaction proceeds in a solvent such as ether, porcine, tetrahydrofuran, benzene, toluene, etc., in the presence of an equal or large excess of alkyl halide, at 0 ° to ⁇ 150 ° C. .
  • the reaction can be carried out after the group is eliminated, and another substituent can be introduced. Even if a place formula (I) of R 2 Gabe Njiruokishi group performs Sekkai reduction, after the R 2 and human Dorokishi group, Ashiru reduction, can be determined promptly by using an force Luba ⁇ I le of.
  • R 2 ′ represents an acyl group.
  • the original reaction can be carried out by using a catalyst such as platinum oxide, palladium carbon, Raney nickel, etc., and keeping the temperature from room temperature to + 100 ° C in a solvent such as alcohol, tetrahydro ⁇ -furan, water or g acid. .
  • the acylation reaction of (X VE) is carried out by reacting (X VI) with an active derivative of a carboxylic acid (acid anhydride, acid halide, etc.) in an inert solvent (ether, phenol, benzene, toluene, dichloromethane). , Tetrahedral mouth furan, dimethylformamide, etc.). This can be done by keeping the temperature at ⁇ 150 ° C.
  • a tertiary amine triethylamine, pyridine, dimethylaminopyridine
  • the reaction referred to as X IX) can be carried out in accordance with the later-described rubamoylation reaction of a raw material compound [Production method of compound (XLIV)].
  • the starting material (VI) can be produced, for example, according to the following reaction scheme. -
  • Q t ′ represents tosyl or mesyl
  • T HP represents tetrahydroxypyran-12-yl
  • Q 4 and Q 5 represent halogens (eg, chloro, bromide, chloride) OTosyi, Indicates OMesyl.
  • Other symbols are as defined above.
  • (IX) and (3 ⁇ 40) can be synthesized by reacting (XI) or (X) with, for example, phenyl phenyl carbonate, phosgene or diphosgene.
  • Compound (XI) used as starting material o in the above reaction can be synthesized, for example, by the following method.
  • R 2a represents an acyloxy group, and R 1 has the same meaning as described above
  • R 1 has the same meaning as described above
  • R 2 b represents an Ashiruami amino group
  • R 1 is the same meaning as defined] compounds of may be prepared for example according to the following reaction scheme.
  • R 2C represents a group represented by the formula (m), and R 1 has the same meaning as described above].
  • the compounds described can be prepared, for example, according to the following reaction scheme.
  • R 2d represents alkoxy or aralkyloxy, and R 1 has the same meaning as described above
  • R 1 has the same meaning as described above
  • R 1 and R 2 are as defined above] can be produced, for example, according to the following reaction formula.
  • the compound having the compound is protected by a protecting group known per se (eg, benzyl, tosyl, trityl, phthalimid, succinimid, benzyloxycarbonyl, tert-butoxycarbonyl), and the reaction is carried out. Thereafter, the target compound can be obtained by subjecting it to a deprotection reaction known per se.
  • a protecting group known per se eg, benzyl, tosyl, trityl, phthalimid, succinimid, benzyloxycarbonyl, tert-butoxycarbonyl
  • the salt of compound (I) may be obtained, for example, by the above-mentioned method for producing compound (I) itself, or may be produced by adding an acid or a base to compound (I), if necessary.
  • the residue was purified by silica gel column chromatography using ethyl acetylacetonate (5: 1) as an eluent to obtain 40611 ⁇ (yield: 37.4%) of the target product (colorless oily substance).
  • Example tosyl member was prepared in 6 2.360 g (3.491 Mi Rimoru) and bromide lithium ⁇ arm (LiBr 'H 2 O) 0.732g of (6.983 Rimoru) in dimethylformamide ⁇ mi de (22 ml), at 60 ° Heated for 2 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (4: 1) as an eluent to obtain 1.855 g (yield: 90.9%) of the desired product (colorless solid).
  • Example 12 tosyl member was prepared in 3.88 (6.045 Mi Rimoru) and bromide lithium ⁇ beam (LiBr ⁇ H 2 O) 1.267g (12.089 Mi Rimoru) dimethylformamide ⁇ mi de (37 ml), to 60 ° C And heated for 42 hours.
  • the crude product obtained in the same manner as in Example 7 was purified by silica gel column chromatography using hexane-ethyl acetate (3: 2) as an eluent, and the desired product [colorless solid] 3.10 g (93% yield).
  • OMP1 W1PO It was dissolved in methane (6 ml) and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform as an eluent. The obtained chloro form was further dissolved in 20% trimethylamine-toluene (20 ml) Then, it was ripened in a sealed tube at 160 ° C for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with acetate (iOml) to obtain colorless powder 2.Og (yield: 85.0%).
  • Example 16 200 nig (0.39 mimol) of the hydroxy compound obtained in Example 16 was dissolved in a mixture of pyridin (2 ml) and chloroform (1 ml), and methyl isocyanate 600 was dissolved.
  • I RCKBrlcm- 1 3400, 2920, 2850, 1720, 1540, 1470, 1270, 1155, 1125, 770
  • the carbonate was dissolved in asym.-dimethylethylenediamine (2 ml) and stirred at 70 ° for 4 hours. N-hexane was added to the reaction solution to remove insolubles, and the solution was purified by silica gel chromatography (eluent, octaform-methanol-water, 65: 25: 4). 466 mg of the desired product (colorless solid) was obtained.
  • IR filmjcm- 1 : 3325, 2910, 2840, 1735, 1700, 1530, 1465, 1368, 1125.
  • I RCfilmlcm- 1 3360, 2930, 2853, 1740, 1710, 1530, 1473, 1375, 1250, 1195, 1130
  • Example 44 607 mg [l.015 mimol] of the compound synthesized in 1ii) (Free base) was dissolved in 12 mU of ethyl ether, and 432 mg [3.046 mimol] of methyl iodide was added. Left for days. Petroleum ether was added to the reaction solution, and the resulting precipitate was collected by furnace to obtain 622 mg [82.8%] of the target product [colorless powder].
  • Example 25 350 mg (0.5 mmol) of the iodide obtained in Example 25 was treated in the same manner as in Example 47, and recrystallized from a mixture of 1 ml of acetate and 4 ml of ether to obtain 297 mg of colorless crystals (yield 97.7%). Obtained. Element analysis C3iH 61 N 2 0 6 Cl-H 2 0
  • the eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized from acetone.
  • the dichloromethane layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified using silica gel (10 g). The mixture was developed with chloroform and methanol (19: 1) to obtain 560 mg of a colorless oil (yield: 98.1%).
  • Example 53 The methylcarbamoyl derivative 50 Omg (0.87 mimol) obtained in Example 53 was used in the Example.
  • Methylation was performed in the same manner as in 52, and the mixture was passed through a 30 ml column of IRA-410 (C1-) to change the salt form, thereby obtaining 327 mg (yield 60.3%) of the target compound (colorless powdery crystals).
  • the organic layer was concentrated to dryness under reduced pressure, and the residue was purified with a silica gel column (50 g), developing solvent ⁇ -hexane, ethyl ethyl epoxide (193: 7), and 5.3 g of colorless needle crystals (yield 83.9%) ).
  • IR (Br) cm- 1 3500, 3450, 29 ⁇ 0, 2850, 1765, 1700, 1465,
  • Example 76 150 mg of the dimethylamino compound obtained in Example 76 was dissolved in 5 ml of ether, 100 mL of methyl iodide was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography. (Eluent: chromatographic form-methanol 5: 1) Further reprecipitated from ether to obtain 115 mg. I got Pale yellow solid
  • Example 81 145 mg (0.28 mmol) of the compound obtained in Example 81 was dissolved in 1 ml of anhydrous tetrahydrofuran, and 8 ml of n-butyllithium Q.i (1.55 N, 0.28 mmol) was added dropwise with stirring under ice-cooling. The solution was poured into acetic anhydride all at once. The reaction solution was diluted with chloroform, washed with a 1% aqueous sodium hydrogen carbonate solution, and dried with sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel 5 g column chromatography for separation and purification. The target product was obtained as a colorless powder from the eluate of ethyl sulphate-acetone (15: 1). Yield 25mg (16%)
  • a powder was added to a solution of 753 mg (3.3 mmol) of the compound obtained in Example 85 and 650 mgal.l of the compound obtained in Example 86) in 5 ml of dimethyl sulfoxide. And stirred vigorously for 2 days at room temperature.
  • the reaction wave was poured into ice water, acidified with an aqueous hydrochloric acid solution, extracted with ethyl acetate, and dried over sodium sulfate.
  • the solvent was distilled off under reduced pressure, 25 ml of ethanol and 1 ml of aqueous hydrochloric acid solution were added to the residue, and the mixture was heated to 80 ° C and stirred for 0.5 hour.
  • the solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in chloroform, washed with water and dried over potassium carbonate.
  • the solvent was distilled off under reduced pressure, and the residue was silica gel
  • Example 90 100 mg (0.15 mmol) of the compound obtained in Example 90 was dissolved in 10 ml of a 20% trimethylamine-toluene solution, heated at room temperature for 3.5 days, further heated at 60 ° C. in a sealed tube, and left for 12 hours.
  • the reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in methanol-water (8: 2) and passed through a column of a strong basic ion exchange resin Dowex 21K (C1 type).
  • the fraction containing the desired product was evaporated to dryness, and the residue was subjected to silica gel 2 g column chromatography for separation and purification.
  • the desired product was obtained as a colorless powder from the eluate of black mouth formum ethanol mono-water (65: 25: 4). Yield 75mg (853 ⁇ 4)
  • Example 90 To 400 mg (0.6 mmol) of the compound obtained in Example 90, 5 ml of thiazole was added, and the mixture was heated to 95 ° C and stirred for 15 hours. The reaction mixture was evaporated to dryness under reduced pressure. Was dissolved in methanol-water (8: 2) and passed through a column of a strong basic ion exchange resin Dowex 2iK (Cl type). The fraction containing the desired product was evaporated to dryness, and the residue was subjected to silica gel 5 g column chromatography to separate and purify. The desired product was obtained as a colorless powder from a chloroform eluate (65: 25: 4) eluate. Yield 27 (kg (73%)
  • the ether layer was dried over sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified with 15 g of silica gel, developing solution n-hexane, ethyl acetate (9: 1) to give a colorless solid 1.2 £ ( Yield 88.6%).
  • reaction mixture was concentrated under reduced pressure to dryness, and the residue was dissolved in 20 ml of 20% methanol.) ⁇ Ad-11 was adsorbed on a 15 ml column, washed with 80% methanol, and then washed.

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Abstract

Lipid derivatives represented by formula (I), (wherein R1 represents alkyl or alkylcarbamoyl, R2 represents H, optionally substituted hydroxy, optionally substituted amino or cyclic amino, R3 represents alkylene, R4 represents H, alkyl or aralkyl, X and Y each represents O, S or optionally substituted imino and, when Y represents imino, Y may form a ring together with the imino group represented by X or with R4, and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring) and salts thereof have a PAF-controlling effect, thus being useful as agents for prophylaxis and treatment of various circulatory organ troubles and allergic disorder and as antineoplastic agents.

Description

明 細 書  Specification
脂 質 誘 導 体  Fat inducer
技術分野 Technical field
本発明は医薬として有用な新規脂質誘導体に関する。  The present invention relates to novel lipid derivatives useful as medicaments.
背景技術 Background art
P A F [P latelet A ct ivat ing F actor]はリ ン脂質構造を有し、 生体内に存在する化学伝達物質である。 P A Fはその生体内機能として、 アレルギー，アナフィラキシーおよび炎症、 さらには血小板凝集に密接 に関与していることが明らかにされており、 また、 強力な血圧下降作用 を有することも知られている。  P A F [P latelet Acting Factor] has a phospholipid structure and is a chemical messenger present in the living body. It has been clarified that PAF is closely related to allergy, anaphylaxis and inflammation as well as platelet aggregation as its in vivo function, and is also known to have a strong blood pressure lowering effect.
一方、 P A Fを動物に投与した場合には、 これらの作用があいまって、 動物がショック症状を呈し、 死に至ることもある。 P A Fによるシ ョ ヅ クはェン ドトキシンによるショ 、ソ ク症状に似ており、ェン ド トキシンショ クに P A Fが関与しているのではないかとも考えられている。  On the other hand, when PAF is administered to animals, these effects combine to cause the animals to exhibit shock symptoms and even death. The shock caused by PAF resembles that of endotoxin-induced shock, suggesting that PAF may be involved in endotoxin shock.
また、 がん転位においては、 がん細胞の着床の段階で血小板凝集が関 与していると考えられ、 さらに、 エーテル結合や力ルバ乇ィル結合を有 する脂質誘導体は、 これらの結合を切断する酵素が特にがん細胞では不 足しているため、 がん細胞内に蓄積されやすく、 がん細胞内の脂質代謝 に変化を与え、 がん細胞を死に至らしめる作用を有する。  In cancer translocation, platelet aggregation is considered to be involved at the stage of implantation of cancer cells.Furthermore, lipid derivatives having an ether bond or a dextrin bond may bind to these bonds. In particular, cancer cells are deficient in enzymes that cleave them, so they easily accumulate in cancer cells, alter lipid metabolism in cancer cells, and have the effect of causing cancer cells to die.
本発明者らは P A F抑制作用を有し、 種々の循環障害疾患、 アレルギ 一性疾患の予防 ·洽療剤および抗腫瘍剤として有用な脂質誘導体を鋭意 探索した結果、 優れた作用を有する脂質誘導体の製造に成功し、 本発明 を完成した。  The present inventors have intensively searched for lipid derivatives that have a PAF inhibitory effect, prevent various circulatory disorders and allergic monogenic diseases, and are useful as therapeutic agents and antitumor agents. The production was successful and the present invention was completed.
発明の開示 Disclosure of the invention
本発明は式  The present invention uses the formula
OMPI C H20 R 1 OMPI CH 2 0 R 1
C HR2 ( I )C HR 2 (I)
CH2-X- C -Y-R3- Z-R + CH 2 -X- C -YR 3 -ZR +
0  0
[式中、 R 1はアルキルまたはアルキル力ルバモイルを、 R 2は水素.置換 されていてもよいヒ ドロキシ，置換されていてもよいアミノまたは環状 アミノを示し、 R3はアルキレンを、 R4は水素，アルキルまたはァラル キルを示.し、 Xおよび Yはそれぞれ 0 (酸素原子） , S (硫黄原子）または 置換されていてもよいイミノ基を示し、 Yが'イミノ基である場合、 Yは Xで示されるィミノ基または R*とともに環を形成してもよく、 Zは置 換されていてもよいィミノまたは含窒素複素環を示す]で表される脂質 誘導体およびその塩に関する。 Wherein R 1 represents alkyl or alkyl rubamoyl, R 2 represents hydrogen, optionally substituted hydroxy, optionally substituted amino or cyclic amino, R 3 represents alkylene, and R 4 represents X and Y each represent 0 (oxygen atom), S (sulfur atom) or an optionally substituted imino group, and when Y is an 'imino group, Y represents X may form a ring together with the imino group or R * represented by X, and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring] and a salt thereof.
上記式（I )に関し、 R1で示されるアルキル基としては直鎖状もしく は分技状のいずれでもよく、 たとえばデシル，ゥンデシル: トリデシル， テトラデシル，ペンタデシル.へキサデシル，ヘプタデシル.ォクタデシル , ノナデシル，エイコサニル，へネィコサニル， ドコサニル， トリコサニル， テトラコサ二ル；ペンタコサニル，へキサコサニル，ヘプタコサニル，ォク タコサニル，ノナコサニル， トリアコンタニ ·'レ，フアルネシール，ジヒ ドロ フイチルなど炭素数 10〜 30程度のアルキル があげられ、 なかでも炭素 数 14〜20のアルキル基が好ましく、 炭素数 15〜18のアルキル基がさらに 好ましい。 また、 R1がアルキル力ルバモイル基を示す場合には、 R1は 式 With respect to the above formula (I), the alkyl group represented by R 1 may be either linear or branched, for example, decyl, pendecyl: tridecyl, tetradecyl, pentadecyl.hexadecyl, heptadecyl.octadecyl, nonadecyl, Alkyl having about 10 to 30 carbon atoms, such as eicosanil, heneicosanil, docosanil, tricosanil, tetracosanil; pentacosanil, hexacosanil, heptacosanil, octacosanil, nonacosanil, triaconthani'le, phnareseal, dihydrofityl, and the like. However, an alkyl group having 14 to 20 carbon atoms is preferable, and an alkyl group having 15 to 18 carbon atoms is more preferable. Further, when R 1 represents an alkylrubumoyl group, R 1 has the formula
R 5 N H C 0 - ( Π ) として表わすことができ、 式（Π)中、 R 5は上記の R 1のアルキル基と 同様な炭素数 10〜30程度のアルキル基をあげることができる。 なかでも アルキルカルパモイル基のアルキル基が炭素数 14〜 20のアルキル基であ るものが好ましく、 炭素数 15〜18のアルキル基であるものがさらに好ま しい。 R 5 NHC 0-(Π) In the formula (Π), R 5 is an alkyl group having about 10 to 30 carbon atoms similar to the alkyl group of R 1 described above. Among them, the alkyl group of the alkylcarbamoyl group is preferably an alkyl group having 14 to 20 carbon atoms, and more preferably an alkyl group having 15 to 18 carbon atoms. New
R 2で示される置換されていてもよいヒ ドロキシ基としては、 たとえ ばヒ ドロキシ，アルコキシ，ァラルキルォキシ，ァシルォキシまたは式 Examples of the optionally substituted hydroxy group represented by R 2 include, for example, hydroxy, alkoxy, aralkyloxy, acyloxy and
T 6  T 6
- 0 C N (Π ) -0 C N (Π)
II 、R 7 II, R 7
w  w
[式中、 Wは酸素原子または硫黄原子を示し、 R 6および R 7はそれぞれ 水素またはアルキルを示すか、 または両者が隣接する窒素原子とともに 環を形成する]で表わされる基などがあげられる。 Wherein W represents an oxygen atom or a sulfur atom, and R 6 and R 7 each represent hydrogen or alkyl, or both form a ring together with an adjacent nitrogen atom.
R 2で示されるアルコキシ基としては炭素数 1〜5程度のアルコキシ基 があげられ、 たとえばメ トキシ，エトキン，プロボキン，イソプロポキン， ブトキシ，イソブトキシ，ペントキシなどがあげられる。 The alkoxy group represented by R 2 includes an alkoxy group having about 1 to 5 carbon atoms, such as methoxy, ethoxy, propoquin, isopropoquin, butoxy, isobutoxy, pentoxy and the like.
R 2で示されるァラルキルォキシ基としてはフエニル— C アルコキ シがあげられ、 たとえばべンジルォキシ，フエネチルォキシ， —メチル ベンジルォキシ， 一メチルフエネチルォキシ， /3—メチルフエネチルォ キシなどがあげられる。 The aralkyloxy group represented by R 2 includes phenyl-C alkoxy, such as benzyloxy, phenethyloxy, —methylbenzyloxy, 1-methylphenethyloxy, and / 3-methylphenethyloxy.
R 2で示されるァシルォキシ基としてはたとえばホルミルォキシ，ァセ チルォキシ，プ crピオニルォキシ，ブチリルォキシ，ィソプチリルォキシ， パレリルォキシ，ィソバレリルォキシなどの炭素数 1〜5程度のアル力ノ ィルォキシ，ベンゾィルォキシ，フエノキシカルボニルォキシ，カルボキ シォキシ， C アルコキシカルボニルォキシ（メ トキシカルボ二ルォキ シ，エトキンカルボニルォキン，プロポキシカルボニルォキン，ブトキシ カルボニルォキシ）などのァシルォキシ基があげられる。 Examples of the acyloxy group represented by R 2 include, but are not limited to, allyloxy, benzoyloxy having about 1 to 5 carbon atoms, such as formyloxy, acetyloxy, prpylionyloxy, butyryloxy, isoptyryloxy, pareryloxy, and isovaleryloxy. , Phenoxycarbonyloxy, carboxy, C alkoxycarbonyloxy (methoxycarboxy, ethoxyquincarbonyl, propoxycarbonyloxy, butoxycarbonyloxy) and the like.
式（ΠΟに関して、 R 6または R 7で示されるアルキル基としてはたとえ ばメチル，ェチル，プロピル，イソプロピル，ブチル，イソブチル，ペンチル などの炭素数 1〜5程度のアルキル基があげられる。 R 6および R 7が隣接 With respect to formula (Paiomikuron, methyl For example The alkyl group represented by R 6 or R 7, Echiru, propyl, isopropyl, butyl, isobutyl, an alkyl group having 1 to 5 carbon atoms such as pentyl and the like. R 6 and R 7 is adjacent
差換え する窒素原子とともに構成する環としては、 該窒素原子の他に窒素原子, 酸素原子，硫黄原子などの異種原子を有していてもよい 3ないし 7員の複 素環があげられ、 たとえば 1一アジリ ジニル， 1—ァゼチジニル， 1一ピロ リ ジニル，ピペリジノ， 1—パ一ヒ ドロアゼピニル， i—ピぺラジニル，乇ル ホリノ ，チオモルホリノ，1—パ一ヒ ドロジァゼピニル， 4 —パーヒ ドロォ キサゼピニル，4一パ―ヒ ド σチアゼピニルなどがあげられる。 Replacement Examples of the ring formed together with the nitrogen atom include a 3- to 7-membered heterocyclic ring which may have a hetero atom such as a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom. Aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydrazinyl, i-pirazinyl, perforino, thiomorpholino, 1-hydroxylazepinyl, 4—perhydroxazepinyl, 4-1 Such as σthiazepinyl.
R 2で示される置換されていてもよいァミノ としてはたとえばアミノ . ァシルァミノなどがあげられる。 Amino example as may Amino substituted represented by R 2. Etc. Ashiruamino the like.
R 2で示されるァシルァミノ基としてはたとえ-ばホルムァミ ド，ァセト アミ ド，プロピオンアミ ド，ブタンアミ ド，イソブタンアミ ドノくレルアミ ド，イソバレルァミ ドなどの炭素数 程度のアルカノィルァミ ノやべ ンゾィルァミノなどのァシルァミ ノ基があげられる。 Examples of the acylamino group represented by R 2 include, for example, formamide, acetoamide, propionamide, butanamide, isobutaneamide, relamide, isovaleramide, etc., having a carbon number of about alkanoylamino or benzoylamino. Group.
' R 2で示される環状ァミノ としてはたとえば 1 -アジリジニル， 1—ァゼ チジニル， 1一ピロリジニル，ピペリジノ ，1 -パーヒ ドロアゼピニル， 1 -ピ ペラジニル，モルホリノ ，チオモルホリノ，1ーパ一ヒ ドロジァゼピニル，4 ーパ—ヒ ドロォキサゼピニル, 4 -パ—ヒ ドロチアゼピニルなどの 3ないし 7員の複素環，たとえば 2—イソィ-ン ドリニルなどの炭素数 8~ 9程度の縮 合環があげられる。 該複素環および縮合環は置-換可能な位置に、 たとえ ばォキソなどの置換基を有していてもよく、 置換された複素環および縮 合環としてはたとえば 2 , 5—ジォキソピロリ ジニル，1 , 3—ジォキソイソ インドリニルなどがあげられる。 Examples of the cyclic amino represented by R 2 include 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-perhydrodolazepinyl, 1-piperazinyl, morpholino, thiomorpholino, 1-hydroxylazepinyl, 4 Examples thereof include 3- to 7-membered heterocycles such as perhydroxoxazepinyl and 4-perhydrothiazepinyl, such as fused rings having about 8 to 9 carbon atoms such as 2-isoindolinyl. The heterocyclic ring and the condensed ring may have a substituent such as oxo at a replaceable position, and examples of the substituted heterocyclic ring and condensed ring include 2,5-dioxopyrrolidinyl, , 3-dioxoisoindolinyl and the like.
R 2としてはアルコキシであるものがより好ましい。 R 2 is more preferably alkoxy.
R 3で示されるアルキレン鎖としては直鎖状もしくは分枝状の炭素数 1 〜8程度のアルキレン鎖があげられ、 たとえばメチレン，エチレン， トリ メチレン，テトラメチレン，ペンタメチレン，へキサメチレン，ヘプタメチ レン，ォクタメチレンなどがあげられ、 好ましくはメチレン，エチレン， Examples of the alkylene chain represented by R 3 include linear or branched alkylene chains having about 1 to 8 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and the like. And methylene, ethylene, and the like.
差換え トリメチレンがあげられ、 より好ましくはメチレンまたはェチレンがぁ げられる。 Replacement Trimethylene is more preferable, and methylene or ethylene is more preferable.
R 4で示されるアルキル基としてはたとえばメチル，ェチル，プロピル， イソプロピル，ブチル，ィソプチル， sec—ブチル， t ert—ブチル，ペンチル, へキシルなどの炭素数 1~ 6程度のァルキル基があげられる。 Examples of the alkyl group represented by R 4 include alkyl groups having about 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, t-butyl, pentyl, and hexyl.
R 4で示されるァラルキル基としてはたとえばべンジル，フエネチル， フエニルプロピル，フエニルブチル， α—メチルフエネチル， —メチル フエネチルなどのフエニル— C 8アルキル基があげられる。 The aralkyl group represented by R 4 includes, for example, phenyl-C 8 alkyl groups such as benzyl, phenethyl, phenylpropyl, phenylbutyl, α-methylphenethyl and —methylphenyl.
Xが置換されていてもよいィミ ノ基である場合、 Xとしてはたとえば 式 When X is an optionally substituted imino group,
- N - .  -N-.
I ） R 8 I) R 8
[式中、 R 8は水素，置換されていてもよいアルキル，ァシルまたは置換さ れていてもよい力ルバモイルを示す]で表わされる基があげられる。 [Wherein, R 8 represents hydrogen, optionally substituted alkyl, acyl, or optionally substituted radical].
上記式（R 中、 R 8で示されるアルキル基としてはたとえばメチル，ェ チル，プロピル，プチル，ペンチルなどのアルキル基があげられ、 該アル キル基は、 たとえばカルボキシル， C アルキルカルボニル（例、 メ ト キシカルボニル，エトキシカルボニル，プロポキシカルボニル，ブトキシ 力ルボニル，ペントキシカルボニル）などで置換されていてもよい。 Examples of the alkyl group represented by the above formula (R and R 8 include alkyl groups such as methyl, ethyl, propyl, butyl, and pentyl. The alkyl group is, for example, carboxyl, C alkylcarbonyl (eg, methyl Carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
R 8で示されるァシル基としてはたとえば、 炭素数 1~ 5程度のアル力 ノィル（例、 ホルミル，ァセチル，プロピオニル，プチリル，ィソプチリル， レリル，ィソバレリル），ベンゾィル，フエノキシカルボニル，カルボキ シル， C t一 5アルコキシカルボニル（例、 メ トキシカルボニル，エトキシカ ルボニル，プロポキシカルボニル，ブトキシカルボニル，ペン トキシカル ボニル）などがあげられる。 Examples of the acyl group represented by R 8 include alkynyl having about 1 to 5 carbon atoms (eg, formyl, acetyl, propionyl, butyryl, isoptyryl, relyl, isovaleryl), benzoyl, phenoxycarbonyl, carboxyl, C t- 15 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl) and the like.
R 8で示される置換されていてもよい力ルバモイル基としてはたとえ Examples of the optionally substituted carbamoyl group represented by R 8 include
換ん ば、 力ルバモイル， C 5アルキル力ルバモイル（例、 メチルカルバモイ ル，ェチルカルバモイル，プロピル力ルバモイル，ブチルカルバモイル）， ジー C i— 5アルキル力ルバモイル（例、 ジメチルカルバモイル，メチルェ チルカルバモイル ，ジェチルカルバ乇ィル ，メチルプロピル力ルバモイ ル）， 3~ 7員環状ァミノ [例、 （アジリ ジン一 1 -ィル）カルボニル，（ァゼチ ジン一 1一ィル）力ルボニル，（ピロリ ジン一 1 -ィル）カルボニル，ピペリ ジ ノカルボニル，（パーヒ ドロアゼピン一 1 -ィル）カルボニル，（ピペラジン - 1 -ィル）カルボニル，モルホリノカルボニル，チオモルホリノカルボニル] などがあげられる。 Exchange If the force Rubamoiru, C 5 alkyl force Rubamoiru (e.g., methyl carbamoylthiopheno Le, E Ji carbamoyl, propyl force Rubamoiru, butylcarbamoyl), G C i-5 alkyl force Rubamoiru (eg, dimethylcarbamoyl, Mechirue Ji carbamoyl, Jechirukaruba乇3-, 7-membered cyclic amino (eg, (aziridin-1-yl) carbonyl, (azetidin-1-yl) carbonyl, (pyrrolidine-1-yl) ) Carbonyl, piperidinocarbonyl, (perhydrodazepine-11-yl) carbonyl, (piperazine-1-yl) carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl].
Yが置換されていてもよいイミ ノ基である場合、 Yとしてはたとえば 式  When Y is an optionally substituted imino group,
- - --
！ (V ) R 9 · で表される基があげられる。 式（V )中、 R 3で示される基としては R 8と 同様な基があげられる。 ! (V) a group represented by R 9 ·. In the formula (V), examples of the group represented by R 3 include the same groups as R 8 .
Xおよび Yがィミ ノ基である場合、 R 8および R 9は同一であっても、 また相異なっていてもよく、 また、 R 8および R 3は連結してアルケニ'ノ ン.アルキレンを形成してもよい。 When X and Y are imino groups, R 8 and R 9 may be the same or different, and R 8 and R 3 may be linked to form alkenyl'alkylene. It may be formed.
R 8および R 3が違結して形成するァルケ二レン，アルキレン橋として は、 たとえばメチレン，エチレン， トリメチレン，テトラメチレン，ビニレ ン.プロぺニレンなどの炭素数丄〜 4程度のアルケニレン.アルキレン橋が あげられ、 置換可能な位置に、 たとえばォキソなどの置換基を有してい てもよい。 置換されたアルキレン，アルケニレンとしてはたとえば、 1 - ォキソエチレン， 3 -ォキソプロぺニレン， 1 , 2—ジォキソエチレンなどが あげられる。 具体的には式 一 X C一 Y Examples of the alkenylene and alkylene bridges formed by combining R 8 and R 3 include alkenylene and alkylene bridges having about 4 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and propenylene. And may have a substituent such as oxo at a substitutable position. Examples of the substituted alkylene and alkenylene include 1-oxoethylene, 3-oxopropenylene, 1,2-dioxoethylene and the like. Specifically, the expression One XC one Y
!1  ! 1
0  0
として表わされる基として、 As a group represented as
Figure imgf000009_0001
Figure imgf000009_0001
などがあげられる。 And so on.
また、  Also,
Υがィミノ基である場合、 R 3および R +は連結してアルケニレン，ァ ルキレンを形成してもよく、 R 9およぴ R 4が連結して形成するァルケ二 j When Υ is an imino group, R 3 and R + may combine to form alkenylene and alkylene, and R 9 and R 4 combine to form an alkylene j
レン，アルキレン橋としてはたとえば、 メチレン，エチレン， トリメチレ ン，テトラメチレン，ビニレン，プロぺニレンなどの炭素数 1〜4程度のァ ルケ二レン，アルキレン橋があげられ、 これらの基は置換可能な位置に、 たとえばォキソなどの置換基を有していてもよい。 置換されたアルキレ ン，アルケニレンとしてはたとえば、 いォキソエチレン， 3 -ォキソプロべ 二レン，し 2—ジォキソェチレンなどがあげられる。 具体的には式 Examples of the len and alkylene bridges include alkenylene and alkylene bridges having about 1 to 4 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, vinylene, and propenylene. These groups can be substituted. It may have a substituent such as oxo at the position. Examples of the substituted alkylene and alkenylene include oxoethylene, 3-oxoprobenylene, 2-dioxoethylene and the like. Specifically, the expression
一 Y— R 3 - Z - R 4 One Y—R 3 -Z-R 4
として表わされる基として、 As a group represented as
+ C H„ • C H 3 + C H „• C H 3
-C H,  -C H,
3 3 などがあげられる。  3 3 and so on.
Yとしては置換されていてもよいィミノ基が好ましく、 置換されたィ ミ ノ基がさらに好ましい。  Y is preferably an optionally substituted imino group, and more preferably a substituted imino group.
Ζで示される置換されていてもよいィミノ基としてはたとえば、 イミ ノ基，炭素数 程度のアルキル基で置換されたィミ ノ基（例、 メチルイ  Examples of the optionally substituted imino group represented by Ζ include an imino group and an imino group substituted with an alkyl group having about carbon atoms (eg, methylimino group).
OiVPI ミノ ，ェチルイミノ，プロピルイミノ ，イソプロピルイミノ，プチルイミ ノ， イソブチルイミノ， sec—ブチルイミ ノ ， tert—プチルイミノ，ペンチルイ ミノ ，へキシルイ.ミノ：)，フエ二ルー c一 βアルキルなどのァラルキル基で 置換されたィミノ基（例、 ベンジルイミ ノ，フエネチルイミノ，フエニル プロピルイミノ ，フエ二ルブチルイミノ ，（ 一メチルフエネチル）ィミ ノ， ( ーメチルフエネチル）ィミノ）があげられる。 また、 Zで示されるィ ミノ基は 4級化されてィミ二ォ基を形成してもよく、 該ィミ二ォ基は炭 素数 1〜6程度のアルキル基，ァラルキル基（例、 フエ二ルー C アルキ ル）で置換されていてもよい。 該置換ィミニォ基としてはたとえば、 ジ メチルイミニォ，メチルェチルイミニォ，メチルプロピルイミニォ，メチ ルブチルイミニォ，メチルペンチルイミニォ，メチルへキシルイミニォ， ジェチルイミニォ，ェチルプロピルイミニォ，ェチルプチルイミニォ，ェ チルペンチルイミニォ，ェチルへキシルイミニォ，ジプロピルイミニォ， プロピルブチルイミニォ，プロピルペンチルイミニォ，プロピルへキシル ィミニォ，ジブチルイミニォ，ブチルペンチルイミニォ，ブチルへキシル ィミニォ，ジペンチルイミニォ，ペンチルへキシルイミニォ，ジへキシル ィミニォ，ベンジルメチルイミニォ，ジベンジルイミニォ，フエネチルメ チルイミニォ，ジフエネチルイミニォなどがあげられる。 なかでも ぉ ジメチルイミニォであり R 4がメチルである場合が好ましい。 OiVPI Mino, Echiruimino, propylimino, isopropyl imino, Puchiruimi Roh, Isobuchiruimino, sec- Buchiruimi Roh, tert- Puchiruimino, Penchirui Mino, to Kishirui. Mino :), substituted with Ararukiru group such as phenylene Lou c one β-alkyl And imino groups (eg, benzylimino, phenethylimino, phenylpropylimino, phenylbutylimino, (1-methylphenethyl) imino, (-methylphenethyl) imino). In addition, the imino group represented by Z may be quaternized to form an iminio group, and the iminio group may be an alkyl group having about 1 to 6 carbon atoms or an aralkyl group (eg, phenyl). Two-way C alkyl). Examples of the substituted iminio group include dimethyliminio, methylethyliminio, methylpropyliminio, methylbutyliminio, methylpentyliminio, methylhexyliminio, ethyliminho, ethylpropyliminio, and ethylheptyl. Minio, ethylpentyliminio, ethylhexyliminio, dipropyliminio, propylbutyliminio, propylpentyliminio, propylhexyliminio, dibutyliminio, butylpentyliminio, butylhexyliminio, Examples include dipentyliminio, pentylhexyliminio, dihexyliminio, benzylmethyliminio, dibenzyliminio, phenethylmethyliminio, and diphenethyliminio. Among them, it is preferable that ぉ is dimethyliminio and R 4 is methyl.
Zで示される含窒素複素環としては、 少なく とも 1個の窒素原子を含 む複素環があげられ、 たとえば該窒素原子の他に窒素原子，酸素原子ま たは硫黄原子を環構成原子として含んでいてもよい単環式もしくは二環 式複素環があげられる。 該複素環は飽和したもの、 部分飽和したもの、 あるいは複素芳香環のような最低水素化複素環のいずれであってもよく、 たとえばァゼチジニル，ピロリジニル，ピペリジニル，パーヒ ドロアゼピ ニル，ピロリニル，ビラゾリニル，ピロリル，ピリジル，ォキサゾリル，チア 3 Rヒ 4 Examples of the nitrogen-containing heterocyclic ring represented by Z include a heterocyclic ring containing at least one nitrogen atom, and include, for example, a nitrogen atom, an oxygen atom or a sulfur atom as a ring-constituting atom in addition to the nitrogen atom. And monocyclic or bicyclic heterocyclic rings which may be substituted. The heterocycle may be saturated, partially saturated, or the lowest hydrogenated heterocycle such as a heteroaromatic ring, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, pyrrolinyl, pyrazolinyl, pyrrolyl, Pyridyl, oxazolyl, thia 3 R
OMPI 難 ゾリル，ピリダジニル，ピリ ミ ジル，ピラジニル，イミダゾリル，モルホリ ニル，チオモルホリニル，ピペラジニル，ピラゾリ ジニル，イン ドリル，ィ ソイ ン ドリル， 1 H—インダゾリル，プリニル，イソイ ン ドリル，イソイ ン ドリル，キノ リニル，イソキノ リニル， 1 , 2 , 3 , 4—テトラヒ ドロキノ リニル， 1 , 2 , 3 , 4—テトラヒ ドロキノ リニル，，パ一ヒ ドロイ ン ドリル，パ一ヒ ドロ イソキノ リニルなどの基があげられ、 なかでも単環式複素環の場合には 4ないし 7員環が好ましく、 5または 6員環がさらに好ましい。 これらの基 は置換可能な位置に C t_ +アルキル基（例、 メチル，ェチル，プロピル，ブ チル），ヒ ドロキシ基.,ァミノ（イミノ）基，モノ もしくはジ C +アルキル ァミ ノ（例、 メチルァミノ，ジメチルァミ ノ），カルパ乇ィル基，ゥレイ ド 基，ヒ ドロキシもしくはァミノ基で置換された C 4アルキル基（例、 ヒ ドロキシェチル，アミノェチル），カルボキシル，カルボキシラー ト， C t_+ アルコキシカルボニル（例、 メ トキシカルボニル）などの置換基を有して いてもよく、 たとえば N—メチルモルホリニル， N—メチルピペリ ジニ ル，Ν—メチルピペラジニル，Ν—メチルピロリジニルなどの基があげら れる。 OMPI difficulty Zolyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrazolidinyl, indolyl, isolinyl, 1H-indazolyl, purinyl, isoindolyl, isoindolyl, quinolinyl, isoquinolinyl , 1,2,3,4-Tetrahydroquinolinyl, 1,2,3,4-Tetrahydroquinolinyl, Hydroxydrill drill, Hydroxyisoquinolinyl, and others are monocyclic In the case of the formula heterocycle, a 4- to 7-membered ring is preferred, and a 5- or 6-membered ring is more preferred. These groups can be substituted at substitutable positions with C t _ + alkyl groups (eg, methyl, ethyl, propyl, butyl), hydroxy groups, amino (imino) groups, mono- or di-C + alkylamino (eg, , Mechiruamino, Jimechiruami Roh), Scarpa乇I group, Urei de group, human Dorokishi or C 4 alkyl group substituted with Amino group (for example, human Dorokishechiru, Aminoechiru), carboxyl, carboxylase DOO, C t _ + alkoxy It may have a substituent such as carbonyl (eg, methoxycarbonyl), for example, a group such as N-methylmorpholinyl, N-methylpiperidinyl, Ν-methylpiperazinyl, Ν-methylpyrrolidinyl Is raised.
該含窒素複素環における窒素原子は R 4で 4級化されていてもよく、 た とえば Ν , Ν—ジメチルピロリ ジニォ， Ν—メチルピリ ジニォ， Ν—メチ ルー Ν—ェチルピロリジニォ， 3—メチルチアゾリオ，などの基があげら れる。 また、 該窒素原子は R 3と結合することにより 4級化されていても よく、 該 4級化された窒素原子を含む複素環としてはたとえば、 ピリ ジ ニォ— 1 —ィル，ォキサゾリオ一 3—ィル，チアゾリオ一 3 -ィル，ピリダジ 二ルオー 1 一ィル，ピリ ミ ジニォ一 1—ィル，ビラジニォ一 1—ィル，キノ リニォ— 1—ィル，ィソキノ リニォー 2—ィル， 4—メチルモルホリニォ一 4 —ィル， 1—メチルビペリジニォ一 1—ィル， 1—メチルビペラジニォ一 1一 ィル， 1 -メチルピロリ ジニォ一 1 -ィル， 1一ェチルピロリ ジニォ— 1一ィル， The nitrogen atom in the nitrogen-containing heterocyclic ring may be quaternized with R 4 , for example, Ν, Ν-dimethylpyrrolidinio, Ν-methylpyridinio, Ν-methylpyrethylpyrrolidinio, 3 —Methylthiazolio, and the like. Further, the nitrogen atom may be quaternized by bonding to R 3. Examples of the heterocyclic ring containing the quaternized nitrogen atom include, for example, pyridinio-1-yl and oxazolio-1 3 —Ir, thiazolio 1-yl, pyridazirniol 11-yl, pyrimidinin 1-yl, virazinio 1-yl, quinolino— 1-yl, isokino-linol 2-yl, 4-Methylmorpholino-1-yl, 1-methylbiperidinyl 1-1-yl, 1-methylbiperazinyl 1-1-yl, 1-methylpyrrolidinio 1-yl, 1-ethylpyrroli Ginyo—11
え 3—メチルチアゾリオ— 2—ィル， 1 -メチルイミダゾリオ一 1—ィル， 3— 力ルボキシラー トピリジニォ— 1—ィル， 3—メ トキシカルボニルピリ ジ ニォー 1—ィル， 4一ジメチルァミノ ピリ ジニォ一1ーィルなどの基があ げられる。 e 3-Methylthiazolio-2-yl, 1-methylimidazolio-1-yl, 3-carboxylar topidinyl-1-yl, 3-methoxycarbonylpyridinyl 1-yl, 4-dimethylaminopyridinio-1 Groups such as 1-yl are available.
また、 R+が Yで示されるィミノ基と連結している場合の例としては、 具体的には式 Examples of the case where R + is linked to the imino group represented by Y are specifically the formulas
-Y-R3- Z-R+ ' で表わされる基として、 As a group represented by -YR 3 -ZR + ',
CC
Figure imgf000012_0001
などの基があげられる。
Figure imgf000012_0001
And the like.
Zで示される含窒素複素環としては、 4級化された窒素原子を含む複 素環がより好ましい。 '  As the nitrogen-containing heterocyclic ring represented by Z, a heterocyclic ring containing a quaternary nitrogen atom is more preferable. '
R 3と結合する複素環の位置は結合可能な位置であればいずれでもよ いが、 窒素原子またはその隣接位 （窒素原子の隣の位置）がより好まし い The position of the heterocyclic ring bonded to R 3 may be any position that can be bonded, but the nitrogen atom or its adjacent position (position next to the nitrogen atom) is more preferable.
化合物（I )の塩としては、 たとえば塩酸塩，臭化水素酸塩，ヨウ化水素 酸塩，硫酸塩，硝酸塩，リ ン酸塩などの薬理学的に許容されうる塩があげ られ、 なかでも酸付加塩が好ましい。 Zが 4級化された窒素原子を有す る場合には、 塩素イオン，臭素イオン，ヨウ素イオン，硫酸イオン，硝酸ィ オン，リ ン酸イオン，酢酸イオンなどの酸のァニオンや水酸イオンなどの ァニオンと塩を形成してもよく、また、 分子内で塩を形成してもよい。 . 化合物（I )は R2で示される置換基の種類により分子内に不斉炭素を 有することもあるが、 R—配位， S—配位の 2種の立体異性体が存在す る場合、 その各々あるいはその混合物のいずれも本発明に包含されるも のである。 Examples of the salt of compound (I) include pharmacologically acceptable salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like. Acid addition salts are preferred. In the case where Z has a quaternized nitrogen atom, anion anions such as chloride ion, bromine ion, iodine ion, sulfate ion, nitrate ion, phosphate ion, acetate ion, and hydroxide ion, etc. A salt may be formed with the anion of the compound, or a salt may be formed in the molecule. Compound (I) may have an asymmetric carbon in the molecule depending on the type of substituent represented by R 2 , but has two stereoisomers, R-coordination and S-coordination. In each case, each of them or a mixture thereof is included in the present invention.
化合物（ I )およびその塩は優れた P A F抑制作用を示し、 P A Fに起 因する循環障害疾患、 たとえば血拴症，脳卒中（例、 脳出血，脳血栓），心 筋梗塞，狭心症.血栓性静脈炎，糸球体腎炎，ショ ッ ク（例、 エン ドトキシ ンショ ッ ク，エン ドトキシンにより生じる血管内血液凝固症候群，ァナフ イラキシーショ 、ソク，出血性ショ 'ソク）やアレルギーに関連する疾病（例、 気管支喘息）などの予防 ·治療剤および抗腫瘍剤として有用である。  Compound (I) and its salts have excellent PAF inhibitory effects, and circulatory disorders caused by PAF such as thrombosis, stroke (eg, cerebral hemorrhage, cerebral thrombosis), myocardial infarction, angina pectoris. Inflammation, glomerulonephritis, shock (eg, endotoxin shock, intravascular blood clotting syndrome caused by endotoxin, anaphylaxis, sok, hemorrhagic shock) and diseases related to allergies (eg, bronchial asthma) ), Etc. · It is useful as a therapeutic and antitumor agent.
化合物（ I )およびその塩は親水性、 親油性ともに優れた性状を有し； . 毒性も低いので、 そのまま粉末剤として、 または適当な剤形の医薬組成 物として、 哺乳動物に対して経口的または非経口的に安全に投与するこ とができる。 投与量は投与対象，対象疾患，症状，投与ル- トなどによつ ても異なるが、 たとえば成人のショ ックに対する予防 ·治療のために使 用する場合 4こは、 静脈注射により投与する時には化合物（ I )またはその 塩を 1回量として通常 0. (U〜20mg/kg体重程度、 好ましくは 0. i〜 iOmg /kg体童程度、 さらに好ましくは Q . l〜 2mg/kg体重程度、 1 日 1〜5回程 度、 好ましくは 1〜 3回程度投与するのが好都合である。また、 化合物（ I ) またはその塩を 1向あたり 0. 01~ 1. 0mg/kg体重/ mi n. 程度を約 1時間 程度、 1 日 1〜5回程度、 好ましくは 1〜3回程度点滴注射により投与する こともできる。 他の非経口投与および錢ロ投与の場合もこれに準ずる量 を投与することができる。 ショック症状が特に重い場合にはその症状に 応じて增量して用いてもよい。  Compound (I) and its salt have excellent properties in both hydrophilicity and lipophilicity;. Low toxicity, so that they can be orally administered to mammals as powders or as appropriate pharmaceutical compositions. Alternatively, it can be safely administered parenterally. The dosage varies depending on the subject of administration, target disease, symptoms, administration route, etc. For example, when used for the prevention and treatment of shock in adults 4. Administer by intravenous injection Sometimes compound (I) or a salt thereof is used as a single dose, usually at a dose of about 0.1 (U to about 20 mg / kg body weight, preferably about 0.1 to about 10 mg / kg body weight, more preferably about Q.l to about 2 mg / kg body weight. It is convenient to administer about 1 to 5 times a day, preferably about 1 to 3 times a day, and 0.01 to 1.0 mg / kg body weight / min of compound (I) or a salt thereof per one patient. It can be administered by infusion for about 1 hour, about 1 to 5 times a day, preferably about 1 to 3 times a day. If the shock symptoms are particularly severe, they may be used in smaller doses depending on the symptoms.
また、 たとえば成人の血栓症に対する予防 ·治療のために経口投与す る場合、 化合物（ I )またはその塩を 1回量として通常 0. 1〜 20mg/kg体 重程度、 1 日 1〜5回程度、 好ましくは 1〜3回程度投与するのが好都合で ある。 さらに詳しくは、 血栓症の予防を目的とする場合、 1回量 0. 5~4 mg/kg体重程度、 治療を目的とする場合、 1回量 4〜10mg/kg体重程度 を、 それぞれ 1 日 1 〜 3回程度投与するのが好ましい。 他の非経口投与 の場合もこれに準ずる量を投与することができる。 Also, for example, in the case of oral administration for the prevention and treatment of thrombosis in adults, Compound (I) or a salt thereof is usually 0.1 to 20 mg / kg body weight as a single dose, 1 to 5 times a day. It is convenient to administer the drug, preferably about 1 to 3 times. More specifically, if the purpose is to prevent thrombosis, a single dose of 0.5 to 4 For the purpose of treatment, it is preferable to administer a dose of about 4 to 10 mg / kg body weight each time, about 1 to 3 times a day. In the case of other parenteral administration, an equivalent dose can be administered.
投与に用いられる医薬組成物は、 有効量の化合物（I )またはその塩と 薬理学的に許容されうる担体もしくは陚形剤とを含むものであり、 該組 成物は経口または非経口投与に適する剤形として提供される。  The pharmaceutical composition used for administration contains an effective amount of compound (I) or a salt thereof and a pharmacologically acceptable carrier or excipient, and the composition is suitable for oral or parenteral administration. It is provided in a suitable dosage form.
経口投与のための組成物としてはたとえば、 固体または液体の剤形、 具体的には錠剤（糖衣錠，フィルムコ -テング錠を含む），丸剤，顆粒剤，散 剤，カプセル剤（ソフ トカプセル剤を含む），シ口ップ剤,乳剤，懸蜀剤など があげられる。 かかる組成物は自体公知の方法によって製造され、 製剤 分野において通常用いられる担体もしくは賦形剤を含有するものである。 たとえば錠剤用の担体，賦形剤どしては乳糖，でんぷん，ショ糖，ステアリ ン酸マグネシウムなどがあげられる。 ·  Compositions for oral administration include, for example, solid or liquid dosage forms, such as tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, and capsules (soft capsules). Agents, emulsions, suspensions, etc. Such a composition is produced by a method known per se and contains a carrier or an excipient usually used in the field of formulation. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like. ·
非経口投与のための組成物としては、 たとえば注射剤,坐剤などがあ げられ、 注射剤としてはたとえば静脈注射剤，皮下注射剤，皮内注射剤， 筋肉内注射剤，点滴注射剤などの剤形があげられる。 かかる注射剤は自 体公知の方法、 たとえば化合物（ I )またはその塩を 常注射剤に甩ぃら れる無菌の水性もしくは油性液に溶解、 懸蜀または乳化することによつ て調製される。 注射用の水溶液としては生理食塩水,ブドウ糖やその他 の捕助薬を含む等張液などがあげられ、 適当な溶解捕助剤，たとえばァ ルコール（例、 エタノール），ポリアルコール（例、 プロピレングリコール: ポリェチレングリ コ—ル），非イオン性界面活性剤 [例、ポリソルベー ト 80 , H C 0— 50 (polyoxyethy lene(50mol) adduct of hydrogenated cas tor oi l)]などと併用してもよい。 油性液としてはゴマ油，大豆油などがあ げられ、 溶解捕助剤として安息香酸べンジル，ベンジルアルコールなど を併用してもよい。 調製された注射液は通常適当なアンプルに充«され、  Compositions for parenteral administration include, for example, injections, suppositories, etc. Examples of injections include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, drip injection, etc. Dosage form. Such injections are prepared by a method known per se, for example, by dissolving, suspending or emulsifying compound (I) or a salt thereof in a sterile aqueous or oily solution used for ordinary injections. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other scavengers, and suitable dissolution scavengers such as alcohol (eg, ethanol) and polyalcohols (eg, propylene glycol). : Polyethylene glycol), nonionic surfactants [eg polysorbate 80, HC0-50 (polyoxyethylene (50mol) adduct of hydrogenated catalyst)], etc. Examples of the oily liquid include sesame oil and soybean oil. Benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizer. The prepared injection is usually filled in an appropriate ampoule,
0-、''PI 注射剤として提供される。 直腸投与に用いられる坐剤は自体公知の方法、 たとえば化合物（ I )またはその塩を通常の坐薬用基剤に混合し、 成型す ることによって調製される。 0-, '' PI Provided as injection. Suppositories to be used for rectal administration are prepared by a method known per se, for example, by mixing compound (I) or a salt thereof with a usual suppository base and molding.
なお、 上記各組成物は化合物（ I )またはその塩との配合により好まし くない相互作用を生じない限り、他の活性成分を含有していてもよい。 化合物（ I )またはその塩はたとえば次のような方法によって製造する ことができる。  Each of the above-mentioned compositions may contain other active ingredients as long as unfavorable interaction does not occur by compounding with compound (I) or a salt thereof. Compound (I) or a salt thereof can be produced, for example, by the following method.
A) (R 3と結合する Z中の原子が窒素原子である場合） A) (When the atom in Z bonded to R 3 is a nitrogen atom)
式  Expression
C H 20 R CH 2 0 R
C H R 2 CHR 2
I (VI ) I (VI)
C H 2 - X C Y - R Q t CH 2 -XCY-RQ t
II  II
0  0
[式中、 C は窒素と容易に置換.する基（例、 塩素，臭素，ヨウ素などのハ ロゲン， OTosyl , OMesyl基など）示し、 他の記号は前記と同意義]で表わ される化合物と置換されていてもよいアミ ン（VE)または含窒素環状化合 物（ )を反応させて化合物（ I )を得る。 化合物（VI )と（V5)または（VI)と の反応は化合物（VI )に対し、 化合物（Vtt)または（VI)を 1当量ないし大過 剰加え、 0〜十 200。Cで溶媒の存在下もしくは無溶媒下に行うことができ る。 溶媒としてはトルエン，ベンゼン，ェ一テル，ジォキサン，テトラ.ヒ ド 口フランなどがあげられ、 また化合物（VE)または（VI)自体を溶媒として 用いることもできる。加熟下においては、封管中で反応を行ってもよい。 B )式  [Wherein, C represents a group which easily substitutes for nitrogen (eg, a halogen such as chlorine, bromine, iodine, OTosyl, OMesyl group, etc.), and the other symbols are as defined above] And optionally substituted amine (VE) or nitrogen-containing cyclic compound () to obtain compound (I). In the reaction of compound (VI) with (V5) or (VI), 1 equivalent to a large excess of compound (Vtt) or (VI) is added to compound (VI), resulting in 0 to 10 200. C can be carried out in the presence or absence of a solvent. Examples of the solvent include toluene, benzene, ether, dioxane, and tetrahydrofuran, and the compound (VE) or (VI) itself can be used as the solvent. During ripening, the reaction may be performed in a sealed tube. B) Formula
差換え C H20 R 1 Replacement CH 2 0 R 1
！  !
C HR2 ( O C HR 2 (O
C H 2 - X C - Q 2  C H 2-X C-Q 2
II  II
0  0
[式中、 Q2はカルボ二ル基を活性化する基（例、 ハロゲン（例、 塩素），フ エノキシなど））を示し、 他の記号は前記と同意義]で表される化合物に、 式 [Wherein, Q 2 represents a group that activates a carbonyl group (eg, halogen (eg, chlorine), phenoxy, etc.), and other symbols have the same meanings as described above]. formula
HY— R3— Z - R+ (X) [式中、各記号は前記と同じ]で表わされる化合物を反応ざせて化合物 HY—R 3 —Z-R + (X) [wherein each symbol is the same as above]
[I ]を る。 （IX)と（X)の反応は、 溶媒の存在下もしくは無溶媒下、  [I]. The reaction between (IX) and (X) is performed in the presence or absence of a solvent,
— 10〜 + 150。Cで行うことができる。 溶媒としてはトルエン，ベンゼン， エーテル，ジォキサン，テトラヒ ドロフラン，クロロホルムなどを用いる — 10 to +150. Can be done in C. Use toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform, etc. as the solvent.
ことができ、 反応を促進するため、 トリェチルァミ ン，ピリ ジンなどの To promote the reaction, such as triethylamine, pyridine, etc.
塩基を加えてもよい。 また（X)を前記の溶媒中で、 水素化ナトリウムや n—ブチルリチウムなどと反応させ、 金属塩に変えた後、 化合物（ )と A base may be added. Further, (X) is reacted with sodium hydride, n-butyllithium, or the like in the above-mentioned solvent, converted into a metal salt, and then compound () and
反応させてもよい。 You may make it react.
C)式C) formula
Figure imgf000016_0001
Figure imgf000016_0001
C HR2 . (XI) C HR 2. (XI)
C H 2 X H CH 2 XH
[式中、 R^I .Xは前記と同意義]で表わされる化合物に、 式  [Wherein R ^ I.X is as defined above]
Q3- C - Y - R3- Z - R* (M) Q 3 -C-Y-R 3 -Z-R * (M)
0  0
[式中、 Q3はカルボ二ル基を活性化する基 、ロゲン（例、 塩素，フエノ [In the formula, Q 3 is a group that activates a carbonyl group, a logen (eg, chlorine, pheno
キシなど））を示し、 他は前記と同意義]で表される化合物を反応させて Etc.), and the others are as defined above.
化合物 [I ]を得る。 化合物（XOと（1 の反応は B)における化合物（IX) Compound [I] is obtained. Compound (IX) in compound (XO and (1 is B)
と（X)の反応に準じておこなうことができる。 And (X).
0 PI0 PI
WiPO ^. D)式 WiPO ^. D) Formula
C H20 R 1 CH 2 0 R 1
CHR2 (XI) C H 2 C = 0 CHR 2 (XI) CH 2 C = 0
：:式中、 R1,!?2は前記と同じ]で表わされる化合物に、 式（X)で表わされ る化合物を反応させて（ I )(X=NH)を得る。 反応は（IX)と（X)の反応に 準じて行うことができる。 -Wherein R 1 ,!? 2 is the same as defined above], and the compound represented by the formula (X) is reacted to obtain (I) (X = NH). The reaction can be carried out according to the reaction of (IX) and (X). -
E)式 E) Formula
0 = C=N - R3— Z - R+ (XIV)0 = C = N-R 3 — Z-R + (XIV)
[式中、 略号は前記と同じ]で表わされる化合物に、 式（a)で表わされる 化合物を反応させて（ I )(Y = NH)を得る。 反応は（ )と（XI)の反応に準 じて行うことができる。 The compound represented by the formula (a) is reacted with the compound represented by the formula (where the abbreviations are as defined above) to obtain (I) (Y = NH). The reaction can be carried out according to the reaction between () and (XI).
化合物（XIY)はたとえば式 H2N— R3— Z - R4(XV) [式中、 各記号 は前記と同意義]で表わされる化合物にジホスゲンを反応させることに より、 または式 HOO C— R3— Z— R+(XVI) [式中、 各記号は前記と 同意義]で表わされる化合物に D P P Aを反応させることにより容易に 合成することができる。 The compound (XIY) can be prepared, for example, by reacting a compound represented by the formula H 2 N—R 3 —Z—R 4 (XV) with each symbol having the same meaning as described above, with diphosgene; —R 3 —Z—R + (XVI) [wherein the symbols are as defined above], and can be easily synthesized by reacting the compound with DPPA.
式（ I )中、 Xおよび/または Yが置換されていないィミ ノ基である化 合物を、 たとえば酸無水物，酸ハライ ド，アルキルハラィ ドと反応させて、 式（I)中、 Xおよび/または Yが置換されたィミノ基である化合物を得 ることができる。 反応は一般に溶媒（例、 ベンゼン， トルエン，クロロホ ルム，ジクロルメ タ ン，エーテル，テ トラヒ ドロフラン，ジメチルスルホキ シ ド，ジメチルホルムアミ ド）中、 反応温度を— iO。Cから + i50。C程度に 保つことによって進行する。 この際、 反応速度促進の目的で塩基（例、 ト リェチルァミ ン，ピリ ジン，ジメチルァミ ノ ピリ ジン，水酸化ナ ト リ ウ ム，水素化ナトリゥム）を反応中に共存させることもできる。 ϋκじ 4 In the formula (I), a compound in which X and / or Y is an unsubstituted imino group is reacted with, for example, an acid anhydride, an acid halide, or an alkyl halide to obtain a compound represented by the formula (I). And / or a compound in which Y is a substituted imino group can be obtained. The reaction is generally carried out in a solvent (eg, benzene, toluene, chloroform, dichloromethane, ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide) at a reaction temperature of -iO. From C + i50. Proceed by keeping it at about C. At this time, a base (eg, triethylamine, pyridine, dimethylaminopyridine, sodium hydroxide, sodium hydride) can be coexisted in the reaction for the purpose of accelerating the reaction rate. ϋκ じ 4
__0ΜΡ[ 式（ I )中、 Zで示される基の中に含まれる窒素原子が、 i級， 2級， 3 級アミ ンである化合物を、 たとえばアルキルハラィ ドと反応させること により、 式（ I )中、 Zで示される基の中に含まれる窒素原子が 2級， 3 級， 4級アミ ンである化合物を得ることもできる。 この反応はエーテル， ク口口ホルム，テ ドラハイ ドロフラン，ベンゼン， トルエンなどの溶媒中、 等量ないし大過剰のアルキルハライ ドの存在下、 0° ~ ÷ 150°Cに保つこ とに つて進行する。 __0ΜΡ [ In the formula (I), a compound in which the nitrogen atom contained in the group represented by Z is an i-, tertiary, or tertiary amine is reacted with, for example, an alkyl halide to obtain a compound represented by the formula (I). Compounds in which the nitrogen atom contained in the group represented by Z is a secondary, tertiary, or quaternary amine can also be obtained. This reaction proceeds in a solvent such as ether, porcine, tetrahydrofuran, benzene, toluene, etc., in the presence of an equal or large excess of alkyl halide, at 0 ° to ÷ 150 ° C. .
また式（I )中に、 容易に脱離する基が含まれる場合、 この基を脱離さ せた後、 反応をおこない、 他の置換基を導入することもできる。 たとえ ば式（ I )で R 2がべンジルォキシ基の場合、 接解還元をおこない、 R 2を ヒ ドロキシ基とした後、 ァシル化，力ルバ乇ィル化をおこなうことがで きる。 In the case where a group which can be easily eliminated is included in the formula (I), the reaction can be carried out after the group is eliminated, and another substituent can be introduced. Even if a place formula (I) of R 2 Gabe Njiruokishi group performs Sekkai reduction, after the R 2 and human Dorokishi group, Ashiru reduction, can be determined promptly by using an force Luba乇I le of.
ル化 Conversion
Figure imgf000018_0001
Figure imgf000018_0001
R 2'はァシル基を示す。 R 2 ′ represents an acyl group.
この反応の際、 Xおよび/または Yが置換されていないィミ ノ基の場 合、 上記のァシル化，力ルバモイル化の際に同時に Xおよぴ /または Y がァシル化.力ルバモイル化することもできる。 本反応における接触還  In this reaction, when X and / or Y is an unsubstituted imino group, X and / or Y are simultaneously acylated and rubamoylated during the above-mentioned acylation and rubamoylation. You can also. Catalytic return in this reaction
■¾し ' 1くじ Aひ 元反応は、 酸化白金，パラジゥム炭素，ラネーニッケルなどの触媒を用い、 アルコール，テ トラハイ ド σフラ ン，水， g乍酸などの溶媒中、 室温から + 100°Cに保つことによっておこなう ことができる。 （X VE)のァシル化 反応は、 （X VI)にカルボン酸の活性誘導体（酸無水物，酸ハライ ドなど） を不活性溶媒中（エーテル，ク口口ホルム，ベンゼン， トルェン，ジクロル メタ ン，テ トラハイ ド口フラン，ジメチルホルムア ミ ドなど），一 10。 〜十 150°Cに保つことによっておこなう ことができる。 この際、 反応を促進 する /"こめ、 三級ァミ ン（ト リェチルァミ ン，ピリ ジン，ジメチルァミ ノ ピ リ ジン）などを加えてもよい。 （X VII)を力ルバ乇ィル化して（X IX)とす る反応は、 後述する原料化合物の力ルバモイル化反応 [化合物（XLIV)の 製造法]に準じておこなう ことができる。 ■ Pashi ' 1 lot A The original reaction can be carried out by using a catalyst such as platinum oxide, palladium carbon, Raney nickel, etc., and keeping the temperature from room temperature to + 100 ° C in a solvent such as alcohol, tetrahydro σ-furan, water or g acid. . The acylation reaction of (X VE) is carried out by reacting (X VI) with an active derivative of a carboxylic acid (acid anhydride, acid halide, etc.) in an inert solvent (ether, phenol, benzene, toluene, dichloromethane). , Tetrahedral mouth furan, dimethylformamide, etc.). This can be done by keeping the temperature at ~ 150 ° C. At this time, a tertiary amine (triethylamine, pyridine, dimethylaminopyridine) or the like may be added to promote the reaction. The reaction referred to as X IX) can be carried out in accordance with the later-described rubamoylation reaction of a raw material compound [Production method of compound (XLIV)].
出発原料の（VI )はたとえば-次に示す反応式に従って製造することがで さる。 -  The starting material (VI) can be produced, for example, according to the following reaction scheme. -
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000019_0001
Figure imgf000020_0001
CH2NHC-Y-R3-Q! or')CH 2 NHC-YR 3 -Q! Or ')
Figure imgf000020_0002
Figure imgf000020_0002
上記式中、 Q t 'はト シルまたはメ シルを示し、 T HPはテトラヒ ドロピ ラン一 2—ィルを示し、 Q4,Q5はハロゲン（例、クロル，ブロム，ョ— ド） OTosyi, OMesylを示す。 他の記号は前記と同意義。 In the above formula, Q t ′ represents tosyl or mesyl, T HP represents tetrahydroxypyran-12-yl, and Q 4 and Q 5 represent halogens (eg, chloro, bromide, chloride) OTosyi, Indicates OMesyl. Other symbols are as defined above.
ΟΜΡΙΟΜΡΙ
, wipo , , この方法は式 H X— C— Y Hで表わされる化合物が 5員環， 6員環化 合物（ヒダン トイン，ゥラシルノくルビツール酸など）の場合に用いると良 い。 , wipo,, This method should be used when the compound represented by the formula HX-C-YH is a 5- or 6-membered ring compound (hydantoin, peracyl-no-rubbituric acid, etc.).
(IX)および（¾0は（XI)または（X)にたとえばク口 σ炭酸フエニル，フ ォスゲン，ジフォスゲンを反応させてそれぞれ合成できる。  (IX) and (¾0) can be synthesized by reacting (XI) or (X) with, for example, phenyl phenyl carbonate, phosgene or diphosgene.
前記反応において原料 oとして用いられた化合物（XI)はたとえば以下の 方法で合成できる。  Compound (XI) used as starting material o in the above reaction can be synthesized, for example, by the following method.
(Xが 0， S ,ΝΗの場合に分けて説明する） 式  (I will explain separately when X is 0, S, ΝΗ) Expression
C H20 R 1 CH 2 0 R 1
C HR ¾a C HR ¾a
！ (XXXV)  ! (XXXV)
C H20 H CH 2 0 H
〔式中、 R2aはァシルォキシ基を示し、 R1は前記と同意義]の化合物は たとえば次の反応式に従って製造できる。 -[Wherein R 2a represents an acyloxy group, and R 1 has the same meaning as described above], for example, can be produced according to the following reaction formula. -
CH20R' CH20Rl + CH20R2 CH 2 0R 'CH 2 0R l + CH 2 0R 2
ァシル化 I a H Acylated I a H
CH0H » CHR2a CHR2a CH0H »CHR 2a CHR 2a
CH20Tri CH20Tri CH20H CH 2 0Tri CH 2 0Tri CH 2 0H
(XX I) (XXXVI)  (XX I) (XXXVI)
式  Expression
C H20 R 1 CH 2 0 R 1
C HR2 C HR 2
C H20 H CH 2 0 H
[式中、 R2bはァシルアミ ノ基を示し、 R1は前記と同意義]の化合物は たとえば次の反応式に従って製造できる。 Wherein, R 2 b represents an Ashiruami amino group, R 1 is the same meaning as defined] compounds of may be prepared for example according to the following reaction scheme.
OMPI OMPI
、 、 WIPO ,¾
Figure imgf000022_0001
,, WIPO, ¾
Figure imgf000022_0001
式
Figure imgf000022_0002
(XLIV) formula
Figure imgf000022_0002
(XLIV)
CH2OH CH 2 OH
[式中、 R2Cは式（m)で表わされる基を示し、 R1は前記と同意義]で表 [Wherein, R 2C represents a group represented by the formula (m), and R 1 has the same meaning as described above].
わされる化合物はたとえば次の^応式に従つて製造できる。 The compounds described can be prepared, for example, according to the following reaction scheme.
Figure imgf000022_0003
Figure imgf000022_0003
[式中、 Qeはハロゲン原子を示し、 他は前記と同意義] [Wherein, Qe represents a halogen atom, and the others are as defined above]
"■■■—- '■ 一 · \ \ "ν ·ο ·'
Figure imgf000023_0001
"■■■ —- '■ one · \ \" ν · ο ·'
Figure imgf000023_0001
式  Expression
C H20 R 1 CH 2 0 R 1
C HR2d C HR 2d
(L Π)  (L Π)
C H20 H CH 2 0 H
[式中、 R2dはアルコキシまたはァラルキルォキシを示し、 R1は前記と 同意義]で表わされる化合物は、 たとえば次の反応式に従って製造でき る。 [Wherein R 2d represents alkoxy or aralkyloxy, and R 1 has the same meaning as described above], for example, can be produced according to the following reaction formula.
Figure imgf000023_0002
Figure imgf000023_0002
- U EAU ΟΜΡΙ-U EAU ΟΜΡΙ
、 [式中、 R1および R 2は前記と同意義]で表わされる化合物は次の反応式 に従って製造できる。 , [Wherein R 1 and R 2 are as defined above] can be produced according to the following reaction formula.
Figure imgf000024_0001
Figure imgf000024_0001
式formula
Figure imgf000024_0002
Figure imgf000024_0002
CHR2 CHR 2
(LVI)  (LVI)
C H 2 N H 2 , CH 2 NH 2 ,
[式中、 R1および R2は前記と同意義]で表わされる化合物はたとえば次 の反応式に従って製造できる。 [Wherein R 1 and R 2 are as defined above] can be produced, for example, according to the following reaction formula.
Figure imgf000024_0003
Figure imgf000024_0003
上記各反応式中、 記号 Pti, Ts, Triおよび DF P Aはそれぞれフエ二 ル， ト シル， ト リチルおよびジフエ二ルホスホリルアジドを示す。 In the above reaction formulas, the symbols Pti, Ts, Tri and DFPA represent phenyl, tosyl, trityl and diphenylphosphoryl azide, respectively.
各反応に用いる化合物において、 反応に支障を及ぼす恐れのある基を 有する化合物は、 自体公知の保護基（例、 ベンジル， トシル， トリチル，フ タルイ ミ ド，スク シンイ ミ ド，ベンジルォキシカルボニル， tert -ブトキシ カルボニル）で該基を保護して反応を行ない、 反応後、 自体公知の脱保 護反応に付し、 目的とする化合物を得ることもできる。 In the compounds used for each reaction, groups that may interfere with the reaction The compound having the compound is protected by a protecting group known per se (eg, benzyl, tosyl, trityl, phthalimid, succinimid, benzyloxycarbonyl, tert-butoxycarbonyl), and the reaction is carried out. Thereafter, the target compound can be obtained by subjecting it to a deprotection reaction known per se.
化合物（I )の塩はたとえば上記した化合物（I )の製造方法自体で得ら れることもあるが、 必要に応じて、 化合物（I )に酸または塩基を加えて 製造することもできる。  The salt of compound (I) may be obtained, for example, by the above-mentioned method for producing compound (I) itself, or may be produced by adding an acid or a base to compound (I), if necessary.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
実施例 1 · Example 1
2— 0—ベンジル一 3— 0— ( 2' —ジメチルァミ ノェチル）カルバモ ィルー 1一 0—ォクタデシルグリセリ ン  2-0-benzyl-1-3- (2'-dimethylaminoethyl) carbamoyl 110-octadecylglycerin
2— 0—ベンジル一 1— 0—才クタデシルグリセリ ン 1.88g(4.325ミ リモル），ピリ ジン， 0.684g(8.65ミ リモル）をジクロルメタ ン（12ml)に溶 解し、 クロ口炭酸フエニル 0.745g(4.i756ミ リモル）を氷冷下滴下した後、 室温にて 1.5時間攪拌した。 反応液を 1 %炭酸水素ナトリゥム溶液で洗 净後、 有機層を硫酸マグネシウムで乾燥し、 溶媒を减圧留去した。 得ら れたカ一ボネ― トを精製することなく asym. —ジメチルェチレンジアミ ン 457mg(5.19ミ リモル）を加え、 70°Cにて 5時間加熟し、 冷後クロロホ ルムーメタノ ール（19:1)を溶出液とするシリ力ゲル力ラムクロマ トグラ フィ—にて精製し、 目的物（無色固形物） 2.37g (収率 99.8%)を得た。  2-0-Benzyl 1-0-year-old Kutadecylglycerin 1.88 g (4.325 mimol), pyridine, 0.684 g (8.65 mimol) are dissolved in dichloromethane (12 ml), and phenyl methyl carbonate 0.745 g (4.i756 mimol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. After washing the reaction solution with a 1% sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained carbonate was added without purification to 457 mg (5.19 mmol) of asym.-dimethylethylenediamine, ripened at 70 ° C for 5 hours, cooled, and cooled to chloroform chloroform (19). Purification by silica gel gel chromatography using 1: 1 as an eluent gave 2.37 g (yield 99.8%) of the desired product (colorless solid).
T L C [シリ力ゲル，クロ口ホルム—メタノ ール（14: 1 )]Rf=0.15 TLC [silicone gel, black form-methanol (14: 1)] Rf = 0.15
R [90 MHz.CDC ] δ :0.83(3Η), 1.28(32Η), 2.20(6Η), 2.37(2Η), 3.23C2H), 3.42C2H), 3.53(2Η), 3.76(1Η), 4.20(2Η), 4.68(2Η), 5.27 (1Η)， 7.32C5H)  R [90 MHz.CDC] δ: 0.83 (3Η), 1.28 (32Η), 2.20 (6Η), 2.37 (2Η), 3.23C2H), 3.42C2H), 3.53 (2Η), 3.76 (1Η), 4.20 (2Η) ), 4.68 (2Η), 5.27 (1Η), 7.32C5H)
I R [film] cm-1 :3330, 2920, 2850, 2815, 1725, 1500, 1468, 1255, 1120, 1060 実施例 2 IR [film] cm -1 : 3330, 2920, 2850, 2815, 1725, 1500, 1468, 1255, 1120, 1060 Example 2
2一 0—ァセチルー 3— Q_— [N— Tセチルー N— ( 2 ' —ジメチルァ ミノェチル）]カルパモイルー 1 一 0—才クタデシルグリセリン  2 1 0—Acetyl 3— Q_— [N—T cetyl—N— (2′—Dimethylaminominethyl)] carpamoyl 1 1—0—Cutadecylglycerin
エタノ ール（5 ml)および 90%酢酸水溶液（50ml)の混液に、 実施例 1で 製造したベンジルェ—テル体 i.097g(2 ミ リモル）および 10%パラジゥム 炭素 250mgを加え、 室温にて 2時間接触還元を行なった。 反応終了後、 触媒を ^別し、 炉液を減圧濃縮して、 粗アルコ -ル体 958mgを得た。 こ のアルコール体に、 ク口口ホルム（10nii)， トリェチルアミ ン（20ml),無水 酢酸（3ml)を加えた後、 室温にて 時間放置し、 反応液を减圧濃縮した。 残渣を胙酸ェチルーァセトン（5： 1 )を溶出液とするシリカゲルカラム クロマトグラフィ一にて精製し、 目的物（無色油状物質）40611^(収率37.4 %)を得た。  To a mixture of ethanol (5 ml) and a 90% acetic acid aqueous solution (50 ml) was added i.097 g (2 mmol) of the benzyl ether compound prepared in Example 1 and 250 mg of 10% palladium carbon, and the mixture was added at room temperature. An hourly catalytic reduction was performed. After the completion of the reaction, the catalyst was separated and the filtrate was concentrated under reduced pressure to obtain 958 mg of a crude alcohol. To this alcohol compound was added form (10nii), triethylamine (20 ml), and acetic anhydride (3 ml), and the mixture was allowed to stand at room temperature for an hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetylacetonate (5: 1) as an eluent to obtain 40611 ^ (yield: 37.4%) of the target product (colorless oily substance).
T L C [シリ力ゲル，クロロホルム一メタノール（5： 1 )]:Rf = 0.66 NMRF90 MHz, CDC13 ] δ :0.88(3Η), 1.27(32Η), 2.10(3ff), 2.23(6TLC [silica force gel, chloroform one methanol (5: 1)]: Rf = 0.66 NMRF90 MHz, CDC1 3] δ: 0.88 (3Η), 1.27 (32Η), 2.10 (3ff), 2.23 (6
Η), 2.40(2Η), 2.δΟ(3Η), 3.46(2Η), 3.58(2Η), 3.85(2Η), 4.42(2Η),Η), 2.40 (2Η), 2.δΟ (3Η), 3.46 (2Η), 3.58 (2Η), 3.85 (2Η), 4.42 (2Η),
5.29(1Η) 5.29 (1Η)
I R [film]cm-1:2924, 2850, 1745, 1710, 1460, 1372, 1234, 1180 実施例 3 IR [film] cm- 1 : 2924, 2850, 1745, 1710, 1460, 1372, 1234, 1180 Example 3
2— 0—ァセチル— 3— 0— [Ν—ァセチル— Ν— (2 ' -一トリメチル アンモニォェチル）]力ルバモイルー 1 一 0—才クタデシルグリセリ ン . ョニジド  2—0—Acetyl—3—0— [Ν-Acetyl—Ν— (2'-Trimethylammonioethyl)] Lubamoyl 1 1—0—Kutadecylglycerin.
実施例 2で製造したジメチルァミ ノ体 355mg(0.709ミ リモル）およびョ ゥ化メチル 2(Umg(1.418ミ リモル）をエーテル 15mlに溶解して、 室温にて 22時間攪拌した。 氷冷下、 折出した沈緞を庐取し、 目的物（無色粉末） 424(1^(収率87.3%)を得た。  355 mg (0.709 mmol) of the dimethylamino compound produced in Example 2 and 2 mg (1.4 mg) of methyl iodide were dissolved in 15 ml of ether, and the mixture was stirred at room temperature for 22 hours. The resulting drape was collected to obtain 424 (1 ^ (yield: 87.3%)) of the target product (colorless powder).
T L C [シリカゲル J乍酸ェチル—酢酸一水（3 : 1 : 1 )]:Rf = 0.39 NMR [90 MHz, CDC13] <5 :0.89(3H), 1.27 (32H), 2.12(3H) , 2.52(3H) , 3.47(2H), 3.48〜3.7KliH), 3.80(2H), 4.22('2H), 4.51(2H), 5.42 (1H) TLC [silica gel J ethyl acetate-acetic acid monohydrate (3: 1: 1)]: Rf = 0.39 NMR [90 MHz, CDC1 3] <5: 0.89 (3H), 1.27 (32H), 2.12 (3H), 2.52 (3H), 3.47 (2H), 3.48~3.7KliH), 3.80 (2H), 4.22 ( ' 2H), 4.51 (2H), 5.42 (1H)
I R[KBr]cni-1 : 3450> 2920, 2840, 1740, 1680, 1465, 1371, 1232, 1200 IR [KBr] cni- 1 : 3450 > 2920, 2840, 1740, 1680, 1465, 1371, 1232, 1200
実施例 4 Example 4
2— 0—べンジルー 1— 0—ォクタデシルー 3— 0— (2' — トリメ チルァンモニォェチル）力ルバモイルグリセリ ン · ョ—ジ ド  2—0—Benziru 1—0—Octadecyl 3—0— (2'—Trime tyranmonyoethyl) Lubamoylglycerin
実施例 1で製造したジメチルァミノ体 906mg(1.651ミ リモル）およびョ ゥ化メチル 469mg(3.302ミ リモル）をエーテル（20ml)に溶解し、 室温にて 2日間攪拌した。 折出した沈澱を'庐取し、 目的物（無色粉末） 1.024g (収 率 89.8%)を得た。  906 mg (1.651 mimol) of the dimethylamino compound produced in Example 1 and 469 mg (3.302 mimol) of methyl iodide were dissolved in ether (20 ml), and the mixture was stirred at room temperature for 2 days. The deposited precipitate was collected to give 1.024 g (yield 89.8%) of the desired product (colorless powder).
T L C [シリ力ゲル， g乍酸ェチルー酢酸一水（3 : 1 : 1 )] :Rf = 0.43 MR [90 MHz, CDC13 + CD30D] δ :0.89(3Η), 1.25(32Η), 3.27(9Η), 3.43C2H), 3.53C2H),' 3.60〜3.91(5Η)， 4.23(2Η), 4.68(2Η), 6.71 (1Η), 7.36(5Η) TLC [silica force gel, g乍酸Echiru acetate monohydrate (3: 1: 1)] : Rf = 0.43 MR [90 MHz, CDC1 3 + CD 3 0D] δ: 0.89 (3Η), 1.25 (32Η), 3.27 (9Η), 3.43C2H), 3.53C2H), '3.60 to 3.91 (5Η), 4.23 (2Η), 4.68 (2Η), 6.71 (1Η), 7.36 (5Η)
I R [KBr]ctn→:3355, 2927, 2850, 1730, 1539, 1473, 1255, 1130, 1044, 759, 703 IR [KBr] ctn → : 3355, 2927, 2850, 1730, 1539, 1473, 1255, 1130, 1044, 759, 703
実施例 5 Example 5
2— 0—ベンジル一 3— 0— (2' —ハイ ドロキシェチル）力ルバモイ ルー 1— 0—ォクタデシルグリセリ ン  2—0—Benzyl 1—0— (2′—Hydroxityl) Lubamoyl 1—0—Octadecylglycerin
2— 0—ベンジル一 1— 0—ォクタデシルグリセリ ン i .739g( 4ミ リ モル），ピリ ジン 632mg(8ミ リモル），クロロ炭酸フエニル 689mg(4.4ミ リ乇 ル），ジクロ口メタン（10ml)より、 実施例 1と同様にして得られたカーボ ネ— トをクロ口ホルム（10ml)に溶解し、 ェタノ —ルアミ ン 293mg(4.8ミ リモル）を加えて 21時間還流した。 反応液を減圧濃縮し、 残渣をへキサ  2-0-benzyl-1- 1-octadecylglycerin i.739 g (4 mmol), pyridine 632 mg (8 mmol), phenyl chlorocarbonate 689 mg (4.4 mmol), dichloromethane methane ( 10 ml), the carbonate obtained in the same manner as in Example 1 was dissolved in chloroform (10 ml), 293 mg (4.8 mmol) of ethanolamine was added, and the mixture was refluxed for 21 hours. The reaction solution is concentrated under reduced pressure, and the residue is
換え ンー蚱酸ェチル（1 ： 1 )を溶出液とするシリカゲルカラムクロマ トグラ フィ一にて精製し、目的物（無色固形物 .S g (収率 93.0%)を得た。 Change The residue was purified by silica gel column chromatography using ethyl acetate (1: 1) as an eluent to obtain the desired product (colorless solid. Sg (93.0% yield)).
TL C [シリカゲル，へキサン—酢酸ェチル（ 1 ： l )]:Rf=0.18 NMR [90 MHz, CDC13] δ :0.87(3Η), 1.27(32Η), 2.82(1Η), 3.15- 3.9Κ9Η), 4.22C2H), 4.68(2Η), 5.37(1Η), 7.33(5Η) TL C [silica gel, hexane - acetic acid Echiru (1: l)]: Rf = 0.18 NMR [90 MHz, CDC1 3] δ: 0.87 (3Η), 1.27 (32Η), 2.82 (1Η), 3.15- 3.9Κ9Η) , 4.22C2H), 4.68 (2Η), 5.37 (1Η), 7.33 (5Η)
I R [KBi cm-L SSS, 2920, 2850, 1700, 1530, 1465, 1259, 1119  I R (KBi cm-L SSS, 2920, 2850, 1700, 1530, 1465, 1259, 1119
元素分忻： C31H55N05 - 計算値： C ,7.1.36; H.10.62;' , 2.68 Elemental Xin: C 31 H 55 N0 5 -Calculated: C, 7.1.36; H.10.62; ', 2.68
実測値： C, 71.65; H.10.62; Ν ,2.40  Found: C, 71.65; H.10.62; Ν, 2.40
実施例 6 Example 6
2— 0—ベンジル一 1 — 0—ォクタデシル一 3— 0— (2' — ρ— トル エンスルホニルォキシェチル）力ルバモイルグリセリ ン  2—0—Benzyl-1—0—Octadecyl-1—3—0— (2'—ρ—Toluenesulfonyloxicetil) Lubamoylglycerin
実施例 5で製造したアルコール体 1.8 g(3.528ミ リモル）を卜リェチ ルアミ ン（10ml)に溶解し、 氷冷下に p— トルエンスルホニルク口ライ ド 0.875g(4.587ミ リモル）を加えた後、 室温にて 12時間攪拌した。 氷冷下 反応液に 5 %塩酸水溶液を加え、 クロ口ホルムにて抽出し、 有機層は硫 酸マグネシウムにて乾燥後、 溶媒を減圧留去した。 残渣はへキサン一酢 酸ェチル（2.5: 1：)を溶出液とするシリカゲルカラムクロマトグラフィ一 にて精製し、 目的物（無色油状物質） 2, 36g (収率 99.0%)を得た。  1.8 g (3.528 mmol) of the alcohol compound produced in Example 5 was dissolved in triethylamine (10 ml), and 0.875 g (4.587 mmol) of p-toluenesulfonyl chloride was added under ice cooling. The mixture was stirred at room temperature for 12 hours. Under ice-cooling, a 5% aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane monoethyl acetate (2.5: 1: 1) as an eluent to obtain 2,36 g of the desired product (colorless oil) (yield 99.0%).
T L C [シリカゲル，へキサンー詐酸ェチル（2： 1 ) :Rf = 0.29 T L C [silica gel, hexane-ethyl acetate (2: 1): Rf = 0.29
NMR [90 MHz, CDC13] 5： 0.88(3H) , 1.23(32H), 2.41(3H), 3.28 〜3.58(6H), 3.72C1H), 3.97-4.37(4H) , 4.64(2H), 5.02(1H), 7.42〜7.22(7H), 7.79(2H) NMR [90 MHz, CDC1 3] 5: 0.88 (3H), 1.23 (32H), 2.41 (3H), 3.28 ~3.58 (6H), 3.72C1H), 3.97-4.37 (4H), 4.64 (2H), 5.02 ( 1H), 7.42 to 7.22 (7H), 7.79 (2H)
I R[film]cm-l:3330, 2930, 2850, 1728, 1600, 1525, 1465, 1365, 1255, 1190, 1180, 1120, 1100, 760 実施例 7 IR [film] cm- l : 3330, 2930, 2850, 1728, 1600, 1525, 1465, 1365, 1255, 1190, 1180, 1120, 1100, 760 Example 7
2一 0—べンジルー 3— 0— (2' —ブロモェチル）力ルバモイル— 1 — 0—才クタデシルグリセリ ン  2-1 0—Benziru 3—0— (2′—Bromoethyl) Power Lubamoyl—1—0—Kutadecylglycerin
実施例 6で製造したトシル体 2.360g(3.491ミ リモル）および臭化リチ ゥム（LiBr ' H2O)0.732g(6.983 リモル）をジメチルホルムァミ ド（22ml) に加え、 60° にて 2時間加熱した。 冷後、 反応液に水を加えてエ-テル 抽出し、 有機層は硫酸マグネシウムで乾燥後、 溶媒を減圧留去した。 残 渣はへキサン— S 酸ェチル（4： 1 )を溶出液とするシリカゲルカラムク 口マ トグラフィ—にて精製し、目的物（無色固形物） 1.855g (収率 90.9%) を得た。 In addition Example tosyl member was prepared in 6 2.360 g (3.491 Mi Rimoru) and bromide lithium © arm (LiBr 'H 2 O) 0.732g of (6.983 Rimoru) in dimethylformamide § mi de (22 ml), at 60 ° Heated for 2 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (4: 1) as an eluent to obtain 1.855 g (yield: 90.9%) of the desired product (colorless solid).
T L C [シリ力ゲル，へキサン一 g乍酸ェチル（2： 1 )] :Rf=0.51 T L C [silicone gel, hexane 1 g while ethyl ester (2: 1)]: Rf = 0.51
MRE90 MHz, CDCU] δ： 0.87(3Η), 1.26(32Η), 3.29〜3J2(9H) 4.22(2Η), 4.66(2Η), 5.06(1Η), 7 30(5Η)  MRE90 MHz, CDCU] δ: 0.87 (3Η), 1.26 (32Η), 3.29-3J2 (9H) 4.22 (2Η), 4.66 (2Η), 5.06 (1Η), 7 30 (5Η)
1 R [KBrlcm-1: 3330, 2920, 2850, 1720, 1538, 1470, 1250, 1215, 1135, 1125 1 R (KBrlcm- 1 : 3330, 2920, 2850, 1720, 1538, 1470, 1250, 1215, 1135, 1125
元素分斤： C31H5 + NO+Br . Elemental loaf: C 31 H 5 + NO + Br.
計算値： C , 63.68; H.9.31; N.2.40 "  Calculated: C, 63.68; H.9.31; N.2.40 "
実測値： C，63.98; H ,9.37; N.2.22  Found: C, 63.98; H, 9.37; N.2.22
実施例 8 Example 8
2— 0—ベンジル一 1 — 0—才クタデシル一 3 0 - (2 ' 一チアゾ リオェチル）力ルバモイルグリセリ ン . ブロマイ ド  2—0—Benzyl 1—0—Citadecyl 1 3 0— (2′-thiazo liethyl) Lubamoylglycerin. Bromide
実施例 7で製造したブロム体 877mg(1.5ミ リモル）にチアゾ―ル 5ilmg (6.0ミ リモル）を加え、 110てにて 12時間加熱した。 反応液を濃縮乾固し、 残渣はクロロホルム—メ タノ ール（3 ： 1 )を溶出液とするシリ力ゲル力 ラムクロマ トグラフィ—にて精製し、 目的物（無色粉末）78111^(収率77.7 %)を得た。  To 877 mg (1.5 mmol) of the bromo compound produced in Example 7, 5 ilmg (6.0 mmol) of thiazole was added, and heated at 110 to 12 hours. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel gel chromatography using chloroform-methanol (3: 1) as eluent to obtain the desired product (colorless powder) 78111 ^ (yield 77.7%). %).
OKPI T L C [シリカゲル.酢酸ェチル—詐酸—水（3 : 1 : 1 )]:Rf=0.41 NMR[90 MHz, CDC13] δ :0.88(3Η), 1.26C32H), 3.42(2Η), 3.50OKPI TLC [silica gel acetate Echiru -詐酸- water. (3: 1: 1) ]: Rf = 0.41 NMR [90 MHz, CDC1 3] δ: 0.88 (3Η), 1.26C32H), 3.42 (2Η), 3.50
(2Η), 3·60〜4.38(5Η)， 4.67(2Η), 4.92(2Η), 6.85(1Η), 7.35(5Η)(2Η), 3 · 60 to 4.38 (5Η), 4.67 (2Η), 4.92 (2Η), 6.85 (1Η), 7.35 (5Η)
8.04C1H), 8.43(1Η), 10.62(1Η) 8.04C1H), 8.43 (1Η), 10.62 (1Η)
1 R [KBrlcm-1： 3380, 2920, 2850, 1701, 1525, 1262, 1250, 1153, 1120, 1105, 753, 700 1 R [KBrlcm -1 : 3380, 2920, 2850, 1701, 1525, 1262, 1250, 1153, 1120, 1105, 753, 700
実施例 9 Example 9
3 - 0 - (2 —ジメチルァミ ノェチル）力ルバモイル一 2— 0—メチ ルー 1 一才クタデシルカルバモィルグリセリ ン  3-0-(2-Dimethylaminoethyl) Lubamoyl 1 2-0-Methyl 1 1-year-old Kutadecylcarbamoylglycerin
2一 0—メチルー 1 一 0—ォクタデシルカルバモイルグリセリ ン 1.607g( ミ リモル），ピリ ジン 632mg(8 ミ リモル），ク口口炭酸フエニル 689mg(4.4ミ リモル），ジクロロメタ ン（10ml)より、 実施例 1および 5と 同様にして得られた力—ボネ― トに asym. -ジメチルェチレンジァミ ン 445mg(4.8ミ リモル）を加え 70°Cにて 5時間加熟した。 冷後、 粗生成物を クロ口ホルムーメタノ ール（10: 1 )を溶出液とするシリ力ゲル力ラムク 口マトグラフィ一にて精製し、 目的物（無色固形物）1.895^収率91.9%) を得た。  210-Methyl-11-octadecylcarbamoylglycerin 1.607g (millimol), pyridine 632mg (8millimol), octyl phenyl carbonate 689mg (4.4millimol), dichloromethane (10ml) 445 mg (4.8 mmol) of asym.-dimethylethylenediamine was added to the force-bone obtained in the same manner as in Examples 1 and 5, and the mixture was ripened at 70 ° C for 5 hours. After cooling, the crude product was purified by silica gel gel chromatography using chloroform-form methanol (10: 1) as eluent to give the desired product (colorless solid) (1.895 ^ yield 91.9%). Obtained.
T L C [シリ力ゲル，クロロホルム一メタノ 一ル（5： 1 )]Rf =0.31 NMRC90 MHz, CDC13] δ :0.88(3Η), 1.27 (32Η), 2.20(6Η) , 2.39TLC [silica force gel, chloroform one methano Ichiru (5: 1)] Rf = 0.31 NMRC90 MHz, CDC1 3] δ: 0.88 (3Η), 1.27 (32Η), 2.20 (6Η), 2.39
(2Η), 3·02〜3.34(4Η), 3.43(3Η), 3.58(1Η), 4.16(4Η), 5.00(1Η)(2Η), 3.02 ~ 3.34 (4Η), 3.43 (3Η), 3.58 (1Η), 4.16 (4Η), 5.00 (1Η)
5.45C1H) (5.45C1H)
1 R [KBrjcni-1： 3300, 2925, 2850, 1695, 1535, 1470, 1280, 1260, 1115, 1075 1 R [KBrjcni- 1 : 3300, 2925, 2850, 1695, 1535, 1470, 1280, 1260, 1115, 1075
実施例 10 Example 10
2— 0—メチル一 1 — 0—ォクタデシルカルバモイルー 3 -0 - (2 ' ー ト リメチルァンモニォェチル）力ルバモイルグリセリ ン . ョージ ド  2—0—Methyl-1—0—Octadecylcarbamoyl 3--0- (2′-trimethylammonioethyl) Lubamoylglycerin.
O PI 実施例 9で製造したジメチルアミ ノ体 947mg(1.836ミ リモル）およびョ ゥ化メチル 339mg(2.387ミ リモル）をエーテル（20ml)に溶解し、 室温にて 2日間攪拌した。 折出した沈澱を泸取し、 クロ口ホルム—メタノ ール一 水（6 5： 2 5： 1 )を溶出液とするシリ力ゲルカラムクロマ トグラフィ一 にて精製して、 目的物（無色粉末） 897mg (収率 74.3%)を得た。 O PI 947 mg (1.836 mmol) of the dimethylamino compound produced in Example 9 and 339 mg (2.387 mmol) of methyl iodide were dissolved in ether (20 ml), and the mixture was stirred at room temperature for 2 days. The precipitated precipitate is collected and purified by silica gel column chromatography using chloroform-methanol-water (65: 25: 1) as an eluent to obtain the desired product (colorless powder). 897 mg (74.3% yield).
T L C [シリカゲル，クロ口ホルムーメタノ ール一水（6 5 : 2 5 :4 ): Rf=0.41  T L C [silica gel, black mouth formum methanol / water (65: 25: 4): Rf = 0.41
NMR[90 MHz, CDC13] 5 :0.89(3H), 1.27(32H), 3.13(2H), 3.50 (12H), 3.62 4.5K9H), 5.50(1H), 6.81(1H) NMR [90 MHz, CDC1 3] 5: 0.89 (3H), 1.27 (32H), 3.13 (2H), 3.50 (12H), 3.62 4.5K9H), 5.50 (1H), 6.81 (1H)
I RCKBrjctn-1: 3498, 2920, 2850, 1708, 1530, 1470, 1260 実施例 U -I RCKBrjctn- 1 : 3498, 2920, 2850, 1708, 1530, 1470, 1260 Example U-
3 - 0 - -—ハィ ドロキシェチル）力ルバモイルー 2— 0—メチル - 1 一 0—ォクタデシルカルバモイルグリセリ ン 3-0---Hydroxitytyl) Lubamoyl 2-0-Methyl-1 1-0-octadecylcarbamoylglycerin
2— 0—メチルー 1 -0-ォクタデシルカルバモイルグリもリ ン 3.213g (8 ミ リモル），ピリ ジン 1.266g(iSミ リモル），クロロ炭酸フエニル 1.378g (8.8ミ リモル），ジクロルメ タ ン（20ml)より 実施例 9と同様にして得ら れたカーボネー トをクロロホルム（16ml)に溶解し、 エタノ ールアミ ン 586mg(9.6ミ リモル）を加えて 1 5時間還流した。 反応液を濃縮乾.固し、 残渣をへキサン—舴酸ェチル（ 1 4)を溶出液とするシリカゲルカラム クロマトグラフィ—にて精製し、 目的物（無色固形物） 3.689g (収率 94.4 %)を得た。  2-0-Methyl-1-0-octadecylcarbamoylglycine is also 3.213 g (8 mimol) of phosphorus, 1.266 g (iS mimol) of pyridine, 1.378 g (8.8 mimol) of phenyl chlorocarbonate, dichloromethane ( From 20 ml), the carbonate obtained in the same manner as in Example 9 was dissolved in chloroform (16 ml), 586 mg (9.6 mmol) of ethanolamine was added, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated to dryness and the residue was purified. The residue was purified by silica gel column chromatography using hexane-ethyl acetate (14) as eluent to give 3.689 g of the desired product (colorless solid) (yield 94.4%) I got
T L C [シリカゲル，へキザン—詐酸ェチル（1 :4)]:Rf=0.19 T L C [silica gel, hexan-ethyl acetate (1: 4)]: Rf = 0.19
MR[90 MHz, CDC13] δ 0.88(3Η), 1.28(32Η), 3.00 3.80(10 MR [90 MHz, CDC1 3] δ 0.88 (3Η), 1.28 (32Η), 3.00 3.80 (10
Η), 4.18C4H), S.13(1H), 5.69(1Η) Η), 4.18C4H), S.13 (1H), 5.69 (1Η)
I RCKBrlcm-1: 3324, 2920, 2850, 1695, 1545, 1275 元素分折： C28 H52N206 I RCKBrlcm- 1: 3324, 2920, 2850, 1695, 1545, 1275 elemental folding: C 2 8 H 52 N 2 0 6
^ 算値： C .63.90; H.10.72: N.5.73 ^ Calculated: C .63.90; H.10.72: N.5.73
実測値： C, 63.57; H.10.73; N.5.84  Found: C, 63.57; H.10.73; N.5.84
実施例 12  Example 12
2 - 0 -メチルー 1— 0—ォク—タデシルカルバ ィル—一 3— 0—（ 2 ' -P- トルエンスルホニルォキシェチル）^ルバモイルグリセリ ン  2-0-Methyl-1-0-octa-tadecylcarbyl-1-3-0- (2'-P-toluenesulfonyloxexetil) ^ rubamoylglycerin
実施例 11で製造したアルコール体 3.539g(7.242ミ リモル）をトリェチ ルァミ ン（22mDに溶解し、 氷冷下に P— トルエンスルホニルクロライ ド 3.539 g (7.242 mimol) of the alcohol compound produced in Example 11 was dissolved in triethylamine (22 mD), and cooled to ice with P-toluenesulfonyl chloride.
1.793g(9.406ミ リモル）を加えた後、 室温にて 8時間攪拌した。 実施例 6と同様に処理し、 得られた粗生成物をへキサン一 S乍酸ェチル（1 ： 1 ) を溶出液とするシリカゲルカラムクロマトグラフィ一にて精製し、 目的 物（無色固形物） 4.039g (収率， 86.8%)を得た。 After adding 1.793 g (9.406 mimol), the mixture was stirred at room temperature for 8 hours. The crude product obtained was treated in the same manner as in Example 6 and purified by silica gel column chromatography using hexane-S-ethyl (1: 1) as an eluent to obtain the desired product (colorless solid). g (yield, 86.8%).
T L C [シリ力ゲル，へキサン—詐酸ェチル（1 ： I )]Rf = 0.21 MRC90 MHz, CDC ] δ： 0.88(3Η), 1.25(32Η), 2.43(3Η) , 3.16 - (2Η), 3.30~3.70(6Η), 4.13C6H), 4.-86(1Η), 5.2δ(1Η), 7.32(2Η)  TLC [silicone gel, hexane-ethyl acetate (1: I)] Rf = 0.21 MRC90 MHz, CDC] δ: 0.88 (3Η), 1.25 (32Η), 2.43 (3Η), 3.16-(2Η), 3.30 ~ 3.70 (6Η), 4.13C6H), 4.-86 (1Η), 5.2δ (1Η), 7.32 (2Η)
7.80C2H)  7.80C2H)
I R [KBrlcm-1: 3380, 2920, 2850, 1695, 1540, L468, 1365, ί260, 1180 IR (KBrlcm- 1 : 3380, 2920, 2850, 1695, 1540, L468, 1365, ί260, 1180
実施例 13  Example 13
3 - Ο -(2 ' ―ブロモェチル）力ルバモイル— 2— 0—メチル— 1 一 0—才クタデシルカル モイルグリセリ ン  3-Ο-(2'-bromoethyl) rubamoyl—2—0—methyl—10—10-year-old cutadecylcarmoylglycerin
実施例 12で製造したトシル体 3.88 （6.045ミ リモル）および臭化リチ ゥム（LiBr · H2O) 1.267g(12.089ミ リモル）ジメチルホルムァミ ド（37ml) に溶解し、 60°Cにて 42時間加熱した。 実施例 7と同様に処理して得られ た粗生成物をへキサン—舴酸ェチル（3： 2)を溶出液とするシリカゲル カラムクロマ トグラフィ一にて精製し、 目的物 [無色固形物] 3.10g (収率 93%)を得た。 T L C [シリ力ゲル.へキサン—昨酸ェチル（ 1 ： 1 )] :Rf = 0.45 Was dissolved in example 12 tosyl member was prepared in 3.88 (6.045 Mi Rimoru) and bromide lithium © beam (LiBr · H 2 O) 1.267g (12.089 Mi Rimoru) dimethylformamide § mi de (37 ml), to 60 ° C And heated for 42 hours. The crude product obtained in the same manner as in Example 7 was purified by silica gel column chromatography using hexane-ethyl acetate (3: 2) as an eluent, and the desired product [colorless solid] 3.10 g (93% yield). TLC [silicone gel. Hexane-ethyl ester (1: 1)]: Rf = 0.45
NMR [90 MHz, CDC ] δ： 0.88(3Η), 1.27 (32Η), 3.17(2Η) , 3.34 〜3.73(8H), 4.18C4H), 4.90(1Η), 5.40(1Η)  NMR [90 MHz, CDC] δ: 0.88 (3Η), 1.27 (32Η), 3.17 (2Η), 3.34 to 3.73 (8H), 4.18C4H), 4.90 (1Η), 5.40 (1Η)
1 RC Brlcm-1: 3330, 2920, 2850, 1695, 1540, 1470, 1310, 1275, 1152, 1120 1 RC Brlcm- 1 : 3330, 2920, 2850, 1695, 1540, 1470, 1310, 1275, 1152, 1120
元素分圻： C 28 Η5ι 205Br Elemental elements: C 28 Η 5 ι 2 0 5 Br
計算値： C, 56.61: Η.9.32; Ν ,5.08  Calculated: C, 56.61: Η.9.32; Ν, 5.08
実測値： C，56.38; H.9.28; N ,4.95 - 実施例 .  Found: C, 56.38; H.9.28; N, 4.95-Examples.
2— 0—メチル一 1 — 0—才クタデシルカルバモイル -3 -0 - (2 ' — チァゾリオェチル）力ルバモイルグリセリ ン ' ブロマイ ド  2—0—Methyl 1—0—Cutadecylcarbamoyl -3 -0- (2'-thiazolioethyl) potassium rubamoylglycerin'bromide
実施例 13で製造したブロム体 1.103g(2 ミ リモル）にチアゾール 681mg(8 ミ リモル）を加え、 にて 12時間加熱した。 反応液を濃縮乾固し、 残 渣は、 クロ口ホルムーメタノ —ルー水（65:25:1)を溶出液とするシリ力 ゲルカラムクロマ トグラフィ—にて精製し、 目的物 [淡褐色粉末 ]84'7mg (収 率 66.5%)を得た。  To 1.103 g (2 mmol) of the bromo compound produced in Example 13 was added 681 mg (8 mmol) of thiazole, and the mixture was heated at for 12 hours. The reaction mixture was concentrated to dryness, and the residue was purified by gel-column chromatography using gel-formum methano-lue water (65: 25: 1) as eluent. '7 mg (yield 66.5%) was obtained.
T L C [シリ力ゲル，酢酸ェチル—詐酸—水（3： 1 ： 1 )] :Rf = 0.34 NMR [90 MHz, CDC13] δ :0.88(3H), 1.25(32H), 3.12(2H), 3.40 - (3H), 3.68C1H), 3.82(2H), 4.15(4H), 5.06(2H), 5.48(1H) , 7.06 ' (1H), 8.38C1H), 8.68C1H), 10.74(1H) TLC [silica force gel, acetic Echiru -詐酸- water (3: 1: 1)] : Rf = 0.34 NMR [90 MHz, CDC1 3] δ: 0.88 (3H), 1.25 (32H), 3.12 (2H), 3.40-(3H), 3.68C1H), 3.82 (2H), 4.15 (4H), 5.06 (2H), 5.48 (1H), 7.06 '(1H), 8.38C1H), 8.68C1H), 10.74 (1H)
1 R [KBr^cm-1: 3370, 2920, 2850, 1702, 1534, 1470, 1255 実施例 15 1 R (KBr ^ cm- 1 : 3370, 2920, 2850, 1702, 1534, 1470, 1255 Example 15
2— 0—ベンジル一 1 ー 0—（2' — ト リ メチ アンモニォェチ ）力 ルバモイルー 3— 0—才クタデシルグリセリ ン · クロライ ド  2—0—Benzyl 1 1—0— (2′—trimethylammoniochi) force Lubamoyl 3—0—year-old kutadecylglycerin chloride
2— 0—ベンジル一 3— 0—ォクタデシルグリセリ ン 2.67g(6.14ミ リ モル）， 2—クロロェチルイソシァネ一 ト 0.84g( 8 ミ リモル）をジクロル  2.67 g (6.14 mmol) of 2--0-benzyl-3-octadecylglycerin and 0.84 g (8 mmol) of 2-chloroethylisocyanate in dichloromethane
OMP1 W1PO メタ ン（6 ml)に溶解し、 一夜室温にてかきまぜた。 反応液を減圧下に濃 縮乾固し、 残渣をクロロホルムを溶出液とするシリ力ゲルカラムクロマ トダラフィ一にて精製し、 得られたクロル体をさらに 20%トリメチルァ ミ ンー トルエン（20ml)に溶解し、 封管中、 160°C24時間加熟した。 反応 液を減圧下に濃縮乾固し、 残渣にアセ ト ン（iOml)を加えて洗い、 無色粉 末 2. Og (収率 85.0%)を得た。 OMP1 W1PO It was dissolved in methane (6 ml) and stirred overnight at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform as an eluent. The obtained chloro form was further dissolved in 20% trimethylamine-toluene (20 ml) Then, it was ripened in a sealed tube at 160 ° C for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was washed with acetate (iOml) to obtain colorless powder 2.Og (yield: 85.0%).
T L C [シリ力ゲル， n- Βιιθίί- AcOH-水（4 : 1 : 1 )] :Rf = 0.36  T L C [silicone gel, n-Βιιθίί-AcOH-water (4: 1: 1)]: Rf = 0.36
I R [KBr]cm→: 3350, 2930, 2850, 1725, 1465, 1250, 1120 , 1060 IR [KBr] cm → : 3350, 2930, 2850, 1725, 1465, 1250, 1120, 1060
実施例 16 Example 16
1 一 O—（2' — ト リメチルアンモニォェチル）カルパ乇ィルー 3— 0 —ォクタデシルグリセリ ン · クロライ ド  1 1 O— (2 '— trimethylammonioethyl) carpiryl 3 — 0 — octadecylglycerin chloride
実施例 15で得たベンジル体 2.0g(3.34ミ リモル）を 70%酢酸（30ml)に溶 解し、 10%パラジウム炭素 200mgを加え、 水素気流中、 4時間激しくか きまぜた。 不溶物を泸去し、 母液は減圧下に濃縮乾固し、 残渣をクロ口 ホルムーアセ ト ン（ i : 1 )(10ml)より熟時再結晶し、 無色結晶性粉末 1.7 g (収率 100%)を得た。 2.0 g (3.34 mmol) of the benzyl compound obtained in Example 15 was dissolved in 70% acetic acid (30 ml), 200 mg of 10% palladium carbon was added, and the mixture was vigorously stirred in a stream of hydrogen for 4 hours. The insolubles were removed, the mother liquor was concentrated to dryness under reduced pressure, and the residue was recrystallized from form-mouth moiecetone (i : 1) (10 ml) when matured to give 1.7 g of a colorless crystalline powder (100% yield). ).
T L C [シリ力ゲル， n- BuOH- AcOH-水（4： 1 ： 1 )]： R f = 0.21  TLC [silicone gel, n-BuOH-AcOH-water (4: 1: 1)]: Rf = 0.21
1 R [KBrJcm-1: 3400, 2935, 2850, 1710, 1530, 1480, 1270, 1130, 960 1 R [KBrJcm- 1 : 3400, 2935, 2850, 1710, 1530, 1480, 1270, 1130, 960
実施例 17 Example 17
2—〇ーメチルカルノく ィル— 1 - 0 - (2 , ニト リ—メ ル―ァンーモ二 ^エ^/)力—ルバモイル一 3— 0—ォクタデシルグリセリ ン . クロライ 上  2-Permethylcarnoyl-1-0-(2, nitrile-m-ammoni ^ e ^ /) force-rubamoyl-3-0-octadecylglycerin.
実施例 16で得たハイ ドロキシ体 200nig (0.39ミ リモル）をピリ ジン (2 ml),クロ口ホルム（ 1 ml)の混液に溶解し、 メチルイソシァネー ト 600  200 nig (0.39 mimol) of the hydroxy compound obtained in Example 16 was dissolved in a mixture of pyridin (2 ml) and chloroform (1 ml), and methyl isocyanate 600 was dissolved.
OO
vsI'C mgを加え、 50°Cで一夜かきまぜた。 反応液を减圧下に濃縮乾固し、 残渣 をクロ口ホルム（0.5ml)，ァセトン（5 ml)の混液より熟時再結晶し、 目的 物（無色粉末） i98mgを得た。 vsI'C mg and stirred overnight at 50 ° C. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from a mixture of chloroform (0.5 ml) and acetone (5 ml) when matured to obtain i98 mg of the desired product (colorless powder).
T L C [シリカゲル，n-BuOH- AcOH-水（4 : 1 : 1 )]:Rf = 0.21  T LC [silica gel, n-BuOH-AcOH-water (4: 1: 1)]: Rf = 0.21
I RCKBrlcm-1: 3400, 2920, 2850, 1720, 1540, 1470, 1270, 1155, 1125, 770 I RCKBrlcm- 1 : 3400, 2920, 2850, 1720, 1540, 1470, 1270, 1155, 1125, 770
NMR[60 MHz, CDC13] <5： 0.88(3H) , 1.25(32H), 2.78(3H), 3.10 -4.00C15H), 4.28C4H), 4.07(1H), 5.72(2H) NMR [60 MHz, CDC1 3] <5: 0.88 (3H), 1.25 (32H), 2.78 (3H), 3.10 -4.00C15H), 4.28C4H), 4.07 (1H), 5.72 (2H)
元素分圻： C23He。N305 Cl * 3 H20 Elemental圻: C 23 H e. N 3 0 5 Cl * 3 H 2 0
計算値： C, 56.15; H.10.72; N.6.77  Calculated: C, 56.15; H.10.72; N.6.77
実測値： C, 56.25; H.10.40; N.6.99  Found: C, 56.25; H.10.40; N.6.99
実施例 18 Example 18
1 —ォクタデシルォキシ一 2—ァセ トアミ ド一 3—（2' —ジメチル ア ミ—ノェチル）力ルバモイルォキンプロパン  1—Octadecyloxy 2—Acetamide 1— (2′—Dimethylamino-noethyl)
i ) 3—才クタデシルォキシー 2—ァミ ノプロパン一 1 —オール 1 — 0—ォクタデシルー 2— 0— ト シル一 3— 0— ト リチルグリセ口 —ル 8.67g(11.7ミ リモル）にベンジルァミ ン（12ml)を加え、 120° で 8時 間加熱したのち、 減圧下、 過剰のベンジルアミ ンを留去した。 残渣に η -へキサンを加えて不溶物を泸去し、 炉液は濃縮乾固した。 残渣に 70% 胙酸（5Qml)を加えて 1Q(TC、 2時間加熱かくはんした。 冷後、 圻出結晶 を泸去し、 泸液にパラジウム炭素を加えて接触還元した後、 泸過、 濃縮 乾固した。 残渣をクロ口ホルムに溶解し、 重曹水で洗った後、 乾燥、 濃 縮し、 シリカゲルクロマ トグラフィーによつて精製した（溶出液，クロ口 ホルムーメタノ —ル（10: 1 ))。 目的物（無色粉末） 3.13g (収率 78%)を得 た。  i) 3-octadecyloxy 2-aminopropane 1-1-all-1-0-octadecyl-2-0-tosyl 1-3-0-tritylglycerol-8.67 g (11.7 mimol) in benzylamine ( 12 ml), and the mixture was heated at 120 ° for 8 hours, and then excess benzylamine was distilled off under reduced pressure. Η-Hexane was added to the residue to remove insolubles, and the filtrate was concentrated to dryness. 70% shaoic acid (5Qml) was added to the residue, and the mixture was stirred under heating for 1Q (TC, 2 hours.) After cooling, the kiide crystals were removed, and palladium on carbon was added to the solution for catalytic reduction, followed by filtration and concentration. The residue was dissolved in chloroform, washed with aqueous sodium bicarbonate, dried, concentrated, and purified by silica gel chromatography (eluent, chloroform: formanol (10: 1)). 3.13 g (78% yield) of the desired product (colorless powder) was obtained.
I R [KBr!!cnT1： 3330, 2925, 2850, 1580, 1470, 1370, 1120, IR [KBr !! cnT 1 : 3330, 2925, 2850, 1580, 1470, 1370, 1120,
差換え 1070, 1040, 722 Replacement 1070, 1040, 722
NMR[90 MHz, CDC13] 5 : 0.87(3H,t), 1.25(32H, m) , 3.05(lH,m), 3.4lC2H,d), 3.42(2H,t), 3.5〜3.7(2H,m) NMR [90 MHz, CDC1 3] 5: 0.87 (3H, t), 1.25 (32H, m), 3.05 (lH, m), 3.4lC2H, d), 3.42 (2H, t), 3.5~3.7 (2H, m)
ii ) 3—才クタデシルォキシー 2—ァセトアミ ドプロパン一 1 -ォ 一ル  ii) 3—Kutadecyloxy 2-Acetamide dopropane 1-ol
前記ァミノアルコ-ル体 857.5mg(2.5ミ リモル），ァセチルクロリ ド 197mg (2.5ミ リモル）， 4 -ジメチルァミ ノ ピリジン 305mg(2.5ミ リモル）をク口 口ホルム（35ml)に溶解し、室温で 28時間かきまぜた。反応液を減圧下に濃 縮乾固し、残渣をシリカゲルクロマトグラフィ -で精製し、（溶出液、クロ σホルム-メタノ -ル， 20:1),目的物（無色粉末） 868nig (収率 90%)を得た。  857.5 mg (2.5 mmol) of the above-mentioned amino alcohol, 197 mg (2.5 mmol) of acetyl chloride and 305 mg (2.5 mmol) of 4-dimethylaminopyridine were dissolved in 35 ml of porcine and stirred at room temperature for 28 hours. Was. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel chromatography-(eluent, chloroform-methanol, 20: 1), the desired product (colorless powder) 868nig (90% yield) ).
NMR [90 MHz, CDC13] <5： 0.87(3H, t) , 1.-25(32H,m) , 2.01(3H, s) , 2.9 (lH),3.43(2H,t), 3.60(2H,d),3.77(2H,ni)I4.05(lH,m),6.1(lH,br,NH) NMR [90 MHz, CDC1 3] <5: 0.87 (3H, t), 1.-25 (32H, m), 2.01 (3H, s), 2.9 (lH), 3.43 (2H, t), 3.60 (2H , d), 3.77 (2H, ni) I 4.05 (lH, m), 6.1 (lH, br, NH)
- iii ) 1—ォクタデシルォキシ一 2—ァセトァ.ミ ドー 3—（ 2 ' —ジメチ ルァミソェチル)力ルバ乇ィルォキシプロパン -iii) 1-octadecyloxy 2--2-acetamide. 3- (2'-dimethylmethamisethyl) power
前記アルコール体 385mg( 1 ミ リモル），ピリジン 158oig(2ミ リモル）を ジクロルメタン（10ml)に溶解し、 氷冷下、 クロ口炭酸フエニル 156mg  385 mg (1 mmol) of the alcohol and 158 oig (2 mmol) of pyridine were dissolved in dichloromethane (10 ml), and the mixture was cooled under ice-cooling.
(1 ミ リモル）を加えた。 室 ¾にて 1時間かきまぜた後、 反応液にクロ口 ホルム、 水を加えて分液し、 有機層を希塩酸、 重曹水で洗い、 乾燥、 濃 縮してフエニル炭酸エステル体を得た。 炭酸エステル体を asym.—ジメ チルエチレンジァミ ン（1.5ml)に溶解し、 70て、 4時間加熟した。 反応 液をシリカゲルクロマトダラフィ一に付して精製し（溶出液、 クロロホ ルムーメタノール， 5： 1 )，目的物（無色粉末） 360mg (収率， 72%)を得た。  (1 mimol) was added. After stirring for 1 hour in the chamber, the reaction mixture was separated by adding chloroform and water, and the organic layer was washed with dilute hydrochloric acid and aqueous sodium hydrogen carbonate, dried and concentrated to obtain a phenyl carbonate ester. The carbonate was dissolved in asym.-dimethylethylenediamine (1.5 ml), and the mixture was ripened for 4 hours. The reaction solution was purified by silica gel chromatography (eluent, chloroformumethanol, 5: 1) to obtain 360 mg of the desired product (colorless powder) (yield, 72%).
I R [KBr]cm-1: 3330, 3280, 2920, 2850, 1695, 1655, 1462, 1378, 1310, 1278, 1130 IR [KBr] cm- 1 : 3330, 3280, 2920, 2850, 1695, 1655, 1462, 1378, 1310, 1278, 1130
NMRC90 MHz, CDC13] 5： 0.87(3H, t) , 1.25(32H,m) , 1.97(3H,s), NMRC90 MHz, CDC1 3] 5: 0.87 (3H, t), 1.25 (32H, m), 1.97 (3H, s),
2.20(6H,s,NMe2), 2.38(2H，t)， 3.1-3.5(4H, in) , 3.40(2H,t), 4.0 2.20 (6H, s, NMe 2 ), 2.38 (2H, t), 3.1-3.5 (4H, in), 3.40 (2H, t), 4.0
差摔ぇ し 一0が ·Ρ1 - ClH.m), 4.17(2H,m)( 5.2,6.0(NH) Sa摔E and 10 is · Ρ1 - ClH.m), 4.17 (2H, m) ( 5.2,6.0 (NH)
T L C [シリ力ゲル， CHC13- MeOH, δ： 1 ] :Rf = 0.20 TLC [silica force gel, CHC1 3 - MeOH, δ: 1]: Rf = 0.20
実施例 19 Example 19
1 —ォクタデシルォキシ一 2—ァセトアミ ドー 3 -一（ 2 ' 一 卜リメ ±_ ルアンモニォェチル）力ルバ乇ィルォキシプロパン . ョージ ド  1—Octadecyloxy 2—Acetamido 3-3-1 (2'1 Trime ± _ Luangmonyeotyl) Power
実施例丄 8で得られたジメチルァミ ノ体 300mg(0.6ミ リモル）をエーテル (30ml)，グ σ口ホルム（3 ml)の混液に溶解し、 ヨウ化メチル 420tng( 3 ミ リモル）を加えて、 室温で 1 日かきまぜた。 圻出した粉末を泸取して、 エーテル—クロ口ホルム混液で洗い、 目的物（無色粉末） 258mg (収率 67%) を得た。  300 mg (0.6 mmol) of the dimethylamino compound obtained in Example 8 was dissolved in a mixture of ether (30 ml) and σ-mouth form (3 ml), and 420 tng (3 mmol) of methyl iodide was added thereto. Stir for one day at room temperature. The powder thus obtained was collected and washed with a mixed solution of ether and black mouth to obtain 258 mg of the desired product (colorless powder) (yield 67%).
I R[KBr]cm-1:3470, 3620. 2920, 2850, 1715, 1665, 1645, 1530, 1470, 1380, 1260, 〖120, 970, 920, 720,IR [KBr] cm- 1 : 3470, 3620. 2920, 2850, 1715, 1665, 1645, 1530, 1470, 1380, 1260, 〖120, 970, 970, 920, 720,
MR[90 MHz, CDC13 <5： 0.87(3H,t), 1.2δ(32Η, m) , 2.00(3H,s, HAc), 3.43(9H,s,¾e3), 3. 0 (2H, t , CH20) , 3.65〜4.0(4H, m) ,MR [90 MHz, CDC1 3 <5: 0.87 (3H, t), 1.2δ (32Η, m), 2.00 (3H, s, HAc), 3.43 (9H, s, ¾e 3 ), 3.0 (2H, t, CH 2 0), 3.65 ~ 4.0 (4H, m),
4.0〜4.35(3H.m, CHN,CH20C0) 4.0~4.35 (3H.m, CHN, CH 2 0C0)
実施例 20 Example 20
1 ーォクタデシルォキシ— —ァセトアミ — 3—「N—ァセチル一 - ( 2 ー トリメチルァンモニォェチル）]力ルバモイルォキシプロパ ン · ョ一ジド  1-octadecyloxy——acetami —3— “N-acetyl- (2-trimethylammonioethyl)] force rubamoyloxypropane
ί ) 1—ォクタデシルオキン一 2—フタルイミ ド一 3—フエノキー ルホ^ルォキシプロパン  ί) 1-octadecyl oxine 2- phthalimid 3-phenoky
3—才クタデシルォキシー 2—フタルイ ミ ドプロパン一 1 一オール 950mg(2 ミ リモル）をジクロルメタン（20mi)に溶解し、 氷冷下ピリ ジン 316mg( ミ リモル）およびクロル炭酸フエニル 313mg(2 ミ リモル）を加え た。氷冷下で 15分、 室温で 45分かきまぜた後、 反応液にクロ口ホルム（40 ml) を加えて、 希塩酸，重曹水で洗い、 乾燥，濃縮して目的の炭酸エステ  950 mg (2 mmol) of 3-octadecyloxy-2-phthalimidopropane-1-ol are dissolved in dichloromethane (20 mi), and 316 mg (pyridine) of pyridine and 313 mg (2 mmol) of phenylcarbonate are dissolved under ice-cooling. ) Was added. After stirring under ice-cooling for 15 minutes and at room temperature for 45 minutes, add chloroform (40 ml) to the reaction mixture, wash with dilute hydrochloric acid and aqueous sodium bicarbonate, dry, and concentrate to obtain the desired carbonate ester.
v-'n ο ル体を得た。 なお、 原料として用いた 3—ォクタデシルォキシ— 2—フタルイ ミ ド プロパン— 1 —オールは、 実施例 18— i )で得た 3—ォクタデシルォキ シ一 2—ァミノ プロパン一 1一オールにカルボエトキシフタ一ルイ ミ ド を反応させて合成した。 v-'n ο I got a body. The 3-octadecyloxy-2-phthalimid propane-1-ol used as a raw material was converted to carboxy- 3-octadecyloxy-2-aminopropane-1-ol obtained in Example 18-i). It was synthesized by reacting ethoxyphthalimide.
ϋ ) 1 ーォクタデシルォキン一 2—ァミ ノ 一 3— ( 2 ' — Ν , Ν—ジ チルアミノェチル）力ルバ乇ィルォキシプロパン  1) 1-octadecyl-quinone 2-amino-1 3- (2'-Ν, Ν-dimethylaminoethyl)
前記炭酸エステル体を asym. —ジメチルエチレンジアミ ン（2 ml)に溶 解し、 70° , 4時間かきまぜた。 反応液に n—へキサンを加えて不溶物を 泸去し、 泸液をシリカゲルクロマトグラフィーで精製した（溶出液，ク口 口ホルム—メタノ ール—水， 65:25 : 4)。 目的物（無色固体） 466mgを得た。  The carbonate was dissolved in asym.-dimethylethylenediamine (2 ml) and stirred at 70 ° for 4 hours. N-hexane was added to the reaction solution to remove insolubles, and the solution was purified by silica gel chromatography (eluent, octaform-methanol-water, 65: 25: 4). 466 mg of the desired product (colorless solid) was obtained.
T L C [シリ力ゲル， CHC13- MeOH-水， 65: 25:4):Rf=0.2 -TLC [silica force gel, CHC1 3 - MeOH-water, 65: 25: 4): Rf = 0.2 -
I R [KBrlcm-1: 3330, 2920, 2850, 1690, 1550, 1465, 127-8, 1130, 1030 IR [KBrlcm -1 : 3330, 2920, 2850, 1690, 1550, 1465, 127-8, 1130, 1030
iii)" 1 —ォクタデシルォキシ 2 -ァセトアミ ド一 3 - [Ν—ァセチ ルー Ν— (2' —ジメチルァミ ノェチル）]力ルバモイルォキシプロパン  iii) "1 —Octadecyloxy 2-acetamide 3- 3- [Ν-acetyl チ-(2'-dimethylaminoethyl)] potassium oxypropane
前記の方法で得た 2—ァミノ体 175mgをクロ口ホルム（3 ml)に溶解し、 トリェチルァミ ン（ 1 ml),無水詐酸（0.3ml)を加えて室温で 1夜かきまぜ た。 反応液を濃縮し、 シリカゲルクロマトグラフィーで精製した（溶出 液，クロ口ホルム一メタノール， 10 ： 1 ) 。目的物（無色固体）を 148mg得 た。  175 mg of the 2-amino compound obtained by the above method was dissolved in chloroform (3 ml), and triethylamine (1 ml) and anhydrous acid (0.3 ml) were added thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated and purified by silica gel chromatography (eluent, chloroform-methanol, 10: 1). 148 mg of the desired product (colorless solid) was obtained.
I R [KBrlcm-1: 3280, 2920, 2850, 1740, 1715, 1655, 1550, 1470, 1370, 1300, 1250, 1185, 1130, 980 IR (KBrlcm- 1 : 3280, 2920, 2850, 1740, 1715, 1655, 1550, 1470, 1370, 1300, 1250, 1185, 1130, 980
NMRC90 MHz, CDC13] δ： 0.87(3H,t), 1.25(32H, m) , 2.00(3H,s), 2.45(6H,s), 2.50(3H,s), 2.68(2H,t), 3.3-3.6(4H, m) , 3.98(2H, t) 4.15~4.60(3H,ni) NMRC90 MHz, CDC1 3] δ: 0.87 (3H, t), 1.25 (32H, m), 2.00 (3H, s), 2.45 (6H, s), 2.50 (3H, s), 2.68 (2H, t), 3.3-3.6 (4H, m), 3.98 (2H, t) 4.15 ~ 4.60 (3H, ni)
''
- -! ¾ - OA1PI iv) 〖 一才クタデシルォキン— 2二アセ ト ^ _ミ ド— 3—「N—ァセチ— ル— N—（2' — ト リメチルアンモニォェチル）]力ルバモイルォキシプ · αパ_ン . ジ ド --! ¾-OA1PI iv) 〖One-year-old Kutadecyloquin—22 Acetate ^ _Mid—3— “N-Acetyl—N— (2′—Trimethylammonioethyl)] Gid
前記化合物 138mgをエーテル（5 ml)に溶解し、 ョゥ化メチル 109mgを加 えた。 室温で 1夜攪拌し、 冷時，折出固体を泸取した。目的物（無色粉末） 141mgを得た。  138 mg of the above compound was dissolved in ether (5 ml), and 109 mg of methyl iodide was added. The mixture was stirred at room temperature overnight, and when cooled, the solids were collected. 141 mg of the desired product (colorless powder) was obtained.
1 R [ Brlcni-1: 3450, '2920, 2850. 1755, 1670, 1540, 1470, 1375, 1260, 1205, 11651 R [Brlcni- 1 : 3450, '2920, 2850. 1755, 1670, 1540, 1470, 1375, 1260, 1205, 1165
MR [90 MHz, CDC13] δ： 0.87(3H,t), 1.25(32H( m) , 2.03(3H,s), 2.52(3H,s), 3.45(9H,s), 3.3〜3.7(4H, m)， 3.7〜4.0(2H,m) , 4.07 ~4.3(2H,m), 4.4〜4.6(3H,m) MR [90 MHz, CDC1 3] δ: 0.87 (3H, t), 1.25 (32H (m), 2.03 (3H, s), 2.52 (3H, s), 3.45 (9H, s), 3.3~3.7 (4H , m), 3.7 to 4.0 (2H, m), 4.07 to 4.3 (2H, m), 4.4 to 4.6 (3H, m)
実施例 21 Example 21
2— 0—ジメチルカルバモイルー 1 — 0—ォクタデシルー 3— 0—（N - 2 ' 一 ト リメチルアンモニォェチル）力ルバ乇ィルグリセ ン プロ マイ ド  2—0—Dimethylcarbamoyl 1—0—Octadecyl 3-—0— (N-2'-trimethylammonioethyl) Lubaylglycine Promide
i ) 3— 0—（2' —プロモェチル）力ルバモイル— 1— 0—ォクタ デシルグリセリ ン  i) 3—0— (2′—promoethyl) Lubamoyl—1—0—octadecylglycerin
2一ベンジル— 3— 0— (2' —ブロモェチル）力ルバモイルー 1 —ォ クタデシルグリセリ ン（実施例 Ίで合成） 949mg[i.623ミ リモル]及び 10%、 Pd/C 250mgに 90%詐酸水溶液 40mlを加え、 室温にて 2時間 ' hydrogenolysisを行う。 触媒を^別後、 母液を減圧濃縮し残渣に n -へ キサン一昨酸ェチル （2： 1 )溶液を加えて沈殿を泸取し、 アルコール体 [無色粉末] 785mg(97.8%)を得た。  2-Mono-benzyl-3-0- (2'-bromoethyl) potassium 1-octadecylglycerin (synthesized in Example Ί) 949 mg [i.623 mimol] and 10%, 90% in Pd / C 250 mg Add 40 ml of acid aqueous solution and perform hydrogenolysis at room temperature for 2 hours. After the catalyst was separated, the mother liquor was concentrated under reduced pressure, and the residue was added with n-hexane ethyl acetic acid (2: 1) solution and the precipitate was collected to obtain 785 mg (97.8%) of an alcohol [colorless powder]. .
T L C [シリ力ゲル；n—へキサン一酢酸ェチル（1 ： 1 )]:Rf = 0.43 T L C [silicone gel; n-ethyl hexyl monoacetate (1: 1)]: Rf = 0.43
NMR[90 MHz, CDC13] 5： 0.88(3H,t), 1.24(32H,s), 2.85(lH,br. d), 3.31~3.72(8H,m), 4.00(lH,m), 4.17(2H,m), 5.33(lH,br.) NMR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.24 (32H, s), 2.85 (. LH, br d), 3.31 ~ 3.72 (8H, m), 4.00 (lH, m), 4.17 (2H, m), 5.33 (lH, br.)
OWPI I R [KBrlcm-1: 3415, 3305, 2920, 2850, 1698, 1562, 1465, 1285 OWPI IR (KBrlcm -1 : 3415, 3305, 2920, 2850, 1698, 1562, 1465, 1285
ii ) 3— 0— (2' —ブロモェチル）力ルバモイル— 2— 0—ジメチ ルカルバモイルー 1 一 0—ォクタデシルグリセリ ン  ii) 3— 0— (2′—bromoethyl) rubamoyl— 2— 0—Dimethylcarbamoyl— 1 0—Octadecylglycerin
i )で得たアルコ―ル体 495mg[ 1 ミ リモル]及びピリ ジン 158mg[2 ミ リ モル]を塩化メチレン 3 mlに溶解し、 氷冷下フエニルク口口ホルメ一 ト 172mg[l.lミ リモル]の CH2C12 溶液（ 1 ml)を加えた後、 室温にて 2.5時間 攪拌する。 常法処理の後、 粗カーボネ― ト 811mgを得た。 495 mg [1 mimol] of the alcohol form obtained in i) and 158 mg [2 mimol] of pyridine were dissolved in 3 ml of methylene chloride, and 172 mg [ll mimol] of the form of the phenylc mouth were cooled under ice-cooling. after addition of CH 2 C1 2 solution (1 ml), stirred at room temperature for 2.5 hours. After the usual treatment, 811 mg of crude carbonate was obtained.
この粗カーボネー 卜のトルエン溶液（4 ml)に 20%ジメチルァミ ン/卜 ルェン溶液 l mlを加え、 室温にて 2時間放置した。 反応液を滅圧濃縮し、 得られた粗生成物をカラムクロマトグラフィ一 [シリカゲル： 25g;溶出液 :n—へキサンー舴酸ェチル（2： 1：)]にて精製し、 ジメチルカルバモイル 体 [無色固体], 473mg[83.6%]を得た。  To a toluene solution (4 ml) of this crude carbonate was added 1 ml of a 20% dimethylamine / triene solution, and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by column chromatography [silica gel: 25 g; eluent: n-hexane-ethyl ester (2: 1 :)] to give a dimethylcarbamoyl compound [colorless] 473 mg [83.6%].
T L C [シリ力ゲル； n—べキサン— 酸ェチル（2： 1 )] :Rf=0.22 T L C [silicone gel; n-hexane-ethyl ester (2: 1)]: Rf = 0.22
NMRC90 MHz, CDC13]<5 : 0.88(3H,t), 1.24(32H,s), 2.90(6H,s), 3.33〜3.72(8H,m), 4.30(2H,m), 5.05(1H, quint) , 5.22(lH,br) NMRC90 MHz, CDC1 3] <5 : 0.88 (3H, t), 1.24 (32H, s), 2.90 (6H, s), 3.33~3.72 (8H, m), 4.30 (2H, m), 5.05 (1H, quint), 5.22 (lH, br)
I R [KBrJctn-1： 3325, 2920, 2850, 1710, 154 , 1470, 1262, 1200, 1123 IR [KBrJctn- 1 : 3325, 2920, 2850, 1710, 154, 1470, 1262, 1200, 1123
iii) 2— 0—ジメチルカルバモイル一 1 — 0—ォクタデシルー 3— 0 - (2 ' 一 トリメチルアンモニォェチル）力ルバモイルグリセリ ン ブ ロマイ ド  iii) 2-0-dimethylcarbamoyl-1--1-0-octadecyl 3--0- (2'-trimethylammonioethyl) rubumoylglycerol bromide
ii)で得たジメチルカルバモイル体 175mg[0.309ミ リモル]を 20%トリ メチルアミ ン /トルエン溶液 5 mlに溶解し、 室温にて 4 日間放置した。 圻出した沈殿を泸取し、 目的物 [無色粉末] 167mg[83.8%]を得た。  175 mg [0.309 mimol] of the dimethylcarbamoyl derivative obtained in ii) was dissolved in 5 ml of a 20% trimethylamine / toluene solution, and left at room temperature for 4 days. The resulting precipitate was collected to give 167 mg [83.8%] of the desired product [colorless powder].
T L C [シリカゲル；詐酸ェチルー酢酸一水（3 : 1 ： 1 ):Rf = 0,47 NMR[90 MHz, CDC13](5 : 0.88(3H,t), 1.23(32H,s), 2.89(6H,s), * 3.30~3.63(13H,m), 3.80(4H, br.) , 4.28(2H,m), 5.03(1H, br . ) , 6.79 (lH.br.) TLC [silica gel;詐酸Echiru acetate monohydrate (3: 1: 1): Rf = 0,47 NMR [90 MHz, CDC1 3] (5: 0.88 (3H, t), 1.23 (32H, s), 2.89 ( 6H, s), * 3.30 to 3.63 (13H, m), 3.80 (4H, br.), 4.28 (2H, m), 5.03 (1H, br.), 6.79 (lH.br.)
1 R [KBrlcm-1： 3275, 2920, 2850, 1719, 1693, 1555, 1472, 1405, 1275, 1200 1 R [KBrlcm- 1 : 3275, 2920, 2850, 1719, 1693, 1555, 1472, 1405, 1275, 1200
実施例 22  Example 22
2— 0—ジメチルカルバモイル— 1— 0—才クタデシル 3 -0 - (2 ' 一チアゾリォェチル）力ルバモイルグリセリ ン ブロマイ ド  2—0—Dimethylcarbamoyl—1—0—Tactadecyl 3--0- (2′-thiazolyoethyl) rubamoylglycerin bromide
実施例 21- ii )で得たジメチルカルバモイル体 235mg[0.415ミ リモル]に チアゾ-ル 2mlを加え、 窒素気流中 110°Cにて 7時間加熟した。 反 £液 を減圧濃縮し、 粗生成物をカラムクロマ トグラフィ— [シリカゲル： 13g; 溶出液：クロ口ホルム—メタノ —ルー水 （65:25:1)]にて精製し、 目的物 [無色粉末] 212mg[78.5%]を得た。  To 235 mg [0.415 mimol] of the dimethylcarbamoyl derivative obtained in Example 21-ii), 2 ml of thiazole was added, and the mixture was ripened in a nitrogen stream at 110 ° C for 7 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography [silica gel: 13 g; eluent: chloroform-methanol-lu-water (65: 25: 1)] to give the desired product [colorless powder] 212 mg [78.5%] was obtained.
- T L C [シリ力ゲル；酢酸ェチル—酢酸一水（3 : 1 : 1 )] :Rf = 0.52 MRC90 MHz, CDC13] (5： 0.87(3H,t), 1.23(32H,s), 2.90(6H,s), 3.30~3.60(4H,m), 3.64-4.40(4H,m) , 5.02(3H, br . ) , 6.80(lH,br. 0, 8.29(lH,br), 8.72(lH,br), 10.77(lH,br) - TLC [silica force gel; acetate Echiru - acid mono (3: 1: 1)] : Rf = 0.52 MRC90 MHz, CDC1 3] (5: 0.87 (3H, t), 1.23 (32H, s), 2.90 ( 6H, s), 3.30-3.60 (4H, m), 3.64-4.40 (4H, m), 5.02 (3H, br.), 6.80 (lH, br.0, 8.29 (lH, br), 8.72 (lH, br), 10.77 (lH, br)
I R [ Br]cm-1: 3400, 2920, 2850, 1703, 1530, 1470, 1400, 1260, 1200 IR [Br] cm- 1 : 3400, 2920, 2850, 1703, 1530, 1470, 1400, 1260, 1200
実施例 23  Example 23
2— 0—ァセチルー 1 — 0—才クタデシルー 3— 0— (2' — ト リメ チルァンモニォェチル）力ルバモイルグリセリ ン ブロマイ ド  2—0—Acetyl- 1—0—Kitadecyl 3—0— (2'—Trime tyranmonyoethyl) Lubamoylglycerin bromide
i ) 2— 0—ァセチルー 3— 0— (2 ' —プロモェチル）力ルバモイ ル一 1 一 0—才クタデシルグリセリ ン  i) 2—0—acetyl—3—0— (2'—promoethyl) Lubamoyl 1 1 0—year-old kutadecylglycerin
実施例 21- ί )で合成したアルコ—ル体 124mg[Q.25ミ リモル]を CHC13 3 mlに溶解し、 ピリ ジン 2.5ml,無水酢酸 0.4mlを加えた後、 室温にて 13 時間放置した。 反応液にェチルェ—テルを加え、 5 %NaHC03水溶液及び Example 21- ί) synthesized in the alcohol - Le body 124mg [Q.25 Mi Rimoru] was dissolved in CHC1 3 3 ml, after adding pyridinium Gin 2.5 ml, acetic anhydride 0.4 ml, allowed to stand at room temperature for 13 hours did. Echirue the reaction solution - ether was added, 5% NaHC0 3 solution and
O P1 5 %塩酸水溶液にて洗浄し有機層は硫酸マグネシゥムにて乾燥後、 溶媒 を減圧留去。 得られた粗生成物をカラムクロマトグラフィ— [シリカゲ ル： 4 g;溶出液： n—へキサン—胙酸ェチル（4： 1：)]にて精製し、 ァセチ ル体 [無色シロップ] 117mg[87.2%]を得た。 O P1 After washing with a 5% aqueous hydrochloric acid solution and drying the organic layer with magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography— [silica gel: 4 g; eluent: n-hexane-ethyl ethyl pyranate (4: 1 :)], and the acetyl group [colorless syrup] 117 mg [87.2] %].
T L C [シリ力ゲル； n—へキサン—酢酸ェチル（2 ： 1 )]:Rf=0.44  T L C [silica gel; n-hexane-ethyl acetate (2: 1)]: Rf = 0.44
NMR[90 MHz, CDC13] 5： 0.89(3H,t), 1.27(32H,s), 2.08(3H,s), 3.35~3.73(8H,m), 4.28(2H,m)， . 5· 04〜5.41(2H,ni) NMR [90 MHz, CDC1 3] 5:. 0.89 (3H, t), 1.27 (32H, s), 2.08 (3H, s), 3.35 ~ 3.73 (8H, m), 4.28 (2H, m), 5 · 04〜5.41 (2H, ni)
I R [filmjcm-1: 3325, 2910, 2840, 1735, 1700, 1530, 1465, 1368, 1125 . IR (filmjcm- 1 : 3325, 2910, 2840, 1735, 1700, 1530, 1465, 1368, 1125.
ii ) 2— 0—ァセチル一 1 — 0—ォクタデシルー 3— 0— (2' — ト リメチルァンモニォェチル）力ルバモイルグリセリ ン プロマイ ド  ii) 2—0—Acetyl 1—0—Octadecyl-3—0— (2′—Trimethylammonioethyl) Lubamoylglycerin Promide
i )で合成したァセチル体， 115mg[0.2Uミ リモル]をトルエン 2m こ溶 解し、 20%トリメチルァミ ン/トルエン溶液 4miを加えた後、 室温にて2 日間放置した。 溶媒を减圧留去し、 残渣をクロ口ホルム—ェチルェ— テルより再沈澱し、 目的物 [無色粉末] 120mg[94.1%]を得た。  115 mg [0.2 U mimol] of the acetyl compound synthesized in i) was dissolved in 2 m of toluene, 4 mi of a 20% trimethylamine / toluene solution was added, and the mixture was allowed to stand at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was re-precipitated from chloroform-ethyl ether to obtain 120 mg [94.1%] of the target compound [colorless powder].
T L C [シリカゲル；詐酸ェチルー 乍酸—水（3 : 1 : 1 )]:Rf=0.62 TLC [silica gel; acid ethyl-water-water (3: 1: 1)]: Rf = 0.62
MRT30 MHz, CDC ] (5： 0.87(3H,t). L 25(32H,s), 2.08(311, s)， 3.32〜3. (ΠΗ,πΟ， 4.30(2H,tn), 5.20(lH,m), 6.82(lH,m)  MRT30 MHz, CDC] (5: 0.87 (3H, t). L25 (32H, s), 2.08 (311, s), 3.32-3. (ΠΗ, πΟ, 4.30 (2H, tn), 5.20 (lH, m), 6.82 (lH, m)
I R [KBrlcm-1: 3450, 2920, 2850, 1730, 1538, 1470, 1265, 1240, 1128 IR (KBrlcm- 1 : 3450, 2920, 2850, 1730, 1538, 1470, 1265, 1240, 1128
実施例 24 Example 24
3— 0— [N—ァセチル一 N— (2' —ジメチルァミ ノェチル）]力ルバ モイルー 2— 0—メチルー 1 一 0—才クタデシルカルバモイルグリセリ ン · ノヽイ ド口クロライ ド  3—0— [N-Acetyl-1-N— (2'-Dimethylaminomethyl)]-lubamoyl 2-—0—Methyl-11—0-year-old octadecylcarbamoylglycerin / noide chloride
3 - 0 - (2 ' 一ジメチルァミ ノェチル）力ルバモイル一 2— 0—メチ ル— 1 一ォグタデシルカルバモイルグリセリ ン（実施例 9で合成） 202mg 3-0-(2'-dimethylaminoethyl) rubamoyl- 1-2-0-methyl-1-octadecylcarbamoylglycerin (synthesized in Example 9) 202 mg
VJKヒ Α(;' VJK Α (; '
ΟΜΡΙΟΜΡΙ
: ί¾·¾ [0.392ミ リモル]を CHCls 15mlに溶解し、 トリェチルァミ ン 4 nd,無水酢 酸 0.4mlを加えた後、 室温にて 4日間放置した。 反応液を減圧濃縮し、残 渣に 1 % NaHC03水溶液を加えて CHC13抽出し、 有機層を炭酸カリウムに て乾燥後、 溶媒を減圧留去した。 得られた粗生成物をカラムクロマトグ ラフィー [シリ力ゲル： 7 g;溶出液：酢酸ェチル—ァセ ト ン（1 ： 1 )]にて 精製し、 無色油伏物， 206mg[94.2%]を得た。 この Free Base U.5mgをェ チルエーテルに溶解し、 氷冷下 塩化水素ガスにて処理し、 目的物 13mg [無色固体]を得た。 : ί¾ · ¾ [0.392 mmol] was dissolved in 15 ml of CHCls, and 4 ml of triethylamine and 0.4 ml of acetic anhydride were added, and the mixture was allowed to stand at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, added 1% NaHCO 3 aqueous solution to a residue and CHC1 3 extracts, after hand drying the organic layer potassium carbonate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by column chromatography [silica gel: 7 g; eluent: ethyl acetate-aceton (1: 1)] to give 206 mg [94.2%] of a colorless oily product. Obtained. 5 mg of this Free Base was dissolved in ethyl ether and treated with hydrogen chloride gas under ice-cooling to obtain 13 mg of the desired product [colorless solid].
く Free Base>  Ku Free Base>
T L C [シリ力ゲル；クロ口ホルム一メ タノ 一ル（5： 1 )]:Rf = 0.62 NMR[90 MHz, CDC13] <5 :0.89(3H,t), 1.25(32H,s), 2.25(6H,s),TLC [silica force gel; black hole Holm Ichime Tano Ichiru (5: 1)]: Rf = 0.62 NMR [90 MHz, CDC1 3] <5: 0.89 (3H, t), 1.25 (32H, s), 2.25 (6H, s),
2.43(2H,t), 2.48(3H,s), 3.13(2H,q), 3.43(3H,s), 3. & 2(1H, quint .) .2.43 (2H, t), 2.48 (3H, s), 3.13 (2H, q), 3.43 (3H, s), 3. & 2 (1H, quint.).
3.86(2H,t), 4.20(2H,d), 4.30(2H,d.d.) , 5.61(lH,br) ' I R [filmlcm-1： 3350, 2925, 2850, 1738, 1710, 1690, 1535,3.86 (2H, t), 4.20 (2H, d), 4.30 (2H, dd), 5.61 (lH, br) 'IR [filmlcm- 1 : 3350, 2925, 2850, 1738, 1710, 1690, 1535,
1465, 1370, 1245, 1180 1465, 1370, 1245, 1180
実施例 25 Example 25
3— 0— [N—ァセチルー N—（2 , — ト リメチルァン乇ニォェチル）] 力ルバモイル— 2— 0—メチル— 1 — 0—才クタデシルカルバモイルグ リセリ ン ョ一ジ ド  3—0— [N-Acetyl-N— (2, —trimethylandiethyl)] Lubamoyl—2—0—Methyl—1—0—Catadecylcarbamoylglyceride
実施例 24で合成した化合物 206nig[(3,369ミ リモル]をェチルエーテル 9 mlに溶解し、 ヨウ化メチル 157mg[1.108ミ リモル]を加えた後、 遮光して 3日間室温にて攪拌した。折出した沈殿を'庐取し、 目的物 [無色粉末] 231 mg[89.5%]も得た。  The compound synthesized in Example 24, 206nig [(3,369 mimol)] was dissolved in 9 ml of ethyl ether, 157 mg [1.108 mimol] of methyl iodide was added, and the mixture was stirred at room temperature for 3 days under light shielding. The precipitate was collected to give the desired product [colorless powder] (231 mg, 89.5%).
T L C [シリカゲル；酢酸ェチル—詐酸—水（3 : 1 : 1 )] :Rf=0.36 T L C [silica gel; ethyl acetate-acid-water (3: 1: 1)]: Rf = 0.36
NMR[90 MHz, CDC ] δ： 0.88(3H,t), 1.25(32H,s), 2.53(3H,s), 3.14(2H,q), 3.48(3H,s), 3.56(9H,s), 3.67〜3.92(3H,m)， 4.22(4 H,m), 4.40(2H,m), 5.03(lH,br) NMR [90 MHz, CDC] δ: 0.88 (3H, t), 1.25 (32H, s), 2.53 (3H, s), 3.14 (2H, q), 3.48 (3H, s), 3.56 (9H, s) , 3.67 to 3.92 (3H, m), 4.22 (4 H, m), 4.40 (2H, m), 5.03 (lH, br)
1 R [KBr]cm 1： 3420, 2930, 2855, 1742, 1700, 1538, 1475, 1380, 1260, 1205, 1170, 1143 1 R [KBr] cm 1 : 3420, 2930, 2855, 1742, 1700, 1538, 1475, 1380, 1260, 1205, 1170, 1143
実施例 26 Example 26
3 - 0 - (2 ' ージメチルァミ ノェチル）力ルバモイルー 2— 0—ジメ チルカルバモィル一 1 — 0—才クタデシルグリセリ ン * ヽィ ドロクロラ イ ド  3-0-(2'-dimethylaminoethyl) rubamoyl 2-0-dimethyl carbamoyl 1-0-octadecylglycerin * diclochloride
2— 0—ジメチルカルバモイルー 1 — 0—ォクタデシルグリセリ ン  2-0-dimethylcarbamoyl 1-0-octadecylglycerin
306mg[0.736ミ リモル],ピリ ジン 116mg[l.472ミ リモル]を塩化メチレン 306 mg [0.736 mimol] and pyridine 116 mg [l.472 mimol] in methylene chloride
5 mUこ溶解し、 フエニルクロロホルメ ― ト 127mg [0.810ミ リモル]を加え た後、 室温にて 40分間攪拌した。 常法処理の後、 得られた粗カーボネー トをジメチルェチレンジアミ ン 1[1.472ミ リモル]と共に 70°Cにて After dissolving 5 mU, phenylchloroformate 127 mg [0.810 mmol] was added, and the mixture was stirred at room temperature for 40 minutes. After the usual treatment, the obtained crude carbonate was mixed with 1 [1.472 mmol] of dimethylethylene diamine at 70 ° C.
14時間加熟した。 冷後、 粗生成物をカラムクロマ トグラフィー [シリカ ゲル： 20g:溶出液： n—へキサン—酢酸ェチル（1 ： 4)及びクロ口ホルム一 Ripened for 14 hours. After cooling, the crude product was subjected to column chromatography [silica gel: 20 g, eluent: n-hexane-ethyl acetate (1: 4) and
メ タノ ―ル（10: 1：)]にて精製し、 目的物 [Free Base] [無色油状物] 374mg Purified with methanol (10: 1 :)], 374 mg of the desired product [Free Base] [colorless oil]
[95.9%]を得た。 この Free Base 38mgをェチルェ—テルに溶解し、 氷冷 下、 塩化水素ガスにて処理し、 塩酸塩 [無色粉末] 4imgを得た。 [95.9%]. 38 mg of this Free Base was dissolved in ethyl ether and treated with hydrogen chloride gas under ice cooling to obtain hydrochloride [colorless powder] 4img.
< Free Base>  <Free Base>
T L C [シリ力ゲル；ク口口ホルムーメ タノ ール（5： 1 )] :Rf = 0.30 T L C [Sili-force gel; lip mouth formum ethanol (5: 1)]: Rf = 0.30
MR[90 MHz, CDC ] <5： 0.88(3H, t) , 1.23(32H,s), 2.22(6H,s)， MR [90 MHz, CDC] <5: 0.88 (3H, t), 1.23 (32H, s), 2.22 (6H, s),
2.40(2H,t), 2.90(6H,s), 3.26(2H,q), 3.42(2H,t), 3.57(2H,d), 2.40 (2H, t), 2.90 (6H, s), 3.26 (2H, q), 3.42 (2H, t), 3.57 (2H, d),
4.28(2H,m), 5.05(1H, quint) . 5.18(iH,br.)  4.28 (2H, m), 5.05 (1H, quint). 5.18 (iH, br.)
I RCfilmlcm"1: 3330, 2930, 2850, 1710, 1465, 1400, 1259,I RCfilmlcm " 1 : 3330, 2930, 2850, 1710, 1465, 1400, 1259,
1193 1193
実施例 27 Example 27
3一 0— [N—ァセチル— N— (2' —ジメチルァミ ノエチル）]力ルバ .  3-1 0— [N-acetyl-N— (2'-dimethylaminoethyl)]
V  V
--- ： モイル一 2— 0—ジメチルカルパモイルー 1 一 0—ォクタデシルグリセ リ ン · ハイ ド口クロライ ド ---: Moyl 1-0-dimethylcarpamoyl-1-0-octadecyl glycerin hydride chloride
実施例 26で合成したジメチルァ ミ ノ体 374mg[0.706ミ リモル]をクロ口 ホルム 20mlに溶解し、 トリェチルァミ ン 8 ml,無水 g乍酸 L5mlを加えた後、 室温にて 19時間放置した。 反応液も減圧濃縮し、 実施例 24と同様に処理 した後、 得られた粗生成物をカラムク口マ トグラフィ— [シリ力ゲル： 13 g;溶出液：酢酸ェチルーァセトン（1:1)]にて精製し、目的物 [Free Base]- [無色油状物] 360mg[89.2%]も得た。 この Free Base 19tngをェチルェ— テルに溶解し、 氷冷下、 塩化水素ガスにて処理し、 目的物 [無色粉末] 21 mgを得た。  374 mg [0.706 mimol] of the dimethylamino compound synthesized in Example 26 was dissolved in 20 ml of chloroform, and 8 ml of triethylamine and 5 ml of anhydrous g were added, followed by standing at room temperature for 19 hours. The reaction solution was also concentrated under reduced pressure, and treated in the same manner as in Example 24. The resulting crude product was subjected to column chromatography [silica gel: 13 g; eluent: ethyl ethyl acetate (1: 1)]. Purification gave the desired product [Free Base]-[colorless oil] 360 mg [89.2%]. This free base (19 tng) was dissolved in ethyl ether and treated with hydrogen chloride gas under ice-cooling to obtain 21 mg of the desired product [colorless powder].
く Free Base>  Ku Free Base>
T L C [シリ力ゲル；クロロホルムーメタノ 一フレ（5： 1 )] :Rf = 0.62 T L C [silicone gel; chloroform-methano-free (5: 1)]: Rf = 0.62
MRC90 MHz, CDC13] 5： 0.88(3H,t), 1.22(32H,s), 2.22(6H,s), MRC90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.22 (32H, s), 2.22 (6H, s),
2.39(2H,t), 2.47(3H,sL 2.90(6H,s), 3.42(2H,t), 3.58(2H,d)( 2.39 (2H, t), 2.47 (3H, sL 2.90 (6H, s), 3.42 (2H, t), 3.58 (2H, d) (
3.82(2H,t), 4.44(2H,m), 5.13(1H, quint) 3.82 (2H, t), 4.44 (2H, m), 5.13 (1H, quint)
I R [filmlcm-1： 2925, 2850, 2815, 2752, 1740, 1706, 1460,IR [filmlcm- 1 : 2925, 2850, 2815, 2752, 1740, 1706, 1460,
1395, 1370, 1242, 1190, 1175, 1155, 1120, 1095 1395, 1370, 1242, 1190, 1175, 1155, 1120, 1095
実施例 28 Example 28
3 - 0 -[N—ァセチルー iN'— (2' — ト リメチルアンモニォェチル）]力 ルバモイル— 2— 0—ジメチルカルバモイル— 1 一 0—才クタデシルグ リセリ ン · ョ一ジ ド  3-0-[N-Acetyl- iN '-(2'-trimethylammonioethyl)] force Lubamoyl—2—0—Dimethylcarbamoyl—11—0—Titadecylglycerine
実施例 27で合成したジメチルァミ ノ体 337mg[0.589ミ リモル]をェチル エーテル 12mlに溶解し、 ヨウ化メチル 25img[1.768ミ リモル]を加えた後、 遮光して室温にて 3日間攪拌した。 反応液を減圧濃縮し、 目的物 [無色 粉末] 36img[85.9%]を得た。  337 mg [0.589 mimol] of the dimethylamino compound synthesized in Example 27 was dissolved in 12 ml of ethyl ether, 25 mg of methyl iodide [1.768 mimol] was added, and the mixture was stirred at room temperature for 3 days while shielding from light. The reaction solution was concentrated under reduced pressure to obtain the desired product [colorless powder] 36img [85.9%].
T L C [シリカゲル；酢酸ェチル—酢酸一水（3 : 1 : 1 )] :Rf = 0.31  TLC [silica gel; ethyl acetate-acetic acid monohydrate (3: 1: 1)]: Rf = 0.31
OMF OMF
差換え NMR[90 MHz, CDC ] <5 : 0.88(3H,t), 1.25(32H,s), 2.50(3H,s), 2.90(6H,s), 3.44(2H,t), 3.53(9H, s)及び（2H, d) , 3.80(2H,br. t), 4.23(2H.br.t), 4.47(2H,m)( 5.24(lH,m) Replacement NMR [90 MHz, CDC] <5: 0.88 (3H, t), 1.25 (32H, s), 2.50 (3H, s), 2.90 (6H, s), 3.44 (2H, t), 3.53 (9H, s ) And (2H, d), 3.80 (2H, br.t), 4.23 (2H.br.t), 4.47 (2H, m) ( 5.24 (lH, m)
1 R [KBr]cm-1： 2925, 2850, 1750, 1705, 1475, 1405, 1379, 1270, 1210 1 R [KBr] cm- 1 : 2925, 2850, 1750, 1705, 1475, 1405, 1379, 1270, 1210
実施例 29 Example 29
2— 0—ァセチルー 3— 0— [N—ァセチルー N—（ 2 ' —ベンジルジ メチルアンモニォェチル）]カルパモイル— 1 — 0—ォクタデシルグリセ リ ン · クロライ ド  2—0—acetyl-3—0— [N-acetyl-N— (2'—benzyldimethylammonioethyl)] carpamoyl—1—0—octadecylglycerin chloride
2— 0—ァセチル— 3— 0— [N—ァセチル— N—（2' —ジメチルァ ミ ノェチル）]力ルバモイルー 1 一 0—ォクタデシルグリセリ ン（実施例 2で合成） 200mg[0.368ミ リモル]にべンジルクロライ ド 127 1 [1.105ミ リ 'モル]を加え、 70° にて 2時間加熱した。 冷後、 反'応物を n—ペンタ ン にて洗浄し、 目的物 [無色粉末] 247mg[100%]を得た。  2—0—Acetyl—3—0— [N-Acetyl—N— (2′—Dimethylaminoethyl)] lubamoyl 110-octadecylglycerin (synthesized in Example 2) 200 mg [0.368 mimol] Benzyl chloride 127 1 [1.105 mi'mol] was added to the mixture and heated at 70 ° for 2 hours. After cooling, the reaction product was washed with n-pentane to obtain 247 mg [100%] of the target product [colorless powder].
T L C [シリ力ゲル；クロロホルム一メタノ 一ル（5： 1 )] :Rf = 0.26 iN*MR[90 MHz, CDC13](5 : 0.87(3H,t), 1.23(32H,s), 2.05(3H,s), 2.46(3H(s),3.28-3.83(12HIni), 4 (！〜 4.58(4H， m) . δ.08(2H,s) , δ.32 (lH，m), 7.47, 7.73(5H,m), TLC [silica force gel; chloroform one methano Ichiru (5: 1)]: Rf = 0.26 iN * MR [90 MHz, CDC1 3] (5: 0.87 (3H, t), 1.23 (32H, s), 2.05 ( 3H, s), 2.46 (3H (s), 3.28-3.83 (12H I ni), 4 (! ~ 4.58 (4H, m). δ.08 (2H, s), δ.32 (lH, m), 7.47, 7.73 (5H, m),
1 R [ Brjcin-1: 3430, 2925, 28F0, 1745, 1690, 1475, 1378, 1250 1 R [Brjcin- 1 : 3430, 2925, 28F0, 1745, 1690, 1475, 1378, 1250
実施例 30 Example 30
2— 0—メチル一 3—〇一 [N—メチルー N—（2' —ジメチルァミ ノ ェチル）]力ルバモイル一 1 一 0—ォクタデシルカルバモイルグリセリ ン • ノヽィ ドロクロライ ド  2—0—Methyl-1-3- [N-Methyl-N— (2'-dimethylaminoethyl)]-lubamoyl-1 1-0-Octadecylcarbamoylglycerin • Neudrochloride
2— 0—メチルー 1 一 0—才クタデシルカルバモイルグリセリ ン 377 mg[0.938ミ リモル],フエニルク口口ホルメ ― ト 162mg[1.032ミ リモル],  2-0-Methyl-11-10-year-old cutadecylcarbamoylglycerin 377 mg [0.938 mimol], phenylc oral formate 162 mg [1.032 mimol],
O PI ピリ ジン 148mg[i.876ミ リモル]及び塩化メチレン 3 mlより常法通り合成 した粗カーボネ— ト 568mgに N , N， N' — ト リ メチルェチレンジアミ ン 158^〖[1.Π9ミ リモル]を加え、 72°Cにて 3時間加熱した。 冷後、 粗生 成物もカラムク口マ トグラフィー [シリ力ゲル； 23g;溶出液： n—へキサン 一酢酸ェチル（ 1 : 4 )及びクロ口ホルム—メタノ ール（8 ： 1 )]にて精製 し、 目的物（Free Base) [無色油状物] 520mg[98.2%]を得た。 この Free Base 20mgをェチルエーテルに溶解し氷冷下、 塩化水素ガスにて処理し、 塩酸塩 [無色シ口ップ状物質] 21mgを得た。 O PI N, N, N'-trimethylethylenediamine 158 ^ 〖[1.Π9 mi was added to 568 mg of crude carbonate synthesized from 148 mg of pyridine [i.876 mimol] and 3 ml of methylene chloride in the usual manner. And the mixture was heated at 72 ° C for 3 hours. After cooling, the crude product was also subjected to column chromatography (Silica gel; 23 g; eluent: n-hexane monoethyl acetate (1: 4) and chromatoform-methanol (8: 1)). Purification was performed to obtain 520 mg [98.2%] of the target product (Free Base) [colorless oily substance]. 20 mg of this Free Base was dissolved in ethyl ether and treated with hydrogen chloride gas under ice-cooling to obtain 21 mg of hydrochloride [colorless dry substance].
< Free Base>  <Free Base>
T L C [シリカゲル：クロ口ホルム一メ タノ ール（7 : 1 )]: Rf = 0.45 MR [90 Mz, CDC ] <5 :0.87(3H(t), 1.26(32H,s), 2.25(6H，，s)，TLC [silica gel: chloroform-methanol (7: 1)]: Rf = 0.45 MR [90 Mz, CDC] <5: 0.87 (3H ( t), 1.26 (32H, s), 2.25 (6H, , S),
2.42(2H,t), 2.92(3H,s), 3.16(2H,q)( 3.37(2H,t), 3.45(3H,s),2.42 (2H, t), 2.92 (3H, s), 3.16 (2H, q) ( 3.37 (2H, t), 3.45 (3H, s),
3.60(lH,quint),4.18(4H,d), 5.00ClH.br.) 3.60 (lH, quint), 4.18 (4H, d), 5.00ClH.br.)
I R [f ilmjcm-1： 3345, 2920, 2850, 2770, 1706, 1535, 1466,IR [filmjcm -1 : 3345, 2920, 2850, 2770, 1706, 1535, 1466,
1405, 1255, 1195, 1135 1405, 1255, 1195, 1135
実施例 31 Example 31
2 一 0— -メチル一 3 — 0— [N—メチル一 N— ( 2 ' — ト リメチルアン モニォェチル）]力ルバモイルー 1 — 0—ォクタデシルカルバモイルグリ セリ ン · ョ一ジ ド  2 1 0— -Methyl-1 3 — 0— [N-Methyl-1 N— (2 '—trimethylammonioethyl)]-Lbamoyl 1 — 0—Octadecylcarbamoylglycerin chloride
実施例 30で合成したジメチルァミ ノ体 540mg[l,0i9ミ リモル]をェチル ェ—テル 20mlに溶解しヨウ化メチル 434mg[3.058ミ リモル]を加えた後室 温にて 3.5日間攪拌した。 反応液を減圧濃縮しァセトン エーテル混液 にて再沈澱を行ない、 目的物 [無色粉末] 607mg[9Q.4%]を得た。  540 mg [1,0i9 mimol] of the dimethylamino compound synthesized in Example 30 was dissolved in 20 ml of ethyl ether, and 434 mg [3.058 mimol] of methyl iodide was added, followed by stirring at room temperature for 3.5 days. The reaction solution was concentrated under reduced pressure, and reprecipitated with a mixed solution of acetone and ether to obtain 607 mg [9Q.4%] of the target compound [colorless powder].
T L C [シリカゲル：クロ口ホルム一メタノ ール（5 : l )] :Rf=0.08 MR [90 MHz, CDC13J 5： 0.88(3H,t), 1.25(32H,s), 3.10(3H,s) (2H,m), 3.42(3H,s), 3.60(9H,s), 3.62〜4.33(9ίΙ,πι) , 4.87(lH,br.) 1 R [KBr]cm-1： 3450, 2925. 2852, 1702 TLC [silica gel: Black port Holm one methanol (5: l)]: Rf = 0.08 MR [90 MHz, CDC1 3 J 5: 0.88 (3H, t), 1.25 (32H, s), 3.10 (3H, s ) (2H, m), 3.42 (3H, s), 3.60 (9H, s), 3.62-4.33 (9ίΙ, πι), 4.87 (lH, br.) 1 R [KBr] cm- 1 : 3450, 2925. 2852, 1702
実施例 32 Example 32
2— 0—メチル一 1一ひ一才クタデシルカルバモイル -3 -0 -(2' — ピ口リ ジノェチル）カルパモイルグリセリ ン ♦ ハイ ド口クロライ ド  2—0—Methyl-one-one-year-old Cutadecylcarbamoyl -3 -0-(2'-pi-ridinoethyl) carbamoylglycerin ♦ Hide-open chloride
2— 0—メチル一 1 一 0—ォクタデシルカルバモイルグリセリ ン 402mg[ 1 ミ リモル]，フエニルク口口ホルメ 一 ト 172mg[l.lミ リモル] ,ピ リ ジン 158mg[2 ミ リモル]及び塩化メチレン 3mlより常法通り合成した 粗カーボネ一 ト 578mgに、 N—（2—ァミ ノェチル）ピロ リ ジン L54/Z 1 [1.2ミ リモル]を加え、 72° にて 8時間加熟した。 冷後、 粗生成物を力 ラムクロマ トグラフィー [シリ力ゲル： 23g;溶出液：n—へキサン—酢酸ェ チル（1 :4—)及びクロ口ホルム一メタノ ―ル（8： 1 )]にて精製し、 目的 物（Free Base) [無色固形物] 503mg[92.8%]を得た。 この Free Base 20mg をェチルェ-テルに溶解し氷冷下、 塩化水素ガスにて処理し、 塩酸塩 [無 色粉末] 21mgを得た  From 2-0-methyl-11-octadecylcarbamoylglycerin 402 mg [1 mimol], phenylc mouth form 172 mg [ll mimol], pyridine 158 mg [2 mimol] and methylene chloride 3 ml N- (2-Aminoethyl) pyrrolidine L54 / Z1 [1.2 mimol] was added to 578 mg of the crude carbonate synthesized as usual, and the mixture was ripened at 72 ° for 8 hours. After cooling, the crude product was subjected to column chromatography [silica gel: 23 g; eluent: n-hexane-ethyl acetate (1: 4–) and chloroform-methanol (8: 1)]. Purification was performed to obtain 503 mg [92.8%] of the target product (Free Base) [colorless solid]. 20 mg of this Free Base was dissolved in ethyl ether and treated with hydrogen chloride gas under ice cooling to obtain 21 mg of hydrochloride [colorless powder]
< Free Base>  <Free Base>
TL C [シリ力ゲル；クロロホルム一メタノ ール（7 : 1 )] :Rf = 0.23 KM-RC90 MHz, CDC 15 : 0.88(3H,t), 1.24(32H,s), 1.77(4H, m) , TLC [silicone gel; chloroform-methanol (7: 1)]: Rf = 0.23 KM-RC90 MHz, CDC 15: 0.88 (3H, t), 1.24 (32H, s), 1.77 (4H, m) ,
2.40〜2.70(6H,m), 3.03〜3.38(4H, m) , 3.43(3H,s), 3.58(iH,quint .) ,2.40 ~ 2.70 (6H, m), 3.03 ~ 3.38 (4H, m), 3.43 (3H, s), 3.58 (iH, quint.),
4.16(4H,d), 4.98(lH,br.), 5.53(lH.br.) 4.16 (4H, d), 4.98 (lH, br.), 5.53 (lH.br.)
I R [KBrlcm-1: 3320, 2920, 2850, 1695, 1535, 1469, 1275 実施例 33 IR (KBrlcm- 1 : 3320, 2920, 2850, 1695, 1535, 1469, 1275 Example 33
3— 0— [N—ァセチルー N— (2 ' —ピロリ ジノエチル）]力ルバモイ ルー 2— 0—メチルー 1 — 0—ォクタデシルカルバモイルグリセリ ン · ハイ ド σクロライ ド  3—0— [N-Acetyl-N— (2'—pyrrolidinoethyl)] rubamoyl 2-—0—Methyl-1—0—Octadecylcarbamoylglycerin halide σ chloride
実施例 32で合成した化合物（Free Base) 370mg[0.683ミ リモル]をク σ 口ホルム 10mlに溶解し、 トリェチルァミ ン 8 ml,無水酢酸し 5mlを加えた  370 mg [0.683 mimol] of the compound synthesized in Example 32 (Free Base) was dissolved in 10 ml of sigma-form, and 8 ml of triethylamine and 5 ml of acetic anhydride were added.
ΟΛΪΡΙ 後、 室温にて 3日間放置した。 反応液を減圧濃縮し、 実施例 24と同様に 処理した後、 得られた粗生成物をカラムクロマ トグラフィ— [シリカゲ ル： 14g; 溶出液： 舴酸ェチル—ァセ ト ン（1： 2)] にて精製し、 目的物 (Free Base) [無色シロ ッ プ伏物質] 398mg[99.8%]を得た。 この Free Base 2Qmgをェチルエ-テルに溶解し、 氷冷下、 塩化水素ガスにて処理 し、 塩酸塩 [無色シロ ッ プ状物質] 21nigを得た。 ΟΛΪΡΙ Then, it was left at room temperature for 3 days. After the reaction solution was concentrated under reduced pressure and treated in the same manner as in Example 24, the obtained crude product was subjected to column chromatography [silica gel: 14 g; eluent: ethyl acetate-acetonate (1: 2)]. Then, 398 mg [99.8%] of the desired product (free base) [free base substance] was obtained. 2Qmg of this Free Base was dissolved in ethyl ether, and treated with hydrogen chloride gas under ice cooling to obtain hydrochloride [colorless syrupy substance] 21nig.
< Free Base>  <Free Base>
T L C [シリカゲル；詐酸ェチルーァセ ト ン（1 :3)]:Rf=0.17  T L C [silica gel; ethyl acetylacetonate (1: 3)]: Rf = 0.17
NMR[90 MHz, CDC13] δ： 0.87(3H,t), 1.26(32H,s), 1·64〜1.89 (4H，m)， 2.49(3H,s), 2.59(6H,m)) 3.12(2H,q), 3.44(3H,s), 3.62 (iH, quint.), 3.89(2H,t). 4.2i(2H(d), 4J0(2H,d.d.), 5.52(1H, br.) NMR [90 MHz, CDC1 3] δ: 0.87 (3H, t), 1.26 (32H, s), 1 · 64~1.89 (4H, m), 2.49 (3H, s), 2.59 (6H, m)) 3.12 (2H, q), 3.44 (3H, s), 3.62 (iH, quint.), 3.89 (2H, t) .4.2i (2H ( d), 4J0 (2H, dd), 5.52 (1H, br.)
I R [film^m- 1 : 3340, 2925, 2852, 1738·, 1710, 1535, 1470, 1375, 1356, 1255. 1225, Π98, 1163 . IR [film ^ m- 1 : 3340, 2925, 2852, 1738, 1710, 1535, 1470, 1375, 1356, 1255. 1225, Π98, 1163.
実施例 34 Example 34
3 - 0一 =N—ァセチル— N—（2 ' — N—メチルピロリ ジニォェチル）] 力ルバモイルー 2— 0—メチルー 1一 0—才クタデシルカルパモイルグ リセリ ン . ョージ ド  3-0-1 = N-acetyl-N-(2 '-N-methylpyrrolidinioethyl)] carbamoyl 2-0-methyl-11-0-year-old octadecylcarpamoyluglycerin.
実施例 33で合成した化合物（Free Base) 378mg〔0.647ミ リモル]をェチ ルエーテル 13mlに溶解し、 ヨウ化メチル 276mg[1.942ミ リモル]を加えた 後、 遮光して室温にて 4 日間攪拌した。 溶媒を減圧留去し、 目的物「_無 色粉末： 428mg:91.1%]を得た。  378 mg [0.647 mimol] of the compound (Free Base) synthesized in Example 33 was dissolved in 13 ml of ethyl ether, 276 mg of methyl iodide [1.942 mimol] was added, and the mixture was stirred at room temperature for 4 days while shielding from light. . The solvent was distilled off under reduced pressure to obtain the target product “_colorless powder: 428 mg: 91.1%”.
T L C [シリカゲル；クロロホルム一メ タノ ール（5： 1 )] :Rf=0.12 MR[90 MHz, CDCl3]o : 0.88(3H,t), 1.26(32H,s)( 2.32(4H,m),TLC [silica gel; chloroform-methanol (5: 1)]: Rf = 0.12 MR [90 MHz, CDCl 3 ] o: 0.88 (3H, t), 1.26 (32H, s) ( 2.32 (4H, m) ,
2.52(3H,s), 3.12(2H,q), 3.39(3H,s), 3.47(3H,s), 3.68〜4.06('7H， m), 4.22(4H.m), 4.42(2H,m), 5.17(iH(br.) I RCKBrlcm-1 : 3415, 2920, 2850, 1738, 1700, 1532, 1468, 1372, L220, 1179 2.52 (3H, s), 3.12 (2H, q), 3.39 (3H, s), 3.47 (3H, s), 3.68 ~ 4.06 ('7H, m), 4.22 (4H.m), 4.42 (2H, m ), 5.17 (iH ( br.) I RCKBrlcm- 1 : 3415, 2920, 2850, 1738, 1700, 1532, 1468, 1372, L220, 1179
実施例 35 Example 35
3— 0— [N—ァセチル- N - ( 2 ' — N—メチルピロ リ ジニォェチル）] 力ルバモイル一 2— 0—メチルー 1 — 0—才クタデシルカルバモイルグ リセリ ン · クロライ ド  3—0— [N-Acetyl-N- (2'—N-Methylpyrrolidinosine)] Lubamoyl-1 2—0—Methyl-1—0—Cutadecylcarbamoylglycerin chloride
実施例 34で合成した化合物 2.694gをメタノ ール一水（7： 3 )混液に溶 解し、 I RA- 410 [C1一] 120mlにて処理し、 目的物 [無色粉末] 2.341g を得た。  2.694 g of the compound synthesized in Example 34 was dissolved in a mixed solution of methanol and water (7: 3) and treated with 120 ml of IRA-410 [C1] to obtain 2.341 g of the desired product [colorless powder]. Was.
T L C [シリ力ゲル；酢酸ェチルー^ ^酸一水（3 : 1 : 1 ):Rf = 0.75 NMR[90 MHz, CDC13] 5： 0.88(3H,t), 1.26(32H,s), 2.29(4H,m),TLC [silica force gel; acetate Echiru ^ ^ acid monohydrate (3: 1: 1): Rf = 0.75 NMR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.26 (32H, s), 2.29 ( 4H, m),
2.50(3H,s), 3.12(2H,q), 3.40(3H,s), 3.45(3H,s), 3.62〜4.08(7H， m), 4.22(4H,m), 4.41(2H,m), 5.04(lH,br.) 2.50 (3H, s), 3.12 (2H, q), 3.40 (3H, s), 3.45 (3H, s), 3.62 ~ 4.08 (7H, m), 4.22 (4H, m), 4.41 (2H, m) , 5.04 (lH, br.)
1 R [KBrjcni-1： 3420, 2920, 2850, 1738, 1700, 1538, 1472, 1380, 1220, 1180， 1 R [KBrjcni- 1 : 3420, 2920, 2850, 1738, 1700, 1538, 1472, 1380, 1220, 1180,
実施例 36 Example 36
2— 0—メチル— 3— 0— [ 2 ' — (N—メチルピロ リ ジニォ） -チル] 力ルバモイルー 1 — 0—ォクタデシルカルバ乇ィルグリセリ ン ' ョージ ド'  2— 0—Methyl— 3— 0— [2 '— (N-Methylpyrrolidinio) -Chill] Powerbamoyl 1 — 0—Octadecylcarbazylglycerin
実施例 32で合成した化合物（Free B ase)95tng[0.175ミ リモル]をェ チルエーテル 4 mlに溶解し、 ヨウ化メチル [0.526ミ リモル]を加えた後、 遮光して室温にて 3日間放置した。 反応液を減圧濃縮し生成物をェチル ェ—テル ペンタン混液にて再沈殿し、 目的物 [無色粉末] 115mg[96.1%] を得た。  95 tng [0.175 mimol] of the compound synthesized in Example 32 (Free Base) was dissolved in 4 ml of ethyl ether, and methyl iodide [0.526 mimol] was added. . The reaction solution was concentrated under reduced pressure, and the product was reprecipitated with a mixed solution of ethyl ether pentane to obtain 115 mg [96.1%] of the target product [colorless powder].
T L C [シリ力ゲル；クロロホルムーメタノ ール（5： 1 )] :R f = 0.08 MR[90 MHz, CDC13] 5： 0.88(3H,t), 1.26(32H,s), 2.28(4H,m), TLC [silica force gel; chloroform: methanolate Lumpur (5: 1)]: R f = 0.08 MR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.26 (32H, s), 2.28 (4H, m),
OMPI 3.12(2H,q), 3.36(3H,br.s), 3.42(3H,s), 3.49-4.01(9H, m) , 4.03 〜4.32(4H,m)， 5.18(1H, br. ) , 6.60ClH.br.) OMPI 3.12 (2H, q), 3.36 (3H, br.s), 3.42 (3H, s), 3.49-4.01 (9H, m), 4.03 to 4.32 (4H, m), 5.18 (1H, br.), 6.60 ClH.br.)
I R [KBrlcm-1: 3400, 2915, 2850, 1705. 1530, 1468, 1265 実施例 37 IR [KBrlcm- 1 : 3400, 2915, 2850, 1705. 1530, 1468, 1265 Example 37
2— 0—メチル- 1 -0—ォクタデシルカルバモイル— 3— 0— (2 ' ピぺリ ジノエチル）力ルバモイルグリセリ ン · ノヽィ ドロクロライ ド  2—0—Methyl-1-O—octadecylcarbamoyl—3—0— (2′-piridinoethyl) force rubamoylglycerin / nodirochloride
実施例 32と同様にして合成した粗カーボネー ト 578ingに N—（2—アミ ノエチル）ピぺリ ジン 175 1[1.2ミ リモル]を加え、 72°Cにて 10時間加熱 した。 冷後、 粗生成物をカラムクロマ トグラフィー [シリカゲル： 25g ； 溶出液： n—へキサン一酢酸ェチル（1 :4)及びクロ口ホルム一メタノ ー ル（8： 〖 ）]にて精製し、 目的物（Free Base) [無色固形物] 555mg[100%] を得た。 この Free Base 2 gをェチルエ-テルに溶解し、 氷冷下、 塩化 水素ガスにて処理し、 塩酸塩 22mgを得た。 '  N- (2-aminoethyl) piperidine 1751 [1.2 mimol] was added to 578ing of the crude carbonate synthesized in the same manner as in Example 32, and the mixture was heated at 72 ° C for 10 hours. After cooling, the crude product was purified by column chromatography [silica gel: 25 g; eluent: n-hexane monoacetate (1: 4) and chloroform-methanol (8: 〖)]. (Free Base) [colorless solid] 555 mg [100%] was obtained. 2 g of this Free Base was dissolved in ethyl ether and treated with hydrogen chloride gas under ice cooling to obtain 22 mg of hydrochloride. '
< Free Base>  <Free Base>
T L C [シリ力ゲル；ク口口ホルム一メ タノ ール（7： 1 )] :Rf=0.39 N R[90 MHz, CDC13]5 : 0.86(3H,t), 1.24(32H,s), 1.41〜1.73 (6H,m), 2.27〜2.53(6H,m), 3.01〜3.37(4H,m) , 3.43(3H,s), 3.58 (iH, quint), 4.18(4H,d), 4.82(1H, br.) , 5.38(lH,br.) TLC [silica force gel; click every mouth Holm Ichime Tano Lumpur (7: 1)]: Rf = 0.39 NR [90 MHz, CDC1 3] 5: 0.86 (3H, t), 1.24 (32H, s), 1.41 ~ 1.73 (6H, m), 2.27 ~ 2.53 (6H, m), 3.01 ~ 3.37 (4H, m), 3.43 (3H, s), 3.58 (iH, quint), 4.18 (4H, d), 4.82 (1H , br.), 5.38 (lH, br.)
I R [KBrlcm"1： 3330, 2920, 285.0, 1692, 1540, 1370, 1273 実施例 38 IR [KBrlcm] 1 : 3330, 2920, 285.0, 1692, 1540, 1370, 1273 Example 38
3一 0— [N—ァセチルー N— ( 2 ' —ピペリ ジノェチル）]力ルバモイ ル一 2— 0—メチル一 1 — 0—ォクタデシルカルバモイルグリセリ ン . ハイ ドロクロライ ド  3-1 0— [N-acetyl-N— (2'-piperidinoethyl)] rubamoyl 1 2—0—methyl 1 1—0—octadecylcarbamoylglycerin.Hydrochloride
実施例 37で合成した化合物（Free Base)565mg[l.017ミ リモル]をクロ 口ホルム^ mUこ溶解し、 トリェチルアミ ン 12ml,無水詐酸 2.3miを加えた 後、 室温にて 4日間放置し、 更に 24時間加熟還流した。 冷後、 反応液を  565 mg [l.017 mimol] of the compound synthesized in Example 37 (Free Base) was dissolved in chloroform-m ^ mU, and 12 ml of triethylamine and 2.3 mi of anhydrous acid were added. The mixture was allowed to stand at room temperature for 4 days. The mixture was refluxed for ripening for another 24 hours. After cooling, the reaction mixture
OMPI OMPI
、 、 W1PO 減圧濃縮し、 実施例 24と同様に処理した後、 得られた粗生成物をカラム クロマトグラフィー [シリカゲル： 21g;溶出液：酢酸ェチル—ァセトン（2 ： 1：)]にて精製し、 目的物（Free Base) [無色シロヅプ状物質] 456mg[75.0 %]を得た。 この Free Base 35mgをェチルエーテルに溶解し、 氷冷下、 塩化水素ガスにて処理し、 塩酸塩 37mgを得た。 ,, W1PO After concentrating under reduced pressure and treating in the same manner as in Example 24, the obtained crude product was purified by column chromatography [silica gel: 21 g; eluent: ethyl acetate-acetone (2: 1 :)]. (Free Base) [Colorless syrupy substance] 456 mg [75.0%] was obtained. This free base (35 mg) was dissolved in ethyl ether, and treated with hydrogen chloride gas under ice-cooling to obtain hydrochloride (37 mg).
< Free Base>  <Free Base>
T L C [シリカゲル；酢酸ェチル—ァセトン（1 ： 1 )]:Rf = 0.27.  TLC [silica gel; ethyl acetate-aceton (1: 1)]: Rf = 0.27.
NMRE90 MHz, CDCUl (5： 0.88(3H,t). 1.26(32H,s), 1.46(6H, m) , 2.41(6H,m), 2.47(3H,s), 3.15(2H,q), 3.45(3H,s), 3.62(1H, uint) , NMRE90 MHz, CDCUl (5: 0.88 (3H, t). 1.26 (32H, s), 1.46 (6H, m), 2.41 (6H, m), 2.47 (3H, s), 3.15 (2H, q), 3.45 (3H, s), 3.62 (1H, uint),
3.88(2H,t), 4.21(2H,d), 4.30(2H,dd) , 5.20(lH,br.) 3.88 (2H, t), 4.21 (2H, d), 4.30 (2H, dd), 5.20 (lH, br.)
I RCfilmlcm-1: 3360, 2930, 2853, 1740, 1710, 1530, 1473, 1375, 1250, 1195, 1130 I RCfilmlcm- 1 : 3360, 2930, 2853, 1740, 1710, 1530, 1473, 1375, 1250, 1195, 1130
実施例 39 Example 39
3— 0— [N—ァセチル- N - (2 ' 一 N—メチルピペリ ジニォェチル）] 力ルバモイル— 2— 0—メチル— 1 — 0—ォクタデシルカルパ乇ィルグ リセリ ン . ョージ ド 実施例 38で合成した化合物（Free Base)42img[0.704ミ リモル]をェチ ルェ—テル 8 mlに ¾解しョゥ化メチル 300mg[2.113ミ リモル]を加えた後、 遮光して室温にて 2日間攪拌した。 反応液を減圧濃縮し、 目的物 [無色 粉末] 467mg[89.7%]を得た。  3—0— [N-Acetyl-N- (2′-N-methylpiperidinethyl)] lvamoyl—2—0—Methyl—1—0—Octadecylcarbadiylglycerin. Compound Synthesized in Example 38 42 mg [0.704 mimol] of the obtained compound (Free Base) was digested in 8 ml of ethyl ether, and 300 mg [2.113 mimol] of methyl iodide was added thereto, followed by stirring at room temperature for 2 days while shielding from light. The reaction solution was concentrated under reduced pressure to obtain 467 mg [89.7%] of the target product [colorless powder].
T L C [シリカゲル；クロロホルム一メタノ ール（5 : 1 )] :Rf = 0.14 TLC [silica gel; chloroform-methanol (5: 1)]: Rf = 0.14
NMR[90 MHz, CDC13] 5： 0.88(3H,t), 1.24(32H,s), 1.89(6H,m), 2.55(3H,s), 3.12(2H,q), 3.42(3H,s), 3.48(3H,s), 3.59〜3.99(7H， m)， 4.22(4H,m), 4.42(2H,m), 5.17(1H, r. ) NMR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.24 (32H, s), 1.89 (6H, m), 2.55 (3H, s), 3.12 (2H, q), 3.42 (3H, s ), 3.48 (3H, s), 3.59 ~ 3.99 (7H, m), 4.22 (4H, m), 4.42 (2H, m), 5.17 (1H, r.)
I RCKBrJcm"1: 3450, 2925, 2852, 1740, 1705, 1530, 1475, 1180, 1252, 1223 I RCKBrJcm " 1 : 3450, 2925, 2852, 1740, 1705, 1530, 1475, 1180, 1252, 1223
( 0:V,PI 実施例 40 (0: V, PI Example 40
2— 0—メチルー 3— 0— [2 ' _(N—メチルビペリ ジニォ）ェチル] 力ルバモイルー 1— 0—ォクタデシルカルバモイルグリセリ ン · ョ一ジ ド、  2—0—Methyl-3—0— [2 '_ (N-Methylbiperidinio) ethyl] 1-0—Octadecylcarbamoylglycerin chloride,
実施例 37で合成した化合物（Free Base)23mg[0.041 ί リモル]をェチル エーテル 1.5mlに溶解し、 ヨウ化メチル 18mg[0.i24ミ リモル]を加えた後、 遮光して室温にて 3日間放置した。 反応液を氷冷し、 折出した沈殿を 取し、 目的物 [無色粉末] 27mg[94.3%]を得た。  23 mg [0.041 mol] of the compound (Free Base) synthesized in Example 37 was dissolved in 1.5 ml of ethyl ether, and 18 mg [0.224 mmol] of methyl iodide was added. I left it. The reaction solution was cooled on ice, and the precipitated precipitate was collected to obtain 27 mg [94.3%] of the target compound [colorless powder].
T L Cシリカゲル；胙酸ェチル— g乍酸一水，（3 : 1： 1 )]Rf = 0.31 TLC silica gel; ethyl ethyl eluate-g while acid-water, (3: 1: 1)] Rf = 0.31
MR[90 MHz, CDC13] 5 : 0.87(3H,t), 1.25(32H,s), 1.88(6H,m). 3.12(2H,q)) 3.40(3H,s), 3.43(3H,s), 3.5(！〜 3.93(9H， m) , 4.13(4H, m), 4.98(lH,br.), 6.53(iH,br.) MR [90 MHz, CDC1 3 ] 5: 0.87 (3H, t), 1.25 (32H, s), 1.88 (6H, m) .3.12 (2H, q) ) 3.40 (3H, s), 3.43 (3H, s ), 3.5 (! ~ 3.93 (9H, m), 4.13 (4H, m), 4.98 (lH, br.), 6.53 (iH, br.)
I R [KBrJcm-1： 3380, 2920, 2848, 1710, 1530, 1465, 1250， 実施例 41 · IR [KBrJcm- 1 : 3380, 2920, 2848, 1710, 1530, 1465, 1250, Example 41
2— 0—メチル一 3— 0—（2' —モルホリノェチル）力ルバモイルー 1— 0—才クタデシルカルバモイルグリセリ ン .ハイ ド σクロライ ド 実施例 '32と同様にして合成した粗力―ボネ一 ト 578mgに N—（ 2—アミ ノエチル）モルホリ ン 162 1 [1.2ミ リモル]を加え、 72てにて 10時間攪拌 した。 冷後、 粗生成物をカラムクロマ トグラフィ—：シリカゲル： 30g:溶 出液： n—へキサン一酢酸ェチル（ 1 :4)及びクロ σホルム一メタノ ール （1 6: 1):にて精製し、 目的物（Free Base) [無色固形物 ] 538mg[96.5%]を得 た。 この Free Base 19mgをェチルエーテルに溶解し、 氷冷下、 塩化水素 ガスにて処理し、 塩酸塩 20mgを得た。  2-0-Methyl-1- 3- (2'-morpholinoethyl) force rubamoyl 1-0-year-old octadecylcarbamoylglycerin.Hide sigma chloride Coarse force synthesized in the same manner as in Example 32. N- (2-Aminoethyl) morpholine 162 1 [1.2 mmol] was added to 578 mg per batch, and the mixture was stirred at 72 ml for 10 hours. After cooling, the crude product was purified by column chromatography: silica gel: 30 g: eluate: n-hexane monoethyl acetate (1: 4) and chloroform-formyl-methanol (16: 1): 538 mg [96.5%] of the desired product (free base) [colorless solid] was obtained. This free base (19 mg) was dissolved in ethyl ether and treated with hydrogen chloride gas under ice-cooling to obtain hydrochloride (20 mg).
< Free Base>  <Free Base>
T L C [シリ力ゲル；クロロホルムーメタノ ール（7： 1 )：: Rf = 0.59 TLC [silica gel; chloroform-methanol (7: 1) :: Rf = 0.59
MR[90 MHz, CDC13]5 : 0.88(3H,t), 1.25(32H,s), 2.38〜2.58 " (6H.m), 3.03〜3.38(4H,m), 3.45(3H,s), 3.49〜3.80(5H, m) , 4.19 (4H,d), 4.8KlH.br.), 5.28(lH,br.) MR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.25 (32H, s), 2.38~2.58 " (6H.m), 3.03 to 3.38 (4H, m), 3.45 (3H, s), 3.49 to 3.80 (5H, m), 4.19 (4H, d), 4.8KlH.br.), 5.28 (lH, br .)
I RCKBrlcm-1: 3325, 2920, 2850, 1692, 1548, 1468, 1272, 1120 I RCKBrlcm- 1 : 3325, 2920, 2850, 1692, 1548, 1468, 1272, 1120
実施例 42 Example 42
2— 0—メチルー 3— 0— [2 ' —（N—メチルモリホリニォ）ェチル] 力ルバモイルー 1一 0—ォクタデシルカルバモイルグリセリ ン ' ョージ K  2— 0—Methyl- 3— 0— [2 '— (N-Methylmorpholino) ethyl] 1-O-octadecylcarbamoylglycerin
実施例 で合成した化合物（Free Base)22mg[0.039 ^ リモル]をェチル エーテル 1.5mlに溶解し、 ヨウ化メチル nmg[0.118ミ リモル]を加えた後、 遮光して室温にて 14日間放置した。 反応液を减圧濃縮し目的物 [無色粉 末] 27mg[98.9%]を得た。  22 mg [0.039 ^ remol] of the compound (Free Base) synthesized in Example was dissolved in 1.5 ml of ethyl ether, and nmg of methyl iodide [0.118 mimol] was added thereto. The reaction solution was concentrated under reduced pressure to obtain 27 mg [98.9%] of the target product [colorless powder].
T L C [シリ力ゲル；酢酸ェチルー酢酸一水，（3 : 1 : 1 ·)] :Rf=0.32 ^NTMR[90 MHz, CDC ]5 : 0.88(3H,t), 1.26(32H,s), 3.12(2H,q), 3.42(3H,s). 3.59(3H,s), 3.66〜4.33(13H， m) , 5.05(1H, br.) , 6.60 (IH.br.) TLC [silicone gel; ethyl acetate-acetic acid monohydrate, (3: 1: 1)]: Rf = 0.32 ^ N T MR [90 MHz, CDC] 5: 0.88 (3H, t), 1.26 (32H, s) , 3.12 (2H, q), 3.42 (3H, s) .3.59 (3H, s), 3.66 ~ 4.33 (13H, m), 5.05 (1H, br.), 6.60 (IH.br.)
I REKBrJcm"1: 3410, 2925, 2855, 1713. 1530, 1475, 1260 実施例 43' I REKBrJcm " 1 : 3410, 2925, 2855, 1713. 1530, 1475, 1260 Example 43 '
3— 0— [N—メ トキシカルボ二ルー N— ( 2 ' — N—メチルピロ リ ジ 二ォェチル）]力ルバモイルー 2— 0—メチルー 1 — 0—才クタデシルカ ルバモイルグリセリ ン · ョージ ド  3—0— [N—Methoxycarbonyl N— (2'—N—Methylpyrrolidiodiethyl)] Lubamoyl 2-—0—Methyl-1—0—Year-octadecylcarbamoylglycerin
i ) 3— 0— [N—メ トキシカルボニル- N- (2' —ピロ リ ジノエチル）] 力ルバモイル一 2— 0—メチル一 1 一 0—ォクタデシルカルバモイルグ リセリ ン  i) 3—0— [N-Methoxycarbonyl-N- (2′—pyrrolidinoethyl)] dirubamoyl-1 2—0—methyl1-110-octadecylcarbamoylglycerin
実施例 32で合成した化合物（Free Base) 813mg[ 1.5ミ リモル]及びト リエチルアミ ン 202mg[2 ミ リモル]を塩化メチレン 10mlに溶解し、 氷冷  813 mg [1.5 mimol] of the compound synthesized in Example 32 (Free Base) and 202 mg [2 mimol] of triethylamine were dissolved in 10 ml of methylene chloride, and ice-cooled.
差渙ぇ 下、 メチルクロ口ホルメ 一 ト 155〃 1[2 ミ リモル]を加えた後、 室温にて 3時間攪拌した。 反応液に 1 % NaHC03水溶液を加えてクロ口ホルム抽 出し、 有機層を硫酸マグネシウムにて乾燥し、 溶媒を減圧留去。 得られ た粗生成物をカラムク口マトグラフィ— [シリ力ゲル： 30g;溶出液：舴酸 ェチル—ァセ ト ン（1 : 2)]にて精製し、 目的物 [無色油状物] 734mg[8し 6 %]を得た。 Difference After addition of methyl chloroform form 155〃1 [2 mmol], the mixture was stirred at room temperature for 3 hours. Adding 1% NaHCO 3 aqueous solution to the reaction solution out black port Holm extraction, the organic layer was dried over magnesium sulfate, the solvent was removed under reduced pressure. The obtained crude product was purified by column chromatography—silica gel [30 g; eluent: ethyl acetate-aceton (1: 2)] to give 734 mg of the target product [colorless oil] [8 6%].
T L C [シリ力ゲル：クロロホルム一メタノ ール（5 : 1 )] Rf = 0.41 N R[90 MHz, CDC ] <5 · 0.85(3H, t) , 1.26(32H，s), 1.72(4H,m), 2.38~2.78(6H>m)> 3.14(2H,q), 3.43(3H,s), 3.62(1H( quint . ) , 3.80TLC [silicone gel: chloroform-methanol (5: 1)] Rf = 0.41 NR [90 MHz, CDC] <5 · 0.85 (3H, t), 1.26 (32H, s), 1.72 (4H, m) , 2.38 ~ 2.78 (6H > m) > 3.14 (2H, q), 3.43 (3H, s), 3.62 (1H ( quint.), 3.80
(3H,s), 3.83(2H,t), 4.08〜4.45(4H, m) , 5.08(lH,br.) (3H, s), 3.83 (2H, t), 4.08-4.45 (4H, m), 5.08 (lH, br.)
I R [filmlcm-1： 3370, 2930, 2860, 1800, 1760, 1735, 1705, 1540, 1475, 1455, 1362, 1298, 1255, 1225, 1200, 1150 ii ) 3— 0— [N—メ トキシカルボ二ルー N—（ 2 ' — N—メチルピロ リ ジニォェチル）]カルバ乇ィルー 2— 0—メチルー 1 — 0—ォクタデシル 力ルバモイルグリセリ ン · ョージ ド IR [filmlcm- 1 : 3370, 2930, 2860, 1800, 1760, 1735, 1705, 1540, 1475, 1455, 1362, 1298, 1255, 1225, 1200, 1150 ii) 3—0— [N—Methoxycarbonyl N— (2'—N-Methylpyrrolidinigoethyl)] carbaziru 2—0—Methyl-1—0—octadecyl rubamoylglycerin
i )で合成した化合物 694mg[1.567ミ リモル]をェチルエーテル 20mlに 溶解し、 ヨウ化メチル 493mg[3.471ミ リモル]を加えた後、 遮光して室温 にて 4日間放置した。 沈澱を泸取し、 目的物 [無色粉末] 757mg[65.1%] を得た。  694 mg [1.567 mimol] of the compound synthesized in i) was dissolved in 20 ml of ethyl ether, and 493 mg [3.471 mimol] of methyl iodide was added. The precipitate was collected by filtration to obtain 757 mg [65.1%] of the desired product [colorless powder].
T L C [シリカゲル；クロ口ホルム一メタノ ール（5： 1 )]:Rf = 0.16 MR [90 MHz, CDC ] <5： 0.88(3H,t), 1.28C32H.S), 2.32(4H)m)) TLC [silica gel; black form-methanol (5: 1)]: Rf = 0.16 MR [90 MHz, CDC] <5: 0.88 (3H, t), 1.28C32H.S), 2.32 (4H ) m) )
3.12(2H,q), 3.40(3H,s), 3.46(3H,s), 3.70〜4.03(iOH, ήι) , .20(4H, m), 4.38(2H,m), 5.07(lH,br.) 3.12 (2H, q), 3.40 (3H, s), 3.46 (3H, s), 3.70 ~ 4.03 (iOH, ήι), .20 (4H, m), 4.38 (2H, m), 5.07 (lH, br .)
I R [ BrJcm-1： 3430, 2925, 2850, 1795, 1750, 1721, 1700,IR [BrJcm- 1 : 3430, 2925, 2850, 1795, 1750, 1721, 1700,
1535, 1470, 1380, 1250, 1115 1535, 1470, 1380, 1250, 1115
実施例 44 Example 44
差換え 3— 0— [N—ァセチル一 — ( 1 ' —ェチルピロリ ジン一 2 ' —ィル） メチル]力ルバモイルー 2— 0—メチル— 1 — 0—ォクタデシルカルバ モイルグリセリ ン · ハイ ド口クロライ ド Replacement 3—0— [N-Acetyl-1— (1'—Ethylpyrrolidin-1-2'—Myl) methyl] bubamoyl 2-—0—Methyl—1—0—Octadecylcarbamoylglycerin hydride chloride
i ) 3 - 0 - [N - ( 1 ' 一ェチルピロ リ ジン一 2' —ィル）メチル]カル バモイルー 2— 0—メチル一 1 — 0—ォクタデシルカルバモイルグリセ リ ン  i) 3-0- [N- (1'-ethylpyrrolidine-1 2'-yl) methyl] carbamoyl 2--0-methyl-1 1-0-octadecylcarbamoylglycerin
2— 0—メチルー 1· 一 0—ォクタデシルカルバモイルグリセリ ン 803 mg[2 ミ リモル],フエニルクロロホルメ ー ト 345mg[2.2ミ リモル] ,ピリ ジ ン 317mg[4 mmol]及び塩化メチレン 5 mlより、 実施例 32と同様に合成し た粗カーボネー トに、 2— (アミ ノ メチル）一 1 一ェチルピロ リ ジン 347 〃 1[2.4ミ リモル]を加え、 窒素気流中 80°Cにて 16時間加熟した。 冷後、 粗生成物をカラムクロマ トグラフィー [シリカゲル： 50g;溶出液： n—へキ サン—詐酸ェチル（ 1 :4)及びクロ口ホルムーメタノ —ル（10:1)]にて精 製し、 目的物 [無色固形物] 1.066g[95.9%]を得た。 - 2-0-Methyl-1-1 0-octadecylcarbamoylglycerin 803 mg [2 mmol], phenyl chloroformate 345 mg [2.2 mmol], pyridine 317 mg [4 mmol] and methylene chloride 5 To the crude carbonate synthesized in the same manner as in Example 32, 2- (aminomethyl) -111-ethylpyrrolidine 347 〃 1 [2.4 mimol] was added to the crude carbonate in a nitrogen stream at 80 ° C. Ripened for hours. After cooling, the crude product was purified by column chromatography [silica gel: 50 g; eluent: n-hexane-ethyl acetate (1: 4) and chloroform-formum methanol (10: 1)]. 1.066 g [95.9%] of the target product [colorless solid] was obtained. -
T L C [シリ力ゲル；クロロホルムーメ タノ ール（10: 1 )] :Rf=0.22 MR [90 MHz, CDC13] 5： 0.88(3H,t), 1.10(3H,t)( 1.28(32H,s), 1.75(4H,m), 2.10〜 2.98(5H. m) , 3.19C4H.ni：, 3.46(3H,s), 3.60(1H, quint), 4.18(4H,d), 4.98C1H, br. t) , 5.4iCiH.br.) TLC [silica force gel; chloroform: main Tano Lumpur (10: 1)]: Rf = 0.22 MR [90 MHz, CDC1 3] 5: 0.88 (3H, t), 1.10 (3H, t) (1.28 (32H, s) , 1.75 (4H, m), 2.10-2.98 (5H.m), 3.19C4H.ni :, 3.46 (3H, s), 3.60 (1H, quint), 4.18 (4H, d), 4.98C1H, br.t ), 5.4iCiH.br.)
I R [KBrlcm-1: 3330, 2925, 2855, 1695, 1540, 1472, 1260 ii ) 3— [N—ァセチル— N—（ 1 ' —ェチルピロ リ ジン— ·2' —ィル） メチル]力ルバモイルー 2— 0—メチル— 1 — 0—ォクタデシルカルバ モイルグリセリ ン · ハイ ド口クロライ ド IR [KBrlcm- 1 : 3330, 2925, 2855, 1695, 1540, 1472, 1260 ii) 3— [N-Acetyl-N— (1'-Ethylpyrrolidine- · 2'-yl) methyl] — 0—Methyl— 1—0—Octadecylcarbamoylglycerin / Hide mouth chloride
i：)で合成した化合物 921mg[1.657ミ リモル]をク口口ホルム 20mlに溶 解し、 無水き乍酸 4 ml, トリェチルァミ ン 20mlを加えた後、 80〜100° にて 24時間加熱還流した。 冷後、 反応液を減圧濃縮し、 残渣に l %NaHC03水 溶液を加えてクロ口ホルム抽出。 有機層を硫酸マグネシウムにて乾燥後、 URt921 mg [1.657 mimol] of the compound synthesized in i :) was dissolved in 20 ml of stomal form, 4 ml of anhydrous acid and 20 ml of triethylamine were added, and the mixture was heated and refluxed at 80 to 100 ° for 24 hours. . After cooling, the reaction mixture was concentrated under reduced pressure, the residue was added with l% NaHCO 3 aqueous solution Black port Holm extraction. After drying the organic layer over magnesium sulfate, URt
_ OMP 纖ぇ 溶媒を減圧留去し、 得られた粗生成物をカラムク口マトグラフィー [シ リ力ゲル： 50g;溶出液： S乍酸ェチル—ァセ ト ン（1 ： 1 )]にて精製し、 目的 物（Free Base) [無色油状物] 948mg[95.7%]を得た。 この Free Base 50mg をェチルエ-テルに溶解し、 氷冷下、 塩化水素ガスにて処理し、 塩酸塩 _ OMP Fiber The solvent was distilled off under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel: 50 g; eluent: ethyl ethyl acetate-S (1: 1)). (Free Base) [colorless oil] 948 mg [95.7%] was obtained. Dissolve 50 mg of this Free Base in ethyl ether, treat with hydrogen chloride gas under ice-cooling, and hydrochloride
53mgを得た。 53 mg were obtained.
< Free Base>  <Free Base>
T L C [シリ力ゲル；ク口口ホルムーメ タノ 一ゾレ（5： 1 )]:Rf=0.56  T L C [Sili force gel; ku mouth mouth horumome tano one zole (5: 1)]: Rf = 0.56
NMRC90 MHz, CDC ]<5 : 0.88(3H,t), 1.10(3H,t), 1.26(32H,s), NMRC90 MHz, CDC] <5: 0.88 (3H, t), 1.10 (3H, t), 1.26 (32H, s),
1.72(4H,m), 2.16〜2.98(5H,m) , 2.50(3H,s), 3.15(2H,q), 3.45(3H, s), 3.64(1Η,πι), 3.80(2H,d), 4.08〜4.40(4H,m)， 4.92(lH,br.) 1.72 (4H, m), 2.16 ~ 2.98 (5H, m), 2.50 (3H, s), 3.15 (2H, q), 3.45 (3H, s), 3.64 (1Η, πι), 3.80 (2H, d) , 4.08-4.40 (4H, m), 4.92 (lH, br.)
I R [filmjcm-1: 3330, 2930, 2850, 1740, 1710, 1535, 1470,IR [filmjcm- 1 : 3330, 2930, 2850, 1740, 1710, 1535, 1470,
1375. 1250, 1220, 1175, 1140 1375.1250, 1220, 1175, 1140
実施例 45 Example 45
3— 0— [N—ァセチル— N— ( 1 ' —ェチルー 一メチルピロ リ ジ ニォ— 2' —ィル）メチル]力ルバモイル一 2— 0—メチルー 1 一 0—ォ クタデシルカルバモイルグリセリ ン . ョージ ド  3—0— [N-Acetyl—N— (1′—Ethyl-methylpyrrolidinio—2′—yl) methyl] rubumamoyl 1—2—0—Methyl-11—0—Octadecylcarbamoylglycerin. Do
実施例 44一 ii )で合成した化合物（Free Base) 607mg[l.015ミ リモル] をェチルエーテル 12mUこ溶解し、 ヨウ化メチル 432mg[3.046ミ リモル]を 加えた後、 遮光して室温にて 5日間放置した。反応液に石油エーテルを 加えて析出した沈殿を炉取し、目的物 [無色粉末] 622mg[82.8%]を得た。  Example 44 607 mg [l.015 mimol] of the compound synthesized in 1ii) (Free base) was dissolved in 12 mU of ethyl ether, and 432 mg [3.046 mimol] of methyl iodide was added. Left for days. Petroleum ether was added to the reaction solution, and the resulting precipitate was collected by furnace to obtain 622 mg [82.8%] of the target product [colorless powder].
T L C [シリカゲル；クロ口ホルム一メ タノ ール（ 3： 1 )]： R f = 0.47  TLC [silica gel; black form-methanol (3: 1)]: Rf = 0.47
NrMR[90 MHz, CDC13]<5 : 0.88(3H,t), 1.26(32H,s), 1.48(3H,t) 1.90〜2.40(4H，m), 2.53(3H,s), 3. i2(5H,m), 3.47(3H,s), 3.60- 4.56(12H,m), 5.15(lH,br.) N r MR [90 MHz, CDC1 3 ] <5: 0.88 (3H, t), 1.26 (32H, s), 1.48 (3H, t) 1.90 ~ 2.40 (4H, m), 2.53 (3H, s), 3 .i2 (5H, m), 3.47 (3H, s), 3.60- 4.56 (12H, m), 5.15 (lH, br.)
I R [KBrlcni-1： 3450, 2920, 2850, i755〜1705, 1470, 1260, 1220, 1200 IR [KBrlcni- 1 : 3450, 2920, 2850, i755-1705, 1470, 1260, 1220, 1200
ΟΛΡΙ ヽ 実施例 46 ΟΛΡΙ ヽ Example 46
2— 0—メチルー 3— 0— [( 1 —メチルピリ ジニォ一 2 ' —ィル） メチル]力ルバモイルー 1 一 0—才クタデシルカルバモイルグリセリ ン • 3—ジ ド  2—0—Methyl-3—0 — [(1—Methylpyridinone 1'—yl) methyl] caprolubamoyl 1—0—Cutadecylcarbamoylglycerin • 3-Zide
i ) 2— 0—メチル— 3— 0— [N— (2' —ピリ ジルメチル）]カルバモ ィル— 1— 0—ォクタデシルカルバモイルグリセリ ン  i) 2—0—methyl—3—0— [N— (2′—pyridylmethyl)] carbamoyl—1—0—octadecylcarbamoylglycerin
2— 0—メチル - 1 - 0 -ォクタデシルカルバモイルグリセリ ン 402mg [ 1 ミ リモル]，フエニルクロロホルメ一 ト 172mg[l Jミ リモル],ピリ ジン 158 mg:2 ミ リモル]及び塩化メチレン 3mlより合成した粗カーボネ— ト 567 mgに 2— (アミ ノ メチル）ピリ ジン 122〃 1 [1.2ミ リ乇ル]，クロ口ホルム 1 mlを加え、 12時間加熱還流した。 反応液を減圧濃縮し、 '得られた粗生成 物をカラムク口マ トグラフィー [シリ力ゲル； 20g;溶出液： η—へキサン— 詐酸ェチル（1 : 3)]にて精製し、 目的物 [無色固形物] 454mg[84.7%]を 得た。  2-0-Methyl-1-0-octadecylcarbamoylglycerin 402 mg [1 mimol], phenyl chloroformate 172 mg [l J mimol], pyridine 158 mg: 2 mimol, and methylene chloride To 567 mg of the crude carbonate synthesized from 3 ml, 2- (aminomethyl) pyridine 122〃1 [1.2 mmol] and 1 ml of chloroform were added, and the mixture was heated under reflux for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography [silica gel; 20 g; eluent: η-hexane-ethyl acetate (1: 3)]. [Colorless solid] 454 mg [84.7%] was obtained.
T L C [シリカゲル;' n—へキサン—酢酸ェチル（ 1 ： 3 )] :Rf=Q.21 NMR[90 MHz, CDC13] 5： 0.87(3H,t), 1.25(32H,s), 3.15(2H,q), 3 43(3H,s), 3.59(iH,quint), 4.18(4H,tn), 4.50(241,(1), 4.90(iH, br .), 6.00(lH,br.), 7.22(2H,m), 7.65(lH,m), 8.52(lH,m) TLC [silica gel; 'n-hexane - acetic acid Echiru (1: 3)]: Rf = Q.21 NMR [90 MHz, CDC1 3] 5: 0.87 (3H, t), 1.25 (32H, s), 3.15 ( 2H, q), 343 (3H, s), 3.59 (iH, quint), 4.18 (4H, tn), 4.50 (241, (1), 4.90 (iH, br.), 6.00 (lH, br.) , 7.22 (2H, m), 7.65 (lH, m), 8.52 (lH, m)
I R [KBrjci-1: 3320, 2925, 2850, 1695, 1535, 1470, 1260, 1250 IR [KBrjci- 1 : 3320, 2925, 2850, 1695, 1535, 1470, 1260, 1250
Π ) 2— 0—メチル— 3— 0— [( 1 ' —メチルピリ ジニォ一 2 ' —ィル メチル]力ルバモイルー 1 — 0—ォクタデシルカルバモイルグリセリ ン ♦ ョージ ド  )) 2— 0—Methyl— 3— 0 — [(1 '—Methylpyridinone-1'-ylmethyl] -powerbamoyl 1 — 0—Octadecylcarbamoylglycerin ♦
i：)で合成した化合物 n0mg[0.317ミ リモル]をク口口ホルム 0.5ml,ェ チルエーテル 6 mlに溶解し、 ヨウ化メチル 135mg [0.952ミ リモル]を加え た後、 遮光して室温にて 14日間放置した。 折出した沈殿を泸取し、 目的  Compound (n0mg [0.317 mimol]) synthesized in i :) was dissolved in Kuguchiguchi form (0.5 ml) and ethyl ether (6 ml), and methyl iodide (135 mg [0.952 mimol]) was added. Left for days. Remove the deposited sediment, and
差換え 物（淡黄色粉末）i23mg[57.i%]を得た。 Replacement (Light yellow powder) i23 mg [57.i%] was obtained.
T L C [シリカゲル；クロ口ホルム一メタノ ール（ 3： 1 )]： R' f = 0.20 NMRC90 MHz, CDC ] 5： 0.87(3H,t), 1.24(32H,s), 3.12(2H,q), TLC [silica gel; black form-methanol (3: 1)]: R 'f = 0.20 NMRC90 MHz, CDC] 5: 0.87 (3H, t), 1.24 (32H, s), 3.12 (2H, q) ,
3.42(3H,s)(3.59(iH(quint), 4.i5(4H,m)， 4.5 (3H,S), 4.89(2H,d)，3.42 (3H, s) ( 3.59 (iH ( quint), 4.i5 (4H, m), 4.5 (3H, S), 4.89 (2H, d),
5.20(lH,br.)， 7.04(1H, br. ) , 7.85〜8.23(2H, m) , 8.46(1H, t) , 9.195.20 (lH, br.), 7.04 (1H, br.), 7.85 to 8.23 (2H, m), 8.46 (1H, t), 9.19
(lH,d) (lH, d)
1 R [KBrjcm-1: 3340, 2920, 2850, 1698, 1635, 1530, 1470, 1260 1 R (KBrjcm- 1 : 3340, 2920, 2850, 1698, 1635, 1530, 1470, 1260
実施例 47 ' Example 47 '
2— 0—ァセチルー 3— 0—ォクタデシル— 1 — 0— [N—ァセチル — N— (2 ' — ト リメチルァン乇ニォェチル）]力ルバモイルグリセリ ン • ク σリ ド  2—0—acetyl—3—0—octadecyl—1—0— [N—acetyl—N— (2'—trimethylpandenoethyl)] force rubamoylglycerin
実施例 3で得たョ―ジ ド 342mg(0.5ミ リモル）を 70%メ タノ —ル 20mlに 瑢かし I R A— 410(C1— )ィォン交換樹脂に通し、 少量の 70%メタノ — ルにて洗い、 溶出液.洗液を合せて、 '减圧下に濃縮乾固し、 残渣をェチ ルエーテル 5 mlより再結晶して無色粉末 289mg (収率 97.5%)を得た。  342 mg (0.5 mmol) of the halide obtained in Example 3 was poured into 20 ml of 70% methanol and passed through an IRA-410 (C1-) ion exchange resin, and a small amount of 70% methanol was used. The combined washings were concentrated and dried under reduced pressure, and the residue was recrystallized from 5 ml of ethyl ether to give 289 mg of a colorless powder (yield 97.5%).
元素分折： C31H81N20eC卜 H20 Elemental folding: C 31 H 81 N 2 0eC Bok H 2 0
計算値： C , 60.91 H.10.39 ,4.58 Cl,5.80  Calculated value: C, 60.91 H.10.39, 4.58 Cl, 5.80
実験値： C .60.98 H.11.03 N ,4.54 Cl,5.82  Experimental value: C .60.98 H.11.03 N, 4.54 Cl, 5.82
実施例 48 Example 48
2— 0—メチルー 3— 0—ォクタデシルカルバモイルー 1 一 0— [N —ァセチル— N— (2' — ト リメチルァンモニォェチル）]力ルバ乇ィル グリセリ ン · クロ リ ド  2—0—Methyl-3—0—Octadecylcarbamoyl 1 1—0— [N—Acetyl—N— (2′—Trimethylammonioethyl)] capillary glyceryl chloride Do
実施例 25で得たィォダイ ド 350mg(0.5ミ リモル）を実施例 47と同様処理 し、 アセ ト ン 1 ml,エーテル 4 mlの混液より再結晶して、 無色結晶 297mg (収率 97.7%)を得た。 元素分折 C3iH61N 206Cl-H20 350 mg (0.5 mmol) of the iodide obtained in Example 25 was treated in the same manner as in Example 47, and recrystallized from a mixture of 1 ml of acetate and 4 ml of ether to obtain 297 mg of colorless crystals (yield 97.7%). Obtained. Element analysis C3iH 61 N 2 0 6 Cl-H 2 0
計算値： C 59.45 H.10.30 N,6.71 CI, 5.66  Calculated value: C 59.45 H.10.30 N, 6.71 CI, 5.66
C 59.56 H.10.58 N.6.71 CI, 5.68  C 59.56 H.10.58 N.6.71 CI, 5.68
実施例 49 Example 49
1 一 0— (3—ジメチルァミノ プロピル）力ルバモイルー 2— 0—メチ  1 1 0— (3-dimethylaminopropyl) rubamoyl 2—0—methyl
ルー 3— 0—ォクタデシルカルバ乇ィルグリセリ ン Lou 3—O—octadecylcarbazylglycerin
1 — 0—ォクタデシルカルバモイルー 2— 0—メチル一 3— 0—フエ  1 — 0—Octadecylcarbamoyl 2—0—Methyl-1 3—0—Hue
ノキシ力ルポニルグリセリ ン 1.5gg(2 Jミ リモル）に asym-ジメチルジァ Asym-dimethyl diamine to 1.5 gg (2 J mimol) of nonoxyl ponylglycerin
ミノプロパン 355mg(3.48ミ リモル）を加え、 70°C , 5時間加熟する。 反応 Add 355 mg (3.48 mimol) of minopropane and ripen at 70 ° C for 5 hours. Reaction
液をシリカゲル（28g)に吸着，クロロホルム，メタノ—ル（19: 1 )にて溶出 The solution is adsorbed on silica gel (28g) and eluted with chloroform and methanol (19: 1)
して、 溶出液を減圧下に濃縮乾固して、 残渣をアセトンより再結晶して The eluate was concentrated to dryness under reduced pressure, and the residue was recrystallized from acetone.
無色結晶 1.53g (収率 H)0%)を得た。 1.53 g of colorless crystals (0% yield H) were obtained.
T L C ,silicagel,n-BuOH, .AcOH, H20(4 : 1 : 1 )Rf=0.31 TLC, silicagel, n-BuOH, .AcOH, H 2 0 (4: 1: 1) Rf = 0.31
I R(KBr)cm-1 : 3330, 2920, 2850, 2750, ' 1690, 1530, 1470, IR (KBr) cm- 1 : 3330, 2920, 2850, 2750, '1690, 1530, 1470,
1275, 1260, 1250, 1230, 1140, 1100, 1070,  1275, 1260, 1250, 1230, 1140, 1100, 1070,
1040  1040
NMR(60 MC, CDC13)(5： 0.88(3H) 1.25(32H) 2.22(6H) 2.37(2H) NMR (60 MC, CDC1 3) (5: 0.88 (3H) 1.25 (32H) 2.22 (6H) 2.37 (2H)
3.20C4H) 3.45(3H) 3.72(1H) 4.17(4H) 4.67(iH) 5 57(1H)  3.20C4H) 3.45 (3H) 3.72 (1H) 4.17 (4H) 4.67 (iH) 5 57 (1H)
実施例 5Q Example 5Q
2— 0—メチル一 3— 0—ォクタデシルカルバモイル— 1 一 0—（3  2— 0—Methyl-1 3-0—Octadecylcarbamoyl— 1 1 0— (3
— トリメチルアンモニォプロピル）力ルバモイルグリセリ ン-ィォダイ ド — Trimethylammoniopropyl) lubamoylglycerin-idide
実施例 49で得たジメチルァミノ プロピル体 450mg(0.85ミ リモル）をョ  450 mg (0.85 mmol) of the dimethylaminopropyl derivative obtained in Example 49
ゥ化メチル 1 mlに溶かし、 室温にて 18時間放置して、 反応液を減圧下に Dissolve in 1 ml of methyl dichloride and leave at room temperature for 18 hours.
濃縮乾固する。 残渣をァセトン 1 ml,エーテル 4mlより再結晶して無色 Concentrate to dryness. The residue was recrystallized from 1 ml of acetone and 4 ml of ether to be colorless.
粉末50711^(収率88.8%)を得た。 Powder 50711 ^ (yield 88.8%) was obtained.
T L C ,silicagel,n-BuOH, AcOH, H20(4： 1: l)Rf = 0.27 TLC, silicagel, n-BuOH, AcOH, H 2 0 (4: 1: l) Rf = 0.27
,HJ ヒ , HJ
C/V.p: 、 ん I R(KBr)cm-1; 3300, 2920, 2850, 1695, 1430, 1465, 1260, 1150 -C / Vp: IR (KBr) cm- 1 ; 3300, 2920, 2850, 1695, 1430, 1465, 1260, 1150-
N.MR(60 MC, CDC13)5 :0.87(3H) 1.25(32H) 2.18(2H) 3.17 N.MR (60 MC, CDC1 3) 5: 0.87 (3H) 1.25 (32H) 2.18 (2H) 3.17
(4H) 3.38C9H) 3.43(3H) 3.63(1H) 3.78(2H) 4.15(4H) 5.07 (1H) 6.07(1H)  (4H) 3.38C9H) 3.43 (3H) 3.63 (1H) 3.78 (2H) 4.15 (4H) 5.07 (1H) 6.07 (1H)
元素分折： C3。H 82N 205 I— 1.2H20 Elemental fold: C 3. H 8 2 N 2 0 5 I— 1.2H 2 0
計算値： C，51.97 - H.9.36 ,6.06 .  Calculated: C, 51.97-H.9.36, 6.06.
実験値： C, 51.93 H.9.38 N.6.31  Experimental value: C, 51.93 H.9.38 N.6.31
実施例 51 Example 51
1 一 0— (N—ジメチルァミ ノェチルー N—プロピオニル）カルバモィ ル— 2— 0—メチルー 3— 0—ォクタデシルカルバモイルグリセリ ン 実施例 9で得たジメチルアミ ノェチル体 516mg( 1 ミ リモル）をジク口 ロメタ ン 1 mlに溶かし、 プロピオニルク口 リ ド 185mg(2 ミ リモル），ピリ ジン 395mgを加え室温にて 64時間放置した。 反応液に炭酸水素ナトリゥ- ム 500mgを含む水 10ml，ジクロロメ タン 9 mlを加え、 しばらくかきまぜた 後、 静置して、 ジクロロメタン層を分取した。 ジクロロメタン層は無水 硫酸ナトリゥムで乾かし減圧下に濃縮乾固してシリカゲル（10g)を用い、 精製した。 クロ口ホルム，メタノ ―ル（19: 1 )にて展開し無色油状物質 560mg (収率 98.1%)を得た。  1 0— (N-dimethylaminoethyl-N-propionyl) carbamoyl—2-0-methyl-3-0-octadecylcarbamoylglycerin 516 mg (1 mmol) of the dimethylaminoethyl compound obtained in Example 9 And 185 mg (2 mmol) of propionyl chloride and 395 mg of pyridine were added, and the mixture was left at room temperature for 64 hours. To the reaction solution, 10 ml of water containing 500 mg of sodium hydrogen carbonate and 9 ml of dichloromethane were added, and the mixture was stirred for a while, then allowed to stand, and a dichloromethane layer was separated. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and purified using silica gel (10 g). The mixture was developed with chloroform and methanol (19: 1) to obtain 560 mg of a colorless oil (yield: 98.1%).
T L C .silicagel, CHCl3, eOH(5:l)Rf = 0.25 単一スポッ ト TLC .silicagel, CHCl 3 , eOH (5: l) Rf = 0.25 single spot
I R [film] cm"1 :3350, 2930, 2850, 1735, 1710, 1675, 1520, IR [film] cm " 1 : 3350, 2930, 2850, 1735, 1710, 1675, 1520,
1460, 1370, 1260, 1175  1460, 1370, 1260, 1175
NMR(60 MC, CDC13)5 :0.90(3H) 1.25(32H) 1.17(3H) 2.28(6H) 2.43C2H) 2.66C2H) 3.08(2H) 3.43C3H) 3.72(1H) 3.92(2H) 4.18(2H) 4.30(2H) 5.33(1H) NMR (60 MC, CDC1 3) 5: 0.90 (3H) 1.25 (32H) 1.17 (3H) 2.28 (6H) 2.43C2H) 2.66C2H) 3.08 (2H) 3.43C3H) 3.72 (1H) 3.92 (2H) 4.18 (2H ) 4.30 (2H) 5.33 (1H)
差換え 実施例 52 Replacement Example 52
2— 0—メチルー 3— 0—ォクタデシルカルバモィルー 1 — 0— [N -プロピオニル— N— (2' — トリメチルァンモニォェチル）]カルバ乇 ィルグリセリ ン · ョ一ジ ド  2—0—Methyl-3—0—Octadecylcarbamoyl 1—0— [N-Propionyl—N— (2′—Trimethylammonioethyl)] carbazylglycerin
実施例 51で得たプロピオニル体 560mg(0.98ミ リモル）をヨウ化メチル 2mlに溶かし室温にて一夜放置後、 減圧下に濃縮乾固して、 残渣をエ- テル 8 mlより再結晶して淡黄色粉末性結晶 453mg (収率 64.7%)を得た。  560 mg (0.98 mmol) of the propionyl compound obtained in Example 51 was dissolved in 2 ml of methyl iodide, allowed to stand at room temperature overnight, concentrated to dryness under reduced pressure, and the residue was recrystallized from 8 ml of ether to obtain pale 453 mg (yield 64.7%) of yellow powdery crystals were obtained.
T L C .silicagel, n-BuOH, AcOH, H20(4: 1： l)Rf = 0.24 TLC .silicagel, n-BuOH, AcOH , H 2 0 (4: 1: l) Rf = 0.24
I R(KBr)cm-1: 3320, 2S20, 2850, 1700, 1530, 1470, 1370, IR (KBr) cm- 1 : 3320, 2S20, 2850, 1700, 1530, 1470, 1370,
1270, 1200, 1150  1270, 1200, 1150
NMR(60 MC, CDC13)<? : 0.83(3H) 1.13(3H) 1.28C32H) 2.93(2H) NMR (60 MC, CDC1 3) <:? 0.83 (3H) 1.13 (3H) 1.28C32H) 2.93 (2H)
3.09(2H) 3.47(3H) 3.5δ(9Η) 3.80(1H) 3.90(2H) 4.22 (2H) 4.30C2H) 4.40(2H) 5.07(1H)  3.09 (2H) 3.47 (3H) 3.5δ (9Η) 3.80 (1H) 3.90 (2H) 4.22 (2H) 4.30C2H) 4.40 (2H) 5.07 (1H)
元素分圻： C32He4N3Oe I - 2.6H20 Elemental 圻: C 32 He 4 N 3 O e I - 2.6H 2 0
計算値： C，50.53 H.9.17 N ,5."52  Calculated value: C, 50.53 H.9.17 N, 5. "52
実験値： C, 50.49 H.8.89 ,δ.97.  Experimental values: C, 50.49 H.8.89, δ.97.
実施例 53 Example 53
1 — 0—（N—ジメチルァ：' ノエチル一 N—メチルカルバモイル）カル バモイル— 2— 0—メチル— 3— 0—才クタデシルカルバモイルグリセ リ ン  1 — 0— (N-dimethyla: 'noethyl-1-N-methylcarbamoyl) carbamoyl— 2—0—methyl—3—0—year-old octadecylcarbamoylglycerin
実施例 9で得たジメチルァミ ノェチル体 500mg(0.97ミ リモル）をメチ ルイソシアナー ト 1 mi,クロロホルム 1 ml,の混液に溶かし 60°C, 6時間 かきまぜて、 反応液を減圧下に濃縮乾固した。 残渣をシリカゲルカラム (10g)展開液クロ口ホルム，メタノ ール（9： 1 )にて精製して無色油状物 質 500tng (収率 90.0%)を得た。  500 mg (0.97 mmol) of the dimethylaminoethyl derivative obtained in Example 9 was dissolved in a mixture of 1 mi of methyl isocyanate and 1 ml of chloroform, stirred at 60 ° C. for 6 hours, and concentrated to dryness under reduced pressure. The residue was purified with a silica gel column (10 g) as eluant, chloroform and methanol (9: 1) to obtain 500 tng of a colorless oil (yield 90.0%).
T L C .silicagel, CHCl3,MeOH(o:l)Rf = 0.70 単一スポ 'ソ ト TLC .silicagel, CHCl 3 , MeOH (o: l) Rf = 0.70 Single spot
差換え 1 R(film)cm-1:3350, 2930, 2850, 1725, 1700, 1525, 1470,Replacement 1 R (film) cm- 1 : 3350, 2930, 2850, 1725, 1700, 1525, 1470,
1420, 1205, 1240, 11901420, 1205, 1240, 1190
MRC60 MC, CDC )  MRC60 MC, CDC)
<5 :0.88(3H) 1.25C32H) 2.27(6H) 2.50(2H) 2.83C3H) 3.22  <5: 0.88 (3H) 1.25C32H) 2.27 (6H) 2.50 (2H) 2.83C3H) 3.22
(2H) 3.43C3H) 3.60(1H) 3.88(2H) 4.17(2H) 4.27(2H) 5.77C1H) 8.42C1H)  (2H) 3.43C3H) 3.60 (1H) 3.88 (2H) 4.17 (2H) 4.27 (2H) 5.77C1H) 8.42C1H)
実施例 54 Example 54
2— 0—メチル— 1— 0— [N—メチルカルバモイルー N - (2 ' — ト リメチルァンモニォェチル）]カルパモイルー 3— 0—ォクタデシルカル バ乇ィルグリセリ ン · クロ リ ド  2—0—Methyl—1—0— [N-Methylcarbamoyl-N-(2'-trimethylammonioethyl)] carpamoyl 3—0—Octadecylcarbylglycerine chloride
実施例 53で得たメチルカルバモイル体 50 Omg (0.87ミ リモル）を実施例  The methylcarbamoyl derivative 50 Omg (0.87 mimol) obtained in Example 53 was used in the Example.
52と同様にしてメチル化して，さ らに I R A— 410(C1— )30mlのカラムを 通過させて塩形を変え、 目的物（無色粉末性結晶） 327mg (収率 60.3%)を 得た。 Methylation was performed in the same manner as in 52, and the mixture was passed through a 30 ml column of IRA-410 (C1-) to change the salt form, thereby obtaining 327 mg (yield 60.3%) of the target compound (colorless powdery crystals).
T L C .silicagel, n-BuOH, AcOH, H20(4： 1： l)Rf = 0.27 1 spot TLC .silicagel, n-BuOH, AcOH, H 2 0 (4: 1: 1) Rf = 0.27 1 spot
I RCKBr)cm-1: 3350, 2920, 2850, 1730, 1700 (sh.) 1695, I RCKBr) cm- 1 : 3350, 2920, 2850, 1730, 1700 (sh.) 1695,
1530, 1470, 1255, 1210, 1050 1530, 1470, 1255, 1210, 1050
MR(60 MC, CDC )  MR (60 MC, CDC)
δ： 0.88C3H) 1.25C32H) 2.87(3H) 3.10(2H) 3.45(3H) δ: 0.88C3H) 1.25C32H) 2.87 (3H) 3.10 (2H) 3.45 (3H)
3.5K9H) 3.75(1H) 3.87(2H) 4.17(2H) 4.26(2H)3.5K9H) 3.75 (1H) 3.87 (2H) 4.17 (2H) 4.26 (2H)
4.37C2H) 5.45(1H) 8.33(1H) 4.37C2H) 5.45 (1H) 8.33 (1H)
実施例 55 Example 55
1 - 0 - [iNT - (2 ' ージメチルアミ ノエチル）一 N—メ トキシカルボ ニル]力ルバモイル— 2— 0—メチルー 3— 0—ォクタデシルカルバモ ィルグリセリ ン 1 - 0 - [iN T - (2 ' Jimechiruami aminoethyl) Single N- menu Tokishikarubo sulfonyl] force Rubamoiru - 2- 0- methyl-3-O-O Kuta decyl carba mode Iruguriseri down
実施例 9で得たジメチルァミ ノェチル体 500tng(0.97ミ リモル））をク口  500 tng (0.97 mimol) of the dimethylaminoethyl derivative obtained in Example 9
_ :-.f-i ― 差換え . 口ホルム 1 mlに溶かしクロロメチルフォーメイ ト 0.5gを加え，氷冷下に トリェチルアミ ン Q.5mlを滴々に加えた。 反応液を減圧下に濃縮乾固し て、 残渣に 5 %炭酸水素ナトリウム水 20ml,エーテル 20mlを加え、 よく かきまぜた後、 エーテル層を分取して、 エーテル層を硫酸ナトリウムで 乾かし、 濃縮乾固した。 _:-. fi-Replacement. Dissolved in 1 ml of mouth form, added 0.5 g of chloromethylformate, and added dropwise 5 ml of triethylamine under ice-cooling. The reaction mixture is concentrated to dryness under reduced pressure, 20 ml of 5% aqueous sodium hydrogen carbonate and 20 ml of ether are added to the residue, and the mixture is stirred well.The ether layer is separated, the ether layer is dried over sodium sulfate, and concentrated to dryness. Hardened.
残渣をシリ力ゲル 10g,展開液，ク口口ホルム，メタノ —ル（19: 1：)にて 精製し、 目的物を無色油状物質 35flmg (収率 62.9%)として得た。  The residue was purified by silica gel 10g, eluent, chloroform, and methanol (19: 1 :) to give the desired product as a colorless oil 35flmg (62.9% yield).
T L C .silicagel, CHC13, MeOH(5： 1 )Rf = 0.75 単一スポッ ト I R(film)cm-1: 3350 , 2920, 2850, 1790, 1750(sh.) 1725, TLC .silicagel, CHC1 3, MeOH ( 5: 1) Rf = 0.75 single spot IR (film) cm- 1: ( . Sh) 3350, 2920, 2850, 1790, 1750 1725,
1710, 1530, 1470, 1360, 1290, 1250, 1180, 1160, 1110  1710, 1530, 1470, 1360, 1290, 1250, 1180, 1160, 1110
NMR(60 MC, CDCl3) NMR (60 MC, CDCl 3 )
δ :0.88(3H) 1.25C32H) 2.25(6H) 2.48(2H) 3.10(2H) 3.4δ(3Η) 3.67C1H) 3.82(3H) 4.20(2H) 4.30(2H) 5.03(iH)  δ: 0.88 (3H) 1.25C32H) 2.25 (6H) 2.48 (2H) 3.10 (2H) 3.4δ (3Η) 3.67C1H) 3.82 (3H) 4.20 (2H) 4.30 (2H) 5.03 (iH)
実施例 56 Example 56
2— 0—メチルー 1— 0— [N—メ トキシカルボ二ルー N— (2' — ト リメチルアンモニォェチル）]力ルバモイル— 3— 0—才クタデシルカル バモイルグリセリ ン · ィオダイ ド  2—0—Methyl- 1—0— [N—Methoxycarbonyl N— (2′—Trimethylammonioethyl)] capsulebamoyl—3—0—Cactadecylcarbamoylglycerin iodide
実施例 55で得たメ トキシカルボニル体 320mg(0.56ミ リモル）を実施例 52と同様に処理し、 目的物（無色粉末） 327mg (収率 81.6%)を得た。 ' 320 mg (0.56 mmol) of the methoxycarbonyl compound obtained in Example 55 was treated in the same manner as in Example 52 to obtain 327 mg (yield: 81.6%) of the target product (colorless powder). '
T L C .silicagel, n-BuOH, AcOH, H20(4： 1 ： 1 )Rf = 0.27 TLC .silicagel, n-BuOH, AcOH, H 2 0 (4: 1: 1) Rf = 0.27
I R(KBr)cm-1: 3400, 2920, 2850, 1800, 1760 , 1710, 1535, IR (KBr) cm- 1 : 3400, 2920, 2850, 1800, 1760, 1710, 1535,
1470, 1480, 1260, 1210, 1150, 1105 1470, 1480, 1260, 1210, 1150, 1105
MR(60 MC, CDCls)  MR (60 MC, CDCls)
δ： 0.88C3H) 1.27C32H) 3.22(2H) 3.45(3H) 3.55(9H) 3.78  δ: 0.88C3H) 1.27C32H) 3.22 (2H) 3.45 (3H) 3.55 (9H) 3.78
. 一 OMPi 差換え C1H) 3.90C3H) 4.13C2H) 4.20(2H) 4.38(2H) 4.97(1H) 元素分折： C3 lHS2N307 I -1.5H20 . One OMPi replacement C1H) 3.90C3H) 4.13C2H) 4.20 (2H) 4.38 (2H) 4.97 (1H) Elemental analysis: C 3 l H S2 N 3 0 7 I -1.5H 2 0
計算値： C , 50.13 H ,8.82 N ,5.66 · 実験値： C , 49.89 H.8.92 N.5.87  Calculated value: C, 50.13 H, 8.82 N, 5.66 · Experimental value: C, 49.89 H.8.92 N.5.87
実施例 57 Example 57
1 - 0 - [ - (2 ' —ジメチルアミ ノエチル）一 N—フエノキシカル ボニル]力ルバモイルー 2— 0—メチル— 3— 0—ォクタデシルカルバ モイルグリセリ ン  1-0-[-(2'-Dimethylaminoethyl) -N-phenoxycarbonyl] -l-bamoyl 2--0-methyl-3-0-octadecylcarbamoylglycerin
実施例 9で得たジメチルァ ミ ノェチル体 i.032mg(2 ミ リモル）をジク ロロメタ ン 5 mlに溶かし、 フエニルクロロホ一メイ ト 470mg(3 ミ リモル） を加え、 氷冷下ピリジン 633mg(8 ミ リモル）を滴々に加えて，室温 4時間 かきまぜる。 反応液にジクロ口メ タ ン 15mi，炭酸水素ナ ト リ ゥム 0.5gを 含む水 20mlを加えてよくふりまぜ、 ジクロロメ タ ン層を分取し、 硫酸ナ ト リ ウムにて乾かし、 '减圧下に濃縮乾固し、 目的物を得た。 収量 1.27g Dissolve i.032 mg (2 mmol) of the dimethylaminoethyl compound obtained in Example 9 in 5 ml of dichloromethane, add 470 mg (3 mmol) of phenylchloroformate, and 633 mg (8 mmol) of pyridine under ice cooling. And stir for 4 hours at room temperature. To the reaction mixture was added 20 ml of water containing 15 mi of dichloromethane and 0.5 g of sodium hydrogen carbonate, and the mixture was shaken well. The dichloromethane layer was separated and dried over sodium sulfate. It was concentrated to dryness under pressure to obtain the desired product. Yield 1.27g
(収率 100%) (100% yield)
実施例 58 Example 58
ί - 0 - [ - (2 ' ージメチルアミ ノエチル）一 Ν—ピロ リ ジノ カル ボニル]力ルバモイルー 2— 0—メチル— 3— 0—ォクタデシルカルバ 乇ィルグリセリ ン  ί-0-[-(2'-Dimethylaminoethyl) -1-pyrrolidinocarbonyl] dirubamoyl 2-0-methyl-3-0-octadecylcarbazylglycerin
実施例 57で得た，フエノキシカルボニル体 636mg( 1 ミ リモル）にピロ リ ジン G .5 miを加え 70て， 5時間かきまぜた。 反応液を'减圧下に濃縮乾固し て、 残渣をシリ力ゲル力ラム（10g),ク口口ホルム，メ タノ ール（19: 1 )に て展開し目的物（無色油状物質） 613mg (収率 100%)を得た。  To 636 mg (1 mimol) of the phenoxycarbonyl compound obtained in Example 57, pyrrolidine G (0.5 mi) was added, and the mixture was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was developed with siegel gel ram (10 g), porcine form, and methanol (19: 1), and the desired product (colorless oil) 613 mg (100% yield).
T L C .silicagel, CHC13, MeOH(5 ： 1 ) f=0.7o 単一スポッ ト I R(film)cm-1: 3350 2940 2850 1730 1690 1530 1470 1450 TLC .silicagel, CHC1 3, MeOH ( 5: 1) f = 0.7o single spot IR (film) cm- 1: 3350 2940 2850 1730 1690 1530 1470 1450
1400 1360 1260, 〖180, 1160, 1110  1400 1360 1260, 〖180, 1160, 1110
0 :PI0: PI
、Ί W WiiFFOO" NMR(60 iC, CDCls) , Ί W WiiFFOO " NMR (60 iC, CDCls)
δ： 0.92(3H) 1.27C32H) 1.88(4Η) 2.22(6Η) 2.45(2Η) . 3.08C2H) 3.42(3Η) 3.53(1Η) 3.67(6Η) 4.17(2Η) 4.23 C2H) δ.05(1Η)  δ: 0.92 (3H) 1.27C32H) 1.88 (4Η) 2.22 (6Η) 2.45 (2Η) .3.08C2H) 3.42 (3Η) 3.53 (1Η) 3.67 (6Η) 4.17 (2Η) 4.23 C2H) δ.05 (1Η)
実施例 59 Example 59
2— 0—メチル一 3— 0—才クタデシルカルパモイル一 1— 0— [Ν —ピロリジノカルボ二ルー Ν— (2 ' — トリメチルアンモニォェチル）] 力ルバモイルグリセリ ン ♦ ィォダイ ド  2—0—Methyl-1—3—0—Cutadecylcarbamoyl—1—0— [Ν—Pyrrolidinocarbone ル ー — (2′—Trimethylammonioethyl)] Lubamoylglycerin ♦ Yidide
実施例 58で得たジメチルァミノ体 613mg( 1 ミ リモル）をヨウ化メチル 2 mlに溶かし 24時間室温に放置後，常法に従って処理し、 目的物（無色粉 末） 551mg (収率 73.0%)を得た。  613 mg (1 mmol) of the dimethylamino compound obtained in Example 58 was dissolved in 2 ml of methyl iodide, allowed to stand at room temperature for 24 hours, treated in a conventional manner, and 551 mg (yield: 73.0%) of the desired product (colorless powder) was obtained. Obtained.
T L C.silicagel, n-BuOH, AcOH, H20(4 : 1 : 1 )Rf = 0.25 TL C.silicagel, n-BuOH, AcOH , H 2 0 (4: 1: 1) Rf = 0.25
I R(KBr)cm-1 : 3320, 2930, 2850, 1720, 1680, 1520 , 1470 , IR (KBr) cm- 1 : 3320, 2930, 2850, 1720, 1680, 1520, 1470,
1440, 1240, L160 *  1440, 1240, L160 *
NMR(60 MC, CDCU)  NMR (60 MC, CDCU)
δ： 0.88(3H) 1.27C32H) 1.97(4H) 3.07(2H) 3.43(3H) 3.52(9H) 3.63(iH) 4.10(4H) 4.22(2H) 4.32(2H) 5.06(1H)  δ: 0.88 (3H) 1.27C32H) 1.97 (4H) 3.07 (2H) 3.43 (3H) 3.52 (9H) 3.63 (iH) 4.10 (4H) 4.22 (2H) 4.32 (2H) 5.06 (1H)
元素分折， C3 + He7N40e I - 2 H20 Elemental analysis , C 3 + He 7 N 4 0 e I-2 H 2 0
計算値： C, 51.64 H.9.05 N.7.08  Calculated value: C, 51.64 H.9.05 N.7.08
実験値： C, 51.49 H.9.22 N ,7.37  Experimental value: C, 51.49 H.9.22 N, 7.37
実施例 60 Example 60
1一 0— [N—力ルバモイルー N—（2 ' 一 トリメチルァンモニォェチ ル）]カルバ乇ィルー 2— 0—メチル— 3 0—ォクタデシルカルバモイ ルグリセリ ン · ィォダイ ド  1 1 0— [N—capillum N— (2′-trimethylammonioethyl)] carbaziru 2—0—methyl—3 0—octadecylcarbamoyl glycerin iodide
実施例 56で得たメ トキシカルボニル体 100mg(0.14ミ リモル）を 8.9%ァ  100 mg (0.14 mmol) of the methoxycarbonyl compound obtained in Example 56 was 8.9%
差換え ンモニァ―メタノ ール溶液 5 mUこ溶かし， 1 日室温にて放置し、 減圧下 に濃縮乾固して、残渣をエーテル 4 nilより再結晶し，目的物（無色粉末） 8丄 mg (収率 82.5%)を得た。 Replacement Dissolve 5 mU of ammonia-methanol solution, leave it at room temperature for 1 day, concentrate to dryness under reduced pressure, recrystallize the residue from 4 nil of ether, and obtain 8 mg of the target compound (colorless powder) (yield) 82.5%).
T L C .silicagel, n-BuOH, AcOH. H20(4 : 1 : 1 ) f = 0.26 TLC .silicagel, n-BuOH, AcOH.H 20 (4: 1: 1) f = 0.26
I R (KBr)cm "l： 3300, 2940, 2850, 1800, 1750 (sh.) 1710, IR (KBr) cm " l : 3300, 2940, 2850, 1800, 1750 (sh.) 1710,
1520, 1470, 1260, 1220, 1150, 1100  1520, 1470, 1260, 1220, 1150, 1100
NMR(60 MC, CDC )  NMR (60 MC, CDC)
δ： 0.88C3H) 1.27C32H) 3.08(2H) 3.47(9H) 3.56 (3H) 3.67C1H) 3.86(2H) 4.13(2H) 4.27(2H) 4.37C2H) 4.70C1H) 4.97(1H) 6.48(1H)  δ: 0.88C3H) 1.27C32H) 3.08 (2H) 3.47 (9H) 3.56 (3H) 3.67C1H) 3.86 (2H) 4.13 (2H) 4.27 (2H) 4.37C2H) 4.70 (1H) 4.97 (1H) 6.48 (1H)
元素分沂： C3。H61N40s I一 1.5H20 Elemental沂: C 3. H 61 N 4 0s I-1.5H 2 0
計算値： C 49.51 H.8.86 N , 7.70 - 実験値： C 49.76 H.8.90 N , 7.59  Calculated: C 49.51 H.8.86 N, 7.70-Experimental: C 49.76 H.8.90 N, 7.59
実施例 61 Example 61
1 — 0— [N—ジ、メチルカルバモイルー N—（ 2 ' —ジメチルアミ ノエ チル）：力ルバモイル一 2— 0—メチルー 3— 0—ォクタデシルカルバモ ィルグリセリ ン  1—0— [N-di, methylcarbamoyl-N— (2'-dimethylaminoethyl): 2- (0-methyl-3-o-octadecylcarbamoylglycerol)
実施例 57で得たフエノキシ体 636mg( 1 ミ リモル）を 20%ジメチルアミ ンー トルエン溶液 10mlに溶かし、 24時間室温に放置して、 反応液を減圧 下に濃縮乾固して残渣をシリ力ゲル 10g,展開液，クロロホルム，メタノ 一 ル （19: 1 ) にて精製して目的物（無色油状物質） 44Qmg (収率 75.0%)を得  636 mg (1 mmol) of the phenoxy compound obtained in Example 57 was dissolved in 10 ml of a 20% dimethylamine-toluene solution, allowed to stand at room temperature for 24 hours, and the reaction solution was concentrated to dryness under reduced pressure. , Developing solution, chloroform, and methanol (19: 1) to give 44Qmg of the desired product (colorless oil) (yield: 75.0%)
T L C .silicagel, CHC13, MeOH(5： 1 )Rf = 0.66 single spot. TLC .silicagel, CHC1 3, MeOH ( 5: 1) Rf = 0.66 single spot.
I R(fil(n)cni-1： 3350. 2930, 2850, 1730, 1690, 1540, H75; IR (fil (n) cni- 1 : 3350. 2930, 2850, 1730, 1690, 1540, H75 ;
1420, 1395, 1360, 1290(sh.), 1260, 1170, 1420, 1395, 1360, 1290 (sh.), 1260, 1170,
1100, 1070 ^ ¾ 実施例 62 1100, 1070 ^ ¾ Example 62
1 — 0— [N—ジメチルカルバモイルー N - (2 ' — トリメチルアンモ 二ォェチル）]力ルバモイルー 2— 0—メチルー 3— 0—ォクタデシルカ ルバモイルグリセリ ン · ョージド  1 — 0— [N-Dimethylcarbamoyl-N-(2'-trimethylammonodiethyl)]-lubamoyl 2-—0—Methyl-3—0—Octadecylcalvamoylglycerin
実施例 61で得たジメチルカルバモイル体 440mg(0.75ミ リモル）をク口 口ホルム 1 mUこ溶かし、 ヨウ化メチル 600mgを加え 1夜室温に放置する。 反応液を減圧下に濃縮乾固して残渣をァセトン 2 ml,エーテル 8 mlより 再結晶して目的物（無色粉末性結晶） 463mg (収率 84.7%)を得た。  440 mg (0.75 mimol) of the dimethylcarbamoyl compound obtained in Example 61 is dissolved in 1 mU of cucum form, 600 mg of methyl iodide is added, and the mixture is left overnight at room temperature. The reaction solution was concentrated to dryness under reduced pressure, and the residue was recrystallized from 2 ml of acetone and 8 ml of ether to obtain 463 mg of the desired product (colorless powdery crystals) (yield: 84.7%).
T L C .silicagel, n-BuOH, AcOH,H20(4 : 1 : 1 )Rf-0.27 TLC .silicagel, n-BuOH, AcOH, H 2 0 (4: 1: 1) Rf-0.27
I RCKBi cm-1: 3400， 2920, 2850， 1710, 1690, 1530, 1470, I RCKBi cm- 1 : 3400, 2920, 2850, 1710, 1690, 1530, 1470,
1400, 1300, 1260, 1200, 11400 1400, 1300, 1260, 1200, 11400
MRC60 MC. CDC13) MRC60 MC. CDC1 3 )
* δ： 0.90(3H) 1.25C32H) 3.00(6H) 3.10(2H) 3.43C3H) * δ: 0.90 (3H) 1.25C32H) 3.00 (6H) 3.10 (2H) 3.43C3H)
3.550H) 3.63C1H) 3.93(2H) 3.98(2H) 4.13(2H) . .30C2H) 4.96(1H)  3.550H) 3.63C1H) 3.93 (2H) 3.98 (2H) 4.13 (2H) ... 30C2H) 4.96 (1H)
元素分折： C32H65N + 06 I - 2 H20 Elemental folding: C 32 H 65 N + 0 6 I - 2 H 2 0
計算値： C ,50.25 H, 9.09 N, 7.33  Calculated value: C, 50.25 H, 9.09 N, 7.33
実験値： C, 50.02 H, 9.14 , 7.65  Experimental values: C, 50.02 H, 9.14, 7.65
実施例 63  Example 63
1 - 0 - [Ν-(2' ージメチルァミノェチル）— Ν—プロピルカルパ モイル]カルパ乇ィルー 2— 0—メチル— 3— 0—才クタデシルカルバ モイルグリセリ ン  1-0-[Ν- (2'-dimethylaminoethyl) -Ν-propylcarbamoyl] carbaziru 2—0-methyl-3 30-year-old kutadecylcarbamoylglycerin
実施例 57で得たフエノキシ体 636mg( 1 ミ リモル）にプロピルアミ ン lml を加え 24時間室温に放置して、 反応液は減圧下に濃縮乾固し、 残渣をシ ' リカゲル， 10g,展開溶媒 クロ口ホルム，メタノ ―ル（19: 1 )にて精製し て目的物（無色油状物質） 586mg (収率 100%)を得た。  To 636 mg (1 mmol) of the phenoxy compound obtained in Example 57, 1 ml of propylamine was added, and the mixture was allowed to stand at room temperature for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel, 10 g, developing solvent. Purification by mouth form and methanol (19: 1) yielded 586 mg (100% yield) of the desired product (colorless oil).
差换ぇ T L C .silicagel, CHC , MeOH(5： 1 )Rf =0.75 Difference TLC .silicagel, CHC, MeOH (5: 1) Rf = 0.75
1 iUfilnOcra-L : 3350 2940 2850 1730 1630 1540 1470 1410  1 iUfilnOcra-L: 3350 2940 2850 1730 1630 1540 1470 1410
1380 1250 1195  1380 1250 1195
実施例 64 Example 64
2— 0—メチルー 1—〇一 [N—プロピル力ルバモイル— N—（2 ' - ト リメチルァン乇ニォェチル）]力ルバモイル一 3— 0—才クタデシルカ ルバモイルグリセリ ン ィォダィ ド  2—0—Methyl-1—N- [N-Propyl-Lubamoyl—N— (2'-trimethyl-anne-no-ethyl)] Rubamoyl 1—3—0—Titadecylcalva-moylglyceride
実施例 63で得たプロピル力ルバモイル体 586mg( 1 ミ リモル）をヨウ化 メチル 2 mlに溶かし、 室温にて 24時間放置してから減圧下に濃縮乾固し て、 残渣を n-へキサンにて洗い目的物（淡黄色固形物） 563mg (収率 77.2 %)を得た。  Dissolve 586 mg (1 mmol) of the propyl-powered rubamoyl compound obtained in Example 63 in 2 ml of methyl iodide, allow to stand at room temperature for 24 hours, concentrate to dryness under reduced pressure, and concentrate the residue in n-hexane. Thus, 563 mg (yield: 77.2%) of the object to be washed (light yellow solid) was obtained.
T L C .silicagel, n-BuOH, Ac OH, H20(4 : 1 : 1 )Rf = 0.25 - I RCKBr)^-1: 3350 2930 2850 1730 1530 1470 1380 1210 TLC .silicagel, n-BuOH, Ac OH, H 2 0 (4: 1: 1) Rf = 0.25-I RCKBr) ^ -1 : 3350 2930 2850 1730 1530 1470 1380 1210
1150 1150
MR(60 MC," CDC13) MR (60 MC, "CDC1 3 )
δ： 0.92C3H) 1.2δ(32Η) 1.57(2H) 3.15(2H) 3.47(3H) 3.50C9H) 3.75(iH) 3.90(2H) 4.17(2H) 4.30(2H) 4.38(2H) 4.67C1H) 5.05(1H)  δ: 0.92C3H) 1.2δ (32Η) 1.57 (2H) 3.15 (2H) 3.47 (3H) 3.50C9H) 3.75 (iH) 3.90 (2H) 4.17 (2H) 4.30 (2H) 4.38 (2H) 4.67C1H) 5.05 ( 1H)
実施例 65 Example 65
1— 0— [N—ァセチル一 N— (2 ' —ジメチルァミ ノェチル）]力ルバ モイルー 2— 0—ベンジル一 3— 0—ォクタデシルグリセリ ン  1—0— [N-acetyl-N— (2'-dimethylaminoethyl)]-l-ba-moyl 2-—0—benzyl-1-3—0—octadecylglycerin
実施例 1で得たジメチルァミ ノェチル体 1.5g(2.71ミ リモル）をピリ ジ ン 15ml,無水酢酸 7.5mlに溶かし、 一夜室温にてかきまぜてから反応液を 減圧下に濃縮乾固した。 残渣をシリカゲル 20g,展開液クロ口ホルム，メ タノ ール（19: 1：)にて精製し、 目的物（無色油状物質） L6Lg (収率 100%) を得た。  1.5 g (2.71 mimol) of the dimethylaminoethyl derivative obtained in Example 1 was dissolved in 15 ml of pyridin and 7.5 ml of acetic anhydride, stirred overnight at room temperature, and concentrated to dryness under reduced pressure. The residue was purified by 20 g of silica gel, chloroform in developing solution and methanol (19: 1 :) to obtain L6 Lg of the desired product (colorless oil) (yield: 100%).
Oi PI 換え ¾IVAT T L C .silicagel.CHCU, MeOH(5： 1 )Rf = 0.59 Oi PI exchange ¾IVAT TLC .silicagel.CHCU, MeOH (5: 1) Rf = 0.59
I R(film)cm-l:2930 2850 1745 1705 1470 1375 1245 1170 NMR(60 MC, CDC13) " IR (film) cm- l: 2930 2850 1745 1705 1470 1375 1245 1170 NMR (60 MC, CDC1 3) "
δ： 0.92(3H) 1.27C36H) 2.45(6H) 2.47(3H) 2.77(2H) δ: 0.92 (3H) 1.27C36H) 2.45 (6H) 2.47 (3H) 2.77 (2H)
3.60C2H) 3.83(1H) 3.97(2H) 4.37(2H) 4.65(2H)3.60C2H) 3.83 (1H) 3.97 (2H) 4.37 (2H) 4.65 (2H)
7.30C5H) (7.30C5H)
実施例 66  Example 66
1 — 0— [N—ァセチルー N— (2' — トリメチルアンモニォェチル）] 力ルバモイル一 2— 0—べンジルー 3— 0—ォクタデシルグリセリ ン - ィォダイ ド  1 — 0— [N-Acetyl-N— (2 '— Trimethylammonioethyl)] 1-0—Benzyru 3—0—Octadecylglycerin-yidide
実施例 65で得たジメチルァミノェチル体 1.61g(2.71ミ リモル）をヨウ 化メチル 4 mlに溶かし、 室温にて一夜放置する。 反応液を減圧下に濃縮 * 乾固して残渣をェ -テル 20mlより再結晶して目的物（無色粉末性結晶）  1.61 g (2.71 mimol) of the dimethylaminoethyl derivative obtained in Example 65 is dissolved in 4 ml of methyl iodide and left overnight at room temperature. The reaction mixture is concentrated under reduced pressure. * The residue is recrystallized from 20 ml of ether to give the desired product (colorless powdery crystals).
丄.833(収率92.3%)を得た。  丄 .833 (92.3% yield) was obtained.
T L C .si.licagel.n-BuOH, AcOH, H20(4 : 1 : 1 )Rf=0.23 TLC .si.licagel.n-BuOH, AcOH, H 2 0 (4: 1: 1) Rf = 0.23
I R(film)cm-1: 2930, 2850 1750 1690, 1465 1375 1350 IR (film) cm- 1 : 2930, 2850 1750 1690, 1465 1375 1350
1260 1200 1160 1145 1120 1095  1260 1200 1160 1145 1120 1095
NMR(60 MC, CDCls)  NMR (60 MC, CDCls)
δ： 0.92C3H) 1.27C32H) 2.50(3H) 3.32(9Ή) 3.45(2H)  δ: 0.92C3H) 1.27C32H) 2.50 (3H) 3.32 (9Ή) 3.45 (2H)
3.53C2H) 3.67(1H) 4.00(2H) 4.13(2H) 4.47(2H) 4.67(2H) 7.33C5H)  3.53C2H) 3.67 (1H) 4.00 (2H) 4.13 (2H) 4.47 (2H) 4.67 (2H) 7.33C5H)
元素分忻 C36He2N 205 I - H20 Elemental Xin C 36 H e2 N 2 0 5 I-H 2 0
計算値： C.57.59 H.8.99 N ,3.73  Calculated value: C.57.59 H.8.99 N, 3.73
実験値： C, 57.70 H.9.19 .3.82  Experimental value: C, 57.70 H.9.19.3.82
実施例 67  Example 67
1 — 0— [N—ァセチルー Ν_(2' — トリメチルァンモニォェチル）]  1 — 0— [N-acetyl-Ν_ (2'—trimethylammonioethyl)]
-一 r -' ~~ ~ 3 - 、 ひ -One r-'~~ ~ 3-, Hi
、' 、 0 一, 力ルバモイルー 3— 0—才クタデシルグリセリ ン-クロ リ ド , ', 0 , Lumbamoyl 3-0-Kutadecyl glycerin-chloride
実施例 66で得たィォダイ ド 1.333g(1.82ミ リモル）を 75%メタノ ール 50 mlに溶かし I R A— 410(C1一） 50mlを通過させ、 少量のメタノ —ルにて 洗い、 通過液、 洗液を合せて減圧下に濃縮乾固した。 残渣を 75%詐酸 25 mlに溶かし、 パラジウム炭素 300mg存在下、 水素気流中一夜かきまぜて から不溶物をろ去し、 母液を威圧下に濃縮乾固し残渣にァセトン 20mlを 加えて洗い、 目的物（無色粉末） 620mg (収率 61.8%)を得た。  1.333 g (1.82 mmol) of the iodide obtained in Example 66 was dissolved in 50 ml of 75% methanol, passed through 50 ml of IRA-410 (C1) and washed with a small amount of methanol, and the passing solution and washing were performed. The liquids were combined and concentrated to dryness under reduced pressure. Dissolve the residue in 25 ml of 75% hydrochloric acid, stir overnight in a stream of hydrogen in the presence of 300 mg of palladium on carbon, filter off insolubles, concentrate the mother liquor under intimidation to dryness, add 20 ml of acetone to the residue and wash. The product (colorless powder) 620 mg (61.8% yield) was obtained.
T L C ,Ε-BUOH, AcOH, H20(4： 1 ： 1 ) R f = 0.28 TLC, Ε-BUOH, AcOH, H 2 0 (4: 1: 1) R f = 0.28
1 R(film)cm-1: 3350 2910 2845 1740 1690 1455 1365 1255 1 R (film) cm- 1 : 3350 2910 2845 1740 1690 1455 1365 1255
1200 1060  1200 1060
元素分析： C 29H59N2O 5C1-H20 Elemental analysis: C 29H59N2O 5 C1-H 2 0
計算値： C , 61.19 H ,10.80 N ,4.92  Calculated value: C, 61.19 H, 10.80 N, 4.92
実験値： C,6i.05 H, 11.25 N.5.07  Experimental value: C, 6i.05 H, 11.25 N.5.07
実施例 68 * Example 68 *
1 — 0—（N—ジメチルアミ ノエチル）力ルバモイル一 3— 0—才クタ デシルグリセリ ン  1 — 0— (N-dimethylaminoethyl) rubamoyl 1 3 — 0—Kuta decylglycerin
実施例 1 で得たジメチルァミ ノェチル体 3.5g(6.33ミ リモル）を 50%酉乍 酸 35mlに溶かしパラジゥム炭素 300mg存在下、 水素気流中一夜室温にて かきまぜ、 不溶物をろ去し、 母液を減圧下に濃縮乾固し、 目的物（無色 固形物） 3.0gを得た。  Dissolve 3.5 g (6.33 mimol) of the dimethylaminoethyl derivative obtained in Example 1 in 35 ml of 50% aqueous acid and stir in the presence of 300 mg of palladium carbon in a stream of hydrogen overnight at room temperature in a stream of hydrogen, remove insolubles by filtration, and depressurize the mother liquor. It was concentrated to dryness below to obtain 3.0 g of the desired product (colorless solid).
T L C .silicagel, CHC , MeOH, H20(65： 25： 4)Rf = 0.33 TLC .silicagel, CHC, MeOH, H 2 0 (65: 25: 4) Rf = 0.33
実施例 69 Example 69
2 - 0 - [ - ( 2 ' —ジメチルアミ ノエチル）一 N—フエノキシカル ボニル]力ルバモイルー 3— 0—ォクタデシルー 2— 0—フエノキシ力 ルボニルグリセリ ン  2-0-[-(2 '-dimethylaminoethyl) -N-phenoxycarbonyl] force rubamoyl 3-0-octadecyl-2-0-phenoxy force rubonyl glycerine
実施例 68で得たジメチルァ ミ ノ体 i.0g(2.24ミ リモル），クロロ炭酸フ  I.0 g (2.24 mmol) of the dimethylamino compound obtained in Example 68,
■r ¾ん ェニルエステル 1.4g(8.95ミ リモル）をジクロロメタン 4 mlに溶かし、 ピ リ ジン 2.8g(35.2ミ リモル）を加え、 室温にて 2時間かきまぜた。 反応液 にジクロロメタン 8nil,水 10mlを加えて、 よくふりまぜてから、 有機層 を分取，硫酸ナトリゥムにて乾かし減圧下に濃縮乾固し、 目的物（無色残 査） 1.56g (収率 100%)を得た。 ■ r ¾ The phenyl ester (1.4 g, 8.95 mmol) was dissolved in dichloromethane (4 ml), and pyridine (2.8 g, 35.2 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was mixed with 8 nil of dichloromethane and 10 ml of water, and mixed well. The organic layer was separated, dried over sodium sulfate, and concentrated to dryness under reduced pressure to give 1.56 g of the desired product (colorless residue). %).
T L C .silicagel, CHC13, eOH( 5： 1 )Rf=0.68 TLC .silicagel, CHC1 3, eOH ( 5: 1) Rf = 0.68
1 R(filtn)cm-1 : 2920 2850 1750 1720 1460 1270 1120 実施例 70 1 R (filtn) cm- 1 : 2920 2850 1750 1720 1460 1270 1120 Example 70
2— 0—メ トキシカルボ二ルー 1— 0— [N—メ トキシカルボ二ルー N - ( 2 ' — トリメチルアンモニォェチル）]力ルバモイルー 3— 0—ォ クタデシルグリセリ ン ♦ ィォダイ ド  2—0—Methoxycarbone 1—0— [N—Methoxycarbone N- (2'—trimethylammonioethyl)] force 3—0—Octadecylglycerin ♦
実施例 69で得たフエノキシ体 0.76g(1.12ミ リモル）をメタノ ール 5 ml, トリエチルァミ'ン 2 mlに溶かし一夜室温にて放置後減圧下に濃縮'乾固し て、 残渣をヨウ化メチル 2 πι1_に溶かし、 24時間室温に放置後、 减圧下 に濃縮乾固する。 残渣をシリ力ゲル 5g，クロロホルム，メタノ ール，水 (65: 25: 4 )にて精製し目的物（無色固形物） 433mg (収率 61.8%)を得た。  0.76 g (1.12 mmol) of the phenoxy compound obtained in Example 69 was dissolved in 5 ml of methanol and 2 ml of triethylamine, allowed to stand at room temperature overnight, concentrated under reduced pressure to dryness, and the residue was methyl iodide. 2 Dissolve in πι1_, leave at room temperature for 24 hours, and concentrate under reduced pressure to dryness. The residue was purified with 5 g of silica gel, chloroform, methanol and water (65: 25: 4) to obtain 433 mg of the desired product (colorless solid) (61.8% yield).
T L C .silicagel, n-BuOH, Ac OH, H20(4 : 1 : 1 )Rf=0.2i TLC .silicagel, n-BuOH, Ac OH, H 2 0 (4: 1: 1) Rf = 0.2i
1 RCfil^cm"1 : 3350 2930 2850 1650(sh) 1720 1280 1： 60 NMR(60 MC, CDC ) 1 RCfil ^ cm " 1 : 3350 2930 2850 1650 (sh) 1720 1280 1:60 NMR (60 MC, CDC)
δ： 0.92C3H) 1.27(3211) 3.43(9H) 3.78(6H) 5.0 (1H) その他 3.3〜4.6  δ: 0.92C3H) 1.27 (3211) 3.43 (9H) 3.78 (6H) 5.0 (1H) Other 3.3 to 4.6
実施例 71 Example 71
2— 0—ジメチルカルバモイルー 1 一 0— [N—ジメチルカルバモイ ルー N— (2' — トリメチルァンモニォェチル）]力ルバモイル— 3— 0一 ォクタデシルグリセリ ン · クロライ ド  2— 0—Dimethylcarbamoyl 1 1 0— [N-Dimethylcarbamoyl) N— (2′—Trimethylammonioethyl)] Lubamoyl— 3—0 1 Octadecylglycerine chloride
実施例 69で得たフエノキシ体 0.76g(1.12ミ リモル）を 20%ジメチルァ  0.76 g (1.12 mmol) of the phenoxy compound obtained in Example 69 was added to 20% dimethyla
差換え ミ ン ' トルエン溶液 iOmlに溶かし室温にて一夜放置し、 減圧下に濃縮乾 固し、 残渣をヨウ化メチル 2mlに溶かし室温 24時間放置して、 再び減圧 下に濃縮乾固し、 残渣を 75%メタノ ール 20mUこ溶かし I R A— 4iO(C厂 ) 15mlに通し、 少量の同メタノ ールにて洗い、 通過液、 洗液を合せて'减圧 下に濃縮乾固して、 残渣をァセトン 2.5ml,エーテル 2.5mlの混液より再結 晶して目的物（無色粉末） 259mg (収率 35.5%)を得た。 Replacement Min 'toluene solution Dissolve in iOml, leave overnight at room temperature, concentrate to dryness under reduced pressure, dissolve the residue in 2 ml of methyl iodide, leave at room temperature for 24 hours, concentrate again to dryness under reduced pressure, and remove the residue to 75 Dissolve 20mU of methanol in 15ml of IRA-4iO (C Factory), wash with a small amount of the same methanol, combine the permeate and washing solution, concentrate under reduced pressure to dryness, and wash the residue with acetone Recrystallization from a mixed solution of 2.5 ml and 2.5 ml of ether gave 259 mg (yield: 35.5%) of the desired product (colorless powder).
T L C .ii-BuOH, Ac OH, H20(4 : 1 : 1 )Rf = 0.21 TLC .ii-BuOH, Ac OH, H 2 0 (4: 1: 1) Rf = 0.21
I R(film)cm-1: 3400 2920 2850 1700 1525 1480 1400 1260 IR (film) cm- 1 : 3400 2920 2850 1700 1525 1480 1400 1260
1215 1.195 1120  1215 1.195 1120
実施例 72  Example 72
1 —ォクタデシルォキシ一 2—フタルイミ ドー 3—（2' —ピリジニ ォェチル）力ルバモイルォキシプロパン クロリ ド  1—Octadecyloxy 1—2-phthalimidole 3— (2′—pyridinoethyl) Lubamoyloxypropane chloride
i ) 3—〇一才クタデシルー 2— 0— トシルー 1 一 0— トリチルダリ セロール .  i) 3-1 year old Kutadecyl-2-0-Tosyl-1-0-Trityldari serol.
3 _ 0—才クタデシル一 1 — 0— ト リチルグリセロール 5.0g(8 , 52ミ リモル）をピリ ジン 9 mlに溶かし塩化トシル 1.95g(10.22ミ リモル）を加 え、 一夜室温にてかきまぜた後減圧下に濃縮乾固した。 残渣を水 50ml, ジクロロメタン 50mlに溶かし、 ふりまぜてから、 ジクロロメタン層を分 取する。 有機層は減圧下に濃縮乾固し、 残渣をシリカゲルカラム（50g), 展開溶媒 η -へキサン，胙酸ェチル（193: 7)にて精製し、 無色針状結晶 5.3g (収率 83.9%)を得た。  3 _ 0—Titadecyl-1 1 — 0—Dissolve 5.0 g (8,52 mimol) of tritylglycerol in 9 ml of pyridine, add 1.95 g (10.22 mimol) of tosyl chloride, and stir at room temperature overnight. Concentrated to dryness under reduced pressure. Dissolve the residue in 50 ml of water and 50 ml of dichloromethane, shake, and separate the dichloromethane layer. The organic layer was concentrated to dryness under reduced pressure, and the residue was purified with a silica gel column (50 g), developing solvent η-hexane, ethyl ethyl epoxide (193: 7), and 5.3 g of colorless needle crystals (yield 83.9%) ).
mp 52° 〜53。C  mp 52 ° -53. C
ii ) 3—ォクタデシルォキシー 2—フタルイ ミ ドー 1 — トリチルォキ シプロパン  ii) 3-Octadecyloxy 2-Phthalimiido 1-Trityloki Cipropane
実施例 72- i )で得たトシル体 5.3g(7.15ミ リモル）をジメチルスルホキ シ ド 53mlに溶かし、 フタルイミ ドカリ 10. も加え浴温 115°C，3.5時阖か きまぜた。 反応液を水 500mlにあけ、 エーテル 500mlにて抽出し、 ェ―テ ル層は硫酸ナトリゥムにて乾かし減圧下に濃縮乾固した。 残渣をシリ力 ゲルカラム（50g).展開溶媒 n—へキサン，酢酸ェチル（193: 7)にて精製し、 無色油状物質 3.0g (収率 58.6%)を得た。 5.3 g (7.15 mimol) of the tosyl compound obtained in Example 72-i) was dissolved in 53 ml of dimethyl sulfoxide, and phthalimidocali was added thereto. The bath temperature was 115 ° C and 3.5 hours. I mixed. The reaction solution was poured into 500 ml of water, extracted with 500 ml of ether, and the ether layer was dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified with a silica gel column (50 g) and developing solvent n-hexane and ethyl acetate (193: 7) to give 3.0 g of a colorless oil (yield: 58.6%).
T L C [silicagel, n-Hexane, EtOAc (9 : 1 )] Rf= 0.25 single spot .  T L C [silicagel, n-Hexane, EtOAc (9: 1)] Rf = 0.25 single spot.
iii) 1 —ハイ ドロキシ一 3—ォクタデシルォキシー 2—フタルイミ ド プロパン iii) 1—hydroxy-1,3-octadecyloxy 2-phthalimid propane
実施例 72- Π)で得たトリチル体 3.0g(4.19ミ リモル）を 70%g乍酸 50mlに 溶かし、 1時間加熱還流した。 反応液を減圧下に濃縮乾固し、 残渣をシ リカゲル力ラム（40g)n へキサン J乍酸ェチル（4： 1 )にて精製し、 無色 針状結晶 l. g (収率 58.9%)を得た。 mp 60° 〜61°C  3.0 g (4.19 mmol) of the trityl compound obtained in Example 72-II) was dissolved in 50 ml of an acid with 70% g, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel ram (40 g) n hexane J ethyl acetate (4: 1) to give 1 g of colorless needle crystals (58.9% yield). I got mp 60 ° to 61 ° C
T L C [silicagel, n-Hexane, EtOAc(4： 1 )]Rf = 0.16 T L C [silicagel, n-Hexane, EtOAc (4: 1)] Rf = 0.16
I R ( Br)cm-1： 3500, 3450, 29Ί0, 2850, 1765, 1700, 1465,IR (Br) cm- 1 : 3500, 3450, 29Ί0, 2850, 1765, 1700, 1465,
1390, 1150, 1060, 875 1390, 1150, 1060, 875
iv) 1—ォクタデシルォキシ一 2—フタルイ ドー 3—（ 2 ' —クロ口 ェチルカルバモイル: ίキシ）プロパン iv) 1-octadecyloxy-2- (phthalidol) 3- (2'-chloroethylcarbamoyl: dioxy) propane
3—ォクタデシルォキシー 2—フタルイミ ドー 1 —プロパノ ール 1.057gをジクロルメタン 6 mlに溶解し、 /3—クロロェチルイソシアナ一 ト 283mgおよび卜リエチルアミ ン 300mgを加え、 室温で 14時間かきまぜた。 反応液を減圧下濃縮乾固し、 シリカゲルクロマトグラフィ—で精製して (溶出液 n -へキサン一酢酸ェチル 3 : 1 )、 無色固体の目的物 1.30gを得 た。  Dissolve 1.057 g of 3-octadecyloxy 2-phthalimidole 1 -propanol in 6 ml of dichloromethane, add 283 mg of / 3-chloroethyl isocyanate and 300 mg of triethylamine, and stir at room temperature for 14 hours. Was. The reaction solution was concentrated to dryness under reduced pressure, and purified by silica gel chromatography (eluent n-hexane monoacetate 3: 1) to obtain 1.30 g of the target compound as a colorless solid.
NMR(90 MHz, CDC13) 0.87(3H,t) L 16, 1.25(32H, m) 3.3-3.65(6 H,m) 4.85(2H,m) 4. -4.9(3H, m) 5.11(lH,br.) 7.6-7.95(4H, m) NMR (90 MHz, CDC1 3) 0.87 (3H, t) L 16, 1.25 (32H, m) 3.3-3.65 (6 H, m) 4.85 (2H, m) 4. -4.9 (3H, m) 5.11 (lH , br.) 7.6-7.95 (4H, m)
鶴え v ) 1 —ォクタデシルォキシー 2—フタルイ ミ ドー 3— ( 2 ' —ピリ ジ ニォェチル）力ルバモイルォキンプロパン クロ リ ド 実施例 72- iv)で得たク口リ ド 200mgをピリ ジン 1 に溶かし、 6時間 加熱還流した。 反応液を濃縮乾固し、 シリカゲルクロマ トグラフィーで 精製して（溶出液クロロホルム—メタノ ール一水 65 :25 :2)、目的物丄 50 mgを得た。 淡褐色固体 Tsurue v) 1—Octadecyloxy 2—Phthalimidol 3— (2′—Pyridinyoethyl) force Lubamoyl quinpropane chloride 200 mg of the cloride obtained in Example 72-iv) was used as pyridine Dissolved in 1 and heated under reflux for 6 hours. The reaction solution was concentrated to dryness and purified by silica gel chromatography (eluent: chloroform-methanol / water 65: 25: 2) to obtain the desired product (50 mg). Light brown solid
I RCKBr.cm-1) 2925, 2850, 1778, 1715, 1635, 1490, 1470, I RCKBr.cm- 1 ) 2925, 2850, 1778, 1715, 1635, 1490, 1470,
1390, 1260, 1120, 730 1390, 1260, 1120, 730
MR(90 MHz, CDC13)(5 0.87(3H,t), 1.16 , 1.25(32H, m) , 3.0- 3.55(2H,m) 3.55- 4.0(4H,m), 4.27(2H,d) 4.53(lH,m) 5.03(2 H,m,CH2 ) 7.12(lH,br,NH) 7.6-7.9(4H,m) 8.05(2H,m) 8.45 (lH.m) 9.31(2H,d) MR (90 MHz, CDC1 3) (5 0.87 (3H, t), 1.16, 1.25 (32H, m), 3.0- 3.55 (2H, m) 3.55- 4.0 (4H, m), 4.27 (2H, d) 4.53 (lH, m) 5.03 (2 H, m, CH 2 ) 7.12 (lH, br, NH) 7.6-7.9 (4H, m) 8.05 (2H, m) 8.45 (lH.m) 9.31 (2H, d)
T L C Rf = 0.6(CHCl3-MeOH-H2O 65:25:4) TLC Rf = 0.6 (CHCl 3 -MeOH-H 2 O 65: 25: 4)
実施例 73 Example 73
1 一才クタデシルォキシ一 2—フタルイ ミ ドー 3— ( 2 ' —チアゾリ ォェチル）力ルバモイルォキシプロパン クロ リ ド 実施例 72- iv)で得たク口リ ド 200mgをチアゾ―ル 1 mlに溶か L 100てで 48時間 加熱した。  1 1-year-old Kutadecyloxy 2- 2-phthalimidole 3- (2'-thiazolyoethyl) rubamoyloxypropane chloride 200 mg of the cloride obtained in Example 72-iv) was dissolved in 1 ml of thiazole. Heated for 48 hours.
実施例（ ）と同様に後処理、 精製をおこない、 目的物 70mgを得た。 淡褐 色固体 Post-treatment and purification were carried out in the same manner as in Example (2) to obtain 70 mg of the desired product. Light brown solid
I RCKBr.cm-1) 3400, 3050, 2925, 2855, 1780, 1715, 丄 530, I RCKBr.cm- 1 ) 3400, 3050, 2925, 2855, 1780, 1715, 丄 530,
1475, 1390, 1260, 1125, 1040, 880 1475, 1390, 1260, 1125, 1040, 880
MR(90 MHz, CDC13) 0.87(3H,t) 1.16, 1.25(32H, m) , 3.4(2H,m) MR (90 MHz, CDC1 3) 0.87 (3H, t) 1.16, 1.25 (32H, m), 3.4 (2H, m)
3.5-4.0(4H,m) 4.33(2H,d) 4.55(lH,m) 4.86(2H, m, CH2N) 7.04(lH,br,NH) 7.6-7.95(4H, m) 8.18(1H) 8.50(1H) 10.70 (1H) ' 、 差渙ぇ3.5-4.0 (4H, m) 4.33 ( 2H, d) 4.55 (lH, m) 4.86 (2H, m, CH 2 N) 7.04 (lH, br, NH) 7.6-7.95 (4H, m) 8.18 (1H) 8.50 (1H) 10.70 (1H) ',
-、 .'' , T L C Rf-0.5 (CHCl3-MeOH-H20 65:25:4) -, '', TLC Rf-0.5 (CHCl 3 -MeOH-H 2 0 65: 25: 4)
実施例' 74  Example '74
1 —ォクタデシルォキシー 2—フタルイミ ド一 3— [N— [ 2 ' - ( ーメチルピロリ ジニォ）ェチル]カルパモイルォキシ]プロパン ' クロリ ド  1—Octadecyloxy 2—Phthalimid 1 3— [N— [2 '-(methylpyrrolidinio) ethyl] carpamoyloxy] propane'chloride
実施例 72- iv)で得たク口リ ド 300mgを N—メチルピロリジン 1 mlに溶 かし、 8時間加熱還流した。 実施例 73と同様に精製をおこない、 目的物 144mgを得た。 淡褐色固体 ·  300 mg of the oxalide obtained in Example 72-iv) was dissolved in 1 ml of N-methylpyrrolidine, and the mixture was refluxed for 8 hours. Purification was carried out in the same manner as in Example 73 to obtain 144 mg of the desired product. Light brown solid ·
I R(KBr,cm' 0 3420, 2925, 2850, 1780, 1718, 1530, 1475,  I R (KBr, cm '0 3420, 2925, 2850, 1780, 1718, 1530, 1475,
1390, 1265, 1125, 1040, 880, 730  1390, 1265, 1125, 1040, 880, 730
' MR(90 MHz, CDC13) 0.87(3H,t) 1.16 , 1.25(32H, m) , 2.22(4H,m) 'MR (90 MHz, CDC1 3 ) 0.87 (3H, t) 1.16, 1.25 (32H, m), 2.22 (4H, m)
3.27(3H,s,Me) 3.5-4.0(10H, m) 4.43(2H,d) 4.67(lH,m) 7.6-7.9(4H,ra)  3.27 (3H, s, Me) 3.5-4.0 (10H, m) 4.43 (2H, d) 4.67 (lH, m) 7.6-7.9 (4H, ra)
T L C Rf = 0.6 (CHCl3-MeOH-H20 65:25:4) TLC Rf = 0.6 (CHCl 3 -MeOH-H 2 0 65: 25: 4)
実施例 75  Example 75
1 一才クタデシルォキシー 2—フタルイ ミ ド一 3— [(2' - N , N - ジメチルァミ ノェチル）力ルバモイルォキシ]プロパン  1 1-year-old Kutadecyloxy 2—phthalimidone 3 — [(2'-N, N-dimethylaminoethyl) rubamoyloxy] propane
実施例 20 - ii ) で得た 1 —ォクタデシルォキン— 2—ァミ ノ — 3— (2 ' -N, N-ジメチルァミ ノェチル）力ルバモイルォキシプロパン 287 mgをクロ口ホルム 3 mlに溶解し、 カルボエトキシフタルイミ ド 151.3mg およびトリエチルァミ ン 69mgを加えた。 室温で 2日間かきまぜたのち、 反応液を濃縮乾固し、 残渣をシリカゲルクロマ トグラフィーに付して精 ' 製をおこなった。 （溶出液 n—へキサン—酢酸ェチル 10: 1 ) 無色固体 292 mgを得た。  Example 20- ii) 1-octadecylquine-2—amino—3— (2′-N, N-dimethylaminoethyl) potency Lubamoyloxypropane 287 mg obtained from Cloii form 3 ml And 151.3 mg of carbethoxyphthalimid and 69 mg of triethylamine were added. After stirring at room temperature for 2 days, the reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography. (Eluent n-hexane-ethyl acetate 10: 1) 292 mg of a colorless solid was obtained.
I R (film, cm-1) 3360, 2920, 2850, 1775, 1710, 1520, 1470, IR (film, cm -1 ) 3360, 2920, 2850, 1775, 1710, 1520, 1470,
1382, 1250, 1120, L035, 875  1382, 1250, 1120, L035, 875
差換え I O MROO MHz, CDC13)<5 0.87(3H,t) 1.17 , 1.25(32H, m) 2.15(6H, s) 2.31(2H,t) 3.17(2H,m) 3.40(2H,m) 3.84(2H,m) 4.4-4.9C3H,m) 5. Ιδ(1Η, br, H) 7.6-8.0(4H,m) Replacement IO MROO MHz, CDC1 3) <5 0.87 (3H, t) 1.17, 1.25 (32H, m) 2.15 (6H, s) 2.31 (2H, t) 3.17 (2H, m) 3.40 (2H, m) 3.84 (2H, m) 4.4-4.9C3H, m) 5.Ιδ (1Η, br, H) 7.6-8.0 (4H, m)
実施例 76 Example 76
1 —ォクタデシルォキシー 2—フタルイ ミ ド一 3— [N—ァセチル- N— (2 ' - N , N -ジメチルァ ミ ノェチル）力ルバモイルォキシ]プロパン 実施例 75で得た化合物 212mgをクロ σホルム 3 mlに溶解し、 ト リェチ ルァミ ン i ml,無水き乍酸 0.3mlを加えて 1夜かきまぜた。 反応液を濃縮乾 固し、 シリカゲルクロマ トグラフィ—に付して精製をおこなった（溶出 液クロ口ホルム一メタノ ール 20: 1 ) 無色固体 153mgを得た。  1—octadecyloxy 2-phthalimid 3 -— [N-acetyl-N— (2′-N, N-dimethylaminoethyl) -rubamoyloxy] propane 212 mg of the compound obtained in Example 75 was converted to σ-form The mixture was dissolved in 3 ml, and triethylamine (i ml) and anhydrous acid (0.3 ml) were added, followed by stirring overnight. The reaction solution was concentrated to dryness, and purified by silica gel chromatography (eluent: chromate form-methanol 20: 1) to obtain 153 mg of a colorless solid.
I RCfilm.cm-1) 2925, 2850, 1775, 1740, 1712, 1470, 1385, I RCfilm.cm- 1 ) 2925, 2850, 1775, 1740, 1712, 1470, 1385,
1245, 1180, 980, 880 1245, 1180, 980, 880
MR(90 MHz, CDC13) 0.87(3H,t) 1.20 , 1.25(32H, m) 2.15(6H,s) MR (90 MHz, CDC1 3) 0.87 (3H, t) 1.20, 1.25 (32H, m) 2.15 (6H, s)
2.33(2H,t) 2.39(3H,s) 3.44(2H,t) 3.69 -3.98(4H, m) 4.4-4.9(3H,m) 7.6-8.0(4H,m)  2.33 (2H, t) 2.39 (3H, s) 3.44 (2H, t) 3.69 -3.98 (4H, m) 4.4-4.9 (3H, m) 7.6-8.0 (4H, m)
Tし C Rf = 0.6 (CHCl3- eOH 10:1) T then C Rf = 0.6 (CHCl 3 -eOH 10: 1)
実施例 77 " Example 77 "
1一才クタデシルォキシ一 2—フタルイ ミ ドー 3— [N—ァセチルー - ( 2 ' — ト リメチルァンモニォェチル）力ルバモイルォキン]プロパ ン ョージ ド  1-year-old Kutadecyloxy 2- 2-phthalimid 3-[N-acetyl- (2'-trimethylammonioethyl) propane]
実施例 76で得られたジメチルァミ ノ体 150mgをエーテル 5 mlに溶解し、 ヨウ化メチル lOOtngを加えて、 室温で一夜かきまぜた。 反応液を濃縮乾 固し、 残渣をシリカゲルクロマ トグラフィーに付して精製し、 （溶出液 クロ口ホルム一メタノ ール 5 : 1 )さ らにェ一テルから再沈殿させて 目 的物 115mgを得た。 淡黄色固体  150 mg of the dimethylamino compound obtained in Example 76 was dissolved in 5 ml of ether, 100 mL of methyl iodide was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel chromatography. (Eluent: chromatographic form-methanol 5: 1) Further reprecipitated from ether to obtain 115 mg. I got Pale yellow solid
I RCKBr.cm"1) 2925, 2850, 1778, 1750, 1715, 1470, 1390 , I RCKBr.cm " 1 ) 2925, 2850, 1778, 1750, 1715, 1470, 1390,
OMPI 1265, 1205, 1160, 1120, 1095, 1040, 880, 778, 730 OMPI 1265, 1205, 1160, 1120, 1095, 1040, 880, 778, 730
NMRC90 MHz, CDC13)5 0.87(3H,t) 1.16, 1.25(32H,m) 2.38(3H,s) NMRC90 MHz, CDC1 3) 5 0.87 (3H, t) 1.16, 1.25 (32H, m) 2.38 (3H, s)
3.52(9H,s) S.3-3.8(4H,m) 3.93(2H,d) 4.15(2H,m) 4.5 -4.95(3H,m) 7.65-7.95(4H, m)  3.52 (9H, s) S.3-3.8 (4H, m) 3.93 (2H, d) 4.15 (2H, m) 4.5 -4.95 (3H, m) 7.65-7.95 (4H, m)
実施例 78 Example 78
3—ォクタデシルォキシー 2— ( 1—ピロリ ジル）一 1—プロパノ -ル 3—ォクタデシルー 2— トシルー 1一 トリチルダリセリ ン 1.89gをピ 口リ ジン 4mlにとかし、 4時間加熱還流した。 反 液を濃縮乾固し、 残 渣のうち、 n—へキサン可溶物をシリカゲルクロマトグラフィ一に付し て精製し、 （溶出液 n—へキサン一詐酸ェチル—アンモニア水 15:5: 1 の上層）、 無色油状の 2位ピロリ ジル体 1.60gを得,た。  3-Octadecyloxy-2- (1-pyrrolidyl) -1-1-propanol 3-octadecyl-2-tosyl-11 1.89 g of trityldaliserin was dissolved in 4 ml of piperidine and heated under reflux for 4 hours. The reaction solution was concentrated to dryness, and the n-hexane soluble matter in the residue was purified by silica gel chromatography. (Eluent n-hexane-ethyl acetate-aqueous ammonia 15: 5: 1 1.60 g of a colorless oily 2-pyrrolidyl compound was obtained.
この化合物を 60%酢酸に溶かし、 100°C 1.5時間加熟したのち、 濃縮 乾固し、 残渣をクロ口ホルムに溶かして、 重曹水で洗い、 乾燥、 濃縮し、 シリ力ゲルクロマトグラフィ—に付して精製した。 （溶出液ク口口ホル ム一メタノ一ル 20: 1 )  Dissolve the compound in 60% acetic acid, ripen it at 100 ° C for 1.5 hours, concentrate to dryness, dissolve the residue in chloroform, wash with aqueous sodium bicarbonate, dry, concentrate and apply to silica gel chromatography. And purified. (Eluent liquid mouth-methanol 20: 1)
淡褐色固体の目的物 789mgを得た。 789 mg of the desired product was obtained as a light brown solid.
I RCKBr.cm-1) 3210, 2925, 2850, 1490, 1475, 1420, 1382, I RCKBr.cm- 1 ) 3210, 2925, 2850, 1490, 1475, 1420, 1382,
1328, 1135  1328, 1135
実施例 79 Example 79
1ーォクタデシルォキシ一 2— ( 1—ピロリ ジル）一 3— ( 2 ' —ジメ チルァミノェチルカルバモイルォキシ）プロパン  1-octadecyloxy-2- (1-pyrrolidyl) -1- (2'-dimethylaminoaminocarbamoyloxy) propane
3—ォクタデシルォキシ一 2—ピロリ ジルー 1一プロパノ ール 397mg をジクロルメタン 5 mlに溶解し 氷冷下 ピリジン 158mgおよびグロル ギ酸フエニル 156mgを加えた。 室温にて 1時間かきまぜた後、 クロロホ ルム 20mi，水 10mlを加えて分液し、 有機層を重曹水で洗ったのち、 乾燥 濃縮してギ酸エステル体を得た。 このものに、 asy -ジメチルエチレン ジァミ ン 1.5mlを加え、 70。Cで 4時間加熱した。 反応液をシリカゲルク 口マトグラフィ一に付し（溶出液 クロ口ホルム一メタノ ―ル一水 65: 25:4) 目的物 200mgを得た。 淡褐色固体 3-97 mg of 3-octadecyloxy-2-pyrrolidyl-l-propanol was dissolved in 5 ml of dichloromethane, and 158 mg of pyridine and 156 mg of phenyl chloroformate were added under ice cooling. After stirring at room temperature for 1 hour, 20 mi of chloroform and 10 ml of water were added to separate the layers, and the organic layer was washed with aqueous sodium hydrogen carbonate and dried. It was concentrated to obtain a formate ester. To this, add 1.5 ml of asy-dimethylethylene diamine, 70. Heated at C for 4 hours. The reaction solution was subjected to silica gel micro chromatography (eluent: black port form-methanol-water 65: 25: 4) to obtain 200 mg of the desired product. Light brown solid
1 RCKBr.cm-1) 3340, 2920, 2850, 2798, 1692, 1542, 1470,1 RCKBr.cm- 1 ) 3340, 2920, 2850, 2798, 1692, 1542, 1470,
1385, 1280, 1130 1385, 1280, 1130
NMR(90 MHz, CDC13) 0.87(3H,t) 1.25(32H(m) 1.77(4H,m) 2.20 (6H,s) 2.37(2H,t) 2.70(5H,m) 3.20(2H,t) 3.40(2H,t) 3.55(2H,d) 4.2o(2H,m) 5.28(1H, r , H) · NMR (90 MHz, CDC1 3) 0.87 (3H, t) 1.25 (32H (m) 1.77 (4H, m) 2.20 (6H, s) 2.37 (2H, t) 2.70 (5H, m) 3.20 (2H, t) 3.40 (2H, t) 3.55 (2H, d) 4.2o (2H, m) 5.28 (1H, r, H)
T L C Rf = 0.33 (CHCl3-MeOH-H20 65:25:4) TLC Rf = 0.33 (CHCl 3 -MeOH-H 2 0 65: 25: 4)
実施例 8Q , Example 8Q,
2 -メ トキシ一 3—ォクタデシルカルバモイルォキシプロピルァミ ン 2—メ トキシ一 3—才クタデシルカルバモイルォキシ一 1一プロパノ ール 4g(10ミ リモル）、 フタルイ—ミ ド 2.94g(20ミ リモル）およびトリフエ ニルホスフノン 5.24g(20ミ リモル）の無水テトラヒ ドロフラン 100ml溶液 にジェチル ジァゾカルボキシレー ト 3.48g.(20ミ リモル）を滴下した。 更に室温で 40時間かきまぜた後、 反応液を減圧下に乾固した。 残留物を シリカゲル 100gカラムクロマトグラフィ一に付し分離精製した。 n—へ キサンー詐酸ェチル（4： 1 )溶出液から粗フタルイミ ド体 5.7gを得た。 このものにメタノ ール 100mlおよぴヒ ドラジンハイ ドレ一 ト 0.5mlを加え 2時間加熱還流した。 反応液を減圧下に乾固し、 残留物にクロ口ホルム を'加え不溶物を^過して除いた。 母液を滅圧下に乾固し、 残留物をシリ 力ゲル 80gカラムクロマ トグラフィ一に付し分離精製した。 クロ口ホル ム—メタノ ール— トリェチルァミ ン（95: 5 :0.125)溶出液から目的物を 無色粉末として得た。 収量 2.7g(68%)  2-Methoxy-1-3-octadecylcarbamoyloxypropylamine 2-Methoxy-13-year-old octadecylcarbamoyloxy-11-propanol 4 g (10 mimol), phthalimid 2.94 g ( To a solution of 20 mmol) and 5.24 g (20 mmol) of triphenylphosphunone in 100 ml of anhydrous tetrahydrofuran, 3.48 g (20 mmol) of getyl diazocarboxylate was added dropwise. After further stirring at room temperature for 40 hours, the reaction solution was dried under reduced pressure. The residue was subjected to silica gel 100 g column chromatography to separate and purify. 5.7 g of a crude phthalimid compound was obtained from the eluate of n-hexane-ethyl acetate (4: 1). To this was added 100 ml of methanol and 0.5 ml of hydrazine hydrate, and the mixture was heated under reflux for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and chloroform was added to the residue to remove insolubles. The mother liquor was dried under reduced pressure and the residue was subjected to 80 g silica gel column chromatography to separate and purify. The desired product was obtained as a colorless powder from the eluate of ethyl acetate-methanol-triethylamine (95: 5: 0.125). Yield 2.7 g (68%)
I l KBi cni-1: 3350(NH2), 2915(CH), 2845CCH), 1690 (C = O), 1520 I l KBi cni- 1 : 3350 (NH 2 ), 2915 (CH), 2845CCH), 1690 (C = O), 1520
差 ¾え (CONH) , 1469(CH2), 1273 Difference (CONH), 1469 (CH 2 ), 1273
NMR δ (CDC13): 0.87(3H), 1.23C32H), 2.7- 2.95(2H.(¾2NH2), 3.03-3.4(3H,CH+CONHCH2), 3,43(3H,s,0CH3), 4.14(2H,d, J = 4,8Hz, CH20), 4.7-4.95(CONH) NMR δ (CDC1 3): 0.87 (3H), 1.23C32H), 2.7- 2.95 (. 2H (¾ 2 NH 2), 3.03-3.4 (3H, CH + CONHCH 2), 3,43 (3H, s, 0CH 3), 4.14 (2H, d , J = 4,8Hz, CH 2 0), 4.7-4.95 (CONH)
実施例 81 Example 81
2一ジメチルァミノェチル [(3—ォクタデシルカルバモイルォキシ 一 2—メ トキシ）プロピル]カルバメ一 ト  2-Dimethylaminoethyl [(3-octadecylcarbamoyloxy-1-2-methoxy) propyl] carbamate
N , N—ジメチルエタノールアミ ン 223mg(2.5ミ リモル）およびトリエ チルマミ ン 253mg(2.5ミ リモル）の塩化メチレン 5 mi溶液に氷冷攙拌下に フエニルクロ口ホルメー ト 391mg(2.5ミ リモル）を滴下した。 更に氷冷下 に 10分、 室温 30分かきまぜた後、 反応液を塩化メチレンで希釈し 1 %炭 酸水素ナトリウム水溶液で洗浄、 硫酸ナトリウムで乾燥した。 溶媒留去 して粗 2—ジメチルアミノエチル フエニル カーボネー トを無色油'と して 465mg得た このものに実施例 80で得られた化合物 880mg(2.2ミ リモ ル）を加え 90° で 2時間加温した。 反応液をシリカゲル（40g)カラムクロ マトグラフィ一に付し分離精製した。 n—へキサン一 S乍酸ェチル （1 :4) 溶出夜で不純物を除いた後、 ク.口口ホルムーメタノ^ル（10: 1 )溶出液 から， 目的物を無色粉末として得た。 収量 800mg(71%)  To a solution of 223 mg (2.5 mmol) of N, N-dimethylethanolamine and 253 mg (2.5 mmol) of triethylmamine in 5 mi of methylene chloride was added dropwise 391 mg (2.5 mmol) of phenyl chloroformate with stirring under ice-cooling. . After stirring for 10 minutes under ice-cooling and at room temperature for 30 minutes, the reaction solution was diluted with methylene chloride, washed with a 1% aqueous solution of sodium hydrogencarbonate, and dried over sodium sulfate. The solvent was distilled off to obtain 465 mg of crude 2-dimethylaminoethyl phenyl carbonate as a colorless oil '. To this, 880 mg (2.2 mmol) of the compound obtained in Example 80 was added, and the mixture was added at 90 ° for 2 hours. Warmed. The reaction solution was subjected to silica gel (40 g) column chromatography for separation and purification. After removing impurities in the night of elution with n-hexane-S-ethyl (1: 4), the desired product was obtained as a colorless powder from the eluate of formum methanol (10: 1). Yield 800mg (71%)
I R(KBr)cm-1: 3300CNH), 2920(CH), 2850(Cfl), 1695(CO), 1532 (C'ONH) , 1472(CH2), 1277 (CONE), 1155IR (KBr) cm- 1 : 3300CNH), 2920 (CH), 2850 (Cfl), 1695 (CO), 1532 (C'ONH), 1472 (CH 2 ), 1277 (CONE), 1155
R(CDC13)<5： 0.87C3H), 1.25(32H), 2.26(6H. s , NMe2) , 2.53 (2H,t, J = 5.9Hz,CH2N), 3.03-3.5(5H) , 3.40(3H,s,OCH3), 4.12(2H, d, J = 4.5Hz,CHCH20), 4.16(2H, t J = 5.9Hz,0CH2CH2N) , 4.8(1H, CONH) , 5.18(1H,C0NH) R (CDC1 3) <5: . 0.87C3H), 1.25 (32H), 2.26 (6H s, NMe 2), 2.53 (2H, t, J = 5.9Hz, CH 2 N), 3.03-3.5 (5H), 3.40 (3H, s, OCH 3 ), 4.12 (2H, d, J = 4.5Hz, CHCH 20 ), 4.16 (2H, t J = 5.9Hz, 0CH 2 CH 2 N), 4.8 (1H, CONH), 5.18 (1H, C0NH)
実施例 82 Example 82
2— トリメチルアン乇ニォェチル N— [2—（メ トキシー 3—才クタ  2— Trimethylampenyoethyl N— [2— (Methoxy 3—
差換え デシルォキシ）プロピル]力—バメイ ト ョーダイ ド Replacement Decyloxy) propyl] force—bamate
実施例 81で得られた化合物 258mg(0. 5ミ リモル）のエーテル 5 ml溶 液にヨウ化メチル 355mg(2.5ミ リモル）を加え室温で一夜放置した。 圻出 物を泸取して目的物を無色結晶として得た。 収量 305mg(93%)  To a solution of 258 mg (0.5 mmol) of the compound obtained in Example 81 in 5 ml of ether was added 355 mg (2.5 mmol) of methyl iodide, and the mixture was allowed to stand at room temperature overnight. The target substance was obtained as colorless crystals by collecting the product. Yield 305mg (93%)
I R(KBr)cm-1:3325(NH)( 2920 (CH), 2850(CH), 1728CCO), 1708IR (KBr) cm- 1 : 3325 (NH) ( 2920 (CH), 2850 (CH), 1728CCO), 1708
(CO), 1530CCONH), 1469(CH2), 1257(CONH) (CO), 1530CCONH), 1469 (CH 2 ), 1257 (CONH)
NMR <5 (CDC13):0.87(3H), 1.26(32H), 3.02-3.45(5H), 3.43(3H, s,0CH3), 3.53(9H,s,NMe3), 3.95-4.20(4H,OCH2 + CH2N) , 4.50-4.70 NMR <5 (CDC1 3): 0.87 (3H), 1.26 (32H), 3.02-3.45 (5H), 3.43 (3H, s, 0CH 3), 3.53 (9H, s, NMe 3), 3.95-4.20 (4H , OCH 2 + CH 2 N), 4.50-4.70
+  +
(2H,CH2CH2N), δ.07(1Η,ΝΗ), 6.15(1H,NH) (2H, CH 2 CH 2 N), δ.07 (1Η, ΝΗ), 6.15 (1H, NH)
実施例 83 Example 83
2—ジメチルアミ ノエチル N—ァセチル一 N— [(2—メ トキシー 3 ーォクタデシルカルバ乇ィルォキシ）プロピル]カーバメィ ト  2-Dimethylaminoethyl N-acetyl-1 N-[(2-Methoxy-3-octadecylcarbazyloxy) propyl] carbamate
実施例 81で得られた化合物 145mg(0.28ミ リモル）を無水テトラヒ ドロ フラン 1 mlに溶かし氷冷攙拌下に n—プチルリチウム Q.i8ml(1.55規定， 0.28ミ リモル）を滴下した。 この溶液を無水酢酸中に一度に注いだ。 反 応液をクロ口ホルムで希釈し、 1 %炭酸水素ナト リ ゥム水溶液で洗净、 硫酸ナトリゥムで乾墚した。 溶媒留去し残留物をシリカゲル 5 gカラム クロマ トグラフィ—に付し分離精製した。 詐酸ェチル—ァセ トン（15: 1 ) 溶出液から目的物を無色粉末として得た。 収量 25mg(16%)  145 mg (0.28 mmol) of the compound obtained in Example 81 was dissolved in 1 ml of anhydrous tetrahydrofuran, and 8 ml of n-butyllithium Q.i (1.55 N, 0.28 mmol) was added dropwise with stirring under ice-cooling. The solution was poured into acetic anhydride all at once. The reaction solution was diluted with chloroform, washed with a 1% aqueous sodium hydrogen carbonate solution, and dried with sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel 5 g column chromatography for separation and purification. The target product was obtained as a colorless powder from the eluate of ethyl sulphate-acetone (15: 1). Yield 25mg (16%)
I RCKBi cnr1: 3330(NH), 2915(CH), 2845(CH)( 1735sh(CO), 1720CCO), 1525CCONH), 1465(CH2), 1373, 1247, 1189, 1152I RCKBi cnr 1 : 3330 (NH), 2915 (CH), 2845 (CH) ( 1735sh (CO), 1720CCO), 1525CCONH), 1465 (CH 2 ), 1373, 1247, 1189, 1152
NMR δ (CDC13): 0.87(3H), 1.25(32H), 2.27(6H, s , NMe2) , 2.4S (3H,s,C0CH3), 2.61(2H(t, J = 6.0Hz,CH2N), 3.03 -3.30(2H( NHCH2) , 3.38(3H,s,0CH3), 3.5-3.7(1H, CH) . 3.84-3.96(2H, m, CH2N) , 4.03- 4.17(2H,m>CH20), 4.29(2H, t , J = 6.0Hz,OCH2CH2N) , 4.78(1H,NH) 実施例 84 NMR δ (CDC1 3): 0.87 (3H), 1.25 (32H), 2.27 (6H, s, NMe 2), 2.4S (3H, s, C0CH 3), 2.61 (2H (t, J = 6.0Hz, CH 2 N), 3.03 -3.30 (2H (NHCH 2), 3.38 (3H, s, 0CH 3), 3.5-3.7 (1H, CH). 3.84-3.96 (2H, m, CH 2 N), 4.03- 4.17 ( 2H, m> CH 2 0) , 4.29 (2H, t, J = 6.0Hz, OCH 2 CH 2 N), 4.78 (1H, NH) example 84
差換え 2— トリメチルアンモニォェチル N—ァセチルー N— [(2—メ トォ キシ一 3—才クタデシルカルバモイルォキシ）プ ピル]カーバメィ ト ョーダイ ド . Replacement 2-Trimethylammonioethyl N-Acetyl-N — [(2-Methoxy-1-3-tadecylcarbamoyloxy) propyl] carbamate
実施例 83で得られた化合物 25tng(0.045ミ リモル）をエ-テル 0.5mlに溶 かし、 この溶液にヨウ化メチル 32mg(0.225ミ リモル）を加えて室温で一 夜放置した。 折出物を' 取して目的物を無色結晶として得た。 収 *25mg (80%)  25 tng (0.045 mmol) of the compound obtained in Example 83 was dissolved in 0.5 ml of ether, and 32 mg (0.225 mmol) of methyl iodide was added to this solution, and the mixture was allowed to stand at room temperature overnight. The precipitate was collected to give the desired product as colorless crystals. Yield * 25mg (80%)
I RCKB^cm-1: 2910CCH), 2845(CH), 1707CCO), 1528(CONH),I RCKB ^ cm- 1 : 2910CCH), 2845 (CH), 1707CCO), 1528 (CONH),
1466(CH2), 1255, 1190, 1150 1466 (CH 2 ), 1255, 1190, 1150
NMR δ (CDCU): 0.87C3H), 1.25(32H), 2.51(3H, s , C0CH3) , NMR δ (CDCU): 0.87C3H) , 1.25 (32H), 2.51 (3H, s, C0CH 3),
+  +
3.03-3.25(2H,NHCH2), 3.32(3H, s , 0CH3) , 8.55(9H, s , Me3) , 3.5-3.7 (1H.CH), 3.85-4.5C6H), 4.6-4.8(2H,0CH2CH2N) , 5.47(1H,NH) 実施例 85 3.03-3.25 (2H, NHCH 2), 3.32 (3H, s, 0CH 3), 8.55 (9H, s, Me 3), 3.5-3.7 (1H.CH), 3.85-4.5C6H), 4.6-4.8 (2H , 0CH 2 CH 2 N), 5.47 (1H, NH) Example 85
3— [2— (2—テトラヒ ドロビラニルォキシ） -ェチル]ヒダントイン 水酸化力リゥム l,24g(0.02モル）をエタノ ール（40ml)に溶かし、 ヒダ ントイン 2 g(0.02モル）を加えて室温下に 30分かきまぜた後、 2—（2— テトラヒ ドロビラニルォキシ）ェチルプロマイ ド 4.6g(0.022モル）を加え 66時間加熱'還流した。 冷後、 反応液を泸過、 母液を減圧下に乾固、 残留 物に水を加えてクロ口ホルムで抽出、 炭酸カリウムで乾燥した。 減圧下 に溶媒留去し残留物に n -へキサンを加えて^過し、 目的物を無色結晶 ' として得た。 収量 1.7g(37%)  3- [2- (2-Tetrahydrobilanyloxy) -ethyl] hydantoin Dissolve 1,24 g (0.02 mol) of hydroxylating water in ethanol (40 ml) and add 2 g (0.02 mol) of hydantoin After stirring at room temperature for 30 minutes, 4.6 g (0.022 mol) of 2- (2-tetrahydrobiranyloxy) ethylpromide was added, and the mixture was heated and refluxed for 66 hours. After cooling, the reaction solution was filtered, the mother liquor was evaporated to dryness under reduced pressure, water was added to the residue, extracted with chloroform, and dried over potassium carbonate. The solvent was distilled off under reduced pressure, n-hexane was added to the residue, and the mixture was filtered to give the desired product as colorless crystals. Yield 1.7 g (37%)
I R(KBr)cm-1: 3300(NH), 2955(CH), 2925(CH), 2860(CH), 1765 (CO), 1720(CO), 1705 (CO), 1450(CH2), 1075 IR (KBr) cm- 1 : 3300 (NH), 2955 (CH), 2925 (CH), 2860 (CH), 1765 (CO), 1720 (CO), 1705 (CO), 1450 (CH 2 ), 1075
NMR δ (CDCls): 1.60(6H), 3.5-3.85(6H) , 3.95(2H, s , NHCH2) , 4.61(1H,CH), 6.57(1H,NH) NMR δ (CDCls): 1.60 (6H), 3.5-3.85 (6H), 3.95 (2H, s, NHCH 2 ), 4.61 (1H, CH), 6.57 (1H, NH)
実施例 86 - 1 - (2一ベンジルォキン一 3—ォクタデシルォキシ）プロピル トシ レー 卜 Example 86- 1- (2-benzyloquin-1-3-octadecyloxy) propyl tosylate
1 — (2—ベンジルォキシ一 3—ォクタデシルォキシ）プロパノール 1.3g(3 ミ リモル）およびトシルク口ライ ド 1.7g(9ミ リ乇ル）をトリェチ ルァミ ン 24mlに溶かし、 65°Cに加温して 1.5日かきまぜた。 反応液を減 圧下に乾固し、 残留物をクロ口ホルムに溶かし、 水洗、 炭酸カリウムで 乾燥した。 減圧下に溶媒留去し、 残留物をシリカゲル 40gカラムクロマ トグラフィ一に付し分離精製した。 n—へキサン一酢酸ェチル（4： 1 )溶 出液から、 目的物を無色油として得た。 収量 1.4g(83%〉  1 — (2-Benzyloxy-3-octadecyloxy) propanol 1.3 g (3 mimol) and Tossil mouth light 1.7 g (9 mirid) are dissolved in 24 ml of triethylamine and added to 65 ° C. Heated and stirred for 1.5 days. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in chloroform, washed with water, and dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel 40 g column chromatography for separation and purification. The desired product was obtained as a colorless oil from the n-hexane monoethyl acetate (4: 1) eluate. Yield 1.4 g (83%)
I R(liq)cm-1 : 2920(CH), 2850(CH), 1465(CH2), 1367(S02), 1173(S02) IR (liq) cm- 1: 2920 (CH), 2850 (CH), 1465 (CH 2), 1367 (S0 2), 1173 (S0 2)
N R δ (CDCla): 0.87C3H), 1.25(32H), 2.42(3H,s.CH3), 3.33 (2H)t,J = 6.0Hz,OCH2CH2)( 3. 2(2H,d, J = 5.5Hz, CHCH20) , 3.73(1H, CH) , 3.96-4.29(2H,CH20S02), 4.57(2H, CH2Ph) , 7.23-7.33(7H, henyl ring-H), 7.77 (2H, phenyl ring-H) NR δ (CDCla): 0.87C3H), 1.25 (32H), 2.42 (3H, s.CH 3 ), 3.33 (2H ) t, J = 6.0Hz, OCH 2 CH 2 ) ( 3.2 (2H, d, J = 5.5Hz, CHCH 2 0) , 3.73 (1H, CH), 3.96-4.29 (2H, CH 2 0S0 2), 4.57 (2H, CH 2 Ph), 7.23-7.33 (7H, henyl ring-H), 7.77 (2H, phenyl ring-H)
実施例 87 Example 87
1 一 [ 1 一（ 2—ベンジルォキン一 3—ォクタデシルォキシ）プロピル] 一 3— (2—ハイ ドロォキシェチル）ヒダントイン  1 1 [1 (2—benzyloquin-1-3-octadecyloxy) propyl] 1 3— (2—Hydroxyxetil) hydantoin
実施例 85で得られた化合物 753mg(3.3ミ リモル）および実施例 86で得ら れた化合物 650mga.lミ リモル）のジメチルスルホキシ ド 5 ml溶液に粉末 水酸化力リゥム 740mg(13.2ミ リモル）を加え室温で 2日はげしくかきま ぜた。 反応波を氷水中に注ぎ、 塩酸水溶液で酸性とし、 詐酸ェチルで抽 出し、 硫酸ナトリウムで乾燥した。 减圧下に溶媒留去し残留物にエタノ —ル 25mlおよび塩酸水溶液 1 mlを加え 80°Cに加温して 0.5時間かきまぜ た。 反応液を減圧下に溶媒留去し、 残留物をクロ口ホルムに溶かし水洗 後、 炭酸カリウムで乾燥した。 減圧下に溶媒留去し、 残留物をシリカゲ  A powder was added to a solution of 753 mg (3.3 mmol) of the compound obtained in Example 85 and 650 mgal.l of the compound obtained in Example 86) in 5 ml of dimethyl sulfoxide. And stirred vigorously for 2 days at room temperature. The reaction wave was poured into ice water, acidified with an aqueous hydrochloric acid solution, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, 25 ml of ethanol and 1 ml of aqueous hydrochloric acid solution were added to the residue, and the mixture was heated to 80 ° C and stirred for 0.5 hour. The solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in chloroform, washed with water and dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was silica gel
ΟΜΡΓ ル 20gカラムクロマトグラフィ—に付し分離精製した。 n—へキサン—舴 酸ェチル溶出液から、 目的物を淡黄色油として得た。 収量 190nig(31%)ΟΜΡΓ The product was separated and purified by 20 g column chromatography. The desired product was obtained as a pale yellow oil from the eluate of n-hexane-ethyl acetate. Yield 190nig (31%)
I R(liq)cm-1: 0.87(3H), 1.26(32H), 2.78(1H, t , J = 5. δΗζ,ΟΗ) .IR (liq) cm- 1 : 0.87 (3H), 1.26 (32H), 2.78 (1H, t, J = 5.δΗζ, ΟΗ).
3.35-3.53(6H>CHCH20CH2 + NCH2), 3.63- 3.83 (5H, NCH2 + CH20H+ CH) , 3.35-3.53 (6H > CHCH 2 0CH 2 + NCH 2 ), 3.63- 3.83 (5H, NCH 2 + CH 2 0H + CH),
0  0
II  II
3.88(2H,ABq,NCH2C ), 4.47 and 4.73(2H,two sets of doublet, J= 12.0 Hz,CH2Ph), 7.29(5H,s, phenyl ring :H) 3.88 (2H, ABq, NCH 2 C), 4.47 and 4.73 (2H, two sets of doublet, J = 12.0 Hz, CH 2 Ph), 7.29 (5H, s, phenyl ring : H)
実施例 88  Example 88
1—[1—(2—ベンジルォキシ一 3—ォクタデシルォキシ）プロピル] 一 3—（ 2— トシルォキシェチル）ヒダン トイン  1- [1— (2-benzyloxy-1-3-octadecyloxy) propyl] 1-3- (2-tosyloxyshetyl) hydantoin
実施例 87で得られた化合物 187mg(0.33ミ リモル）およびトシルク口 'ラ ィ ド 70mg(0.37ミ リモル）のトリェチルァミ ン 2.6ml溶液を室温で一夜放 置した。 更に 50— 55°Cに加温して 4時間かきまぜた。 反応液を減圧下に ' 乾固し、 残留物をシリカゲル 5gカラムクロマトグラフィーに付し分離 精製した。 n—へキサン一昨酸ェチル（4： 1 )溶出液から、 目的物を淡黄 色油として得た。 収量 200mg(84%)  A solution of 187 mg (0.33 mmol) of the compound obtained in Example 87 and 70 mg (0.37 mmol) of tosyl mouth ラ -lide in 2.6 ml of triethylamine was left overnight at room temperature. The mixture was further heated to 50-55 ° C and stirred for 4 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel 5 g column chromatography to separate and purify. The desired product was obtained as a pale yellow oil from the eluate of n-hexane / ethyl acetate (4: 1). Yield 200mg (84%)
I R(liq)cm-1 : 2925(CH), ¾850(CH), 1772 CCO), 1720(CO), 1467 (CH2), 1370(SO2), 1178(S02), 760 IR (liq) cm- 1: 2925 (CH), ¾850 (CH), 1772 CCO), 1720 (CO), 1467 (CH 2), 1370 (SO 2), 1178 (S0 2), 760
NMR δ (CDC13): 0.87C3H), 1.25(32H), 2.41(3H,s,CH3), 3.35 -3.53(6H,CH20CH2 + NCH2), 3.64-3.76(3H, CH2 + CH) , 3.83 (2H,ABq, 0 NMR δ (CDC1 3): 0.87C3H ), 1.25 (32H), 2.41 (3H, s, CH 3), 3.35 -3.53 (6H, CH 2 0CH 2 + NCH 2), 3.64-3.76 (3H, CH 2 + CH), 3.83 (2H, ABq, 0
NCH2C), 4.22(2H,t,J = 5.7Hz,CH20Ts)) 4.48 と 4.7K2H, two sets of doublet, J = 12.0 Hz,CH2Ph). 7.25-7.33(7H,phenyl ring- H), 7.76 (2H,d, phenyl ring- H) NCH 2 C), 4.22 (2H, t, J = 5.7Hz, CH 2 0Ts) ) 4.48 and 4.7K2H, two sets of doublet, J = 12.0 Hz, CH 2 Ph) .7.25-7.33 (7H, phenyl ring- H), 7.76 (2H, d, phenyl ring- H)
実施例 89  Example 89
1一 [1—(2—ハイ ドロォキシ一 3—才クタデシルォキシ）プロピル]  1- [1— (2-Hydroxy-1-3-Kutadecyloxy) propyl]
ζし 一 3—（ 2— トシルォキシェチル）ヒダントイン Pashi One 3— (2—Tosylokishetil) Hydantoin
実施例 88で得られた化合物 200mg(0.28ミ リモル）および 10%Pd- C (50 % wet)150mgに鲊酸 8 mlを加え水素ガス気流下で室温一夜かきまぜた。 触媒を泸過して除き、 母液を'减圧下に乾固、 残留物をシリカゲル 10g力 ラムクロマトグラフィ一に付し分離精製した。 n—へキサン—詐酸ェチ ル（1 : 1)溶出液から、 目的物を無色固型物として得た。 収量 100mg(57 %)  To 200 mg (0.28 mmol) of the compound obtained in Example 88 and 150 mg of 10% Pd-C (50% wet) was added 8 ml of sulfuric acid, and the mixture was stirred overnight at room temperature under a stream of hydrogen gas. The catalyst was removed by filtration, the mother liquor was dried under reduced pressure, and the residue was subjected to silica gel 10 g column chromatography for separation and purification. The desired product was obtained as a colorless solid from the eluate of n-hexane-ethyl acetate (1: 1). Yield 100mg (57%)
I R (film) cm"1: 2925(CH), 2850(CH), 1772(CO), 1713(CO), 1470(CH2), 1370(SO2), 1178(S02), 760 " IR (film) cm "1: 2925 (CH), 2850 (CH), 1772 (CO), 1713 (CO), 1470 (CH 2), 1370 (SO 2), 1178 (S0 2), 760"
N R δ (CDC ) ： 0.87 (3H), 1.25 (32H), 2. 3C3H, s , CH3) , 2.80 (lH.d, J = 4.0 Hz, OH), 3.35-3.53(6H, CH20CH2 + NCH2) , 3.76(2H, t , J = NR δ (CDC): 0.87 ( 3H), 1.25 (32H), 2. 3C3H, s, CH 3), 2.80 (lH.d, J = 4.0 Hz, OH), 3.35-3.53 (6H, CH 2 0CH 2 + NCH 2 ), 3.76 (2H, t, J =
0  0
II  II
5.5Hz,NCH2), 3.9-4. K1H.CH), 4.02(2H, s , CH2C) , 4.25(2H,t,'J = 5.5Hz,CH20T^), 7.31(2H,d, henyl ring-H), 7.76(2H, d, phenyl ring -H) 5.5Hz, NCH 2), 3.9-4. K1H.CH), 4.02 (2H, s, CH 2 C), 4.25 (2H, t, 'J = 5.5Hz, CH 2 0T ^), 7.31 (2H, d , henyl ring-H), 7.76 (2H, d, phenyl ring -H)
実施例 90 Example 90
1一 [1— (2—ァセトキシ一 3—ォクタデシルォキシ）プロピル]— 3 一（2— トシルォキシェチル）ヒダントイン  1- [1— (2-Acetoxy-1-3-octadecyloxy) propyl] —3-1- (2—tosyloxyshetyl) hydantoin
実施例 89で得られた化合物 75mg (0.12ミ リモル） にピリ ジン 0.5mlお 'よび無水舴酸 Q.5miを加え室温で一夜放置した。 反応液を威圧下に乾固 し、 残留物をシリカゲル 5gカラムクロマトグラフィ一に付し分離精製 した。 n—へキサン一酢酸ェチル（2： 1 )溶出液から、 目的物を無色結晶 として得た。 収量 55nig(69%)  To 75 mg (0.12 mmol) of the compound obtained in Example 89, 0.5 ml of pyridine and Q.5 mi of anhydrous acetic acid were added, and the mixture was allowed to stand at room temperature overnight. The reaction solution was dried under pressure and the residue was subjected to silica gel 5 g column chromatography for separation and purification. The desired product was obtained as colorless crystals from the eluate of n-hexane monoethyl acetate (2: 1). Yield 55nig (69%)
I R(KBr)cm-1 : 2920CCH), 2850(CH), 1760(CO), 1738(OAc), 1712CCO), 1478(CH2), i360(SO2), 1230(OAc), 1172(S02) IR (KBr) cm- 1: 2920CCH ), 2850 (CH), 1760 (CO), 1738 (OAc), 1712CCO), 1478 (CH 2), i360 (SO 2), 1230 (OAc), 1172 (S0 2 )
MR δ (CDC ): 0.87C3H), 1.25(32H), 2.05(3H, s , C0CH3) , MR δ (CDC): 0.87C3H) , 1.25 (32H), 2.05 (3H, s, C0CH 3),
差換え 2.43(3H,s. CH3), 3.35-3.67(6H, CH20CH2 + CH2) , 3.75(2H, t , J = 5.5Hz,Replacement 2.43 (3H, s. CH 3 ), 3.35-3.67 (6H, CH 2 0CH 2 + CH 2), 3.75 (2H, t, J = 5.5Hz,
0 0
II II
NCH2), 3.92(2H(ABq,NCH2C), 4.23(2H, t , J = 5.5Hz, CH2OTs) , 5.11(1H, CH), 7.3i(2H,d, phenyl ring-H), 7.76 (2H,d, phenyl ring-H) 実施例 91 NCH 2 ), 3.92 (2H ( ABq, NCH 2 C), 4.23 (2H, t, J = 5.5 Hz, CH 2 OTs), 5.11 (1H, CH), 7.3i (2H, d, phenyl ring-H) , 7.76 (2H, d, phenyl ring-H) Example 91
1 - [ 1 — (2—ァセ トキシ— 3—ォクタデシルォキシ）プロピル ]一 3 一（2— トリメチルアンモニォェチル）ヒダン トイン クロライ ド  1- [1— (2-Acetoxy-3-octadecyloxy) propyl] -1- (2-trimethylammonioethyl) hydantoin chloride
実施例 90で得られた化合物 100mg(0.15ミ リモル）を 20%トリメチルァ ミ ン— トルエン溶液 10mlに溶かし室温で 3.5日、 更に封管中 60°Cに加温 して 12時間放置した。 反応液を减圧下に乾固し、 残留物をメタノール一 水（8 : 2)に溶かし、 強塩基性イオン交換樹脂 Dowex 21K(C1 型）の力 ラムを通過させた。 目的物を含む分画液を乾固し、 残留物をシリカゲル 2 gカラムクロマトグラフィ一に付し分離精製した。 クロ口ホルムーメ タノ ール一水 （65:25:4)溶出液から目的物を無色粉末として博た。 収量 75mg(85¾)  100 mg (0.15 mmol) of the compound obtained in Example 90 was dissolved in 10 ml of a 20% trimethylamine-toluene solution, heated at room temperature for 3.5 days, further heated at 60 ° C. in a sealed tube, and left for 12 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was dissolved in methanol-water (8: 2) and passed through a column of a strong basic ion exchange resin Dowex 21K (C1 type). The fraction containing the desired product was evaporated to dryness, and the residue was subjected to silica gel 2 g column chromatography for separation and purification. The desired product was obtained as a colorless powder from the eluate of black mouth formum ethanol mono-water (65: 25: 4). Yield 75mg (85¾)
I RCKB cm-1 : 2920CCH), 2850(CH), 1767CCO), i735(OAc),I RCKB cm- 1 : 2920CCH), 2850 (CH), 1767CCO), i735 (OAc),
1709CCO), 1470(CH2), 1235(OAc) 1709CCO), 1470 (CH 2 ), 1235 (OAc)
NMR δ (CDC13) ： 0.87 (3H) , 1.25(32H), 2.06(3H, s, C0CH3), NMR δ (CDC1 3): 0.87 (3H), 1.25 (32H), 2.06 (3H, s, C0CH 3),
+  +
3.35- 3.67 (6H, CH20CH2 +NCH2), 3.43(9H,s,NMe3), 3.96- 4.06 (6H， 3.35- 3.67 (6H, CH 2 0CH 2 + NCH 2 ), 3.43 (9H, s, NMe 3 ), 3.96- 4.06 (6H,
0  0
+ II  + II
NCH2CH2N + NCH2C), 5.02- 5.20 (1H, CH) NCH 2 CH 2 N + NCH 2 C), 5.02- 5.20 (1H, CH)
実施例 92 Example 92
1 - [ 1 —(2—ァセ トキシー 3—ォクタデシルォキシ）プロピル]— 3 一（2—チアゾリオェチル）ヒダン トイン クロライ ド  1- [1— (2-Acetoxy 3-octadecyloxy) propyl] —31- (2-thiazolioethyl) hydantoin chloride
実施例 90で得られた化合物 400mg(0.6ミ リモル）にチアゾ―ル 5 mlを加 え 95°Cに加熱して 15時閭かきまぜた。 反応液を减圧下に乾固し、 残留物 をメタノ —ルー水（8 : 2)に溶かし、 強塩基性イオン交換樹脂 Dowex 2iK(Cl型）のカラムを通過させた。 目的物を含む分画液を乾固し、 残留 物をシリカゲル 5 gカラムクロマ トグラフィ—に付し分離精製した。 ク ロロホルムーメタノ一ルー水（65 :25 :4)溶出液から、 目的物を無色粉末 として得た。 収量 27(kg(73%) To 400 mg (0.6 mmol) of the compound obtained in Example 90, 5 ml of thiazole was added, and the mixture was heated to 95 ° C and stirred for 15 hours. The reaction mixture was evaporated to dryness under reduced pressure. Was dissolved in methanol-water (8: 2) and passed through a column of a strong basic ion exchange resin Dowex 2iK (Cl type). The fraction containing the desired product was evaporated to dryness, and the residue was subjected to silica gel 5 g column chromatography to separate and purify. The desired product was obtained as a colorless powder from a chloroform eluate (65: 25: 4) eluate. Yield 27 (kg (73%)
1 R(KBr)cm-1: 2920 CCH), 2850(CH), 1767(CO)( 1737(OAc), 1703(CO), 1470(CH2), 1236(OAc)1 R (KBr) cm- 1 : 2920 CCH), 2850 (CH), 1767 (CO) ( 1737 (OAc), 1703 (CO), 1470 (CH 2 ), 1236 (OAc)
MR δ (CDCls) ： 0.87 (3H), 1.25 (32H), 2.07 (3H, s,  MR δ (CDCls): 0.87 (3H), 1.25 (32H), 2.07 (3H, s,
+ +
COCHs), 3.34- 3.63 (6H, CH20CH2+ NCH2), 4.08 (4H, CH2 +COCHs), 3.34- 3.63 (6H, CH 2 0CH 2 + NCH 2 ), 4.08 (4H, CH 2 +
0 0
NCH2C), 4.95- 5.23 (3H, NCH2CH2N + CH), 8.16 (1H, thiazole ring -H), 8.75 (1H, thiazole ring-H), 11.23 (1H, thiazole ring-H) NCH 2 C), 4.95- 5.23 (3H, NCH2CH2N + CH), 8.16 (1H, thiazole ring-H), 8.75 (1H, thiazole ring-H), 11.23 (1H, thiazole ring-H)
実施例 93 -Example 93-
2— 0—べンジルー 3— 0—才クタデシル一 1 — 0— トシルグリセリ ン 2—0—Benziru 3—0—Kitadecyl 1—0—Tosylglycerin
2— 0—ベンジル— 3— 0—ォクタデシルグリセリ ン 1 g (2.3ミ リモ ル）， トシルクロリ ド i.l44g (6.0ミ リモル） をピリ ジン 5 miに溶かし 一夜室温にてかきまぜる。 反応液を減圧下に濃縮乾固し残渣に 10%炭 酸水素水 20ml,エーテル 20mlを加えてよくふりまぜ、 エーテル層を^ 取する。 エ-テル層は硫酸ナトリウムにて乾かし、 '减圧下に濃縮乾固し て残渣をシリカゲル 15g, 展開液 n—へキサン，酢酸ェチル（9： 1 )にて 精製して無色固形物 1.2£(収率88.6%)を得た。  Dissolve 1 g (2.3 mimol) of 2-0-benzyl-3-0-octadecylglycerin and i.l44 g (6.0 mimol) of tosyl chloride in 5 mi of pyridine and stir overnight at room temperature. The reaction solution is concentrated to dryness under reduced pressure, 20 ml of 10% aqueous hydrogencarbonate and 20 ml of ether are added to the residue, and the mixture is shaken well to remove the ether layer. The ether layer was dried over sodium sulfate, concentrated to dryness under reduced pressure, and the residue was purified with 15 g of silica gel, developing solution n-hexane, ethyl acetate (9: 1) to give a colorless solid 1.2 £ ( Yield 88.6%).
I R(film)cm-1: 2920 2850 1460 1365 1190 1180 1120 1100 IR (film) cm- 1 : 2920 2850 1460 1365 1190 1180 1120 1100
990 820  990 820
NMR (60 MC, CDC ) δ :0.85(3H) 1.28C32H) 2.43(3H) 3.37C4H) 3.77(1H) 4.15(2H) 4.57(2H) 7.2(2H) 7.27(5H) 7.77(2H) 実施例 94 NMR (60 MC, CDC) δ: 0.85 (3H) 1.28C32H) 2.43 (3H) 3.37C4H) 3.77 (1H) 4.15 (2H) 4.57 (2H) 7.2 (2H) 7.27 (5H) 7.77 (2H) Example 94
1 一（2—ベンジルォキシー 3—ォクタデシルォキシ）プロピルゥラシ ル  1 1- (2-benzyloxy-3-octadecyloxy) propylperoxyl
ゥラシル 0.91g(8.16ミ リモル），実施例 93で得たトシレー ト 1.2g(2.04ミ リモル），炭酸ナトリウム 865mg(8.16ミ リモル）をジメチルホルムアミ ド 20ml，ジメチルスルホキシ ド 5 mlの混液に溶かし 50。C.5時間かきまぜた c 反応液を滅圧下に濃縮乾固し、 残渣に水 5mlを加え濃塩酸で pH 7.0に調 整し再び減圧下に濃縮乾固し、 残渣にクロ口ホルム 15ml, メタノ ール 10 mlを加えて抽出し、 不溶物をろ去し、 母液は再び濃縮乾固する。 残渣を シリ力ゲル lOg，展開液クロ口ホルム，メタノ ール（49: 1 )にて精製し無色 粉末7101^(収率65.8%)を得た。 ゥ 0.91 g (8.16 mimol) of racil, 1.2 g (2.04 mimol) of the tosylate obtained in Example 93, and 865 mg (8.16 mimol) of sodium carbonate were dissolved in a mixture of 20 ml of dimethylformamide and 5 ml of dimethylsulfoxide. 50. C.5 h c reaction mixture was concentrated to dryness to blink pressure was stirred, the residue in water 5ml was added concentrated hydrochloric acid pH 7.0 two adjusted Mr again concentrated to dryness under reduced pressure, the residue black port Holm 15 ml, methanol Then, add 10 ml of water and extract, remove the insoluble matter by filtration, and concentrate the mother liquor again to dryness. The residue was purified by silica gel 10g, developing solution Cloth Form, and methanol (49: 1) to obtain colorless powder 7101 ^ (yield 65.8%).
•T L C ,silicagel,CHCl3-MeOH(19:l) Rf = 0.46 TLC, silicagel, CHCl 3 -MeOH (19: l) Rf = 0.46
I R (film) cm"1: 2930, 2850 1690 1460 1380 1360 1240 1120 IR (film) cm " 1 : 2930, 2850 1690 1460 1380 1360 1240 1120
1060  1060
ϋ V spectrum, λ max(90¾MeOH) 266(η, λ min(90%MeOD 233m z  ϋ V spectrum, λ max (90¾MeOH) 266 (η, λ min (90% MeOD 233m z
Amax(pH60,90%MeOH) 264.5m^  Amax (pH60,90% MeOH) 264.5m ^
Amin(pH10,90%MeOH) 242m^  Amin (pH10,90% MeOH) 242m ^
実施例 95 Example 95
1 一（ 2—ベンジルォキシ一 3—ォクタデシル）プロピル一 3— ( 2— テトラハイ ドロビラニルォキシ）ェチルゥラシル  1- (2-benzyloxy-3-octactadecyl) propyl-3- (2-tetrahydrobilanyloxy) ethylperacyl
実施例 94で得た 1 一置換ゥラシル 710mg .34ミ リモル）， 2—ビラニル ォキシェチルブロマイ ド 842mg(4.08ミ リモル），水酸化カリウム 30Qnig (5.36ミ リモル）をジメチルスルホキシ ド 3nii中 50。C, 2時間激しくかき まぜた。 反応液を氷水 20mlにあけエーテル 20mlを加えてよくふりまぜ、  The mono-substituted dilacyl obtained in Example 94 (710 mg; 34 mimol), 2-biranyloxyshetyl bromide 842 mg (4.08 mimol), potassium hydroxide 30Qnig (5.36 mimol) were dissolved in dimethyl sulfoxide 3nii. 50. C, Stir vigorously for 2 hours. Pour the reaction mixture into 20 ml of ice water, add 20 ml of ether and shake well.
¾換え エーテル層を分取して、 減圧下に濃縮乾固する。 残渣をシリカゲル 10g. n—へキサン，舴酸ェチル（19: 1 )にて精製し無色固形物 570mg (収率 64.7%)を得た。 Exchange Separate the ether layer and concentrate to dryness under reduced pressure. The residue was purified by silica gel 10 g. N-hexane and ethyl acetate (19: 1) to obtain 570 mg of a colorless solid (yield 64.7%).
T L C .silicagel, CHCl3-MeOH (19： l)Rf = 0.80 TLC .silicagel, CHCl 3 -MeOH (19: l) Rf = 0.80
I RCfilm)^-1: 2910 2850 1700 1660 1445 1380 1355 1115 I RCfilm) ^ -1 : 2910 2850 1700 1660 1445 1380 1355 1115
1070 1030 750 1070 1030 750
MR(60 MC, CDCls)  MR (60 MC, CDCls)
δ； 0.87C3H) 1.26(32H) 1.60(6H) 3.2〜4.1(12H) 4.22(1H) 4.53C2H) 4.67C1H) 5.57(1H) 7.13(1H) 7.20(5H) U V spectrum,  δ; 0.87C3H) 1.26 (32H) 1.60 (6H) 3.2 ~ 4.1 (12H) 4.22 (1H) 4.53C2H) 4.67C1H) 5.57 (1H) 7.13 (1H) 7.20 (5H) U V spectrum,
λ max(MeOH) 267m i λ min(MeOH) 240m/ λ max (MeOH) 267m i λ min (MeOH) 240m /
max(0.05N-NaOH in MeOH) 267m  max (0.05N-NaOH in MeOH) 267m
λ max(0.05N-NaOH in MeOH) 2 0m^  λmax (0.05N-NaOH in MeOH) 20m ^
実施例 96 Example 96
1 — ( 2—ベンジルォキシ一 3—才クタデシルォキシ）プロピル一 3— ( 2—ハイ ドロキシ）ェチルゥラシル  1— (2-Benzyloxy-1 3-—Kutadecyloxy) propyl-3- (2-Hydroxy) ethylperacyl
実施例 95で得たテトラヒ ドロゼラニル体 570mg(0.868ミ リモル）をテト ラヒ ドロフラン 30ml,水 6 mlに溶かし、 濃塩酸 2mlを加え、 室温にて 1 時間かきまぜた。 反応液を減圧下に濃縮乾固し、 残渣をシリカゲル 10g, 展開液，クロロホルム，メタノ —ル（195:5)にて精製して無色固形物 496mg (収率 100%)を得た。  570 mg (0.868 mmol) of the tetrahydrozeranyl compound obtained in Example 95 was dissolved in 30 ml of tetrahydrofuran and 6 ml of water, 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel (10 g), developing solution, chloroform and methanol (195: 5) to obtain 496 mg of a colorless solid (yield: 100%).
T L C .silicagel, CHCU, MeOH(19： l)Rf = 0.25  T L C .silicagel, CHCU, MeOH (19: l) Rf = 0.25
I R(film)cm-1: 3460 2920 2850 1700 1465 1345 1220 1120 IR (film) cm- 1 : 3460 2920 2850 1700 1465 1345 1220 1120
1090 1060 825 770  1090 1060 825 770
実施例 97 Example 97
1 —(2—ベンジルォキシ一 3—才クタデシルォキシ）プロピル一 3— 差換え (2—クロロェチル）ゥラシル 1— (2-benzyloxy-1-3-tacutadecyloxy) propyl-1 3-substitution (2-Chloroethyl) peracyl
実施例 96で得たハイ ドロキシ体 510nig(0.868ミ リモル）， トシルクロリ ド 339mg(1.78ミ リモル），ピリジン 282mg(3.56ミ リモル）をジクロロメタ ン 2.5oilに溶かし 16時間室温にてかきまぜ、反応液にジクロロメタン 20ml, 2.5%炭酸水素水201111を加ぇて、 よくふりまぜてから、 ジクロロメタン 層を分取した。 これを 0.5N—塩酸，水の順に洗い、 ジクロロメタン層は 硫酸ナトリウムで乾かし減圧下に濃縮乾固し、 表記クロリ ド 513mg (収率 100%)を得た。  510 nig (0.868 mmol) of the hydroxy compound obtained in Example 96, 339 mg (1.78 mmol) of tosyl chloride and 282 mg (3.56 mmol) of pyridine were dissolved in 2.5 oil of dichloromethane and stirred at room temperature for 16 hours. After adding 20 ml and 2.5% aqueous hydrogencarbonate 201111 and shaking well, the dichloromethane layer was separated. This was washed with 0.5N hydrochloric acid and water in this order, and the dichloromethane layer was dried over sodium sulfate and concentrated to dryness under reduced pressure to obtain 513 mg (yield: 100%) of the title chloride.
T L C ,silicagel, CHCU. MeOH (19:1) 0.93  TLC, silicagel, CHCU.MeOH (19: 1) 0.93
I R(film)c(n~1: 2940 2850 1715 1670 1460 1400 1370 1350 IR (film) c (n ~ 1 : 2940 2850 1715 1670 1460 1400 1370 1350
1120  1120
NMR(60 MC, CDC13) NMR (60 MC, CDC1 3)
δ： 0.85C3H) 1.25C32H) 3.48(4H) 3.68(2H) 3.82(1H) 4.03 (2H) 4.25(2H) 4.50(2H) δ.δ7(1Η) 7.12(1H) 7.20 ' (5H)  δ: 0.85C3H) 1.25C32H) 3.48 (4H) 3.68 (2H) 3.82 (1H) 4.03 (2H) 4.25 (2H) 4.50 (2H) δ.δ7 (1Η) 7.12 (1H) 7.20 '(5H)
実施例 98 Example 98
1 一（2—ベンジルォキシ一 3—才クタデシルォキシ）プロピル一 3 - (2—チアゾリオェチル）ゥラシル  1 1- (2-benzyloxy-1 3--ta-tadecyloxy) propyl-1-3- (2-thiazolioethyl) ゥ racil
実施例 97で得たクロリ ド 30mg(0.051ミ リモル）をチアゾール 1 mlに溶 かし、 油温 120°C,—夜加熟した。 反応液を減圧下に濃縮乾固し、 残渣を シリカゲル 2 g,クロ口ホルム，メタノール，水（65 :25 :4)にて精製して、 無色固形物 6.2nig (収率 18.0%)を得た。  30 mg (0.051 mmol) of chloride obtained in Example 97 was dissolved in 1 ml of thiazole, and the mixture was ripened at an oil temperature of 120 ° C. overnight. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with silica gel (2 g), chloroform, methanol and water (65: 25: 4) to give a colorless solid (6.2 nig, yield 18.0%). Was.
T L C .silicagei, n-BuOH, AcOH, H20(4 : 1 : 1 )Rf=0.19 実施例 99 TLC .silicagei, n-BuOH, AcOH, H 2 0 (4: 1: 1) Rf = 0.19 Example 99
1—(2—ベンジルォキシー 3—ォクタデシルォキシ）プロピル一 3— (2— トリメチルアン乇ニォェチル）ゥラシル クロリ ド  1- (2-Benzyloxy-3-octadecyloxy) propyl-1- (2-trimethylampenyoethyl) -racil chloride
差換え 実施例 97で得たク口リ ド 490mg(0.83ミ リモル）を 20%トリメチルァミ ン— トルエン溶液 lOmUこ溶かし、 120。C，24時間加熱した。 反応液を減圧 下に濃縮乾固して残渣を siHcagel 5 g,展開液，クロ口ホルム，メタノ ー ル，水（65 : 25: 4)にて精製し無色固形物 115mg (収率 2i.3%)を得た。 Replacement 490 mg (0.83 mimol) of the closlide obtained in Example 97 were dissolved in a 20% trimethylamine-toluene solution lOmU, and 120 was obtained. C, heated for 24 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified with 5 g of siHcagel, developing solution, chloroform, methanol and water (65: 25: 4) to give 115 mg of a colorless solid (yield 2i.3). %).
T L C .silicagel, CHC , MeOH , H20(65： 2δ： 4)Rf = 0.31 TLC .silicagel, CHC, MeOH, H 2 0 (65: 2δ: 4) Rf = 0.31
NMR(60 MC, CDC13 + CD30D) NMR (60 MC, CDC1 3 + CD 3 0D)
6 0.87C3H) 1.2δ(32Η) 3.30(9H) 3.47(4H) 3.67(2H) 3.87 (1H) 4.22C2H) 4.52(2H) 5.67(1H) 7.13(1H) 7.20(5H) 実施例 100  6 0.87C3H) 1.2δ (32Η) 3.30 (9H) 3.47 (4H) 3.67 (2H) 3.87 (1H) 4.22C2H) 4.52 (2H) 5.67 (1H) 7.13 (1H) 7.20 (5H) Example 100
1 —(2—ハイ ドロキシー 3—才クタデシルォキシ）プロピル一 3—(2 — トリメチルアンモニォ）ェチルゥラシル · クロリ ド  1— (2—Hydroxy 3—Kitadecyloxy) propyl 1 3- (2—Trimethylammonio) ethylperacyl chloride
実施例 99で得たトリメチルァンモニゥム体 112mg(0.17ミ リモル）を 60 %舴酸 5 mlにに溶かし、 パラジウム炭素 28mg存在下に 4時間水素気流中 かきまぜた。 反応液より不溶物をろ去し、 少量のメタノ ールにて洗い、 母液，洗液を合せて、 減圧下に濃縮乾固して、 無色固形物 95mg (収率 100.0%)を得た。  112 mg (0.17 mmol) of the trimethylammonium compound obtained in Example 99 was dissolved in 5 ml of 60% sulfuric acid and stirred in a hydrogen stream for 4 hours in the presence of 28 mg of palladium carbon. The insoluble material was removed by filtration from the reaction solution, washed with a small amount of methanol, and the mother liquor and the washing solution were combined and concentrated to dryness under reduced pressure to obtain a colorless solid (95 mg, yield: 100.0%).
T L C .silicagel, CHC13, MeOH , H20(65:25:4)Rf = 0.19 TLC .silicagel, CHC1 3, MeOH, H 2 0 (65: 25: 4) Rf = 0.19
実施例 101 Example 101
1 — ( 2—ジメチルカルバモイルォキシ一 3—ォクタデシルォキシ）プ 口ピル一 3—（2— トリメチルァンモニォ）ェチルゥラシル クロリ ド 実施例 100で得たハイ ドロキシ体 47.5mg(0.085ミ リモル），クロ口炭酸 フエニル 0.1ml,ピリ ジン をジク口口メタン 0.5mlに溶かし、 室温に て 2時間かきまぜた。 反応液を減圧下に濃縮乾固して、 残渣をよく乾か して 20%ジメチルァミ ン— トルエン溶液 5 mlを加え、 一夜室温にて放置 した。 反応液を减圧下に濃縮乾固し、 残渣を 20%メタノ -ル 20mlに溶か し） { AD— 11 15mlのカラムに吸着させ 80%メタノ ールにて洗った後メ  1- (2-Dimethylcarbamoyloxy-1-3-octadecyloxy) p-pyr-3- (2-trimethylammonio) ethylperacyl chloride 47.5 mg (0.085 mg) of the hydroxy form obtained in Example 100 Lmol), 0.1 ml of phenyl carbonate and pyridine were dissolved in 0.5 ml of methane, and stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was thoroughly dried, 5 ml of a 20% dimethylamine-toluene solution was added, and the mixture was left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was dissolved in 20 ml of 20% methanol.) {Ad-11 was adsorbed on a 15 ml column, washed with 80% methanol, and then washed.
、、 ノ タノ ール 40mlにて溶出し、 これを減圧下に濃縮乾固し、 残渣をシリカゲ ル 2 g,展開液，クロロホルム，メタノ—ル，水（65 :25: 4)にて精製し無色固 形物 30mg (収率 5'5.9%)を得た。 ,, no Elution was carried out with 40 ml of ethanol, and this was concentrated to dryness under reduced pressure. The residue was purified with 2 g of silica gel, developing solution, chloroform, methanol, and water (65: 25: 4) to give a colorless solid. 30 mg (yield 5'5.9%) was obtained.
T L C .silicagel, CHC13, MeOH , H20(6D:25:4)Rf =0.39 TLC .silicagel, CHC1 3, MeOH, H 2 0 (6D: 25: 4) Rf = 0.39
I R(film)cm-1; 3360 2920 2850 1710 1660 1400 1240 1220 IR (film) cm- 1 ; 3360 2920 2850 1710 1660 1400 1240 1220
1195 1125 930 915  1195 1125 930 915
NMRC90 MC, CDCU)  NMRC90 MC, CDCU)
δ :0.87(3H) 1.23C32H) 2.83(6H) 3.47(9H) 3.58(4H) 3.85  δ: 0.87 (3H) 1.23C32H) 2.83 (6H) 3.47 (9H) 3.58 (4H) 3.85
(4H) 4.37C2H) 5.15C1H) 5.73(1H) 7.20(1H)- 7.25(δΗ) 実施例 102  (4H) 4.37C2H) 5.15C1H) 5.73 (1H) 7.20 (1H)-7.25 (δΗ) Example 102
1 - (2—ァセチルォキン 3—ォクタデシルォキシ）プロピル一 3 - (2— トリメチルアン乇ニォェチル）ゥラシル ' ク σリ ド  1-(2-acetyloquine 3-octadecyloxy) propyl-1- 3-(2-trimethylampenyoethyl) ゥ
実施例 100で得たハイ ドロキシ体 47.5mg(0.085ミ リモル）を無水詐酸  47.5 mg (0.085 mmol) of the hydroxy compound obtained in Example 100 was treated with anhydrous acid
0.5ml,ピリジン Q.5mlに溶かし、 50。C , 1時間加熟した。 反応液を减圧下 に濃縮乾固して、 残渣をシリカゲル 2g,展開液，クロ口ホルム，メタノ一 Dissolve in 0.5ml, pyridine Q.5ml, 50. C, ripened for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was treated with silica gel (2 g), developing solution, chloroform, and methanol.
ル，水（65: 25:4)にて精製し無色固形物 42mg (収率 82.0%)を得た。 Purified with water and water (65: 25: 4) to obtain 42 mg of a colorless solid (yield: 82.0%).
T L C .silicagel, CHCU, MeOH , H20(65:25:4)Rf = 0.43 TLC .silicagel, CHCU, MeOH, H 20 (65: 25: 4) Rf = 0.43
I R (film) cm"1; 3400 2930 2850 1730 1705 1655 1460 1370 IR (film) cm "1; 3400 2930 2850 1730 1705 1655 1460 1370
1235 1120 1060 1010 810 760  1235 1120 1060 1010 810 760
NMR(60 MC. CDCU)  NMR (60 MC. CDCU)
δ； 0.92C3H) 1.23C32H) 2.03(3H) 3.30(9H) 3.58(4H) 3.67  δ; 0.92C3H) 1.23C32H) 2.03 (3H) 3.30 (9H) 3.58 (4H) 3.67
(2H) 4.15C2H) 4.38C2H) 5.25(1H) 7.25(1H)  (2H) 4.15C2H) 4.38C2H) 5.25 (1H) 7.25 (1H)
実施例 103 Example 103
3一 [N—ァセチルー N— (2—ピリジル）メチル]力ルバモイルー 2 - メチル一 1—ォクタデシルカルバモイルグリセリ ン  3- [N-Acetyl-N- (2-pyridyl) methyl] dirubamoyl-2-methyl-1-octadecylcarbamoylglycerin
実施例 46-い）で得た 3 - 0 - [ - (2一ピリ ジル）メチル]力ルバモイ  3-0-[-(2- (Pyridyl) methyl] methyl) obtained in Example 46-i)
- 0MPI— 、 ルー 2— 0—メチルー 1 — 0—ォクタデシルカルバモイルグリセリ ン -0MPI —, Lou 2—0—Methyl-1—0—Octadecylcarbamoylglycerin
252mgをクロロホルム 7 mlに溶解し、 ト リェチルァミ ン 5.5ml及び無水詐 酸 l iiUを加え、 3日間加熱還流した。 冷後、 反応液に 3 %炭酸水素ナト リ ゥムを加えてクロ口ホルムで抽出し、 有機層を硫酸マグネシウムにて 乾燥後、 溶媒を減圧下に留去した。 得られた残渣をカラムクロマ トグラ フィ— [シリカゲル， 15g,溶出液， n—へキサン一詐酸ェチル， 1 ： 2]にて 精製し、 目的物 89mgを得た。 252 mg was dissolved in 7 ml of chloroform, 5.5 ml of triethylamine and liiU of anhydrous anhydride were added, and the mixture was heated under reflux for 3 days. After cooling, 3% sodium bicarbonate was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography [silica gel, 15 g, eluate, n-hexane monoethyl acetate, 1: 2] to obtain 89 mg of the desired product.
T L C :Rf=0.33 [シリカゲル， n—へキサン—酢酸ェチル， 1 : 3]  T LC: Rf = 0.33 [silica gel, n-hexane-ethyl acetate, 1: 3]
I RCKB ctn-1 : 3370, 2923, 2850, 1740, 1700, 1600, 1535,I RCKB ctn- 1 : 3370, 2923, 2850, 1740, 1700, 1600, 1535,
1475, 1370, 1232, 1090, 1065, 985, 775 1475, 1370, 1232, 1090, 1065, 985, 775
NMR(90 MHz, CDC13)<5： 0.88(3H, t , Me) , 1.28(32H, s , CH2) , 2.60 NMR (90 MHz, CDC1 3) <5: 0.88 (3H, t, Me), 1.28 (32H, s, CH 2), 2.60
(3H，s,NAc), 3.i2(2H,q，CONHCg2), 3.29(3H(s,OMe), 3.46(1H, quint,CH-0), 3.98(2H,d, CH20 CO), 4.21(2H(d, CH20C0) , 4.92 • (IH, road t NH) , 5.09(2H,s,CH2 -pyridyl), 7.11 , 7.60 , 8. 8(4H, pyridine) (3H, s, NAc), 3.i2 (2H, q, CONHCg 2), 3.29 (3H (s, OMe), 3.46 (1H, quint, CH-0), 3.98 (2H, d, CH 2 0 CO ), 4.21 (2H ( d, CH 2 0C0), 4.92 • (IH, road t NH), 5.09 (2H, s, CH 2 -pyridyl), 7.11, 7.60, 8.8 (4H, pyridine)
実施例 104 Example 104
3— 0— [N—ァセチルー N—（N—メチルピリ ジニォ一 2—ィル）メ チル]力ルバモイルー 2— 0—メチルー 1 — 0—才クタデシルカルバ乇 ィルグリセリ ン クロライ ド  3—0— [N-Acetyl-N— (N-methylpyridinyl-2-yl) methyl] capitarum 2—0—Methyl-1—0—Y-octadecylcarbylglyceryl chloride
実施例 103で得た化合物 85mgに沃化メチル 0.5mlを加え遮光して 2 日間 還流した。 冷後、 反応液を減圧濃縮し、 残渣を I R A— 410[C1— ](5ml, 溶出液： MeOH-H20, 7： 3 )にて処理した。 得られた粗クロライ ド体をカラ ムクロマ トグラフィー [シリ力ゲル， 5 g,溶出液：ク口口ホルム一メ タノ ール， 6： 1〜4： 1 ]にて精製し、 目的物 52mgを得た。 To 85 mg of the compound obtained in Example 103, 0.5 ml of methyl iodide was added, and the mixture was refluxed for 2 days while protecting from light. After cooling, the reaction solution was concentrated under reduced pressure, the residue IRA- 410 [C1-] (5ml, eluent: MeOH-H 2 0, 7 : 3) was treated with. The obtained crude chloride was purified by column chromatography [silica gel, 5 g, eluent: cholesterol form-methanol, 6: 1 to 4: 1] to obtain 52 mg of the desired product. Obtained.
T L C :Rf = 0.i7(シリカゲル， CHC13: eOH , 4:1) TLC: Rf = 0.i7 (silica gel, CHC1 3: eOH, 4: 1)
I R (film) cm-1: 3340, 2920, 2850, 1740, 1700, 1630, 1465, し 差換ん OMPI 1370, 1210 IR (film) cm- 1 : 3340, 2920, 2850, 1740, 1700, 1630, 1465, then replace OMPI 1370, 1210
-ヽ r MR (90 MHz, CDC13) 5： 0.88(3H, t , Me) , 1.24(32H, s , CH2) . -ヽ r MR (90 MHz, CDC1 3 ) 5: 0.88 (3H, t, Me), 1.24 (32H, s, CH 2).
2.61(3H,s(NAc), 3.10(2H,q,CONH CH2), 3.38(3H, s , OMe) , 2.61 (3H, s (NAc) , 3.10 (2H, q, CONH CH 2), 3.38 (3H, s, OMe),
3.70(lH,m,CHO), 3.99(4H, m, CH.OCOx 2) , 4.35(1H, m, NH) ,  3.70 (lH, m, CHO), 3.99 (4H, m, CH.OCOx 2), 4.35 (1H, m, NH),
4.70(3H,s,NMe), 5. 3(2H, br , s , CH2 -pyridinio), 7.71, 8.02,4.70 (3H, s, NMe) , 5. 3 (2H, br, s, CH 2 -pyridinio), 7.71, 8.02,
8.43,9.65(4H,ni,pyridiiiio) 8.43,9.65 (4H, ni, pyridiiiio)
実施例 105  Example 105
2— 0—メチルー 1— 0—ォクタデシルカルバモイル一 3 - 0 - (N —ァセチルー N— 2— トリメチルアンモニォェチル）力ルバモグリセロ ール · ァセテ— ト  2-0-Methyl-1-0-octadecylcarbamoyl-1-3-N- (N-Acetyl-N-2-trimethylammonioethyl) rubumoglycerol acetate
実施例— 25で得たィォダイ ド 350mg(0.5ミ リモル）を 75%メタノ ール 20 mlに溶かし I R C— 410(酢酸形） 15mlのカラ をゆつく り通過させ少量 の 75%メタノ —ルにて洗い通 il液.洗液を合せて減圧下に濃縮乾固し浅 渣をエーテル 1 ml, n -へキサン ml混液から再結晶して激しい吸湿性無 色粉末 315mg (収率 100%)を得た。  Example—350 mg (0.5 mmol) of the iodide obtained in 25 was dissolved in 20 ml of 75% methanol, and slowly passed through a 15 ml of IRC-410 (acetic acid form) with a small amount of 75% methanol. After washing, the combined washings were concentrated to dryness under reduced pressure, and the shallow residue was recrystallized from a mixture of 1 ml of ether and n-hexane to obtain 315 mg of a strongly hygroscopic colorless powder (100% yield). Was.
元素分 |！斤： C33He5N 308 - 1.5H20 Elements |! Catty: C 33 H e5 N 3 0 8 - 1.5H 2 0
計算値： C , 60.15 H.10.40 ,6.33 , 0  Calculated values: C, 60.15 H.10.40, 6.33, 0
実験値： C , 60.22 H.10.87 .6.32 ： , 0 以下に実施例で合成した化合物の構造式を参考のため記載する。  Experimental value: C, 60.22 H.10.87 2.6.32:, 0 The structural formulas of the compounds synthesized in the examples are described below for reference.
実施例 1 H2CH2-ヽ CH3)2 Example 1 H 2 CH 2-ヽ CH 3 ) 2
Figure imgf000094_0001
Figure imgf000094_0001
gAD OP 氧 gAD OP 氧
^J-l J¾ ,  ^ J-l J¾,
ΰ 実施例 2 rX 2〇 C 18 H 37 ΰ Example 2 rX 2〇 C 18 H 37
I I
C H 0 C 0 C H3 CH 0 C 0 CH 3
cccll  cccll
CH H H H2O C -Nr- CH2CH2N(CH3) CH HHH 2 OC -N r -CH 2 CH 2 N (CH 3 )
II I  II I
o 0 C 0 C H  o 0 C 0 C H
c  c
実施例 3 H p Example 3 H p
Figure imgf000095_0001
Figure imgf000095_0001
0 C 0 C H3 実施例 4 0 C 0 CH 3 Example 4
Figure imgf000095_0002
実施例 δ
Figure imgf000095_0003
Figure imgf000095_0002
Example δ
Figure imgf000095_0003
CHO C H2Ph CHO CH 2 Ph
I I
CH20 C HCH2CH20H CH 2 0 C HCH 2 CH 2 0H
II  II
0  0
OMPI OMPI
差換え W1PO  Replacement W1PO
' 実施例 6
Figure imgf000096_0001
' Example 6
Figure imgf000096_0001
C H 0 C H2Ph CH 0 CH 2 Ph
CH2O CNH CH2CH2O Ts CH 2 O CNH CH 2 CH 2 O Ts
II  II
0 実施例 7  0 Example 7
渙 H2CH2Br
Figure imgf000096_0002
Lysis H 2 CH 2 Br
Figure imgf000096_0002
0 実施例 8  0 Example 8
Figure imgf000096_0003
実施例 9
Figure imgf000096_0003
Example 9
Figure imgf000096_0004
Figure imgf000096_0004
o ¾施例 1 0 o ¾Example 1 0
Figure imgf000097_0001
Figure imgf000097_0001
0  0
実施例 1 1 O HExample 1 1 O H
Figure imgf000097_0002
Figure imgf000097_0002
0  0
実施例 1 2 O TsExample 1 2 O Ts
Figure imgf000097_0003
Figure imgf000097_0003
0  0
実施例 1 3 BrExample 13 Br
Figure imgf000097_0004
Figure imgf000097_0004
0  0
実施例 i 4 Example i 4
/、s  /, S
■ B
Figure imgf000097_0005
実施例 1 5 ■ B
Figure imgf000097_0005
Example 15
Figure imgf000098_0001
Figure imgf000098_0001
0 実施例 1 6
Figure imgf000098_0002
0 Example 1 6
Figure imgf000098_0002
C H 0 H  C H 0 H
+  +
C H20 C NH C H2C H2 CC H3): CI CH 2 0 C NH CH 2 CH 2 CC H 3 ) : CI
II  II
o  o
実施例 1 7 H 2 O C l 8 H 37 Example 17 H2OCl8H37
CHO C ONHCHs  CHO C ONHCHs
C H20 C HCH2CH2 CCH3); C 1 CH 2 0 C HCH 2 CH 2 CCH 3 ) ; C 1
II  II
0 実施例 1 8  0 Example 1 8
Figure imgf000098_0003
Figure imgf000098_0003
0 実施例 1 9 0 Example 19
ccctlccctl
Figure imgf000099_0001
H H H 2 C H 2 N (C H 3)：
Figure imgf000099_0001
HHH 2 CH 2 N (CH 3 ):
0 実施例 2 0 H
Figure imgf000099_0002
0 Example 2 0 H
Figure imgf000099_0002
C H H C 0 C H 3  C H H C 0 C H 3
CH2O C-N-CH2CH2 CCH3): CH 2 O CN-CH2CH 2 CCH 3 ):
II I  II I
0 C 0 C H3
Figure imgf000099_0003
0 C 0 CH 3
Figure imgf000099_0003
C H H C 0 C H 3  C H H C 0 C H 3
I 十  I ten
C H2O C— N— CH2CH2N(CH3): CH 2 OC— N— CH 2 CH 2 N (CH 3 ) :
II I  II I
0 C 0 C H3 実施例 2 1
Figure imgf000099_0004
0 C 0 CH 3 Example 2 1
Figure imgf000099_0004
C H 0 C 0 (C H3)2 CH 0 C 0 (CH 3 ) 2
C H 20 C H C H 2 C H 2 N ( C H 3)； B CH 2 0 CHCH 2 CH 2 N (CH 3 ); B
II - II-
0 実施例 2 2 0 Example 2 2
Figure imgf000099_0005
実施例 2 3
Figure imgf000100_0001
Figure imgf000099_0005
Example 2 3
Figure imgf000100_0001
CH2O CNHCH2CH2N(CH3): B CH 2 O CNHCH 2 CH 2 N (CH 3 ): B
II.  II.
0 実施例 24  0 Example 24
2N(C H3) H C 1
Figure imgf000100_0002
実施例 2 5 2N (CH 3 ) HC 1
Figure imgf000100_0002
Example 2 5
++
2 (C Ha): 2 (C Ha):
Figure imgf000100_0003
Figure imgf000100_0003
0 C 0 C H3 実施例 2 6 0 C 0 CH 3 Example 2 6
Figure imgf000100_0004
Figure imgf000100_0004
0 実施例 2 7 0 Example 2 7
Figure imgf000101_0001
Figure imgf000101_0001
実施例 2 8
Figure imgf000101_0002
Example 2 8
Figure imgf000101_0002
C H 0 C 0 (C H3)2 CH 0 C 0 (CH 3 ) 2
+  +
C H20 C - C H2C H2 (CH3): CH 2 0 C-CH 2 CH 2 (CH 3 ):
II  II
0 C 0 C H3 実施例 2 9
Figure imgf000101_0003
0 C 0 CH 3 Example 2 9
Figure imgf000101_0003
C H 0 C 0 C H3 CH 0 C 0 CH 3
C H , 0 C - X - C H , C H a M ( C H3) C Γ CH, 0 C-X-CH, CH a M (CH 3 ) C Γ
一 11 1 I 1 11 1 I
0 C 0 C H3 C H2Ph 実施例 3 0 0 C 0 CH 3 CH 2 Ph Example 3 0
Figure imgf000101_0004
Figure imgf000101_0004
0 C H3 0 CH 3
OMPI 実施例 3 1 2N(CH3):OMPI Example 3 1 2N (CH 3 ):
Figure imgf000102_0001
Figure imgf000102_0001
0 C H  0 C H
実施例 3 2 2 C H 2 N H C 1Example 3 2 2 C H 2 N H C 1
Figure imgf000102_0002
Figure imgf000102_0002
0  0
実施.例 3 3 2 H C 1Example 3 3 2 H C 1
Figure imgf000102_0003
Figure imgf000102_0003
C O C H3 COCH 3
実施例 34 2 N'Example 34 2 N '
Figure imgf000102_0004
Figure imgf000102_0004
C〇 C H C H  C〇 C H C H
C.'PlC.'Pl
、 T vy'f0 .¾ 実施例 3 δ , T vy ' f0 .¾ Example 3 δ
Figure imgf000103_0001
実施例 3 6
Figure imgf000103_0001
Example 3 6
Figure imgf000103_0002
実施例 3 7
Figure imgf000103_0002
Example 3 7
Figure imgf000103_0003
実施例 3 8
Figure imgf000103_0003
Example 3 8
2 N H C 1
Figure imgf000103_0004
2 NHC 1
Figure imgf000103_0004
差換え 実施例 3 9Replacement Example 3 9
Figure imgf000104_0001
Figure imgf000104_0001
実施例 40Example 40
Figure imgf000104_0002
Figure imgf000104_0002
実施例 4 IExample 4 I
Figure imgf000104_0003
Figure imgf000104_0003
実施例 42
Figure imgf000104_0004
Example 42
Figure imgf000104_0004
C.VPI φ Wi?o 実施例 4 3
Figure imgf000105_0001
C.VPI φ Wi? O Example 4 3
Figure imgf000105_0001
CH,O C-N- CH2CH2N CH, O CN- CH 2 CH 2 N
0 C 00 C H3 C H 実施例 44 0 C 00 CH 3 CH Example 44
Figure imgf000105_0002
Figure imgf000105_0002
実施例 4 5 Example 4 5
Figure imgf000105_0003
Figure imgf000105_0003
実施例 4 6 Example 4 6
Figure imgf000105_0004
Figure imgf000105_0004
1 :，·' 1 実施例 4 7 1 :, ' 1 Example 4 7
Figure imgf000106_0001
実施例 4 8
Figure imgf000106_0001
Example 4 8
Figure imgf000106_0002
Figure imgf000106_0002
C H2O G— N— C H2C H2N(C H3): C 1 CH 2 OG— N— CH 2 CH 2 N (CH 3 ): C 1
II I  II I
0 C 0 C H3 実施例 4 9 0 C 0 CH 3 Example 4 9
Figure imgf000106_0003
実施例 5 0
Figure imgf000106_0003
Example 5 0
C H2 (C H3)3 I
Figure imgf000106_0004
実施例 5 1 CH 2 (CH 3 ) 3 I
Figure imgf000106_0004
Example 5 1
Figure imgf000107_0001
実施例 5 2
Figure imgf000107_0001
Example 5 2
Figure imgf000107_0002
Figure imgf000107_0002
C H2O C— N— C H2C H2N(C H3): CH 2 OC— N— CH 2 CH 2 N (CH 3 ):
II I  II I
0 C 0 C 2H5 実施例 5 3 0 C 0 C 2 H 5 Example 5 3
C H2O C O H C 1 8 H 37 CH 2 OCOHC 1 8 H 37
C H O C O NH C Hs  C H O C O NH C Hs
C H 20 C N C H 2 C H 2 ( C H 3)： CH 20 CNCH 2 CH 2 (CH 3 ):
II  II
0 実施列 54
Figure imgf000107_0003
0 Execution 54
Figure imgf000107_0003
C H , 0 C - X - C H 2 C H 2 X ( C H 3)： C 1' CH, 0 C-X-CH 2 CH 2 X (CH 3 ): C 1 '
II !  II!
0 C 0 H C H 3 〇一 o ~ o 0 C 0 HCH 3 〇 一 o ~ o
N 0〇 〇 X cri N 0〇 〇 X cri
7 〇  7 〇
(222〇 〇 C ti〇 ¾ ffi C〇 OO 〇  (222〇 〇 C ti〇 ffi ffi C〇 OO 〇
〇 〇 〇 〇 〇 〇 〇 〇
O o o O o o
〇= =o o 〇: =o 〇 〇=〇  〇 = = o o 〇: = o 〇 〇 = 〇
X X
" 〇〇 C H X  "〇〇 C H X
1 〇 1 〇  1 〇 1 〇
o- - 2： o- 20 CHCNHC0  o--2: o-20 CHCNHC0
〇 1 〇 1  〇 1 〇 1
〇 o 〇 〇 〇 〇  〇 o 〇 〇 〇 〇
o  o
X X  X X
〇 o  〇 o
2： 2:
0 K  0 K
O  O
X  X
0 H  0 H
〇 H 〇 H
Ci〇〇〇 t Ci〇〇〇 t
2 ( 2 H M C C〇 H " H 00 H 実施例 5 9 2 (2 HMCC〇 H "H 0 0 H Example 5 9
Figure imgf000109_0001
+
Figure imgf000109_0001
+
C H 20 C - N - C H 2 C H 2 N ( C H 3)： CH 20 C-N-CH 2 CH 2 N (CH 3 ):
II I 、  II I,
0 C O 実施例 6 0  0 C O Example 6 0
Figure imgf000109_0002
Figure imgf000109_0002
CH2O C - N - CH2CH2 (CH3): CH 2 OC-N-CH 2 CH 2 (CH 3 ):
0 C O N H 2  0 C O N H 2
実施例 6 1 Example 6 1
-
Figure imgf000109_0003
-
Figure imgf000109_0003
C H , O C - Nr - C H 2 C H 2 ( C H 3)： CH, OC-N r -CH 2 CH 2 (CH 3 ):
II I  II I
0 C 0 N(C H3)2 実施例 6 2 0 C 0 N (CH 3 ) 2 Example 6 2
2 N ( C H 3)；2 N (CH 3 );
Figure imgf000109_0004
2
Figure imgf000109_0004
Two
_0Λ!ΡΙ_ 実施例 6 3 _0Λ! ΡΙ_ Example 6 3
2N(C H 3)
Figure imgf000110_0001
7 実施例 64
Figure imgf000110_0002
2N (CH 3 )
Figure imgf000110_0001
7 Example 64
Figure imgf000110_0002
+  +
CHzO C - - CH2CH2 (CH3); CHzO C--CH 2 CH 2 (CH 3 );
II I  II I
0 C 0 H C 3 H 7 実施例 6 5  0 C 0 H C 3 H 7 Example 6 5
Figure imgf000110_0003
実施例 6 6
Figure imgf000110_0004
Figure imgf000110_0003
Example 6 6
Figure imgf000110_0004
+  +
CH,O C -N- CH2CHzN(CH3); CH, OC -N- CH 2 CH z N (CH 3 ) ;
II I  II I
0 C 0 C H3 実施例 6 7
Figure imgf000111_0001
0 C 0 CH 3 Example 6 7
Figure imgf000111_0001
C H 20 C - N - C H 2 C H 2 ( C H 3) 3 C CH 20 C-N-CH 2 CH 2 (CH 3 ) 3 C
II I  II I
0 C 0 C H3 実施例 6 8
Figure imgf000111_0002
0 C 0 CH 3 Example 6 8
Figure imgf000111_0002
CH2O C HCH2CH2 (CH 3) CH 2 OC HCH 2 CH 2 (CH 3 )
II  II
0 実施例 6 9  0 Example 6 9
Figure imgf000111_0003
実施例 7 0
Figure imgf000111_0003
Example 7 0
H,CH2NT(CH3):
Figure imgf000111_0004
C H3 -no H, CH 2 N T (CH 3 ) :
Figure imgf000111_0004
CH 3 -no
実施例 7 1 Example 7 1
C Γ
Figure imgf000112_0001
C Γ
Figure imgf000112_0001
実施例 7 3
Figure imgf000112_0002
実施例 74 Example 7 3
Figure imgf000112_0002
Example 74
2 C H 2 C Γ
Figure imgf000113_0001
ノ 2 CH 2 C Γ
Figure imgf000113_0001
No
0 C H3 0 CH 3
実施例 7 5
Figure imgf000113_0002
Example 7 5
Figure imgf000113_0002
0  0
実施例 7 6
Figure imgf000113_0003
実施例 7 7 Example 7 6
Figure imgf000113_0003
Example 7 7
++
H2CH2N(CH3)3
Figure imgf000114_0001
H3 H 2 CH 2 N (CH 3 ) 3
Figure imgf000114_0001
H 3
実施例 7 8 Example 7 8
Figure imgf000114_0002
Figure imgf000114_0002
実施例 7 9 Example 7 9
Figure imgf000114_0003
OAVζ 8 εl3!df/c00寸 8寸/ 9
Figure imgf000114_0003
OAVζ 8 εl3! Df / c00 Dimensions 8 Dimensions / 9
Figure imgf000115_0001
〇 H 0 H H X〇〇〇 ffi〇 H〇 0
Figure imgf000115_0001
〇 H 0 HHX〇〇〇 ffi〇 H〇 0
〇 〇
N 3 000〇 H " o N 3 000〇 H "o
o n ϋ〇 o  o n ϋ〇 o
oo oo oo ) H〇 H 00 H〇〇 c n：- "  oo oo oo) H〇 H 00 H〇〇 c n:-"
†rn\ tms 械  † rn \ tms machine
ΗΗΚΟϋο:Η〇ΟΞ" ΗΗΚΟϋο: Η〇ΟΞ "
H ϋ ffi〇〇 ) ΗΟΝΗΟΗΟΟΝΟ〇:Η""Ν 実施例 83 H 〇〇 ffi〇〇) ΗΟΝΗΟΗΟΟΝΟ〇: Η "" Ν Example 83
0 CH2CH2N(CH3):
Figure imgf000116_0001
0 CH 2 CH 2 N (CH 3 ):
Figure imgf000116_0001
実施例 84 Example 84
+ +
H2C H2 CC H3); H 2 CH 2 CC H 3 ) ;
Figure imgf000116_0002
Figure imgf000116_0002
C 0 C H3 0 C 0 CH 3 0
実施例 8 5 Example 8 5
Figure imgf000116_0003
Figure imgf000116_0003
': 'し . • - ノ':' Then. •-no
： ノ .0 実施例 8 6: No .0 Example 8 6
Figure imgf000117_0001
Figure imgf000117_0001
C H 0 C H2Ph CH 0 CH 2 Ph
C H20 Ts 実施例 8 7 CH 2 0 Ts Example 8 7
I I
C H 0 C H2P h
Figure imgf000117_0002
実施例 8 8CH 0 CH 2 P h
Figure imgf000117_0002
Example 8 8
Figure imgf000117_0003
Figure imgf000117_0003
C H 0 C H2Ph
Figure imgf000117_0004
CH 0 CH 2 Ph
Figure imgf000117_0004
OMPI OMPI
差換え 、 i y  Replacement, i y
、 ノ 実施例 8 9 rl O C H , No Example 8 9 rl OCH
C H O H  C H O H
Figure imgf000118_0001
Figure imgf000118_0001
実施例 9 0 C H20 C t8H Example 9 0 CH 2 0 C t8 H
I I
C H O C 0 C H3 CHOC 0 CH 3
0  0
C H N N C H2C H20 Ts CHNNCH 2 CH 20 Ts
0 0
実施例 9 1 O C i H Example 9 1 O C i H
C H 0 C 0 C H3 CH 0 C 0 CH 3
0  0
+  +
C H N-' N C H2C H2N(C H3): C Γ CH N- 'NCH 2 CH 2 N (CH 3 ): C Γ
0 0
差！ ¾え 実施例 9 2 リ n 20 C t 8 H 37 difference! Pee Example 9 2 Li n 20 C t 8 H 37
C H 0 C 0 C H3 CH 0 C 0 CH 3
0  0
十  Ten
C H2 '' ' X C H 2 C H a C Γ CH 2 '''XCH 2 CH a C Γ
w  w
0  0
s. s.
実施例 9 3  Example 9 3
C H20 C l8H 37 C H 0 C H2Ph CH 2 0 Cl 8 H 37 CH 0 CH 2 Ph
* C H20 Ts * CH 2 0 Ts
実施例 9 4
Figure imgf000119_0001
Example 9 4
Figure imgf000119_0001
ΟΜΡΙ ΟΜΡΙ
差換え 実施例 9 δReplacement Example 9 δ
Figure imgf000120_0001
Figure imgf000120_0001
実施例 9 6Example 9 6
Figure imgf000120_0002
Figure imgf000120_0002
実施例 9 7Example 9 7
Figure imgf000120_0003
Figure imgf000120_0003
υκ u υκ u
Λ. " ii-0 ノ ί¾え 実施例 9 8 Λ. "Ii-0 ノ ί¾ Example 9 8
C H20 C 18H 37 CH 2 0 C 18 H 37
C H 0 C H2Ph CH 0 CH 2 Ph
Figure imgf000121_0001
Figure imgf000121_0001
実施例 9 9 Example 9 9
C H 20 18 tl 3？ C H 20 18 tl 3?
C H 0 C H,Ph C H 0 C H, Ph
C H 2
Figure imgf000121_0002
CH 2
Figure imgf000121_0002
実施例 1 0 0 Example 1 100
C H a 0 C 18 H 37 C H a 0 C 18 H 37
C H 0 H C H 0 H
〇  〇
+  +
C H 2 N C H2C H2NCC H3): C 1' CH 2 NCH 2 CH 2 NCC H 3 ): C 1 '
0 0
UKヒ ΛΤΓUK ΛΤΓ
Ο ΡΙ Ο ΡΙ
ノ 実施例 1 0 1 No Example 10 1
Figure imgf000122_0001
Figure imgf000122_0001
実施例 1 0 2
Figure imgf000122_0002
Example 10
Figure imgf000122_0002
C H O C O C H3 CHOCOCH 3
0  0
C H2 N C H2C H2N(C H3): CI' CH 2 NCH 2 CH 2 N (CH 3 ) : CI '
0 0
実施例 1 0 3 Example 1 0 3
-ク、、-
2^. 2 ^.
Figure imgf000122_0003
' N'
Figure imgf000122_0003
'N'
0 C 0 C H3 0 C 0 CH 3
え 実施例 1 0 4 e Example 1 0 4
C Γ
Figure imgf000123_0001
C Γ
Figure imgf000123_0001
実施例 1 0 5 Example 1 0 5
2N(C H3)3 C H3 C 00
Figure imgf000123_0002
2N (CH 3 ) 3 CH 3 C 00
Figure imgf000123_0002
0 C 0 C H3 0 C 0 CH 3
上記構造式中、 ？11はフェニルを 3はトシルを示す。 In the above structural formula,? 11 represents phenyl and 3 represents tosyl.
実験例 1 Experimental example 1
血小板凝集抑制作用  Platelet aggregation inhibitory action
験方法」  Test method "
雄性ゥサギより血液凝固防止剤として、 3.15%クェン酸（血液 9に対 して 1の割合）を含む注射筒を用いて、 直接採血した。 次いで室温下、 800rpmで 10分間遠心分離することにより多血小板血漿（P R P： platelet rich plasma)を得た。残りの血液をさらに 3000rpm で 10分間遠心して 上清液として乏血小板血漿（P P P :platelet poor plasma)を分離した。 P P Pで P RPを希釈して血小板数を約 50万個/ 1に調整した。 この Blood was directly collected from male male herons using a syringe containing 3.15% citric acid (1 to 9 blood) as an anticoagulant. Subsequently, platelet-rich plasma (PRP) was obtained by centrifugation at 800 rpm for 10 minutes at room temperature. The remaining blood was further centrifuged at 3000 rpm for 10 minutes to separate platelet poor plasma (PPP) as a supernatant. PRP was diluted with PPP to adjust the platelet count to about 500,000 / l. this
PR P 250 1を 37てで 2分攪拌後、 被験薬物を加えさらに 2分間攪拌 After stirring PRP 250 1 at 37 ° C for 2 minutes, add the test drug and stir for an additional 2 minutes
後に P AF 1 X10 8Mを加えた。 血小板凝集は凝集計（理化電機製）で測 定した。 被験薬物の凝集抑制活性は、 対照 P RPにおける P AFによる 最大の光透過度（最大凝集率）に対する抑制率から求めた。 Later, P AF 1 X10 8 M was added. Platelet aggregation was measured with an aggregometer (manufactured by Rika Denki). The aggregation inhibitory activity of the test drug was determined from the inhibition rate against the maximum light transmittance (maximum aggregation rate) by PAF in the control PRP.
[結果] [Result]
第 1表に示す。  It is shown in Table 1.
第 1表 P AFによるゥサギ血小板凝集抑制作用  Table 1 Inhibitory effect of P AF on aggregation of platelets of egrets
試-験化合物 試験薬物濃度と抑制率（％)  Test compound Test drug concentration and inhibition rate (%)
(実施例 O.) IX 10一6 M 3 X10"6M 3 X10— 5M (Example O.) IX 10 one 6 M 3 X10 "6 M 3 X10- 5 M
3 86 100 100  3 86 100 100
8 100  8 100
10 82  10 82
U 100  U 100
19 72  19 72
20 100 100 実験例 2  20 100 100 Experimental example 2
マウスにおける P A F致死に対する防止作用 Preventive effect on PAF lethality in mice
[試験方法] [Test method]
雄性 Jcl— I CRマウスに P AF50 g/kgを G.lml/kgの生理食塩水 溶液として静脈内投与した場合の 30分以内のショ ック死に対する被験薬 物 5分前静脈内投与による防止作甩を調べた。  Prevention of shock death within 30 minutes by intravenous administration of 50 g / kg of PAF as a G.lml / kg saline solution to male Jcl-ICR mice by intravenous administration 5 minutes before test drug I checked the work.
[桔果] [Kika]
表 2に示す。 P A Fの投与によりマウスの生存率は 19%であったが  See Table 2. The survival rate of mice was 19% by administering P AF
実施例 3の化合物の 0.1および 1 mg/kg静脈内投与による前処置により、 By pretreatment of the compound of Example 3 with 0.1 and 1 mg / kg iv,
OMPI OMPI
、 WiPO 、\ , WiPO, \
1( 生存率はそれぞれ 38および 100%と著明に改善され、 本化合物は強力な 1 ( Survival rates were markedly improved at 38 and 100%, respectively.
P AF致死防止薬である。 P AF is a lethal inhibitor.
表 2 マウスにおける P A F致死に対する防止作用  Table 2 Preventive effects on PAF lethality in mice
Figure imgf000125_0001
Figure imgf000125_0001
し'ト:ヒ 4 ΓI'm 4 ヒ
ΟΥ ΐ >.、 0 / 実験例 3 ΟΥ ΐ>., 0 / Experiment 3
実験例 1 と同じ方法により、 PAFによる血小板凝集抑制作用を調べ た。 結果 49 o 2346 o 524 5525236を表 3に示す。  In the same manner as in Experimental Example 1, the effect of PAF on inhibiting platelet aggregation was examined. Table 3 shows the results 49 o 2346 o 524 5525236.
表 3 P AFによるゥサギ血小板凝集抑制作用  Table 3 Inhibitory effect of P AF on aggregation of platelets
試験化合物 試験薬物濃度と抑制率（％)  Test compound Test drug concentration and inhibition rate (%)
(実施例 NO) 3X 471.80 1"7M 1X10"8M 3X 10"6Μ 3ΧΐΟ' Μι (Example NO) 3X 471.80 1 " 7 M 1X10" 8 M 3X 10 " 6 Μ 3ΧΐΟ 'Μι
40 100  40 100
45 100  45 100
100  100
64  64
34  34
100  100
100  100
100  100
72 100 oooooooooo oooooooooo  72 100 oooooooooo oooooooooo
100 100 実験例 4  100 100 Experimental example 4
実験例 2と同じ方法により、 マウスにおける P A F致死に対する防止 作用を調べた。 結果を表 4に示す。  In the same manner as in Experimental Example 2, the preventive effect on PAF lethality in mice was examined. Table 4 shows the results.
ijRヒ 4ひ、ijR hi,
― OWPI 表 4 マウスにおける P A F致死に対 ― OWPI Table 4 PAF lethality in mice
する防止作用  Prevention action
I試験化合物 投与量 生存率  I Test compound Dose Survival rate
\ 実験例 NO. mg/kg, i . v. (96)  \ Experimental example NO.mg/kg, i.v. (96)
Ί (対照） 24  Ί (control) 24
： 25 1.0 94  : 25 1.0 94
； 35 1.0 80  ; 35 1.0 80
！ 43 1.0 100  ! 43 1.0 100
45 i.o 100  45 i.o 100
！  !
1 45 0.3 77  1 45 0.3 77
91 1.0 100  91 1.0 100
' 92 1.0 ' 100  '92 1.0' 100
92 0.3 77  92 0.3 77
実験例 5 Experimental example 5
P AF降圧に対する回復作用  Recovery effect on P AF pressure drop
方法） 16週令の雄性 S . D . ラ 'ソ トを用いた。 Method) A 16-week-old male S.D.
ペン トバルビタールによる麻酔下で、 股動静脈内に力二ュ―レを 入れ、 それぞれ血圧測定及び薬物投与を行った。  Under anesthesia with pentobarbital, pressure was applied to the arteries of the hip, and blood pressure measurement and drug administration were performed, respectively.
P AF l,«g/kg(0.25%B S A生理食塩水溶液；容量 0.2ml/kg)静 脈内投与 3分後に被験薬物（生理食塩水溶液；容量 0.5ml/kg)を静脈 内投与し、 その後 1時間血圧測定を続けた。 ' P A Fによる降圧に対する被験薬物による昇圧の割合を回復率と し f二。  P AF l, «g / kg (0.25% BSA physiological saline solution; volume 0.2 ml / kg) Intravenous administration 3 minutes after the test drug (physiological saline solution; volume 0.5 ml / kg) was intravenously administered, and then 1 The time blood pressure measurement was continued.割 合 The ratio of the increase in pressure by the test drug to the decrease in pressure by PAF was taken as the recovery rate.
被験薬物 i.v.直前の血圧-被験薬物 i.v.l分後の血圧 回復率 = X 100 Blood pressure immediately before test drug i.v.- Blood pressure recovery rate after test drug i.v.l minutes = X 100
(%) P AF i.v.直前の血圧一被験薬物 i.v.直前の血圧 結果を表 5にまとめた < 表 5 P A F.降圧に対する回復 (%) P AF Blood pressure just before iv-Blood pressure just before test drug iv The results are summarized in Table 5 <Table 5 PA F. Recovery from step-down
Figure imgf000128_0001
製剤例 1 -
Figure imgf000128_0001
Formulation Example 1-
2 — 0—ァセチルー 3— 0— [Ν—ァセチル— Μ—（2 ' — ト リメチル ァンモニォェチル）]カルパモイルー I — 0—才クタデシルグリセリ ン ， ョ—ジ ド 10gを蒸留水 1. 0 1に溶解し、 無菌 過後、 無菌条件下に l mlず つ 1000本のバイアルに分注し、 凍結乾燥を行い、 密栓する。 2 — 0—Acetyl 3 — 0— [Ν-Acetyl—Μ— (2'—trimethylammonioethyl)] carpamoyl I — 0—10 g After sterilization, dispense into 1000 vials each with 1 ml under sterile conditions, freeze-dry, and stopper tightly.
一方、 マンニトール 100gを含有する 2 1の注射用蒸留水を無菌的に 2 m lずつ注射用アンブルに分注後、 熔閉し、 1000本に調製する。  On the other hand, 21 ml of distilled water for injection containing 100 g of mannitol is aseptically dispensed into 2 ml of injection ambles, and then sealed to prepare 1,000 tubes.
用時、 注射用マンニト -ル液に前者 1パイアル分の粉末を溶解して用 いる。  At the time of use, the powder of the former one pial is dissolved in the mannitol solution for injection.
製剤例 2 Formulation Example 2
錠剤  Tablets
1錠あたりの使用量として  As the amount used per tablet
, - 、 し (1 ) 2— 0—ァセチルー 3 — 0— [N—ァセチルー N—（2'— ト リ メチルァンモニォェチル）]力ルバモイルー 1 一 0—ォクタデシ ルグリセリ ン · ョージ ド 100 mg,-, Then (1) 2—0—acetyl-3—0— [N-acetyl-N— (2'—trimethylammonioethyl)]-l-bamoyl 110-octadecylglycerin chloride 100 mg
(2) 乳糖 200 mg(2) Lactose 200 mg
(3 ) コーンスターチ 51 mg (4 ) ヒ ドロキンプロピルセルロース 9 mg を常法により混合、 顆粒化し、 コ―ンスターチ（8 mg),ステアリ ン酸マ グネシゥム（2mg)と混和後、 打錠して 1錠 370mg,直径 9.5nunの錠剤とす る。 (3) 51 mg of corn starch (4) 9 mg of hydroquinine propylcellulose are mixed and granulated in a conventional manner, mixed with corn starch (8 mg) and magnesium stearate (2 mg), and compressed into tablets. Tablets 370 mg, 9.5 nun diameter tablets.
製剤例 3 Formulation Example 3
製剤例 2の錠剤を 1錠あたりの使用量として、 ヒ ドロキンプロピルメ チルセル口一スフタ レー ト（Umg)とヒマシ油（ 1 mg)を濃度 7 %となるよ うに溶解したァセ ト ンーェタノ —ノレ（4： 6)混液を用いてコ—ティング を施すことにより腸溶性の被覆錠とする。  Using the tablet of Formulation Example 2 as an amount of 1 tablet per tablet, hydroquinol propyl methylcellulose monophthalate (Umg) and castor oil (1 mg) were dissolved to a concentration of 7% in acetone-ethanol. Coating with a mixture of Nore (4: 6) to give enteric coated tablets.
産業上の利用可能性 Industrial applicability
本発明によって提供される新規脂質誘導体は医薬として有用である。  The novel lipid derivative provided by the present invention is useful as a medicine.

Claims

請 求 の Billing
式  Expression
C H20 R CH 2 0 R
C HR C HR
CH X— C一 Y— R3— Z— R + CH X— C— Y— R 3 — Z— R +
0 0
[式中、 R 1はアルキルまたはアルキル力ルバモイルを、 R2は水素，置換 されていてもよいヒ ドロキシ，置換されていてもよいァミ ノまたは環状 アミ ノを示し、 R3はアルキレンを、 R4は水素.アルキルまたはァラル キルを示し、 Xおよ.び Yはそれぞれ 0 , Sまたは置換されていてもよい イミ ノ基を示し、 Yがィミノ基である場合、 Yは Xで示されるイミ ノ基 または R +とともに環を形成してもよく、 Zは置換されていてもよいィミ ノまたは含窒素複素環を示す]で表わされる脂質誘導体またはその塩。 [In the formula, R 1 represents alkyl or alkyl group rubamoyl, R 2 represents hydrogen, optionally substituted hydroxy, optionally substituted amino or cyclic amino, R 3 represents alkylene, R 4 represents hydrogen; alkyl or aralkyl; X and Y each represent 0, S or an optionally substituted imino group, and when Y is an imino group, Y is represented by X Or a salt thereof, wherein Z may form a ring together with an imino group or R + , and Z represents an optionally substituted imino or nitrogen-containing heterocyclic ring.
換え Change
PCT/JP1984/000476 1984-04-03 1984-10-11 Lipid derivatives WO1986002349A1 (en)

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PCT/JP1984/000476 WO1986002349A1 (en) 1984-10-11 1984-10-11 Lipid derivatives
DE8585302202A DE3586746D1 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, YOUR PRODUCTION AND USE.
EP85302202A EP0157609B1 (en) 1984-04-03 1985-03-29 Lipid derivatives their production and use
DE8585302202T DE3586746T2 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, YOUR PRODUCTION AND USE.
AT85302202T ATE81501T1 (en) 1984-04-03 1985-03-29 LIPID DERIVATIVES, THEIR PRODUCTION AND USE.
JP60069628A JPH0745454B2 (en) 1984-04-03 1985-04-01 Lipid derivative
CA000478129A CA1281324C (en) 1984-04-03 1985-04-02 Lipid derivatives, their production and use
KR1019850002240A KR930004361B1 (en) 1984-04-03 1985-04-03 Method for producing lipid derivatives
US06/906,310 US4737518A (en) 1984-04-03 1986-09-12 Lipid derivatives, their production and use
US07/556,280 US5025005A (en) 1984-04-03 1990-07-23 Lipid derivatives, their production and use
JP4068728A JPH0819080B2 (en) 1984-04-03 1992-03-26 Lipid derivative

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2239243A (en) * 1989-12-22 1991-06-26 Scras Glycerol derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5931738A (en) * 1982-08-17 1984-02-20 Ono Pharmaceut Co Ltd Glycerol derivative, preparation thereof and drug containing said derivative
JPS5988447A (en) * 1982-11-11 1984-05-22 Ono Pharmaceut Co Ltd Glycerol derivative, its production and agent containing said derivative
JPS59110663A (en) * 1982-12-16 1984-06-26 Ono Pharmaceut Co Ltd Novel glycerol derivative, its preparation and drug containing the same
JPS59112961A (en) * 1982-12-21 1984-06-29 Ono Pharmaceut Co Ltd Glycerol derivative, its preparation and drug containing said derivative

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5931738A (en) * 1982-08-17 1984-02-20 Ono Pharmaceut Co Ltd Glycerol derivative, preparation thereof and drug containing said derivative
JPS5988447A (en) * 1982-11-11 1984-05-22 Ono Pharmaceut Co Ltd Glycerol derivative, its production and agent containing said derivative
JPS59110663A (en) * 1982-12-16 1984-06-26 Ono Pharmaceut Co Ltd Novel glycerol derivative, its preparation and drug containing the same
JPS59112961A (en) * 1982-12-21 1984-06-29 Ono Pharmaceut Co Ltd Glycerol derivative, its preparation and drug containing said derivative

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2239243A (en) * 1989-12-22 1991-06-26 Scras Glycerol derivatives
GB2239243B (en) * 1989-12-22 1993-05-12 Scras Glycerol derivatives

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